EP2501360A1

EP2501360A1 - Tetrapeptides for brightening the skin

Info

Publication number: EP2501360A1
Application number: EP10765644A
Authority: EP
Inventors: Mike Farwick; Ursula Maczkiewitz; Tim KÖHLER
Original assignee: Evonik Goldschmidt GmbH
Current assignee: Evonik Operations GmbH
Priority date: 2009-11-17
Filing date: 2010-10-18
Publication date: 2012-09-26
Also published as: WO2011061024A1; DE102009046780A1; JP2013510809A; KR20120107944A; CN102573776A; US20120244094A1

Abstract

The invention relates to the use of the tetrapeptide PKEK for brightening human skin, for bleaching pigmented spots and/or for leveling out irregularities in skin coloration.

Description

Tetrapeptides for lightening the skin

Field of the invention

The present invention is the use of the tetrapeptide PKEK for lightening the human skin color, for bleaching of pigment spots and / or for compensating for irregularities in the skin color.

State of the art

The task of nourishing cosmetics is to give the impression of an external youthful appearance,

For example, the skin and hair to get.

In principle, there are several ways open to reach this path. So existing skin damage, such as irregular pigmentation or wrinkling, can be compensated by covering powder or creams. Another approach is to protect the skin from environmental influences that lead to permanent damage and thus aging of the skin. So the idea is to intervene preventively and thereby the aging process

delay. The most important function of the skin is the protection of the body against the uncontrolled release of water on the one hand and against the ingress of harmful chemicals or bacteria as well as solar radiation on the other hand. Exposing the human skin to prolonged exposure to sunlight may cause the appearance of light-induced skin

Skin aging and pigmentation disorders lead. This damaging effect of sunlight is inter alia on the in the Sunlight spectrum contained UVB radiation (280 - 320 nm).

Pigmentation disorders are perceived as a cosmetic blemish. As examples of this local

Hyperpigmentation could be mentioned: freckles,

Melasma, chloasma, postinflammatory hyperpigmentation, liver spots and many more. All forms of

Hyperpigmentation has in common that a disorder in melanogenesis occurs.

The pigmentation of the skin is essentially determined by the skin's own pigment melanin. This is formed by specialized cells of the epidermis, the melanocytes. In melanin synthesis, tyrosinase plays a crucial role as a pacemaker enzyme.

The skin responds to the influence of UV radiation with the formation of melanin. Human melanins are from the

Melanocytes synthesized biopolymers. The melanocytes are localized in the epidermis of the skin. They have dendritic foothills through which they communicate with the keratinocytes. In the melanocytes, the melanin is formed and then with the help of melanosomes in the

transferred to adjacent keratinocytes. To the

Induce melanin formation, send the keratinocytes

paracrine signals out. For example, NO is formed in the keratinocytes as a result of UV-A and UV-B irradiation, causing melanin formation in the melanocytes. The

Melanocytes respond to NO with an increased

Cell growth, increased dendrites and increase melanogenesis. The regulation of melanogenesis in the

Melanocytes are also under the control of the alpha-MSH hormone. Local hyperpigmentation or the natural

Skin pigmentation is often perceived as a cosmetic blemish. Therefore, different strategies have been developed to reduce the pigmentation of the skin.

One of the most commonly used skin and hair whiteners is hydroquinone or the hydroquinone glycoside arbutin. However, these compounds have a cytotoxic effect on melanocytes and irritating the skin.

Another possibility is the inhibition of

Melanin synthesis by inhibition of the pacemaker enzyme

Tyrosinase. For this purpose, among others, the substances kojic acid and derivatives of kojic acid such as e.g.

Kojisäuredipalmitat kojic acid, azelaic acid,

Oxyresveratrol, linolenic acid, vitamin C and derivatives of ascorbic acid such as. As ascorbyl phosphate or

Ascorbyl palmitate used. However, these substances either have a high sensitizing potential, cause contact allergies, show insufficient

chemical stability in cosmetic formulations or have only an insufficient effect on the skin.

In addition, strategies are known that facilitate the transfer of melanin from the melanocytes to the surrounding

Prevent keratinocytes. Thus protease inhibitors are described which inhibit on the surface of the keratinocytes the PAR2 receptor and thereby the transfer of the

Reduce melanin. Hydrolysates of soybeans and

Niacinamide should in this way the pigmentation

Reduce .

