Prevention and reduction of keratinization disorders and related cosmetic agents

Abstract

To provide a non-therapeutic method for preventing and / or reducing a keratinization disorder, and a composition used in the method.SOLUTION: The invention is directed to the use of ectoine and / or hydroxyectoine for the prevention and / or reduction of keratinization disorders, and to ectoine and / or hydroxyectoine and formulations for use in the prevention and / or reduction of keratinization disorders. The present invention is further directed to the use of ectoine and / or hydroxyectoine as a cosmetic agent for reducing the carbonylization of one or more proteins selected from the group consisting of filaggrin, formelin, LAMP2a and / or filaggrin-2 and / or for upregulating one or more proteins selected from the group consisting of filaggrin, formelin and LAMP2a, and to a cosmetic composition comprising said cosmetic agent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention is directed to the use of ectoine and / or hydroxyectoine for preventing and / or reducing keratinization disorders, and to ectoine and / or hydroxyectoine and formulations for use in preventing and / or reducing keratinization disorders. The present invention is further directed to the use of ectoine and / or hydroxyectoine as a cosmetic agent that reduces the carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin, LAMP2a and / or filaggrin-2, and / or upregulates one or more proteins selected from the group consisting of filaggrin, hornerin and LAMP2a, and to cosmetic compositions comprising said cosmetic agent. [Background technology]

[0002] The stratum corneum is the outermost layer of the epidermis, composed of dead cells (corneocytes). It consists of 15-20 layers of flattened cells without nuclei or organelles. Filamentous keratin is found in the cytoplasm of these cells. These corneocytes are embedded in a lipid matrix composed of ceramides, cholesterol, cholesterol esters, and fatty acids. The stratum corneum forms a barrier that protects the underlying tissue from infection, dehydration, chemicals, and mechanical stress. Desquamation, the process by which cells are shed from the surface of the stratum corneum, balances the number of keratinocytes proliferating from the basal layer. These cells migrate from the epidermis to the surface over a period of approximately 14 days.

[0003] Keratinization is the process by which the epidermal barrier is formed in stratified squamous epithelium. During this process, epidermal keratinocytes undergo terminal differentiation and programmed cell death. This leads to the formation of the keratinized skin layer as well as hair and nails. Keratinization is characterized by the replacement of intracellular organelles and contents with a compact proteinaceous cytoskeleton, the cross-linking of proteins around the cell periphery to form a cornified cell envelope, and the joining of corneocytes into a multicellular, functional but biologically dead structure. Several variants of keratinization result in different keratinized structures.

[0004] The epidermis consists of several layers at different stages of keratinocyte differentiation. Cells in the basal layer are attached to the basement membrane by hemidesmosomes, have the ability to proliferate, and provide new cells that differentiate toward the skin's surface. Cells in the spinous layer no longer divide. In the granular layer, keratohyalin granules are present and proteins of the epidermal differentiation complex (EDC) are expressed. Filaggrin, also encoded by the EDC, is the main component of keratohyalin granules. Upon dephosphorylation and proteolysis of the profilaggrin precursor, filaggrin disperses, causing the aggregation of keratin intermediate filaments. Several events, including filaggrin degradation and keratin cross-linking by transglutaminase, then trigger the transition to the cornified layer. On the cytoplasmic side of the plasma membrane, protein cross-linking forms a cornified envelope, which is tightly bound via corneodesmosomes. The skin barrier is formed by tight junctions that form strong cell-cell interactions and lipids in the intercellular spaces of the corneal layer. Ultimately, the corneodesmosomes are proteolyzed by extracellular enzymes and the corneocytes are desquamated (see Eckhart et al, 2013, Biochimica et Biophysica Acta 1833, 3471-3480).

