Imperfections, wrinkles, brown spots, enlarged pores... Retinoids are versatile agents that can target various skin concerns. However, their use is often associated with skin irritation. That's why, for several years, cosmetic brands have implemented solutions to reduce the risks of side effects related to retinoids. Which ones? Discover them by continuing your reading.

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- The solutions implemented to reduce the side effects of retinoids.
The solutions implemented to reduce the side effects of retinoids.
- Retinoids: Why are they associated with side effects?
- Solution No. 1: Encapsulate the retinoids
- Solution No. 2: Alter the structure of retinoids
- Solution No. 3: Combine retinoids with other active ingredients
- Sources
Retinoids: Why are they associated with side effects?
While retinoids are renowned for their effectiveness and versatility, they are also associated with common side effects, such as redness, peeling, and tingling sensations, due to their mode of action. Indeed, when they bind to nuclear receptors RAR and RXR, these vitamin A derivatives trigger a cascade of signals that influence the proliferation of keratinocytes, cell differentiation, and collagen synthesis. However, this rapid activation of cell renewal can temporarily impair the skin barrier, leading to an increase in transepidermal water loss (TEWL) and skin sensitivity.
To counter these side effects, skincare brands have had to find solutions by relying on vectorisation technologies, combinations of active ingredients, and the creation of gentler retinoids.
Solution No. 1: Encapsulate the retinoids.
The first approach to reducing irritation associated with retinoids is to encapsulate them in systems that allow for a gradual and controlled release. This can include liposomes, structures made up of lipid bilayers similar to those of cell membranes. Encapsulating retinoids in liposomes allows for a uniform distribution of the active ingredient in the skin and limits its accumulation in the stratum corneum, as well as the rapid activation of retinoic acid receptors. It is also possible to encapsulate retinoids in polymeric nanocapsules, a similar approach that protects retinoids from oxidation while ensuring controlled penetration. By allowing slow diffusion into the epidermis, encapsulation again limits the risk of accumulation and helps to improve the tolerance of retinoids.
Several studies have demonstrated a better skin tolerance of encapsulated retinoids compared to free retinoids. Notably, a study conducted in 2015 can be cited. This study focused on two formulations: a cream containing 0.025% tretinoin and another containing the same concentration of tretinoin but encapsulated in proniosomes, nanometric vesicles. An irritation test, carried out on ten volunteers, showed a much better tolerance of the formulation with the encapsulated tretinoin. For this, average erythema scores were recorded from 0 to 4, where 0 indicates an absence of erythema, 1 a mild erythema, 2 a moderate erythema, 3 a moderate to severe erythema, and 4 a severe erythema.
Formulation tested | Average erythema score |
---|---|
0.025% free tretinoin | 1.70 ± 0.755 |
0.025% encapsulated tretinoin | 0.143 ± 0.377 |
Solution No. 2: Alter the structure of retinoids.
All retinoids are not equal in terms of potency and tolerance. Retinoic acid, or tretinoin, only available on medical prescription, is the most effective active form but also the most irritating. In skincare, gentler forms, such as retinol, retinaldehyde or retinol esters (palmitate, propionate and retinyl acetate), which must be converted before they act, are preferred. Retinol esters are among the gentlest retinoids as they require the most conversion steps. They are therefore particularly suitable for people wishing to start using a retinoid or those with sensitive skin.
A clinical study from 2023 examined the synergy between Hydroxypinacolone Retinoate (HPR) and Retinyl Propionate (RP), two synthetic retinoids, and their skin tolerance. For this purpose, 33 volunteers were recruited and subjected to patch tests. Various concentrations of retinol were tested, as well as formulations containing Hydroxypinacolone Retinoate and Retinyl Propionate in a 5:9 ratio. The results show that creams containing HPR and RP were significantly better tolerated than those with retinol.

Solution No. 3: Combine retinoids with other active ingredients.
Finally, to limit the risks of irritation, erythema, and flaking associated with retinoids, it may be wise to combine them with ingredients capable of offsetting their impact on the skin barrier. The ceramides, lipids that make up the corneal layer, are good candidates for this. Indeed, by occupying the space between the corneocytes, ceramides improve the skin's barrier function and prevent water from evaporating from skin cells, which can help reduce the sensations of tightness often associated with retinoids. The incorporation of certain biomimetic peptides or niacinamide, acting by modulating the inflammatory response, can also be relevant to limit redness.
Sensitivity to retinol is suspected to be linked to genetic predispositions. With this in mind, researchers conducted a clinical study with 91 volunteers comparing the tolerance of a cream containing 3300 IU of retinol to an identical formulation but containing ingredients capable of genetically inhibiting irritation (glucosamine, trehalose, ectoine, sucralfate, omega-9, and 4-t-butylcyclohexanol). The evaluation of irritation scores showed significantly better skin tolerance with the second cream.

Sources
MAIBACH H. I. & al. The specificity of retinoid-induced irritation and its role in clinical efficacy. Exogenous Dermatology (2002).
KANG K.-S. & al. The mechanism of retinol-induced irritation and its application to anti-irritant development. Toxicology Letters (2003).
WEINDL G. & al. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clinical Interventions in Aging (2006).
EL RAMLY & al. Formulation of tretinoin-loaded topical proniosomes for treatment of acne: in-vitro characterization, skin irritation test and comparative clinical study. Drug Delivery (2015).
GREWAL P. & al. A Clinician’s Guide to Topical Retinoids. Journal of Cutaneous Medicine and Surgery (2021).
KANG N.-G. & al. Anti-Irritant Strategy against Retinol Based on the Genetic Analysis of Korean Population: A Genetically Guided Top–Down Approach. Pharmaceutics (2021).
YE R. & al. The synergistic effect of retinyl propionate and hydroxypinacolone retinoate on skin aging. Journal of Cosmetic Dermatology (2023).
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