Undecylenoyl Phenylalanine: Skin-Lightening Agent

Undecylenoyl Phenylalanine is a substituted amino acid derivative of Phenylalanine and Undecylenic acid. It is a white crystalline powder whose amphiphilic molecular structure provides cutaneous bio affinity. In vitro tests have shown the enhanced effectiveness and good tolerance (at the recommended dosage of 2%) of Undecylenoyl Phenylalanine compared to these active reference lightening agents. It shows distinct lightening action evidenced by an increase in light, a decrease in color parameters, and a decrease in the melanin content of human epidermis reconstructs. This material is stable and can be incorporated into all types of formulations (including white and slightly perfumed formulations). It is perfectly compatible with the reference agents. In addition, a formula containing Undecylenoyl Phenylalanine is resistant to UV rays over time and keeps its whiteness, which is not the case for conventional lightening agents.

Release studies of undecylenoyl phenylalanine from topical formulations

The active substance is one of the most crucial factors that influence the effectiveness of pharmaceutical products because it is responsible for their therapeutic effect. In recent years cosmetics and pharmaceutical industries have focused much attention on the application of amino acids and their derivatives as active substances (Burnett et al., 2017). Amino acids are components of the natural moisturizing factor as well as exhibit regenerative and anti-inflammatory activity (Lintner, 2007, Robinson et al., 2010). So far the formulations containing Ude-Phe were tested only in in vivo studies, however to our best knowledge there has been no research concerning the stability of these preparations and in vitro release test of active compound from these topical semi-solids. The aim of this study was to characterize the stability of new vehicles for the undecylenoyl phenylalanine that is used as skin-lightening agent in the melasma treatment. The purpose of this research was also to analyse the release kinetics of phenylalanine derivative from topical preparations through different synthetic membranes.[1]

Novel topical formulations containing the undecylenoyl phenylalanine were successfully obtained. The pH values of all semi-solid preparations resemble the skin’s pH, therefore they can be intended for dermal applications. Moreover, the obtained results proved that the storage conditions, preparation method and composition influenced the stability of formulations. The macroemulsion 2 prepared at RT was more stable than macroemulsion 1 obtained at high temperature. The results proved that macroemulsion 2 was much more stable than macroemulsion 1 irrespective of the storage conditions. The preparation method and composition of the emulsion could have an impact on the better stability of the macroemulsion 2. The greater stability of this formulation can be explained by the presence of the auto-emulsifier (Creagel EZIN). Additionally, the presence of phenylalanine derivative enhanced the stability of both macroemulsions regardless the storage conditions. The in vitro release studies proved that the membrane structure had the influence on the release rate of undecylenoyl phenylalanine. The release profile of Ude-Phe through Strat-M membrane was completely different than through other membranes. Furthermore, it was observed that with the increase in viscosity of the formulation decrease the ability of Ude-Phe to diffuse through the membrane. Therefore, hydrogels and microemulsion-based hydrogels could be recommended as proper vehicles for this active compound. Additional studies are required to assess the influence of the formulation type on skin permeation of Ude-Phe and to determine its bioavailability.

Optimizing a Skin Depigmentation Formula Using a 24 Factorial Design

Hyperpigmentation is a common dermatological concern that can affect individuals across different skin types, particularly those with fairer skin, and age groups, and may have a psychological impact in some cases. This condition results from excessive melanin production, which leads to uneven skin tone, dark spots, and conditions such as melasma, postinflammatory hyperpigmentation (PIH), and solar lentigines. The process of melanin synthesis, known as melanogenesis, occurs in melanocytes located in the deepest layer of the epidermis. This process begins with the oxidation of l-tyrosine to l-3,4-dihydroxyphenylalanine (L-DOPA), catalyzed by copper-dependent enzyme tyrosinase, which serves as a critical rate-limiting step in melanogenesis. Undecylenoyl phenylalanine (UP) is a novel depigmenting agent inhibiting the activity of α-MSH. According to Katoulis et al., a 2% concentration of UP gave a significant improvement of solar lentigines of the hand in a randomized, double-blind, vehicle-controlled trial. This suggests a promising potential for synergistic effects when combined with BR. While BR blocks the enzyme needed for melanin production, UP modulates the signaling pathway that triggers melanin synthesis, offering a complementary approach to controlling pigmentation. Based on the manufacturer’s recommendation, the effective concentration range of Undecylenoyl phenylalanine is 0.5–2%. The selected concentration ranges, 4-n-Butylresorcinol (0.1–1%), Undecylenoyl phenylalanine (0.5–2%), Diglucosyl gallic acid (1–4%), and trans-Resveratrol (0.1–0.5%), are based on manufacturer recommendations. While these ranges are commonly used in commercial formulations, they may not necessarily reflect the optimal concentrations for synergistic activity in combination. Further research and formulation optimization may be necessary to maximize the efficacy.[2]

Although the regression models exhibited moderate R2 values, valuable insights were obtained regarding the synergistic roles of the compounds in modulating melanogenesis. Undecylenoyl phenylalanine was shown to enhance anti-MSH activity, likely by mimicking α-MSH binding, while BR displayed strong tyrosinase inhibition. Although DG exhibited anti-inflammatory activity at lower concentrations, its efficacy was markedly reduced at 4%. This may reflect limitations of the in vitro model, where the absence of microbiota-like enzymatic conversion could lead to underestimation of its true activity. TR contributed to copper ion sequestration, albeit modestly, in the presence of the other three actives. Notably, significant interaction effects─particularly between 4-n-Butylresorcinol and Undecylenoyl phenylalanine─were observed for both anti-inflammatory and anti-tyrosinase responses, suggesting synergistic enhancement of bioactivity when these agents are combined. The optimized formulation, consisting of 1.0% BR, 0.5% UP, 1.0% DG, and 0.1% TR, achieved high predicted responses across all parameters, with a composite desirability of 0.8642.

References

[1]Olejnik A, Glowka A, Nowak I. Release studies of undecylenoyl phenylalanine from topical formulations. Saudi Pharm J. 2018 Jul;26(5):709-718. doi: 10.1016/j.jsps.2018.02.019. Epub 2018 Feb 8. PMID: 29991915; PMCID: PMC6036107.

[2]Panapisal, V., Kopandung, T., Liew, C. V., & Chutoprapat, R. (2025). Optimizing a skin depigmentation formula using a 2? factorial design: Evaluating 4-n-butylresorcinol, undecylenoyl phenylalanine, diglucosyl gallic acid, and trans-resveratrol. ACS Omega, 10(42), 49949–49961.

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