inolex pcasia skinlight jan13

January 2013 PERSONAL CARE 25

Martina Heldermann – Inolex, Germany SKIN LIGHTENING

Having clear and bright skin is consideredan important feature for female beauty inAsian cultures. In these markets there is a large and growing demand for skinwhitening and lightening products. But there are also needs in other marketsfor use in anti-ageing products ortreatments against uneven pigmentation,like age spots and post-inflammatoryhyperpigmentation, a common problemseen in people with dark skin. Cosmeticproducts that lighten, brighten, or whitenskin are widely used for reduction ofnatural skin pigmentation but also toaccomplish a matching, consistent toneor to influence pigmentation disorderssuch as melasma, freckles, sun or agespots, and scarring lesions.

Several active ingredients have shownto be effective in skin whitening, althoughsome have shown to be toxic or, at least,have questionable safety profiles, e.g.hydroquinone. Some commonly usedwhitening agents like arbutin, kojic acid,and ascorbic acid derivatives have shown interesting efficacy in a variety ofhyperpigmentary disorders. As significantlylightening the skin is a difficult task,systems which can optimise delivery,therefore enhancing bioavailability, are of particular interest in these cases.

Mode of actionEspecially for hydrophilic actives, theappropriate delivery system is essential.The ideal delivery system is supposed to optimise delivery, enhance efficacy,reduce irritation through controlleddelivery, and improve activity at reducedconcentration. Lexorez TL-8 (INCI:Trimethylpentanediol/Adipic AcidCopolymer) supports topical delivery ofactive ingredients. It can be used tofacilitate high loading levels of actives at moderate costs. Lexorez TL-8 (nowreferred to by its INCI name) is based on polymeric liquid reservoir technologyand controls diffusion of actives into theepidermis through partitioning. Due to its low molecular weight (800 MW) itfacilitates uniform distribution of activesthroughout the stratum corneum for an

extended period of time. The active willslowly 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 notnormally penetrate efficiently through this route. Trimethylpentanediol/Adipic Acid Copolymer facilitates efficientpenetration by creating a vesicle containing the hydrophilic active ingredients and partitioning them from the surrounding lipophilic matrix. Besidesthe facilitation of penetration, also thebioavailability is improved while the activityis enhanced. Studies demonstrate thatTrimethylpentanediol/Adipic Acid Copolymeraccelerates the rate of skin lighteningallowing a reduction of the required use level of active ingredients.

Skin pigmentationUp to 10% of skin cells in the innermostlayer of the epidermis produce a darkpigment known as melanin. Upon exposure

of the skin to UV radiation, melanogenesisis initiated with the first step of tyrosineoxidation through an enzyme calledtyrosinase. The type and amount ofmelanin synthesised by the melanocyte,and its distribution pattern in thesurrounding keratinocytes, determines theactual colour of the skin. The degree of coloration is related to the number and distribution of subcellular units ofmelanin. Melanin is synthesised in dendritic cells known as melanocytes,which are normally found in the epidermalbasal layer. These melanocytes secretespecialised brown organelles that arereferred to as melanosomes. Themechanism by which melanin is formed is as follows. Melanosomes bear thecopper containing enzyme tyrosinase.Tyrosinase catalyses the oxidation oftyrosine to dihydroxyphenylalaline (DOPA).DOPA is then oxidised to dopaquinone.Through a series of autoxidation reactions,dopaquinone is then converted todopachrome next to dihydroxyindole-2-

Lightening efficacy enhancedvia polymeric technology

Trimethylpentanediol/Adipic Acid Copolymerwas just irrelevantly faster and moreeffective than 2.5%.

Hydroquinone studyTrimethylpentanediol/Adipic Acid Copolymer(5% use level) has been combined with 2%hydroquinone and compared to a controlcontaining no polymer but 2% of the skinwhitening active. The base formulationemployed for this study is a specific O/Wemulsion that is typically used whenincorporating hydroquinone. Due to theoxidative nature of the hydroquinone andthe subsequent instability of the active theformulations were processed and packagedwith a nitrogen blanket to reduce theoxidative potential. Figure 3 shows theresults, it can be concluded that theaddition of 5% Trimethylpentanediol/AdipicAcid Copolymer leads to a significantimprovement of hydroquinone efficacy.