[0005] Disturbances in the keratinization process can result in a variety of cosmetic problems that affect the visual appearance of the skin or even dermatological problems such as ichthyosis. It is therefore an object of the present invention to provide active substances which can be used for the prevention or reduction of keratinization disorders, or alternatively for the prevention or reduction of disorders in the keratinization process. Surprisingly, it has now been found that ectoine or hydroxyectoine can be effectively used for such purposes.

[0006] A keratinization disorder in the sense of the present application is a disorder in the keratinization process as previously described. Carbonylation in the sense of the present application includes the oxidation of proteins. The use of compatible solutes, especially ectoine and hydroxyectoine, for various cosmetic and pharmaceutical purposes is already known. For example, WO 94 / 15923 describes that (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid or (S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acid can be used, for example, for the preparation of cosmetic compositions or medicaments for the treatment of skin diseases.

[0007] Furthermore, DE 4342560 describes the use of ectoine and ectoine derivatives as moisturizers in cosmetic products, which are suitable, for example, for the care of aged, dry or irritated skin. Furthermore, DE19933466 describes that ectoine and derivatives, such as hydroxyectoine, can be used as free radical scavengers in cosmetic and dermatological compositions.The compositions can be used to treat and / or prevent skin aging caused by oxidative stress and inflammatory reactions.

[0008] Further applications of ectoine and ectoine derivatives in cosmetic formulations are described, for example, in WO00 / 07558, WO00 / 07559, WO00 / 07560 and US7981899, such as the care and prevention of dry and / or flaky skin, the protection of human skin against dryness and / or high salt concentrations, the protection of cells, proteins and / or biological membranes of human skin, the protection of the microflora of human skin, the stabilization of the skin barrier and the protection and stabilization of nucleic acids in human skin cells.

[0009] JP2002302444 discloses the use of a preparation containing ectoine to restore the expression of the filaggrin gene caused by dry skin. However, it has not been previously known that these compounds are advantageously suitable for preventing and reducing keratinization disorders of the skin and / or keratinizing skin appendages, such as hair or nails. Summary of the Invention

[0010] Thus, in a first aspect, the present invention relates to the non-therapeutic use of ectoine and / or hydroxyectoine for preventing and / or reducing keratinization disorders of the skin and / or keratinizing skin appendages in mammals. In the biological context of biological production of gene products, downregulation is the process by which cells decrease the amount of a cellular component, such as a protein, in response to an external stimulus. The complementary process of increasing such a component is called upregulation.

[0011] The non-therapeutic use of the compound can be carried out in vitro or in vivo. The sensitivity of specific cells to treatment with the compound can be determined by in vitro testing. Cultured cells from biopsy samples can be used for in vitro testing. The use of ectoine and / or hydroxyectoine as defined above is typically topical, preferably for non-therapeutic or cosmetic use.

[0012] Cosmetic uses are possible, for example, when impaired keratinization is manifested in skin conditions such as itchy skin, keratosis pilaris and / or impure skin. Therefore, in a further aspect, the present invention relates to the non-therapeutic use of ectoine and / or hydroxyectoine for improving a mammalian skin condition selected from itchy skin, keratosis pilaris and / or impure skin.

[0013] The non-therapeutic or cosmetic use of ectoine and / or hydroxyectoine to improve the skin condition of keratosis pilaris and / or impure skin is preferred. The non-therapeutic or cosmetic use of ectoine and / or hydroxyectoine to improve the skin condition of keratosis pilaris is particularly preferred.

[0014] Nevertheless, the present invention also relates to ectoine and / or hydroxyectoine for use in preventing and / or reducing keratinization disorders of the skin and / or keratinizing skin appendages in mammals. Such pharmaceutical or dermatological applications are possible when keratinization disorders are manifested in ichthyosis and / or atopic skin.

[0015] The present invention therefore relates to ectoine and / or hydroxyectoine for use in the prevention and / or reduction of keratinization disorders, characterized in that the keratinization disorders are manifested in ichthyosis and / or atopic skin.