Likewise, various plant extracts such as

Example: sweet wood extract, mulberry tree extract or

Bearberry extract certifies skin lightening effect. Here is the problem of inadequate Standardization of the extracts for a constant effectiveness on the skin.

Also, an increased renewal of the skin becomes

Skin whitening described. For this procedure u. a. Alpha hydroxy acids such as lactic acid and glycolic acid are used. Through this treatment, the uppermost skin layers are etched and the melanin-containing corneocytes are removed. Disadvantage of this method is a common one

occurring irritation of the skin.

Thus, there is still an increasing demand for new, further and improved active ingredients for the treatment of hyperpigmentation but also for the purely cosmetic brightening of larger skin areas, which are quite suitably pigmented for the individual skin type.

The peptide PKEK is described in the patent application WO / 2008/085494 as well as in WO / 2009/068351. It owns

immunomodulatory properties as well as anti-aging

Effectiveness.

The object of the invention was to provide a care active which has a skin-lightening effect, which is well tolerated and can be well formulated.

Description of the invention

Amazingly, the task is solved by the

Use of the tetrapeptide PKEK (SEQ ID NO: 1) against undesired pigmentation of the skin. The subject of the present invention is therefore the

Use of the tetrapeptide PKEK or one of its

Derivatives for lightening human skin color, for bleaching pigment spots and / or for compensating for irregularities in skin coloration.

Another object of the invention is the use of the tetrapeptide PKEK or one of its derivatives for

Preparation of a formulation such as these specific formulations themselves

An advantage of the present invention is that the

Tetrapeptide itself has other properties that are more beneficial in the context of skin lightening, such as the ability to tighten skin and smooth skin wrinkles as well as relieve inflammation.

All stated percentages (%) are if not different

expressed mass percent. A derivative of the tetrapetide is to be understood in particular acyl derivatives; for the acyl derivatization of the tetrapeptide used in the invention by amide compound an alkylic lipophilic chain or an arylic radical or its alkyloxic or aryloxische or alkylaryloxische variant at the N-terminal end of the oligopeptide and / or at the C-terminal end by ester compound an alkylic alcohol or by Amide compound a H ₂ - or such N-alkylisch substituted ^¬ group attached.

According to the invention, an acyl group is preferably arranged at the N-terminal end of the amino acid sequence. This may optionally be branched or straight chain, long or short chain wear, ge ^¬ saturated or unsaturated radicals, unsubstituted or be substituted with one or more hydroxyl, amino, acylamino, sulfate ^¬ or sulfide groups. Such N-acylic derivatives can be used, for example, with acetic acid, biotinic acid, caprylic acid, capric acid, lauric acid, myristic acid,

Octanoic acid, palmitic acid, stearic acid, behenic acid,

Linoleic acid, linolenic acid, lipoic acid, oleic acid, isostearic acid, elaidic acid, 2-ethylhexanoic acid, coconut oil fatty acid,

Talc fatty acid, hardened talc fatty acid, palm kernel oil fatty acid, lanolin fatty acid, or mixtures thereof.

Preferred acyl groups include substituted or unsubstituted acetyl, palmitoyl, hexanoyl, myristyl, biotinyl and octanoyl groups.

The inventive use of the tetrapeptide PKEK or one of its derivatives for brightening the human

Skin color, for bleaching of pigment spots and / or for compensating for irregularities in the skin coloration is to settle in particular in the cosmetic, non-therapeutic area.

The tetrapeptide PKEK or one of its derivatives can be used advantageously for the preparation of a formulation for

Lightening of human skin color, bleaching of pigmentation marks and / or to compensate for

Irregularities in the skin coloration can be used.

A formulation to brighten the human

Skin color, for bleaching of pigment spots and / or to compensate for irregularities in the skin coloration are those, preferably cosmetic, formulation

clearly formulated for such purposes. This is particularly evident from the fact that other skin whitening ingredients are included. These may in particular be kojic acid, koj acid derivatives, niacin / niacinamides, alfa Hydroxycarboxylic acids such as lactic acid, arbutin,

Arbutin derivatives, ascorbic acid, ascorbic acid derivatives such as sodium ascorbyl phosphate, magnesium ascorbyl phosphate and ascorbyl glucoside, hydroquinone, hydroquinone derivatives,

Glabridin in licorice, oleanoic acid, sulfur-containing molecules such as e.g. Glutathione or cysteine or other synthetic or natural skin lightening agents. Another object of the invention is the use of the tetrapeptide PKEK or one of its derivatives for

Preparation of a sunscreen formulation.

