Active ingredient combinations consisting of alkylamidothiazoles and delta-decalactone

Abstract

The invention relates to active ingredient combinations consisting of one or more alkylamidothiazoles and Δ-decalactone.

Description

[0001] Beiersdorf Aktiengesellschaft Hamburg Description Active ingredient combinations of alkylamidothiazoles and Δ-decalactone. The present invention relates to active ingredient combinations of one or more alkylamidothiazoles and Δ-decalactone. Furthermore, the present invention relates to cosmetic or dermatological preparations containing such an active ingredient combination and their use for lightening human skin. Melanocytes are responsible for skin pigmentation. These pigment-forming cells are found in the lowest layer of the epidermis, the stratum basale, alongside the basal cells as pigment-forming cells - depending on the skin type, either individually or in greater or lesser numbers. Melanocytes contain melanosomes as characteristic cell organelles, in which melanin is formed. Among other things, melanin formation is increased when stimulated by UV radiation.This is ultimately transported through the living layers of the epidermis (keratinocytes) into the stratum corneum (corneocytes), producing a more or less pronounced brownish to brown-black skin color. Melanin is formed as the final stage of an oxidative process in which tyrosine, with the assistance of the enzyme tyrosinase, is converted via several intermediate stages into the brown to brown-black eumelanins (DHICA and DHI melanin) or, with the involvement of sulfur-containing compounds, into the reddish pheomelanin. DHICA and DHI melanin are formed via the common intermediates dopaquinone and dopachrome. The latter, sometimes with the involvement of other enzymes, is converted into either indole-5,6-quinonecarboxylic acid or indole-5,6-quinone, from which the two aforementioned eumelanins are formed. The formation of pheomelanin occurs, among other things, via the intermediates dopaquinone and cysteinyldopa.The expression of the melanin-synthesizing enzymes is controlled by a specific transcription factor (microphthalmia-associated transcription factor, MITF). In addition to the described enzymatic processes of melanin synthesis, other proteins in the melanosomes are also important for melanogenesis. The so-called p-protein appears to play an important role here, although its exact function is still unclear.

[0002] In addition to the previously described process of melanin synthesis in melanocytes, the transfer of melanosomes, their retention in the epidermis, and their degradation and the degradation of melanin are also crucial for skin pigmentation. It has been shown that the PAR-2 ​​receptor is important for the transport of melanosomes from the melanocytes to the keratinocytes (M. Seiberg et al., 2000, J. Cell. Sci., 113:3093-101).

[0003] Furthermore, the size and shape of melanosomes influence their light-scattering properties and thus the color appearance of the skin. For example, black Africans tend to have larger, solitary spheroidal melanosomes, while Caucasians tend to have smaller, clustered melanosomes.

[0004] Problems with hyperpigmentation of the skin have a variety of causes or are side effects of many biological processes, e.g. UV radiation (e.g. freckles, ephelides), genetic predisposition, incorrect pigmentation of the skin during wound healing or scarring (post-inflammatory hyperpigmentation) or skin aging (e.g. lentigines seniles).

[0005] Following inflammatory reactions, the skin's pigmentation system reacts with partially opposite reactions. Both post-inflammatory hyperpigmentation and hypopigmentation can occur. Post-inflammatory hypomelanosis frequently occurs in association with atopy, lupus erythematosus, and psoriasis, among other conditions. The various reactions of the human skin's pigmentation system following inflammatory phenomena are only very incompletely understood.

[0006] Problems with post-inflammatory hyperpigmentation often occur in darker skin types. Pseudofolliculitis barbae, which is associated with or results in cosmetically undesirable pigmentation, is particularly common in black men. Forms of melasma, which occur particularly in Asian women on the face and décolleté area, as well as various forms of irregular skin pigmentation, are also considered post-inflammatory hyperpigmentation. Dark circles under the eyes are also considered a form of post-inflammatory hyperpigmentation, although the underlying inflammation is usually subclinical.

[0007] In many cases, such post-inflammatory dyspigmentation is further aggravated by exposure to sunlight (UV light) without UV-induced inflammation (sunburn) occurring.

[0008] Active ingredients and preparations that counteract skin pigmentation are known. Hydroquinone-based preparations are primarily used in practice. However, some of these only become effective after several weeks of use, and excessively long-term use is questionable for toxicological reasons. Albert Kligman et al. developed a so-called "triformula" consisting of a combination of 0.1% tretinoin, 5.0% hydroquinone, and 0.1% dexamethasone (A. Kligman, 1975, Arch. Dermatol., 111:40-48). However, this formulation is also highly controversial due to potential irreversible changes in the skin's pigmentation system.

