Martina Heldermann Inolex, Germany

SKIN LIGHTENING

Lightening efficacy enhanced via polymeric technology

Having clear and bright skin is considered an important feature for female beauty in Asian cultures. In these markets there is a large and growing demand for skin whitening and lightening products. But there are also needs in other markets for use in anti-ageing products or treatments against uneven pigmentation, like age spots and post-inflammatory hyperpigmentation, a common problem seen in people with dark skin. Cosmetic products that lighten, brighten, or whiten skin are widely used for reduction of natural skin pigmentation but also to accomplish a matching, consistent tone or to influence pigmentation disorders such as melasma, freckles, sun or age spots, and scarring lesions. Several active ingredients have shown to be effective in skin whitening, although some have shown to be toxic or, at least, have questionable safety profiles, e.g. hydroquinone. Some commonly used whitening agents like arbutin, kojic acid, and ascorbic acid derivatives have shown interesting efficacy in a variety of hyperpigmentary disorders. As significantly lightening the skin is a difficult task, systems which can optimise delivery, therefore enhancing bioavailability, are of particular interest in these cases.

Mode of action

Especially for hydrophilic actives, the appropriate delivery system is essential. The ideal delivery system is supposed to optimise delivery, enhance efficacy, reduce irritation through controlled delivery, and improve activity at reduced concentration. Lexorez TL-8 (INCI: Trimethylpentanediol/Adipic Acid Copolymer) supports topical delivery of active ingredients. It can be used to facilitate high loading levels of actives at moderate costs. Lexorez TL-8 (now referred to by its INCI name) is based on polymeric liquid reservoir technology and controls diffusion of actives into the epidermis through partitioning. Due to its low molecular weight (800 MW) it facilitates uniform distribution of actives throughout the stratum corneum for an

extended period of time. The active will slowly penetrate into the viable epidermis. For the penetration of active ingredients, the intercellular route is essential. The intercellular matrix consists of lipids so hydrophilic active ingredients do not normally penetrate efficiently through this route. Trimethylpentanediol/Adipic Acid Copolymer facilitates efficient penetration by creating a vesicle containing the hydrophilic active ingredients and partitioning them from the surrounding lipophilic matrix. Besides the facilitation of penetration, also the bioavailability is improved while the activity is enhanced. Studies demonstrate that Trimethylpentanediol/Adipic Acid Copolymer accelerates the rate of skin lightening allowing a reduction of the required use level of active ingredients. Skin pigmentation Up to 10% of skin cells in the innermost layer of the epidermis produce a dark pigment known as melanin. Upon exposure

of the skin to UV radiation, melanogenesis is initiated with the first step of tyrosine oxidation through an enzyme called tyrosinase. The type and amount of melanin synthesised by the melanocyte, and its distribution pattern in the surrounding keratinocytes, determines the actual colour of the skin. The degree of coloration is related to the number and distribution of subcellular units of melanin. Melanin is synthesised in dendritic cells known as melanocytes, which are normally found in the epidermal basal layer. These melanocytes secrete specialised brown organelles that are referred to as melanosomes. The mechanism by which melanin is formed is as follows. Melanosomes bear the copper containing enzyme tyrosinase. Tyrosinase catalyses the oxidation of tyrosine to dihydroxyphenylalaline (DOPA). DOPA is then oxidised to dopaquinone. Through a series of autoxidation reactions, dopaquinone is then converted to dopachrome next to dihydroxyindole-2January 2013 P E R S O N A L C A R E 25

SKIN LIGHTENING
carboxylic acid, then to 5,6 indolequinone and lastly to melanin. Among the skin lightening and depigmenting agents, magnesium-Lascorbyl-2-phosphate (MAP), hydroxyanisole, N-acetyl-4-S-cysteaminylphenol, alphahydroxy acids and arbutin (hydroquinonebeta-D-glucopyranoside) are the most widely prescribed worldwide. Although hydroquinone (HQ) is not permitted in, for instance, Europe anymore, it is still considered to be the benchmark skin lightener by most cosmetic chemists. Magnesium Ascorbyl Phosphate (MAP) MAP is a stable, water-soluble vitamin C (ascorbic acid) derivative. For many years, vitamin C has been known for its inhibitory effect on melanin formation. However, it has not been widely used for this function due to instability in formulation. MAP which , has greater hydrolytic stability than vitamin C, is created in vivo through a conversion from ascorbic acid. This liberation of the free acid results in pigment suppression, thereby preventing the formation of melanin and resulting in a lightening of the skin. MAP has also been shown to protect the skin against damages induced by UVB irradiation. Lactic acid Lactic acid is a low molecular weight organic acid which belongs to the group of alpha-hydroxy acids (AHA) and is derived from sour milk, or can be produced synthetically. It has some effect on skin whitening and is often combined with other bleaching agents. AHAs work by inhibiting tyrosinase, which catalyses a key step in pigment synthesis. Hydroquinone Hydroquinone was once a more than well-accepted agent for bleaching