This is justified in that as one

Sunscreen formulation was obviously prepared to also counteract a coloring of the skin, prophylactic only in this case.

The ocular preparation of a sunscreen formulation can be made in particular from the fact that UV radiation absorbing substances are included. Examples of such substances are listed below.

Thus, yet another object of the present invention is a formulation, preferably a cosmetic containing

a) an effective amount of the tetrapeptide PKEK or one of its derivatives

b) a safe and effective amount of at least one additional active ingredient selected from the group consisting of the skin bleaching agents which

Depigmentation, the sunscreen and the blocking of UV rays and, where appropriate

c) a dermatologically acceptable carrier. As used herein, the term "dermatologically acceptable carrier" means that the carrier is suitable for topical application to the horn tissue, has good aesthetic properties, is compatible with the active ingredients of the present invention and any other components and does not give rise to unfavorable safety or toxicity concerns. The wearer can come in many different forms

available. For example, here are emulsion carrier

including oil in water, water in oil, water in oil in water, and oil in water in silicone emulsions.

In the context of the invention

Formulations are preferred agents for the

Skin bleaching and depigmentation kojic acid,

Koj acid dipalmitate, niacin / niacinamide, alfa

Hydroxycarboxylic acids such as lactic acid, arbutin, ascorbic acid, ascorbic acid derivatives such as sodium ascorbyl phosphate,

Magnesium ascorbyl phosphate and ascorbyl glucoside

Ascorbyl pimitate, sodium ascorbyl phosphate,

Magnesium ascorbyl phosphate and ascorbyl glucoside,

Hydroquinone, glabridin in licorice, oleanoic acid,

Glutathione, cysteine, azelaic acid, oxyresveratrol,

Linolenic acid, dicarboxylic acids such as dioic acid.

These are in particular included when the formulation according to the invention is a formulation for lightening the human skin color, for bleaching pigmentation spots.

In the context of the invention

Formulations are preferred agents for the

Sunscreen and the blocking of UV rays selected from the group consisting of: 3-benzylidene camphor,. 3- (4-methylbenzylidene) camphor,

4- (dimethylamino) benzoic acid 2-ethylhexyl ester,

Methyl 4- (dimethylamino) benzoate, esters of cinnamic acid, esters of salicylic acid, benzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, esters Benzalmalonic acid, triazines, 2, 4, 6-trianilino- (p-carbo-2'-ethyl-1 '-hexyloxy) -1, 3, 5-triazine, octyltriazone, propane-1,3-dione, 1- ( 4-tert-butylphenyl) -3- (4'-methoxyphenyl) propane-1, 3-dione, 2-phenylbenzimidazole-5-sulfonic acid, sulfonic acid derivatives of benzophenone,

Sulfonic acid derivatives of the 3-Benzylidencamphers, derivatives of benzoylmethane, finely dispersed metal oxides or salts such as titanium dioxide or zinc oxide, 2, 2 'methylene-bis- {6- (2H-benzotriazole-2-yl) -4- (1, 1, 3 , 3-tetramethylbutyl) phenol. These are especially included when the formulation according to the invention is a

Sunscreen formulation is.

Particularly preferred according to the invention is a formulation which contains a formulation for balancing

Irregularities in the skin coloration represents. This is in particular characterized in that it has a

contains additional component d), which comprises self-tanner, preferably consists of these.

According to the invention in this context suitable

Self-tanning agents are selected from the group consisting of dihydroxyacetone and erythrulose.

The formulations according to the invention contain from 0.00001% by mass to 1% by mass, preferably 0.00005

Percent by mass to 0.5 percent by mass, more preferably 0.0001% by mass to 0.1% by mass of tetrapeptide or derivative based on the total weight of the formulation.