[0009] Skin peeling methods (chemical and mechanical peels) are also used, but these often result in inflammatory reactions and, due to subsequent post-inflammatory hyperpigmentation, can even lead to increased rather than reduced pigmentation. All of these common procedures, which are also used to treat post-inflammatory hyperpigmentation, are characterized by significant side effects.

[0010] Furthermore, various other substances are known for which a skin-lightening effect has been described. These include, among others, hexadecene-1,16-dicarboxylic acid, kojic acid and derivatives, arbutin, ascorbic acid and derivatives, flavonoids, ellagic acid and derivatives, tranexamic acid, and various resorcinol derivatives, such as 4-n-butylresorcinol, 4-n-hexylresorcinol, and 4-(1-phenylethyl)benzene-1,3-diol.

[0011] JM Ready describes in a publication (Bioorganic & Medicinal Chemistry Letter 17 (2007) 6871-6875) the effect of substituted thiazole derivatives on the inhibition of mushroom tyrosinase.

[0012] Shiseido's patent application (WO 2009099195) describes substituted thiazolamines or hydrothiazolamines for skin lightening. The substances described in the above-mentioned prior art demonstrate moderate efficacy.

[0013] Dark circles under the eyes can also result from a pigmentation disorder, although they can also appear as a reaction to general stress, such as lack of sleep or simply due to eye strain. In younger people, the symptoms disappear after a sufficient night's rest, but over longer periods, the condition can become chronic and very bothersome for those affected. There is also a lack of sufficiently effective active ingredients and treatment options for such skin conditions.

[0014] Smell is one of the five human senses. Odors, highly volatile substances, are bound by olfactory receptors in the nasal mucosa. The stimulus is transmitted via a signaling cascade to the nerve cells and forwarded to the brain. There, the actual sensation of smell arises. Pleasant smells are distinguished from unpleasant smells.

[0015] However, cosmetic products often have a somewhat unpleasant odor, which is caused by the raw materials used. Alkylamidothiazoles can also, under certain circumstances, contribute to a deterioration in the fragrance experience of a cosmetic base. This problem needed to be remedied.

[0016] This task is solved by active ingredient combinations of one or more alkylamidothiazoles and A-decalactone.

[0017] A-Decalactone is characterized by the following structural formula:

[0018] O-Decalactone occurs as a flavoring agent in various foods. It is one of the most important components of butter flavor and also contributes to the flavor of other dairy products such as UHT milk and various cheeses. It also occurs in various fruits such as peaches, apricots, coconuts or raspberries. δ-Decalactone can exist in two different enantiomers, the R- and the S-form. Both enantiomers as well as racemic mixtures with the same or different contents of both enantiomers are equally advantageous according to the invention. The preparations according to the invention preferably contain 0.00001 - 1 wt% of Δ-decalactone, preferably 0.0001 - 0.5 wt% of Δ-decalactone, particularly preferably 0.0005 - 0.3 wt% of Δ-decalactone. Preparations or uses according to the invention are particularly advantageous, characterized in that the preparations contain 0.000001 to 10 wt%, in particular 0.0001 to 3 wt%, very particularly 0.001 to 1 wt%.-% of one or more alkylamidothiazoles, based on the total weight of the preparation. Advantageous alkylamidothiazoles within the meaning of the present invention are substances of the general formula. at which R 1 , R 2 , X and Y can be different, partially the same or completely the same and can independently mean:R1 = -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1-C8-cycloalkyl-alkylhydroxy, -C1-C 24 Alkylhydroxy (linear and branched), -C1-C 24 Alkylamine (linear and branched), -C1–C 24 –Alkylaryl (linear and branched), -C1–C 24 –Alkylaryl- Alkyl-Hydroxy (linear and branched), -C1–C 24 –Alkylheteroaryl (linear and branched), -C1-C 24- Alkyl-O-C1-C24-alkyl (linear and branched), -C1-C24 alkyl-morpholino, -C1-C24 alkyl-piperidino, - C1-C24 alkyl-piperazino, -C1-C24 alkyl-piperazino-N-alkyl means,R2 = H, -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1-C 24 -Hydroxyalkyl (linear and branched), -C1–C 24 –Alkylaryl (linear and branched), -C1–C 24 –Alkylheteroaryl (linear and branched), means,X = -H, -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1–C24–aryl (optionally mono- or polysubstituted with -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN), -C1–C 24-Heteroaryl (optionally mono- or polysubstituted with -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN), -C1–C24–alkylaryl (linear and branched), -C1–C24–alkylheteroaryl (linear and branched), -aryl (optionally mono- or polysubstituted with -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN), -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4-dimethoxyphenyl, -2,3-dimethoxyphenyl, Y = H, -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1–C24–aryl, -C1–C24-heteroaryl, -C1–C24–alkylaryl (linear and branched), -C1–C24–alkylheteroaryl (linear and branched), -aryl, -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4-dimethoxyphenyl, -2,3-dimethoxyphenyl, -COO-alkyl, -COO-alkenyl, -COO-cycloalkyl, -COO-aryl, -COO-heteroaryl, and X, Y can optionally also mean = condensed aromatic,where X and Y can form aromatic or aliphatic homo- or heterocyclic ring systems with up to n ring-forming atoms, and where n can assume values ​​from 5 to 8, and the respective ring systems can in turn be substituted with up to n-1 alkyl groups, hydroxyl groups, carboxyl groups, amino groups, nitrile functions, sulfur-containing substituents, ester groups, and / or ether groups. The thiazoles mentioned can exist both as free bases and as salts: e.g., as fluoride, chloride, bromide, iodide, sulfate, carbonate, ascorbate, acetate, or phosphate. In particular, as halogen salts,such as chloride and bromide. Furthermore, an advantageous embodiment of the present invention consists in cosmetic or dermatological preparations with an effective content of one or more of the aforementioned alkylamidothiazoles. The invention further provides for the use of the aforementioned alkylamidothiazoles for the treatment and / or prophylaxis of unwanted skin pigmentation. The treatment and / or prophylaxis of unwanted skin pigmentation can be carried out both in a cosmetic and a pharmaceutical context. Pharmaceutical (or dermatological) treatment is understood to be primarily for pathological skin conditions, whereas cosmetic treatment and / or prophylaxis of undesirable skin pigmentation primarily concerns healthy skin. X is advantageously selected from the group of substituted phenyls, where the substituents (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN,Acetyl and can be the same or different. Particularly advantageously, X is selected from the group of phenyl groups substituted with one or more hydroxy groups, where the substituent (Z) can be selected from the group -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN, acetyl and the following generic structure is preferred, in which Y, R 1 and R 2 which may have the properties defined above. Particularly advantageous are those compounds in which Y = HR1 = -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1-C8-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and branched), -C1-C24 alkylamine (linear and branched), -C1–C24–alkylaryl (linear and branched), -C1–C24–alkylaryl-alkyl-hydroxy (linear and branched), -C1–C 24 –Alkylheteroaryl (linear and branched), -C1-C 24- Alkyl-O-C1-C24-alkyl (linear and branched), -C1-C24 alkyl-morpholino, -C1-C24 alkyl-piperidino, - C1-C24 alkyl-piperazino, -C1-C24 alkyl-piperazino-N-alkyl, R2 = H, -C1–C24–alkyl (linear and branched). Z = -H, -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN, acetyl. Particularly preferred are those compounds in which Y = HR1 = -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1-C8-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and branched), -C1-C24 alkylamine (linear and branched), -C1–C24–alkylaryl (linear and branched), -C1–C24–alkylaryl-alkyl-hydroxy (linear and branched), -C1–C 24 –Alkylheteroaryl (linear and branched), -C1-C 24 - Alkyl-O-C1-C 24 -Alkyl (linear and branched), -C1-C 24 Alkyl-Morpholino, -C1-C 24 Alky-Piperidino, - C1-C24 Alky-Piperazino, -C1-C24 Alky-Piperazino-N-Alkyl means, The compounds

[0019] N -(4-(2,4-dihydroxyphenyl)thiazol-2-yl)pivalamide

[0020] N -(4-(2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide

[0021] N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)butyramide

[0022] N -(4-(2,4-dihydroxyphenyl)thiazol-2-yl)heptane amide H

[0023] N -(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-6-hydroxyhexane amide

[0024] N -(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-4-(hydroxymethyl)cyclohexanecarboxamide

[0025] N

[0026] N are the preferred ones according to the invention.

[0027] The most preferred option is

[0028] N r -(4-(2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide The above alkylamidothiazoles, their synthesis and application were described in the

[0029] EP2758381A1 described.