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Days Figure 1: Results of MAP study.

hyperpigmented lesions. As a matter of fact, by most cosmetic chemists it was, and still is considered to be the best skin lightener there has ever been, although in most parts of the world it cannot be used in cosmetic formulations anymore. Arbutin Arbutin is another bleaching compound extracted from Arctostaphylos uva orsi (bearberry). It functions as a skin whitener by inhibiting the formation of melanin. The depigmentation effect of arbutin works through an inhibition of the melanosomal tyrosinase activity, rather than suppression of the expression and synthesis of tyrosinase in melanocytes. Arbutin is less cyctotoxic than hydroquinone to melanocytes.

and 28 for evaluation. The change in skin colour was graded by a trained investigator and documented on the grading sheet. Criteria for efficacy 0 No Pigmentation 1 Very Light Brown 2 Moderate Brown 3 Dark Brown or No Change

Results

Materials and methods

Test panel Healthy Filipinos, male and female. Age 16 to 60. Dark Skin Type 3 or 4. Testing and reading All tests have been double blind studies. Product A was evaluated against product C on the left and right arm respectively. Product B was evaluated against product C on the left and right arm respectively. The contents were unknown to the investigator and subjects. The subjects were instructed to apply the given product on the appropriate arm from the elbows to the wrist. There were 30 subjects for each product comparison. Test products were applied to each arm respectively twice daily for 4 weeks/ 28 days. Subjects were instructed to return to the testing centre on days 7, 14, 21

By increasing the partitioning and diffusion of active agents into and throughout the epidermis Trimethylpentanediol/Adipic Acid Copolymer can provide sustained and controlled delivery, enhance desquamation rates, and reduce the irritation potential associated with most active ingredients. Trimethylpentanediol/Adipic Acid Copolymer is a linear 800 MW hydroxy terminated polyester. The constituents of Trimethylpentanediol/Adipic Acid Copolymer are trimethylpentanediol and adipic acid. MAP study This study examined the effect of MAP and Trimethylpentanediol/Adipic Acid Copolymer in a skin lightening lotion. The research was conducted as a controlled, doubleblind clinical human panel test. Three test formulations were analysed: 1) 3% MAP and 2.5% TL-8, 2) 5% MAP and 2.5% Trimethylpentanediol/Adipic Acid Copolymer, and 3) control with 10% MAP and no Trimethylpentanediol/Adipic Acid Copolymer. The purpose of the evaluation was to determine if the inclusion of the ingredient enhanced the performance of MAP by eliciting a faster and more pronounced skin whitening response. The base formulation employed for this study was a simple O/W emulsion with nonionic emulsifiers.

www.en.wikipedia.org Regis.gallois

Arctostaphylos Uva Orsi (bearberry).

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SKIN LIGHTENING
Lactic acid study Trimethylpentanediol/Adipic Acid Copolymer in two different concentrations has been combined with 10% undissociated lactic acid to determine which of these two combinations can not only enhance the skin whitening effect attributed by lactic acid, but also which concentration can give a faster rate of efficacy. The study therefore seeks to determine which polyester variation will give a superior skin whitening response. The responses were monitored periodically throughout the study. The base formulation employed for this study is a basic O/W emulsion with nonionic emulsifiers. Product A served as the control, containing 10% undissociated lactic acid, while Product B contained 10% undissociated lactic acid and 5% Trimethylpentanediol/Adipic Acid Copolymer, and Product C contained 10% undissociated lactic acid and 2.5% Trimethylpentanediol/Adipic Acid Copolymer. Based on the results of this study shown in Figure 2, it can be concluded that 2.5% and 5% Trimethylpentanediol/ Adipic Acid Copolymer were both more effective than Product A the control in producing lightening of the skin. 5%

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Days Figure 2: Results of lactic acid study.