The formulation of the invention may e.g. contain at least one additional component selected from the group of

Emollients,

emulsifiers,

Thickeners / viscosity regulators / stabilizers,

antioxidants

Hydrotropes (or polyols),

Solids and fillers,

Perlglänzadditive,

Deodorant and antiperspirant active ingredients,

insect repellents,

Self,

Preservatives,

Conditioning agent,

perfumes,

dyes,

cosmetic agents,

Care additives,

Superfatting agent,

Solvent.

Substances which can be used as exemplary representatives of the individual groups are known to the person skilled in the art and can be used, for example, in the German application DE

102008001788.4 are taken. This patent application is hereby incorporated by reference and thus forms part of the disclosure. With regard to further optional components as well as the amounts of these components used, reference is expressly made to the relevant manuals known to the person skilled in the art, eg. BK Schräder, "Foundations and Formulations of Kosemtika", 2nd edition, pages 329 to 341, Hüthig book publisher

Heidelberg, directed.

The quantities of the respective additives depend on the intended use.

Typical frame formulations for the respective applications are known in the art and are included, for example, in the brochures of the manufacturers of the respective basic substances and active ingredients. These existing formulations can usually be adopted unchanged. in the

If necessary, the desired modifications can be made by simple experiments for adjustment and optimization without complications.

As described above for the tetrapeptide itself, the formulations according to the invention may also be advantageously used for lightening the human skin color, for bleaching pigmentation spots and / or for compensating for irregularities in the skin coloration.

Another object of the invention is a method for whitening the human skin color, for bleaching of pigment spots and / or for balancing

Irregularities in skin coloration include the

steps

A) providing a formulation according to the invention

B) Application of the formulation according to the invention to the skin at least once a day in an effective amount. In the examples below, the

The present invention is described by way of example, without the invention, the scope of which is apparent from the entire description and the claims, to be limited to the embodiments mentioned in the examples.

The following figures are part of the examples:

Figure 1: Melanin decrease in the panel test

FIG. 2: Color space L * a * b *

FIG. 3: Typing of the different skin tones

Figure 4: ΔΔΙΤΑ after 6 weeks of application of

test formulations

FIG. 5: Improvement of the uniformity of the skin appearance (** p <0.01 in comparison PKEK / vehicle)

Examples:

Example 1: in vivo lightening (2 month study)

20 volunteers wore a test formulation without peptide or with 0.005% PKEK over a period of 8 weeks on one forearm each. Before the start of the study and after 8 weeks, the melanin concentration was measured both on the inside and on the outside of the forearm with a mexameter probe (Courage & Khazaka, Cologne).

The measurement of melanin concentration in the skin is based on the principle of absorption / reflection. The

Mexametersonde emits light of a specific wavelength, which coincides with the absorption maxima of melanin in the skin

matches. The light reflected from the skin is measured and set in relation to the amount of emitted light. The obtained measurements are given as index numbers.

Test formulation:

FIG. 1 shows the difference in the melanin values after 8 weeks in comparison to the starting value. Both on the

Inside as well as on the outside of the forearms a significant decrease of the skin tan is noticeable compared to the vehicle. Example 2: Example formulations

In the following, example formulations are described; percentages given are percent by mass and are based on the total weight of the example formulation. To prepare the formulations, customary formulation methods known to the person skilled in the art were used.

O / W formulation

W / 0-formulation

Phase A

Polyglyceryl-4 isostearates 1.5%

Cetyl PEG / PPG-10/1 Dimethicone 1.0%

Ethylhexyl palmitate 11.0%

Decyl Oleate 10.5%

Hydrogenated Castor Oil 0.8%

Microcrystalline wax 1.2%

Phase B

Glycerol 3, 0%

Magnesium sulphates Heptahydrate 0, 6% PKEK 0, 002%

Water 70, 398%

Phase Z

Preservative, perfume q. s.

shower gel

O / W cream with licorice extract

Phase A

Stearyl Alcohol 3, 5 ~ 6

Glyceryl Stearate 1.5%

Cetearyl ethylhexanoate 7.8%

Caprylic / Capric Triglycerides 10.0%

Macadamia Ternifolia Nut Oil 4.0%

Tocopheryl Acetate 1.0%

Dimethicone 0.2%

Phase B

Cetearyl Glucosides 1.0%

Sucrose stearate 2.0%

Glycerol 3, 0%

PKEK 0.005%

Glycyrrhiza Glabra (Licorice) Extract 0.1%

Water 64, 895% Phase C

Carbomer 0.2%

Cetearyl ethylhexanoate 0.8%

Phase D

Sodium hydroxides (10%) q. s.