Arbutin studyIn this study a double blind controlledclinical human panel testing wasconducted. Two test formulations wereanalysed; control containing 10% arbutin,the other containing 5% arbutin and 2.5% Trimethylpentanediol/Adipic AcidCopolymer. The purpose of the evaluationwas to determine if the inclusion ofTrimethylpentanediol/Adipic AcidCopolymer enhanced the performance ofthe active by eliciting a more pronouncedskin whitening response.

The base formulation employed for this study is a basic O/W emulsion withnonionic emulsifiers.

The results of this study shown inFigure 4 indicate that by the seventh day both formulations were effective inwhitening of the skin. During the first two weeks of product application, theformulation containing

Trimethylpentanediol/Adipic Acid Copolymerelicited a faster whitening response thanthe control. The data also indicated thatthe control, which contained twice theamount of arbutin was only slightly longerlasting than the other. The study suggeststhat the inclusion of the polyesterTrimethylpentanediol/Adipic Acid Copolymerproduced a faster whitening response with 50% less active.

ConclusionPrevious studies, as well as market-basedsuccess factors in self-tanning products,have demonstrated that Lexorez TL-8polymeric delivery system enhances theefficacy of certain skin actives. Byincreasing the partitioning and controllingthe diffusion of active agents through the epidermis, Lexorez TL-8 can providesustained and controlled delivery.

In general, skin whitening products areconsidered modestly effective at low uselevels that do not lead to any skin irritation.In all studies, Lexorez TL-8 improved the activity of the selective whiteningingredient. The addition of 2.5% Lexorez TL-8 allowed for the reduction of activeingredients by approximately 50% providinggreater formulation flexibility and reducingthe irritation potential of the actives.

Lexorez TL-8 can be added directly toformulations and does not need to be pre-mixed with the active. It can have a negative impact on lather in mousseformulations but there are no otherformulation incompatibilities known.

References1 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 andbleaching preparations. In: Handbook ofCosmetic 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. Harry’s Cosmeticology 7th edn.1982: 267-73.

6 Masuda M, Tejima T, Suzuki T, Imokawa G. SkinLighteners. Cosmetic and Toiletries Magazine1996; 3 (10): 65-6.

7 Goldemberg RL. Depigmentation. DCI 1997; 2: 54-6.

8 Parvez S, Kang M, Chung HS et al. Survey andmechanism of skin depigmenting and lighteningagents. Phytother Res 2006; 20 (11): 921-34.

9 Maeda K, Fukuda M. Arbutin: mechanism of itsdepigmenting action in human melanocyteculture. J Pharmacol Exp Ther 1996; 276 (2):765-9.

PC

SKIN LIGHTENING

28 PERSONAL CARE January 2013

Figure 3: Results of hydroquinone study.

� Control 2% hydroquinone� 2% hydroquinone and 5.0% TL-8

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Figure 4: Results of arbutin study.

� Control 10.0% arbutin� 5.0% arbutin and 2.5% TL-8

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Inolex_PCEAsia_SkinLight_Jan12_Print.indd 1 1/14/13 11:14 AM

carboxylic acid, then to 5,6 indolequinoneand lastly to melanin.

Among the skin lightening anddepigmenting agents, magnesium-L-ascorbyl-2-phosphate (MAP), hydroxyanisole,N-acetyl-4-S-cysteaminylphenol, alpha-hydroxy acids and arbutin (hydroquinone-beta-D-glucopyranoside) are the most widely prescribed worldwide. Althoughhydroquinone (HQ) is not permitted in, for instance, Europe anymore, it is stillconsidered to be the benchmark skinlightener 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 inhibitoryeffect on melanin formation. However, ithas not been widely used for this functiondue to instability in formulation. MAP, whichhas greater hydrolytic stability than vitaminC, is created in vivo through a conversionfrom ascorbic acid. This liberation of thefree acid results in pigment suppression,thereby preventing the formation ofmelanin and resulting in a lightening of the skin. MAP has also been shown toprotect the skin against damages inducedby UVB irradiation.