[0016] According to a general definition, compatible solutes are stress protectants from extremely halophilic and salt-tolerant eubacteria, which accumulate in large amounts in them through biosynthesis or efficient transport mechanisms. These osmotically active substances owe their name to the fact that they prevent liquid loss into the medium (drying out) and do not impair cellular metabolism, i.e., are metabolically compatible, even at high cytoplasmic concentrations (E.A. Galinski, M. Stein, B. Amendt, M. Kinder Comp. Biochem. Physiol., 117 (3) (1997) 357-365).

[0017] Ectoine and ectoine derivatives are low molecular weight cyclic amino acid derivatives that can be isolated from a variety of halophilic microorganisms or prepared synthetically. Both ectoine and hydroxyectoine have the advantage of being insensitive to cellular metabolism. Ectoine refers to (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid, and hydroxyectoine refers to (S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acid.

[0018] According to the invention, ectoine and hydroxyectoine can be used in the form of their physiologically tolerable salts and stereoisomeric forms and can be present in the composition in the form of optical isomers, diastereomers, racemates, zwitterions, cations or mixtures thereof. Preferably, ectoine ((S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) is used according to the invention.

[0019] Preferred physiologically tolerable salts of the compounds are, for example, alkali metal, alkaline earth metal or ammonium salts, such as Na, K, Mg or Ca salts, and salts derived from organic bases, such as triethylamine or tris(2-hydroxyethyl)amine. Further preferred physiologically tolerable salts of the compounds are formed by reaction with inorganic acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, or with organic carboxylic or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.

[0020] The preparation of the compound is described in the literature (DE 4342560). (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid or (S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acid can also be obtained by microbiological methods (Severin et al., J. Gen. Microb. 138 (1992) 1629-1638 or EP 1409707A). According to the present invention, impaired keratinization of mammalian skin and / or keratinizing skin appendages may be prevented and / or reduced. The term mammal relates to vertebrate animals and humans, preferably humans.

[0021] Keratinized appendages include human nails and hair, as well as animal horns, hooves, claws, and fur. In living mammals, such keratinized appendages are subject to numerous traumatic events from the environment to which they are exposed during daily activities. In humans, the hardness and strength of nails, including fingernails and toenails, are particularly important not only for their aesthetic appearance but also for personal health. Nail brittleness is a common aging complication. However, various activities expose nails to numerous substances that adversely affect their physical and mechanical condition, such as exposure to soaps, detergents, and nail polish. Additionally, certain diseases with a wide variety of causes and symptoms can lead to nail brittleness or associated disfigurement due to a decrease in nail hardness and strength.

[0022] Preferably, the present invention is used to prevent and / or reduce keratinization disorders of the skin. Preferably, the non-therapeutic use according to the present invention is for preventing and / or reducing impaired keratinization of keratinizing skin appendages.

[0023] According to the present invention, keratinization disorders may be prevented and / or reduced by preserving the normal levels of proteins involved in keratinization and / or by up- and / or down-regulating such proteins. For the skin barrier to function, on the one hand, the necessary balance of proteins and lipids must be constantly renewed, mainly in the upper layers of the stratum corneum, and on the other hand, the proteins and lipids produced during the keratinization process must remain active to ensure functionality and avoid inactivation by events such as degradation or carbonylation, ideally until desquamation. Both effects can enhance the barrier function of intact skin at the stratum corneum.

[0024] In particular, the present invention involves upregulating and / or reducing the carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin and LAMP2a, and / or reducing the carbonylation of the protein filaggrin-2. In particular, the present invention involves the upregulation of one or more proteins selected from the group consisting of filaggrin, hornerin and LAMP2a. In particular, the present invention involves reducing the carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin, LAMP2a and / or filaggrin-2.