Phase Z

Preservative, perfume q. s.

O / W Cream with Licorice Root Extract

Phase A

Stearyl Alcohol 3, 0%

Glyceryl Stearate 1.0%

Stearic acid 1.0%

Caprylic / Capric Triglycerides 9, 0%

Decyl Cocoate 4.5%

Avocado (Persea Gratissima) Oil 5, 0%

Tocopheryl acetate 0.5%

Phase B

Cetearyl Glucosides 1.0%

Glycerol 3, 0%

Allantoin 0.2%

Panthenol 0.5%

PKEK 0, 002%

Glycyrrhiza Glabra (Licorice) Root 0.1% Extract

Water 69, 198%

Phase C

Sodium lactate; Sodium PCA; fructose; 2.0% urea; Niacinamide; inositol; Sodium

benzoate; Lactic acid

Phase Z

Preservative, perfume q. s. O / W body lotion with kojic acid

Phase A

Glyceryl Stearate Citrate 1.5%

Cetearyl Alcohol 1.0%

Caprylic / Capric Triglyceride 7.0%

Mineral Oil 5 _r 5 "6

Phase B

Glycerol 5, 0%

PKEK 0.003%

Kojic acid 0.2%

Water 78, 197%

Phase C

Carbomer 0.2%

Mineral Oil 0.8%

Phase D

Sodium hydroxides (10%) 0, 6%

Phase Z

Preservative, perfume q. s.

W / O body lotion with arbutin

Phase A

Diisostearoyl Polyglyceryl-3 Dimer Dilinoleate 3, 0%

Hydrogenated Castor Oil 0.2%

Microcrystalline wax 0.3%

Isocetyl palmitate 8.0%

Ethylhexyl palmitate 5 _r 5 "6

Isopropyl Palmitate 8.0%

Phase B

Glycerine 2.0%

Magnesium sulphates Heptahydrate 1,0%

PKEK 0.001%

Arbutin 2.0%

Water 69, 999%

Phase Z

Preservative, perfume q. s.

O / W Body Butter with Hydroquinone

Phase A

Glyceryl stearates; PEG-100 Stearate 6, 0%

Cetearyl Alcohol 1.5%

Myristyl myristate 1.0%

Cetyl ricinoleate 1.0%

Cyclomethicone 6, 0%

Behenoxy Dimethicone 1.0%

Soybean (Glycine soy) Oil 7.0%

Butyrum sperm parkii (Shea Butter) 7.0%

Lanolin Alcohol 1.0%

Theobroma cacao (cocoa butter) 7.0%

Phase B

Glycerol 5, 0%

EDTA 0.1%

PKEK 0, 002%

Hydroquinone 0.5%

Water 55, 898%

Phase Z

Preservative, perfume q. s.

O / W cream with mulberry extract

Phase A

Bis-PEG / PPG-16/16 PEG / PPG 16/16 1.5% Dimethicone; Caprylic / Capric

triglycerides

Ceteareth-25 1.0%

Glyceryl Stearate 3, 0%

Stearyl Alcohol 2.0%

Stearic acid 1.0%

Isocetyl Palmitate 5 _r 5 "6

Ethylhexyl palmitate 6, 0%

Phase B

Glycerine 2.0%

PKEK 0.005%

Water 76, 495%

Phase C

Carbomer 0.1%

Isocetyl palmitate 0.4%

Phase D

Sodium hydroxides (10%) q. s.

Phase E

Butylene Glycol, Morus Alba root 1.0% extract

Phase Z

Preservative, perfume q. s.

