The solutions implemented to reduce the side effects of 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. One such study was conducted in 2015. It 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 no erythema, 1 indicates mild erythema, 2 indicates moderate erythema, 3 indicates moderate to severe erythema, and 4 indicates severe erythema.

All retinoids are not created equal in terms of potency and tolerance. Retinoic acid, or tretinoin, only available by medical prescription, is the most effective active form but also the most irritating. In cosmetics, 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 because 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.

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 feelings 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 with 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.