Natural skin brightening

Mother Nature blessed mankind with a skin that provides a multitude of functions: from protection from environemntal adversities to the expression of beauty. For the expression of beauty, consumers desire younger looking, vibrant, supple and wrinkle-free skin. With chronological ageing, dark spots, skin pigmentation, freckles, and other visually perceptible skin disorders, they often require treatment with skin lightening products. Modern science has focused on this omnipresent consumer desire to open new opportunities for marketers and formulators worldwide. New ingredients or improving visual appearance of skin are constantly developed. This article focuses on new skin brightening ingredients, discovered in the past five years. For these ingredients to deliver their function optimally, innovative topical delivery systems are required to transport such ingredients to reach their targeted biological site of action in skin. For example, the efficacy of such ingredients can be significantly reduced, or even lost, if they penetrate too deeply or not at all into skin or fail to reach their biological site of action in optimal quantities. Sunscreens, for example, must not penetrate too deeply into the skin. Otherwise, their efficacy would be compromised and skin irritation would increase. Skin whitening and brightening agents, however, must penetrate skin to reach tyrosinase-active cellular layers. Any antioxidant or anti-inflammatory agent can also function as a skin brightening agent. The efficacy of such ingredients can be maximized by formulating via appropriate delivery systems. This requires a consideration of both the physical and chemical properties of such ingredients.

Reaching the right skin layer

For example, popular skin brightening agents, hydroquinone, kojic acid, and arbutin, are fairly water soluble (5.0 – 6.0 g/100 mL). The use of such ingredients in formulations for rinseoff products, such as a suntan, sunscreen, bar soap, or body wash, can lead to significantly reduced skin brightening  benefits. In the case of sunscreens formulations, which must not penetrate deep into skin, skin brightening ingredients may not reach tyrosinase active centres in efficacious concentrations. In case of bar soap or body wash products such brightening agents may simply get washed off when rinsing the body after body wash application, resulting in an insufficient deposit on skin. Formulations  designed for leave-on or night-time use of such ingredients can provide greater efficacy.

Problem of stability and discolouration

Formulation stability is another concern. A large number of skin brightening ingredients contain a hydroxy-, dihydroxy-, or polyhydroxyphenyl chemical backbone. Such chemical compositions – besides being yellow to orange in colour – are also good antioxidants. They naturally tend to discolor in the presence of air and/ or light. This is not unexpected, as most antioxidants do tend to produce some discolouration under their normal storage conditions. Additionally, the presence of oxidizing metals such as Fe, Cu, and Ni, even in trace amounts, can lead to discolorations from reddish brown to bluish green tints in topical formulations. Usually, the greater their antioxidant or skin brightening efficacy the faster this discolouration. This leads to ever-present formulation challenges with such ingredients. Hydroxyphenyl ingredients, including flavones, isoflavones, and flavonoids, are better formulated in an acidic pH range (preferably 5.5 to 6.5), as their degradation is faster under pH conditions higher than 8.0. The inclusion of appropriate metal chelating agents is also recommended. A carefully planned protocol for formulation stability, efficacy, and safety gives best results for developing an efficacious consumer acceptable product adaptable for international markets.

New skin brightening ingredients

Researchers, formulators, and marketers are always focused on “what is new and exciting”. An unquenchable search for skin brightening ingredients and technologies has ensued since Elizabethan era.¹ In practical terms, this effort has been successful via the pursuit of two basic biochemical mechanisms: oxidase  and monooxygenase functions. This can either prevent melanin formation by blocking tyrosinase (tyrosinase inhibitors) or reduce existing melanin pigment (or melanin precursor biochemical intermediates) to a decolourised chemical species. For example, hydroquinone and arbutin can function via both  mechanisms: they can block tyrosinase antagonistically or reduce melanin colour (eliminating double bond conjugation in melanin’s chemical structure). In this regard arbutin, a glycoside of hydroquinone, is first converted into hydroquinone in vivo, which then carries out its dual function as hydroquinone. Ideally, a truly elegant new skin brightening ingredient should function by the above two mechanisms without imparting any undesirable after effects, such as skin irritation caused by hydroquinone, which has caused regulatory concerns in several international markets.² In general, the incorporation of more than one skin brightening ingredient in a formulation is more beneficial in producing the desired skin lightening effect than a single ingredient on an equal weight basis, especially if such ingredients provide their biochemical function via different pathways.