[0030] Cosmetic or dermatological preparations containing alkylamidothiazoles and biopolymers according to the invention or their use for the treatment and / or prophylaxis of undesired skin pigmentation are also advantageous embodiments of the present invention.

[0031] It is particularly advantageous if such preparations contain 0.000001 to 10% by weight, in particular 0.0001 to 3% by weight, very particularly 0.001 to 1% by weight of one or more of the alkylamidothiazoles used according to the invention, based on the total weight of the preparation.

[0032] It is of great advantage in the sense of the present invention if the preparations have slightly basic pH values, i.e. values ​​between 7 and 9, preferably between 7 and 8, in particular between 7.4 and 7.6.

[0033] Cosmetic and dermatological preparations according to the invention can be in various forms. For example, they can be a solution, an anhydrous preparation, an emulsion or microemulsion of the water-in-oil (W / O) or oil-in-water (O / W) type, a multiple emulsion, for example of the water-in-oil-in-water (W / O / W) type, a gel, a solid stick, an ointment, or even an aerosol. It is also advantageous according to the invention to administer the substances used according to the invention and / or their derivatives in encapsulated form, e.g., in collagen matrices and other conventional encapsulation materials, e.g., as cellulose encapsulations, in gelatin, or liposomally encapsulated.

[0034] It is also possible and advantageous within the meaning of the present invention to incorporate the substances used according to the invention and / or their derivatives into aqueous systems or surfactant preparations for cleansing the skin and hair.

[0035] The cosmetic and dermatological preparations according to the invention can contain cosmetic auxiliaries as are customarily used in such preparations, e.g. preservatives, bactericides, perfumes, substances for preventing foaming, dyes, pigments which have a coloring effect, thickeners, surface-active substances, emulsifiers, softening, moisturizing and / or humectant substances, fats, oils, waxes or other customary components of a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.

[0036] The lipid phase can advantageously be selected from the following group of substances: mineral oils, mineral waxes

[0037] Oils such as triglycerides of capric or caprylic acid, and natural oils such as castor oil;

[0038] Fats, waxes and other natural and synthetic fatty substances, preferably esters of fatty acids with low carbon alcohols, e.g. with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with low carbon alkanoic acids or with fatty acids;

[0039] alkyl benzoates;

[0040] Silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixtures thereof.

[0041] The oil phase of the emulsions, oleogels or hydrodispersions or lipodispersions within the meaning of the present invention is advantageously selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids with a chain length of 3 to 30 C atoms and saturated and / or unsaturated, branched and / or unbranched alcohols with a chain length of 3 to 30 C atoms, from the group of esters of aromatic carboxylic acids and saturated and / or unsaturated, branched and / or unbranched alcohols with a chain length of 3 to 30 C atoms.Such ester oils can then advantageously be selected from the group isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyl decyl stearate, 2-octyldodecyl palmitate, oleyl oleate, dibutyl adipate, propylheptyl caprylate, diisopropyl adipate, cetearyl isononanoate, oleyl erucate, erucyl oleate, erucyl erucate as well as synthetic, semi-synthetic and natural mixtures of such esters, e.g. jojoba oil.

[0042] The aqueous phase of the preparations according to the invention optionally advantageously contains humectants such as propylene glycol, panthenol or hyaluronic acid, individually or in combination.

[0043] In particular, mixtures of the aforementioned solvents are used. In the case of alcoholic solvents, water may be a further component. Emulsions according to the invention are advantageous and contain, for example, the aforementioned fats, oils, waxes, and other fatty substances, as well as water and an emulsifier, as is typically used for this type of formulation.

[0044] Gels according to the invention usually contain low carbon alcohols, e.g. ethanol, propylene glycol, and water or an above-mentioned oil in the presence of a thickener.

[0045] Suitable propellants for preparations according to the invention that can be sprayed from aerosol containers are the usual, readily volatile, liquefied propellants, for example, hydrocarbons (propane, butane, isobutane), which can be used alone or in mixtures with one another. Compressed air can also be used advantageously.

[0046] Preparations according to the invention can advantageously also contain substances that absorb UV radiation in the UVB range, with the total amount of filter substances being, for example, 0.1% to 30% by weight, preferably 0.5 to 10% by weight, in particular 1.0 to 6.0% by weight, based on the total weight of the preparations, in order to provide cosmetic preparations that protect the hair or skin from the entire range of ultraviolet radiation. They can also serve as sunscreens for the hair or skin.