Lactic acidLactic acid is a low molecular weightorganic acid which belongs to the group ofalpha-hydroxy acids (AHA) and is derivedfrom sour milk, or can be producedsynthetically. It has some effect on skinwhitening and is often combined with otherbleaching agents. AHAs work by inhibitingtyrosinase, which catalyses a key step inpigment synthesis.

HydroquinoneHydroquinone was once a more than well-accepted agent for bleaching

hyperpigmented lesions. As a matter offact, 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 itcannot be used in cosmetic formulationsanymore.

ArbutinArbutin is another bleaching compoundextracted from Arctostaphylos uva orsi(bearberry). It functions as a skin whitenerby inhibiting the formation of melanin. The depigmentation effect of arbutinworks through an inhibition of themelanosomal tyrosinase activity, ratherthan suppression of the expression andsynthesis of tyrosinase in melanocytes.Arbutin is less cyctotoxic thanhydroquinone to melanocytes.

Materials and methodsTest panel� Healthy Filipinos, male and female.� Age 16 to 60.� Dark Skin Type 3 or 4.

Testing and readingAll tests have been double blind studies.Product A was evaluated against productC on the left and right arm respectively.Product B was evaluated against productC on the left and right arm respectively.The contents were unknown to theinvestigator and subjects. The subjectswere 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 armrespectively twice daily for 4 weeks/28 days.

Subjects were instructed to return tothe testing centre on days 7, 14, 21

and 28 for evaluation. The change in skincolour was graded by a trained investigatorand documented on the grading sheet.

Criteria for efficacy 0 – No Pigmentation 1 – Very Light Brown 2 – Moderate Brown 3 – Dark Brown or No Change

ResultsBy increasing the partitioning and diffusionof active agents into and throughout theepidermis Trimethylpentanediol/Adipic AcidCopolymer can provide sustained andcontrolled delivery, enhance desquamationrates, and reduce the irritation potentialassociated with most active ingredients.Trimethylpentanediol/Adipic Acid Copolymer is a linear 800 MW hydroxyterminated polyester. The constituents of Trimethylpentanediol/Adipic AcidCopolymer are trimethylpentanediol andadipic acid.

MAP studyThis study examined the effect of MAP andTrimethylpentanediol/Adipic Acid Copolymerin a skin lightening lotion. The researchwas conducted as a controlled, double-blind clinical human panel test. Three testformulations were analysed: 1) 3% MAPand 2.5% TL-8, 2) 5% MAP and 2.5% Trimethylpentanediol/Adipic AcidCopolymer, and 3) control with 10% MAPand no Trimethylpentanediol/Adipic AcidCopolymer. The purpose of the evaluationwas to determine if the inclusion of theingredient enhanced the performance ofMAP by eliciting a faster and morepronounced skin whitening response.

The base formulation employed for this study was a simple O/W emulsion with nonionic emulsifiers.

SKIN LIGHTENING


Figure 1: Results of MAP study.

� Control� 5.0% MAP and 2.5% TL-8� 3.0% MAP and 2.5% TL-8

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Arctostaphylos Uva Orsi (bearberry).

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The results are shown in the Figure 1which indicate that Product A (3% MAPand 2.5% Trimethylpentanediol/Adipic AcidCopolymer) and Product B (5% MAP and2.5% Trimethylpentanediol/Adipic AcidCopolymer) were both more effective thanProduct C (control, 10% MAP) in skinlightening. Formulations containing 2.5%Trimethylpentanediol/Adipic Acid Copolymerproduced a significantly greater lightening

effect earlier in the study than the control,indicating that the addition of theingredient increases the distribution of MAP within the stratum corneum. The dataalso suggest that its incorporation intoformulations produces an increasedresponse to lower MAP concentrations.This allows for the maximisation of MAPefficacy, providing the formulator withgreater flexibility and cost efficiency.