O / W cream with Oxyresveratrol

O / W cream with octadecenedioic acid

Phase A

Ceteareth-25 2.0%

Stearyl Alcohol 2 _r 5 "6

Glyceryl Stearate 1.5%

Stearic acid 1.0%

Ethylhexyl stearate 10.0%

Mineral Oil 8.0%

Octadecenedioic acid 1.0%

Phase B

Water 69, 999%

PKEK 0.001%

Phase C

Betaine 2.0%

Water 2.0%

Phase Z

Preservative, perfume q. s. W / O Cream with Magnesium Ascorbyl Phosphate

O / W body lotion with sodium ascorbyl phosphate

Phase A

Glyceryl Stearate SE 4.0%

Stearic acid 0.5%

Myristyl alcohol 0.5%

Mineral Oil 4, 6%

Ethylhexyl stearate 5, 0%

Phase B

Glycerol 3, 0%

PKEK 0.001%

Water 70,399

Phase C

Carbomer 0.1%

Mineral Oil 0.4% Phase D

Sodium ascorbyl phosphate 1.5%

Water 10.0%

Phase E

Sodium hydroxides (10%) q. s.

Phase Z

Preservative, perfume q. s.

Cream bath with niacinamide

0 / W sunscreen lotion

Phase A

Polyglyceryl-3 methylglucose distearate 2, 5 ~ 6

C12-15 alkyl benzoate 4.0%

Decyl Cocoate 2 _r 5 "6

Isopropyl Palmitate 1, 6%

Tocopheryl acetate 0.5%

Ethylhexyl methoxycinnamate 5, 0%

4-methylbenzylidene camphor 3, 0%

Butyl methoxydibenzoylmethane 2.0% Phase B

Glycerine 2.0%

EDTA 0.1%

PKEK 0.003%

Water 75, 897%

Phase C

Carbomer 0.05%

Acrylates / C10-30 Alkyl Acrylates Crosspolymer 0.05%

Isopropyl Palmitate 0.4%

Phase D

Sodium hydroxides (10%) 0.4%

Phase Z

Preservative, perfume q. s.

W / O sunscreen cream

Phase A

Cetyl PEG / PPG-10 / l Dimethicone 2, 5 ~ 6

Diethylhexyl carbonates 7.4%

C12-15 alkyl benzoate 2.0%

Cera Alba 0.5%

Hydrogenated Castor Oil 0.5%

Tocopheryl Acetate 0, 6%

Ethylhexyl salicylate 3, 0%

Ethylhexyl methoxycinnamate 7.5%

Benzophenone-3 5, 0%

Phase B

Sodium Carboxymethyl Beta Glucan 0.2%

Glycerine 1.0%

Allantoin 0.1%

PKEK 0, 002%

Sodium Chloride 0.5%

Water 69, 198% Phase Z

Preservative, perfume q. s.

Example 3: Reduction of age spots on the face Age spots (Latin: Lentigines seniles, Lentigines solares) are pigmentary disorders of the skin. They are caused by increased, chronic exposure

ultraviolet radiation, e.g. Sunlight. This leads to local, sharply delineated light brown stains ("maculae") with an increase in the melaninproduzierenden

Melanocytes, predominantly in the back of the hands,

Forearms and facial skin.

To quantify such age spots

Color measurements of the skin performed. To do this

Chromameter used. The chromameter measures the color values L *, a * and b *. These describe a three-dimensional color space, with the help of which every perceptible color can be described, cf. FIG. 2.

On the a * -axis lie the opposite colors green and red, on the b * -axis the opposite colors blue and yellow.

The axis L * indicates the brightness. The endpoints are black (L = 0) and white (L = 100).

To be able to classify the skin tone, the

Parameter L * and b * required. The skin tone ITA ° is given in degrees and calculated using the formula:

ITA "= [arctane ((L * -50) / b *)] * 180/3, 14159

The skin tone is classified as follows, cf. 3:

ITA "> 55 ° very bright

55 °> ITA "> 41 ° light

41 °> ITA "> 28 ° medium 28 °> ITA "> 10 ° browned.

See also: COLIPA Guideline: Guideline for the colometric Determination of skin color typing and

prediction of the minimal erythema dose (MED) without UV exposure,

The following study aimed to investigate whether the tetraeptide PKEK is able to visibly reduce age spots.

The study was performed as a half-side test. Forty women between the ages of 30 and 70 who had visible age spots on their faces were selected. she

each received 2 test formulations, one for the right, the other for the left half of the face. The

Test formulations had to be done twice a day over a

Be applied over a period of six weeks.