[0047] Furthermore, preparations according to the invention can advantageously additionally contain substances which mask the unpleasant inherent odor of the remaining raw materials used, the total amount of the perfume ingredients being, for example, 0.001% by weight to 5% by weight, preferably 0.05 to 3% by weight, in particular 0.1 to 1% by weight, based on the total weight of the preparations, in order to provide cosmetic preparations.

[0048] The following examples are intended to illustrate the present invention. Unless otherwise stated, the numerical values ​​refer to percentages by weight.

Claims

Claims 1. Active ingredient combinations of one or more alkylamidothiazoles and Δ-decalactone.

2. Active ingredient combinations according to claim 1, characterized in that the alkylamidothiazole or alkylamidothiazoles are substances of the general formula Is or are, at which R 1 , R 2 , X and Y can be different, partially the same or completely the same and can independently mean: R1 = -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1-C8-cycloalkyl-alkylhydroxy, -C1-C24 alkylhydroxy (linear and branched), -C1-C24 alkylamine (linear and branched), -C1–C24–alkylaryl (linear and branched), -C1–C24–alkylaryl-alkyl-hydroxy (linear and branched), -C1–C24–alkylheteroaryl (linear and branched), -C1-C24-alkyl-O-C1-C24-alkyl (linear and branched), -C1-C24 alkyl-morpholino, -C1-C24 Alkyl-Piperidino, -C1-C 24 Alkyl-Piperazino, -C1-C 24Alky-piperazino-N-alkyl means,R2 = H, -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1-C 24 -Hydroxyalkyl (linear and branched), -C1–C 24 –Alkylaryl (linear and branched), -C1–C 24 –Alkylheteroaryl (linear and branched), means,X = -H, -C1–C24–alkyl (linear and branched), -C1–C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1–C 24 –Aryl (optionally mono- or polysubstituted with -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN), -C1–C 24 -Heteroaryl (optionally mono- or polysubstituted with -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN), -C1–C 24 –Alkylaryl (linear and branched), -C1–C 24 –Alkylheteroaryl (linear and branched), -Aryl (optionally mono- or polysubstituted with -OH, -F, -Cl, -Br, -I, -OMe, -NH2, -CN), -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4-dimethoxy-phenyl, -2,3-dimethoxyphenyl means, Y = H, -C1-C24-alkyl (linear and branched), -C1-C24-alkenyl (linear and branched), -C1-C8-cycloalkyl, -C1–C24–aryl, -C1–C24 heteroaryl, -C1–C24 alkylaryl (linear and branched), -C1– C24 alkyl heteroaryl (linear and branched), -aryl, -phenyl, -2,4-dihydroxyphenyl, -2,3-dihydroxyphenyl, -2,4-dimethoxyphenyl, -2,3-dimethoxyphenyl, -COO-alkyl, -COO-alkenyl, -COO-cycloalkyl, -COO-aryl, -COO-heteroaryl, and X, Y may optionally also mean = condensed aromatic, where X and Y can form aromatic or aliphatic homo- or heterocyclic ring systems with up to n ring-forming atoms, and where the number n can assume values from 5 to 8, and the respective ring systems in turn with up to n - 1 alkyl groups, hydroxyl groups, carboxyl groups, amino groups, nitrile functions, sulfur-containing substituents,Ester groups and / or ether groups, wherein the alkylamidothiazole(s) may be present both as a free base and as cosmetically and dermatologically usable salts.

3. Active ingredient combinations according to one of the preceding claims, characterized in that the alkylamidothiazole(s) have the following structure: N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide A'-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)butyramide N N'-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-4-(hydroxymethyl)cyclohexanecarboxamide 4. Active ingredient combinations according to one of the preceding claims, characterized in that the alkylamidothiazole(s) can be present as a halide, carbonate, ascorbate, sulfate, acetate, and / or phosphate.

5. Cosmetic or dermatological preparations containing active ingredient combinations according to one of the preceding claims.

6. Preparations according to claim 5, characterized in that they contain 0.000001 to 10% by weight, in particular 0.0001 to 3% by weight, very particularly 0.001 to 1% by weight, of one or more alkylamidothiazoles, based on the total weight of the preparation.

7. Preparations according to one of the preceding claims, characterized in that the total amount of the preparations is 0.00001 - 1 wt% of Δ-decalactone, preferably 0.0001 - 0.5 wt% of Δ-decalactone, particularly preferably 0.0005 - 0.3 wt% of Δ-decalactone.8.Cosmetic, non-therapeutic use of preparations or active ingredient combinations according to one of the preceding claims for lightening human skin.

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