Lactic acid studyTrimethylpentanediol/Adipic Acid Copolymerin two different concentrations has beencombined with 10% undissociated lacticacid to determine which of these twocombinations can not only enhance theskin whitening effect attributed by lacticacid, but also which concentration can give a faster rate of efficacy. The studytherefore seeks to determine whichpolyester variation will give a superior skinwhitening response. The responses weremonitored periodically throughout thestudy.


Product A served as the control,containing 10% undissociated lactic acid, while Product B contained 10%undissociated lactic acid and 5%Trimethylpentanediol/Adipic AcidCopolymer, and Product C contained 10% undissociated lactic acid and 2.5% Trimethylpentanediol/Adipic AcidCopolymer.

Based on the results of this studyshown in Figure 2, it can be concludedthat 2.5% and 5% Trimethylpentanediol/Adipic Acid Copolymer were both moreeffective than Product A the control inproducing lightening of the skin. 5%

SKIN LIGHTENING


Figure 2: Results of lactic acid study.

� Control� 5.0% TL-8� 2.5% TL-8

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Martina Heldermann – Inolex, Germany SKIN LIGHTENING

Having clear and bright skin is consideredan important feature for female beauty inAsian cultures. In these markets there is a large and growing demand for skinwhitening and lightening products. But there are also needs in other marketsfor use in anti-ageing products ortreatments against uneven pigmentation,like age spots and post-inflammatoryhyperpigmentation, a common problemseen in people with dark skin. Cosmeticproducts that lighten, brighten, or whitenskin are widely used for reduction ofnatural skin pigmentation but also toaccomplish a matching, consistent toneor to influence pigmentation disorderssuch as melasma, freckles, sun or agespots, and scarring lesions.

Several active ingredients have shownto be effective in skin whitening, althoughsome have shown to be toxic or, at least,have questionable safety profiles, e.g.hydroquinone. Some commonly usedwhitening agents like arbutin, kojic acid,and ascorbic acid derivatives have shown interesting efficacy in a variety ofhyperpigmentary disorders. As significantlylightening the skin is a difficult task,systems which can optimise delivery,therefore enhancing bioavailability, are of particular interest in these cases.

Mode of actionEspecially for hydrophilic actives, theappropriate delivery system is essential.The ideal delivery system is supposed to optimise delivery, enhance efficacy,reduce irritation through controlleddelivery, and improve activity at reducedconcentration. Lexorez TL-8 (INCI:Trimethylpentanediol/Adipic AcidCopolymer) supports topical delivery ofactive ingredients. It can be used tofacilitate high loading levels of actives at moderate costs. Lexorez TL-8 (nowreferred to by its INCI name) is based on polymeric liquid reservoir technologyand controls diffusion of actives into theepidermis through partitioning. Due to its low molecular weight (800 MW) itfacilitates uniform distribution of activesthroughout the stratum corneum for an

extended period of time. The active willslowly 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 notnormally penetrate efficiently through this route. Trimethylpentanediol/Adipic Acid Copolymer facilitates efficientpenetration by creating a vesicle containing the hydrophilic active ingredients and partitioning them from the surrounding lipophilic matrix. Besidesthe facilitation of penetration, also thebioavailability is improved while the activityis enhanced. Studies demonstrate thatTrimethylpentanediol/Adipic Acid Copolymeraccelerates the rate of skin lighteningallowing a reduction of the required use level of active ingredients.

Skin pigmentationUp to 10% of skin cells in the innermostlayer of the epidermis produce a darkpigment known as melanin. Upon exposure

of the skin to UV radiation, melanogenesisis initiated with the first step of tyrosineoxidation through an enzyme calledtyrosinase. The type and amount ofmelanin synthesised by the melanocyte,and its distribution pattern in thesurrounding keratinocytes, determines theactual colour of the skin. The degree of coloration is related to the number and distribution of subcellular units ofmelanin. Melanin is synthesised in dendritic cells known as melanocytes,which are normally found in the epidermalbasal layer. These melanocytes secretespecialised brown organelles that arereferred to as melanosomes. Themechanism by which melanin is formed is as follows. Melanosomes bear thecopper containing enzyme tyrosinase.Tyrosinase catalyses the oxidation oftyrosine to dihydroxyphenylalaline (DOPA).DOPA is then oxidised to dopaquinone.Through a series of autoxidation reactions,dopaquinone is then converted todopachrome next to dihydroxyindole-2-

Lightening efficacy enhancedvia polymeric technology

Trimethylpentanediol/Adipic Acid Copolymerwas just irrelevantly faster and moreeffective than 2.5%.