PKEK Asc. Phos. PKEK + Asc. Phos. vehicle

Polyglyceryl-3 3, 0 3, 0 3, 0 3, 0

methyl glucose

Distearate

Stearyl Alcohol 1.0 1.0 1.0 1.0

Glyceryl Stearate 2.0 2.0 2.0 2.0

C12-15 9.5 9.5 9.5 9.5

benzoates

Caprylic / Capric 9.5 9.5 9.5 9.5

triglycerides

Water 61, 496 59, 7 59, 696 61, 5

Sodium ascorbyl-1,5 1,5

phosphate

Sodium bisulfite 0.3 0.3 (39%)

Urea 2.5 2.5 2.5 2.5

PKEK 0.004 0.004

Water 10.0 10.0 10.0 10.0

Microcare MEM 0.8 0.8 0.8 0.8 (Conservator)

Perfume 0.2 0.2 0.2 0.2 pH> = 7> = 7> = 7> = 7

Test formulation (information in GeW ~ 6)

Before the study and after 6 weeks, the color of the skin was measured directly on the age spot as well as in the surrounding area. This happened with a Chromameter CR 400 from Minolta. The skin tone ITA ° was determined both for the age spot (ITA ° _A ) and the adjacent environment

(ITA ° u) and the difference formed: ΔΙΤΑ ° = ITA ° u - ITA ° _A

The larger ΔΙΤΑ °, the more visible is the

Age spot. Subsequently, the difference of ΔΙΤΑ ° before the application of the test formulations and after 6 weeks was calculated (ΔΔΙΤΑ):

ΔΔΙΤΑ = AITA ° _start - ΔΙΤΑ ° _{6 Μο}

There is a visible reduction in age spots if:

AITA ° _start > ΔΙΤΑ ° ₆ wk

^■ = AITA ° _start - ΔΙΤΑ ° _{6 where} > 0

^ ΔΔΙΤΑ> 0 FIG. 4 shows the values for ΔΔΙΤΑ after 6 weeks

Application of the test formulations.

Both PKEK alone and sodium ascorbyl phosphate resulted in a visible reduction in age spots. PKEK even led to a greater reduction than sodium ascorbyl phosphate. This is because there was no active ingredient, the negative effect on the skin, e.g. caused by UV radiation, could compensate. By combining PKEK with

Sodium ascorbyl phosphate could reduce the effectiveness of

cosmetic formulation can be increased synergistically.

Example 4: Improvement of the appearance of the skin in dark-skinned persons

For the following study were dark-skinned women

(Fitzpatrick type VI-V). The Fitzpatrick scale is used to classify the different skin types:

Skin characterization sensitivity to type sun

I Celtic type, very not brown, very

light skin color, often sunburn, reddish or self-protection time <10 blond hair, minutes.

blue, green or

light gray eyes,

freckles

II Nordic type, light slow, minimal browning,

Skin color, blonde often sunburn, or light brown self-protection time: 10-20 Hair, blue, gray minutes.

or green eyes, often

freckles

III mixed type, medium slow, but

Skin color, progressive browning, dark brown or sometimes sunburn, light brown hair, self-protection time:

brown (blue, green 20-30 minutes

or gray) eyes,

hardly any freckles

IV Mediterranean type, Fast browning, rarely brownish or sunburn,

olive skin also own protection time:> 30 in untanned minutes.

Condition, brown

Eyes, brown or

black hair, none

freckles

V Dark skin type, fast tanning, hardly

dark skin even in sunburn,

Unbranded condition, self-protection time:> 60 minutes dark eyes,

black hair, none

freckles

VI Black skin type, Virtually never sunburn, dark brown to self-protection time:> 90 black skin even in minutes.

ungrounded condition,

black eyes,

black hair, none

freckles Compare too

http: // dermatology. about. com / od / cosmeticprocedure / a / fitzpat rick. In each case 25 subjects received a face cream containing either the tetrapeptide PKEK or no active ingredient

(Vehicle). They had to complete this formulation twice daily over a 12-week period throughout

Apply face. Before the study was started and after 2, 4, 8 and 12 weeks, the uniformity of the skin appearance was assessed visually by an expert.