Brightened horizon for anti-ageing skin care

A non-comprehensive listing of recently discovered skin brightening agents is provided in Table 1.3 A number of these ingredients may not be commercially available at this time, which signals an opportunity for ingredient manufacturers, formulators, and marketers worldwide. In several articles both natural and synthetic skin whitening agents have been reviewed.⁴ A natural product, bis(4-hydroxybenzyl) sulfide, extracted from a Chinese herbal source, Glastrodia elata, has shown exceptional tyrosinase inhibition properties superior to kojic acid.⁵ In practical formulations the development of off-odours due to its sulfide bond may have to be addressed, since this molecule is easy to manufacture commercially by simple synthesis. It is worthy to note that most prior studies of tyrosinase inhibition have been carried out with mushroom tyrosinase. In a recent study the use of recombinant human tyrosinase for screening purposes has been more predictive. The introduction of a new skin brightening agent, isobutylamido thiazolyl resorcinol (Thiamidol) resulted from this research.⁶ Although it is a synthetic ingredient, it offers an insight into the biochemical mechanisms by which skin brightening can be achieved for future research. Glutathione has long been proposed as a skin whitening natural tripeptide ingredient. However, controversy has shrouded its real efficacy.⁷ Despite of this, it should be noted that even a 0.2% use of this ingredient in a topical skin care product can lead to sulphur odours which are unacceptable to the customer (practical experience of this author). Dihydromyricetin (DMY), a new peptide that is structurally related to glutathione, has shown tyrosinase inhibition via a mechanism unrelated to that of glutathione.⁸ Since this is a sulfhydryl peptide the odour contribution to  formulations is unknown as it is not yet commercially available.

Identification with modern tools

Computational modelling has become a successful tool in the identification of potential new tyrosinase inhibitors. DMY has been reported to inhibit tyrosinase. Molecular modelling found that this ingredient interacted with amino acid residues Tyr78, His85, and Ala323, occupying the active site leading to the inhibition of tyrosinase. This study may provide a new method for screening tyrosinase inhibitors.⁹ In another study, computational modelling showed validamycin to be a potent tyrosinase inhibitor by binding at HIS85, HIS244, GLU256, HIS259, and ASN260 of the tyrosinase active-site.¹⁰ Similar computational modelling has been successful in evaluating tyrosinase inhibition by several Chinese medicinal plant extracts.¹¹ A recombinant enzyme complex has been proposed as the next generation skin whitening agent. However, its commercial viability is yet unknown.¹² Moreover, its practical formulation may pose skin delivery challenges.13 As mentioned earlier, a proper delivery system is required for most topical skin brightening agents to assure both their physically stability and their targeted delivery into the skin.¹³ It is remarkable that none of the nature-based skin brightening ingredients have matched the efficacy of hydroquinone in a formulated cosmetics product. This may be due to its unique ability to perform both reduction and oxidation steps efficiently via hydroquinone/quinole/ quinone redox pathway.¹⁴ Many new and exciting whitening actives have been developed in the past five years; their discovery often aided by computational modelling techniques. These new actives, coupled with tailor-made delivery systems, can help marketers, formulaters and ingredients suppliers worldwide find innovative solutions for enhancing the customer’s topical beauty.

References

^1. Blay, The Journal of Pan African Studies, vol. 4, (2011). http://www.academia.edu/602086/Skin_Bleaching_and_Global_White_Supremacy_By_Way_of_Introduction.

