Retinaldehyde Pairings and Trojan Horses: Expanded Edition


Editor's note: A short-form version of this article appeared in the March 2016 edition of Global Cosmetic Industry magazine.

Retinaldehyde offers a less-irritating, cost-effective and formulation-friendly alternative to a wide array of skin care treatment products. Among the newest topical delivery systems, retinaldehyde γ-cyclodextrin complex (RCC) provides multifunctional opportunities for cosmetics utilizing stabilized retinaldehyde.

Retinaldehyde, in conjunction with complementary treatments including chemical peels, dermabrasion and lasers, can provide a wide-spectrum skin care arsenal to estheticians, dermatologists and in-home use consumers. They offer multifaceted attributes (see Multifaceted Benefits sidebar), described next.1

Retinoids & Retinaldehyde: From Anti-aging to Zits

Anti-acne and skin strength: Retinoids are a group of compounds that impart effects in the body like those of vitamin A, e.g., antioxidant benefits. They have found application in the treatment of both chronological aging and photo-aging,2 and are potent therapeutics, used topically and systemically as anti-acne agents.Retinaldehyde also has found application in the treatment of dermatoporosis—a new term proposed to describe the chronic cutaneous insufficiency/fragility syndrome characterized by extreme skin atrophy.4

Antibacterial: Furthermore, retinaldehyde imparts antibacterial benefits. β-Defensins are a family of antimicrobial peptides implicated in the resistance of epithelial surfaces to microbial colonization. In relation, topical retinaldehyde has been found to induce β-defensin-3 expression, thus acting as an antibacterial agent.5

Anti-aging: In addition, retinaldehyde and retinol have been reported to regulate gene expression in keratinocytes to improve the appearance of aged skin. Keratinocyte proliferation and hyaluronan synthesis are believed to be partly mediated through the heparin-binding epidermal growth factor (HB-EGF)-like receptor (EGFR) pathway.6 As such, retinaldehyde has been shown to increase the expression of HB-EGF, as well as the skin's involucrin protein gene (IVL); in both cases, greater than that of retinol.7

Skin discoloration: Lichen sclerosus is an uncommon chronic dermatosis recognized to occur on the anogenital area in perimenopausal women. It appears as small white, shiny, smooth spots on the skin that grow into bigger plaques that become thin and crinkled. In relation, topical retinaldehyde has found application in the treatment of Lichen sclerosus.Retinoids also exert skin-depigmenting activity. Unlike most depigmenting agents that target tyrosinase, retinoids are not phenolic agents and may act via different mechanisms.9 

Sensitivity Considerations

Topical retinoids have been used to treat rosacea. Retinoic acid, for example, has beneficial effects on the vascular aspect of rosacea. However, while retinoids show promise in the treatment of skin aging, irritant reactions such as burning, scaling or dermatitis associated with some of these therapies can limit their acceptance by patients.2

Retinoic acid treatment has the drawback of a delayed efficacy onset, which can lead to the development of skin dryness, erythema, burning and stinging. A higher tolerance to retinaldehyde vs. retinoic acid has been shown in photo-damaged skin, and with similar efficacy. Therefore, retinaldehyde may be more suited for sensitive, irritated skin conditions such as rosacea and red face syndrome.10 One proposed treatment for rosacea, for example, combines retinaldehyde with the anti-inflammatory agents dextran sulfate and hesperidin methyl chalcone.10

Managing Interactions

To predict the skin's metabolism of retinoids, tools such as MetaSite have been developed. This approach uses a computation to project metabolic transformations related to cytochrome and flavin-containing monooxygenase-mediated reactions, to identify potential skin irritation behavior.11

In addition, as noted, topical retinoic acid precursors such as retinaldehyde or retinol can be used as they are less irritating than acidic retinoids.12 All-trans retinaldehyde is most commonly used. However, retinaldehyde is increasingly rising in the marketplace, possibly due to perceived retinoid-related skin irritations. In response, new topical delivery systems are being developed to circumvent skin irritation-related issues.

Formulating Optimal Delivery

As noted, retinoids are a class of compounds that are chemically related to vitamin A.13 In broader terms, retinoids are any of a group of compounds providing the same biological benefits of vitamin A. The chemical structures of select retinoids and compounds having the biological activity of retinoids are illustrated in Figure 1.

Nanoparticles have shown good potential in improving the stability, tolerability and efficacy of retinoids.14 However, consumer concern over the safety of nanomaterials has made them less favorable.

Other approaches to retinal delivery systems include certain Schiff's bases with polylysine, and retinaldehyde-hyaluronic acid fragments.15 Liposomes of retinaldehyde and other retinoids have been reported for topical applications;16 and a system to deliver retinaldehyde for treating obesity has even been patented.17

Further, various emulsion-based delivery systems for retinaldehyde and other retinoids have been reported18 as well as encapsulated retinaldehyde formulated in a gel-based system for topical applications.19

Combinatorial Therapies

Combinations of retinoids with other agents for greater efficacy and reduced skin irritation is also of renewed interest, especially in dermatological applications. For example, retinaldehyde or tretinoin paired with a skin depigmenting agents has been shown to significantly improve solar lentigines.22

Retinaldehyde, in combination with glycolic acid, also has been reported to treat mild to moderate acne during sun exposure with good skin tolerability.23 Meanwhile, glycylglycine oleamide, a peptide derivative claimed to protect connective tissue from damage caused by glycation and elastosis, has been combined with retinaldehyde to provide a treatment for skin aging.24

Interestingly, it has been found that Epidermal Retinol Dehydrogenase 2 (RDH2) levels are elevated in psoriatic skin. And the potential role of RDH2 in the oxidation of retinol to retinaldehyde for retinoic acid biosynthesis in human keratinocytes has been acknowledged. In relation, 11-cis-retinoic acid, an oxidation product of 11-cis-retinaldehyde, has found application in the treatment of psoriasis.25

Incognito Delivery: Trojan Horse and Carrots

Beyond base formula solutions and ingredient combinations, a novel Trojan-horse delivery system for retinaldehyde, i.e., retinaldehyde γ-cyclodextrin complex (RCC), has been developed to release it in a controlled manner upon topical application.

Gene-expression data indicate RCC offers topical relief from symptoms associated with conditions ranging from melanogenesis and oxidative damage, to inflammation, loss of cell adhesion, skin aging, topical wounds20 and more. RCC and related compounds are prepared by the reaction of a polyene aldehyde, such as retinaldehyde, with a cyclodextrin, such as γ-cyclodextrin.21

How else might retinaldehyde be delivered? Via the human body. The well-known adage that eating carrots (vitamin A) is good for eyesight is also true for the availability of retinaldehyde in human body: β-carotene is converted into retinaldehyde, which is then converted into vitamin A (see Figure 2).26


Retinaldehyde offers a less-irritating, safer, cost-effective and formulation-friendly alternative to retinoic acid for a wider array of skin care products. And to get it where it needs to go, retinaldehyde γ-cyclodextrin complex (RCC) is among the latest delivery systems to provide multifunctional opportunities for cosmetics utilizing stabilized retinaldehyde.


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