To assess the appearance of the skin, a five-part scale was used:

5 = no contrast, very even skin

4 = slight contrast, slightly irregular complexion

3 = medium contrast, irregular complexion

2 = high contrast, very irregular skin texture

1 = very high contrast, very strong irregular skin texture

The following table gives the composition of

Test formulation again:

PKEK vehicle

Polyglyceryl-3 methylglucose 3, 0% 3, 0%

Distearate

Glyceryl Stearate 2.0% 2.0%

Stearyl Alcohol 1.0% 1.0%

PPG-3 myristyl ether 9, 5% 9, 5%

C12-15 alkyl benzoate 9, 5% 9, 5%

Water 74.196% 74.2% PKEK 0.004% -

Microcare MEM (preservative) 0.8% 0.8%

pH (lactic acid 10%) 6.0 + 6.0 +

0.5 0.5

Test formulation for the in-vivo study on dark skin

FIG. 5 shows that within the first 8 weeks, the skin image of the test subjects visibly improved with both test formulations, wherein the improvement by the tetrapeptide PKEK over time was increasingly stronger than with the vehicle. After 12 weeks, no further improvement takes place with the vehicle, while PKEK significantly improves the appearance of the skin even further.

SEQUENCE LISTING

<110> Evonik Goldschmidt GmbH

<120> Tetrapeptides to lighten the skin

<130> 200900345

<160> 1

<170> Patent version 3.4

<210> 1

<211> 4

<212> PRT

<213> Artificial

<220>

<223> artificial peptides

<400> 1

Pro Lys Glu Lys

1

Claims

claims

1. Use of the tetrapeptide PKEK or one of its derivatives for lightening the human skin color, for bleaching of pigment spots and / or for compensating for irregularities in the skin color.

2. Use of the tetrapeptide PKEK or one of its derivatives for the preparation of a formulation for

Irregularities in the skin coloration.

3. Use of the tetrapeptide PKEK or one of its derivatives for the preparation of a

Sunscreen formulation.

4. containing formulation

a) an effective amount of the tetrapeptide PKEK or

one of his derivatives

b) a safe and effective amount of at least

an additional active ingredient selected from the group consisting of the active ingredients for skin bleaching, depigmentation, the

Sunscreen and the blocking of UV rays and, if necessary

c) a dermatologically acceptable carrier.

5. Cosmetic formulation according to claim 4 for

Lightening of the human skin color or

Bleaching of pigment spots, characterized in that the active ingredient for skin bleaching or the

Active substance for depigmentation is selected from the group consisting of:

Kojic acid and its esters, niacin / niacinamide, alfa-hydroxycarboxylic acids such as lactic acid, arbutin,

Ascorbic acid and its esters, hydroquinone, glabridin in licorice, oxyresveratrol and its derivatives,

Linolenic acid and its esters

6. Sunscreen formulation according to claim 4, characterized

in that the active substance for the sunscreen or the active substance for the blocking of the UV rays is selected from the group consisting of:

3-benzylidene camphor,. 3- (4-methylbenzylidene) camphor,

4- (dimethylamino) benzoic acid 2-ethylhexyl ester,

4- (dimethylamino) benzoic acid, esters of

Cinnamic acid, esters of salicylic acid, benzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, esters of benzalmalonic acid, triazines, 2, 4, 6-trianilino (p-carbo-2'-ethyl-1'-hexyloxy) -1, 3, 5-triazine,

Octyltriazone, propane-1,3-dione, 1- (4-tert-butylphenyl) -3- (4'-methoxyphenyl) propane-1,3-dione, 2-phenylbenzimidazole-5-sulfonic acid, sulfonic acid derivatives of benzophenone, sulfonic acid derivatives of 3-benzylidene camphors, derivatives of benzoylmethane, finely dispersed metal oxides such as titanium dioxide or zinc oxide or salts, 2, 2'-methylene-bis- {6- (2H-benzotriazole-2-yl) -4- (1, 3, 3 tetramethylbutyl) phenol.

7. Cosmetic formulation according to claim 4 for

Compensating for irregularities in the skin color, characterized in that it provides an additional

component

d) self-tanner contains.

8. Use of a formulation according to any one of claims 4 to 7 for the lightening of the human skin color, for the bleaching of pigment spots and / or for compensating for irregularities in the

Skin staining.