². S. Gupta, Beauty Brightened: New Skin Brightening Ingredients,

GCI, 30 – 32 (2014).

³. Zolghadri et al., A comprehensive review on tyrosinase inhibitors,J Enzyme Inhib Med Chem. 2019 Dec;34(1):279-309. DOI: 0.1080/14756366.2018.1545767; Pillaiyar et al., Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors, J Enzyme Inhib Med Chem. 2017 Dec; 32(1):403-425. DOI: 10.1080/14756366.2016.1256882; Lee et al., Natural,Semisynthetic and Synthetic Tyrosinase Inhibitors, J Enzyme Inhib Med Chem, 31 (1), 1-13, 2016;DOI: 10.3109/14756366.2015.1004058; Kanlayavattanakul, Plants and Natural Products for the Treatment of Skin Hyperpigmentation – A Review, Planta Med 2018; 84(14):

988-1006; DOI: 10.1055/a-0583-0410. 

^4. Chen et al., Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular

modeling, Sci Rep. 2015 Jan 23; 5:7995. DOI: 10.1038/ srep07995.

^5. Mann et al., Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different From Mushroom Tyrosinase, J Invest Dermatol, 138 (7), 1601-1608 Jul 2018; DOI: 10.1016/j.jid.2018.01.019.

^6. Dilokthornsakul et al., The Clinical Effect of Glutathione on Skin Color and Other Re-lated Skin Conditions: A Systematic Review, J Cosmet Dermatol, 18 (3), 728-737 Jun 2019; DOI: 10.1111/jocd.12910; Sonthalia et al., Glutathione

for skin lightening: a regnant myth or evidence-based verity?, Dermatol Pract Concept. 2018 Jan 31; 8(1):15- 21. DOI: 10.5826/dpc.0801a04. eCollection 2018 Jan.

^7. Shen et al., Novel Tyrosinase Inhibitory Peptide With Free Radical Scavenging Abili-ty, J Enzyme Inhib Med Chem, 34 (1), 1633-1640 Dec 2019; DOI:

10.1080/14756366.2019.1661401.

^8. Fan et al., An Inhibition Mechanism of Dihydromyricetin on Tyrosinase and the Joint Effects of Vitamins B 6, D 3 or E,Food Funct, 8 (7), 2601-2610 2017 Jul 19; DOI: 10.1039/c7fo00236j.

^9. Wang et al., The effect of validamycin A on tyrosinase: Inhibition kinetics and computational simulation, Int J Biol Macromol, 55, 15-23 Apr 2013; DOI: 10.1016/j.ijbiomac. 2012.12.040.

¹⁰. Gao et al., Predicting Tyrosinase Inhibition by 3D QSAR Pharmacophore Models and Designing Potential Tyrosinase Inhibitors From Traditional Chinese Medicine Database, Phytomedicine, 38, 145-157 2018 Jan 1; DOI:

10.1016/j.phymed.2017.11.012. Laccase-Peroxidase Enzyme Complex for Skin

Whitening and Other Practical Applications, Int J Biol Macromol, 129, 181-186 2019 May 15; DOI: 10.1016/j. ijbiomac.2019.02.027.

^12. Shin et al., Development and evaluation of topical formulations for a novel skin whitening agent (AP736) using Hansen solubility parameters and PEG-PCL polymers, Int J Pharm, 552 (1-2), 251-257 2018 Dec 1; DOI: 10.1016/j.ijpharm.2018.09.064; S. Gupta, Topical delivery of skin care ingredients, Cosmetics & Toiletries, Vol 129, No. 8, 26 – 39 (2014).

^13. Chen et al., Unveiling characteristics of dye-bearing microbial fuel cells for energy and materials recycling: Redox mediators, Int J Hyd Energy, Volume 38, Issue 35, 22 November 2013, Pages 15598-15605.