Hydroquinone studyTrimethylpentanediol/Adipic Acid Copolymer(5% use level) has been combined with 2%hydroquinone and compared to a controlcontaining no polymer but 2% of the skinwhitening active. The base formulationemployed for this study is a specific O/Wemulsion that is typically used whenincorporating hydroquinone. Due to theoxidative nature of the hydroquinone andthe subsequent instability of the active theformulations were processed and packagedwith a nitrogen blanket to reduce theoxidative potential. Figure 3 shows theresults, it can be concluded that theaddition of 5% Trimethylpentanediol/AdipicAcid Copolymer leads to a significantimprovement of hydroquinone efficacy.

Arbutin studyIn this study a double blind controlledclinical human panel testing wasconducted. Two test formulations wereanalysed; control containing 10% arbutin,the other containing 5% arbutin and 2.5% Trimethylpentanediol/Adipic AcidCopolymer. The purpose of the evaluationwas to determine if the inclusion ofTrimethylpentanediol/Adipic AcidCopolymer enhanced the performance ofthe active by eliciting a more pronouncedskin whitening response.


The results of this study shown inFigure 4 indicate that by the seventh day both formulations were effective inwhitening of the skin. During the first two weeks of product application, theformulation containing

Trimethylpentanediol/Adipic Acid Copolymerelicited a faster whitening response thanthe control. The data also indicated thatthe control, which contained twice theamount of arbutin was only slightly longerlasting than the other. The study suggeststhat the inclusion of the polyesterTrimethylpentanediol/Adipic Acid Copolymerproduced a faster whitening response with 50% less active.

ConclusionPrevious studies, as well as market-basedsuccess factors in self-tanning products,have demonstrated that Lexorez TL-8polymeric delivery system enhances theefficacy of certain skin actives. Byincreasing the partitioning and controllingthe diffusion of active agents through the epidermis, Lexorez TL-8 can providesustained and controlled delivery.

In general, skin whitening products areconsidered modestly effective at low uselevels that do not lead to any skin irritation.In all studies, Lexorez TL-8 improved the activity of the selective whiteningingredient. The addition of 2.5% Lexorez TL-8 allowed for the reduction of activeingredients by approximately 50% providinggreater formulation flexibility and reducingthe irritation potential of the actives.

Lexorez TL-8 can be added directly toformulations and does not need to be pre-mixed with the active. It can have a negative impact on lather in mousseformulations but there are no otherformulation incompatibilities known.

References1 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 andbleaching preparations. In: Handbook ofCosmetic 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. Harry’s Cosmeticology 7th edn.1982: 267-73.

6 Masuda M, Tejima T, Suzuki T, Imokawa G. SkinLighteners. Cosmetic and Toiletries Magazine1996; 3 (10): 65-6.

7 Goldemberg RL. Depigmentation. DCI 1997; 2: 54-6.

8 Parvez S, Kang M, Chung HS et al. Survey andmechanism of skin depigmenting and lighteningagents. Phytother Res 2006; 20 (11): 921-34.

9 Maeda K, Fukuda M. Arbutin: mechanism of itsdepigmenting action in human melanocyteculture. J Pharmacol Exp Ther 1996; 276 (2):765-9.

PC

SKIN LIGHTENING


Figure 3: Results of hydroquinone study.

� Control 2% hydroquinone� 2% hydroquinone and 5.0% TL-8

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our

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ng

Days

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00 7 14 21 28 42

Figure 4: Results of arbutin study.

� Control 10.0% arbutin� 5.0% arbutin and 2.5% TL-8

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inolex pcasia skinlight jan13

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