The results are shown in the Figure 1 which indicate that Product A (3% MAP and 2.5% Trimethylpentanediol/Adipic Acid Copolymer) and Product B (5% MAP and 2.5% Trimethylpentanediol/Adipic Acid Copolymer) were both more effective than Product C (control, 10% MAP) in skin lightening. Formulations containing 2.5% Trimethylpentanediol/Adipic Acid Copolymer produced a significantly greater lightening

effect earlier in the study than the control, indicating that the addition of the ingredient increases the distribution of MAP within the stratum corneum. The data also suggest that its incorporation into formulations produces an increased response to lower MAP concentrations. This allows for the maximisation of MAP efficacy, providing the formulator with greater flexibility and cost efficiency.

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SKIN LIGHTENING
Trimethylpentanediol/Adipic Acid Copolymer elicited a faster whitening response than the control. The data also indicated that the control, which contained twice the amount of arbutin was only slightly longer lasting than the other. The study suggests that the inclusion of the polyester Trimethylpentanediol/Adipic Acid Copolymer produced a faster whitening response with 50% less active.

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Conclusion

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Days Figure 3: Results of hydroquinone study.

Trimethylpentanediol/Adipic Acid Copolymer was just irrelevantly faster and more effective than 2.5%. Hydroquinone study Trimethylpentanediol/Adipic Acid Copolymer (5% use level) has been combined with 2% hydroquinone and compared to a control containing no polymer but 2% of the skin whitening active. The base formulation employed for this study is a specific O/W emulsion that is typically used when incorporating hydroquinone. Due to the oxidative nature of the hydroquinone and the subsequent instability of the active the formulations were processed and packaged with a nitrogen blanket to reduce the oxidative potential. Figure 3 shows the results, it can be concluded that the addition of 5% Trimethylpentanediol/Adipic Acid Copolymer leads to a significant improvement of hydroquinone efficacy.

Arbutin study In this study a double blind controlled clinical human panel testing was conducted. Two test formulations were analysed; control containing 10% arbutin, the other containing 5% arbutin and 2.5% Trimethylpentanediol/Adipic Acid Copolymer. The purpose of the evaluation was to determine if the inclusion of Trimethylpentanediol/Adipic Acid Copolymer enhanced the performance of the active by eliciting a more pronounced skin whitening response. The base formulation employed for this study is a basic O/W emulsion with nonionic emulsifiers. The results of this study shown in Figure 4 indicate that by the seventh day both formulations were effective in whitening of the skin. During the first two weeks of product application, the formulation containing

Previous studies, as well as market-based success factors in self-tanning products, have demonstrated that Lexorez TL-8 polymeric delivery system enhances the efficacy of certain skin actives. By increasing the partitioning and controlling the diffusion of active agents through the epidermis, Lexorez TL-8 can provide sustained and controlled delivery. In general, skin whitening products are considered modestly effective at low use levels that do not lead to any skin irritation. In all studies, Lexorez TL-8 improved the activity of the selective whitening ingredient. The addition of 2.5% Lexorez TL-8 allowed for the reduction of active ingredients by approximately 50% providing greater formulation flexibility and reducing the irritation potential of the actives. Lexorez TL-8 can be added directly to formulations and does not need to be pre-mixed with the active. It can have a negative impact on lather in mousse formulations but there are no other PC formulation incompatibilities known.

References
1 Li EPH, Min HJ, Belk RW, Kimura J, Bahl S. Skin lightening and beauty in four Asian cultures. Advances in Consumer Research 2008; 35: 444-9. 2 Zhai H, Maibach HI. Skin-whitening products. In: Handbook of Cosmetic Science and Technology. Marcel Dekker, 2001: 567-73. 3 Shai A, Baran R, Maibach HI. Bleaching and bleaching preparations. In: Handbook of Cosmetic Skin Care. Informa UK, 2009: 158-65. 4 Mortangi P Tiberi L, Randazzo SD. Pale face. , SPC Asia 1996; Oct/Nov: 27-8. 5 Skin lightener for bleaches. In: Wilkinson JB, Moore RJ eds. Harrys Cosmeticology 7th edn. 1982: 267-73. 6 Masuda M, Tejima T, Suzuki T, Imokawa G. Skin Lighteners. Cosmetic and Toiletries Magazine 1996; 3 (10): 65-6. 7 Goldemberg RL. Depigmentation. DCI 1997; 2: 54-6. 8 Parvez S, Kang M, Chung HS et al. Survey and mechanism of skin depigmenting and lightening agents. Phytother Res 2006; 20 (11): 921-34. 9 Maeda K, Fukuda M. Arbutin: mechanism of its depigmenting action in human melanocyte culture. J Pharmacol Exp Ther 1996; 276 (2): 765-9.

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Days Figure 4: Results of arbutin study.

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