[0025] Filaggrin (filament aggregation protein) is a filament-associated protein that binds to keratin fibers in epithelial cells. Ten to twelve filaggrin units are post-translationally hydrolyzed from a large profilaggrin precursor protein (350 kDa) during terminal differentiation of epidermal cells. In humans, profilaggrin is encoded by the FLG gene, part of the S100 condensation protein (SFTP) family within the epidermal differentiation complex on chromosome 1q21. Disorders in filaggrin expression strongly predispose to dry skin, severe forms of ichthyosis vulgaris, or eczema.

[0026] Filaggrin-2 is encoded by the gene FLG2. The protein is essential for normal cell-cell adhesion in the stratum corneum and is important for the proper integrity and mechanical strength of the stratum corneum of the epidermis. Filaggrin-2 has been shown to be important for proper keratinization and a functional stratum corneum. Patients with atopic dermatitis show decreased expression of filaggrin-2 (Pendaries et al, 2015, Cell Death and Disease 6, page e1656). Ectoine has been shown to reduce the carbonylation of this protein, which is required for cell-cell junction interactions, resulting in a loss of function, which in turn may negatively affect keratinocyte connectivity and reduce barrier function.

[0027] Hornerin is a protein with 2496 amino acids, containing an EF-hand domain at the N-terminus, followed by a spacer sequence and a large repeat domain. Hornerin has been found to be expressed in tissues such as keratinized stratified epithelium. Hornerin has also been detected in the granular layer and stratum corneum of mature epidermis (Makino et al., 2001, The Journal of Biological Chemistry 276, 47445-47452). This publication further suggests that the close similarity of hornerin to profilaggrin indicates that hornerin is related to some hereditary ichthyosis disorders.

[0028] LAMP2A (lysosome-associated membrane protein 2A) is a lysosome-associated membrane glycoprotein and a receptor for chaperone-mediated autophagy. The protein has 410 amino acids and is linked to the X chromosome. It is known to be moderately expressed in all skin cell types in the skin. LAMP2A is involved in autophagy and cell renewal processes, which compromise the established skin barrier. Nucleophagy (nuclear removal) of epidermal keratinocytes is a critical step in the keratinization process. During this process, some nuclear contents are removed by autophagolysosomes, which are LC3-positive / LAMP2-positive bodies (Rogerson et al., 2018, Nucleus 9, 56-64).

[0029] In this regard, ectoine and / or hydroxyectoine have been found to affect the presence of filaggrin, filaggrin-2, LAMP2a, and hornerin, positively impacting the keratinization process. Ectoine reduces the carbonylation of filaggrin-2, resulting in faster keratinization. Ectoine also reduces the carbonylation of LAMP2a, maintaining autophagy (nucleophagy) during the keratinization process. The effect of ectoine on filaggrin and hornerin is to maintain their functionality, as carbonylation can lead to loss of function. This means that these proteins can no longer perform important tasks in the keratinization process, as proteins are known to aggregate as a result of carbonylation, which interferes with cells in multiple ways. Cells are stressed, and aggregates need to be recycled through the ubiquitination-proteasome pathway, which also leads to increased autophagy. In both cases, cells are somewhat disrupted to achieve their primary goal of building proteins for the stratum corneum. The result is a loss of skin barrier function. Ectoine reduces the inactivation of filaggrin and hornerin, thereby reducing the symptoms of both.

[0030] The present invention therefore further relates to the non-therapeutic use of ectoine and / or hydroxyectoine as a cosmetic agent for reducing the carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin, LAMP2a and / or filaggrin-2 in the skin and / or keratinized skin appendages in a mammal, preferably a human.

[0031] Thus, the present invention further relates to the non-therapeutic use of ectoine and / or hydroxyectoine as a cosmetic agent for upregulating one or more proteins selected from the group consisting of filaggrin, hornerin, and LAMP2a in the skin and / or keratinized skin appendages in mammals, preferably humans.

[0032] The present invention therefore further relates to ectoine and / or hydroxyectoine for use in preventing and / or reducing keratinization disorders of the skin and / or keratinizing skin appendages in mammals, characterized in that they are involved in reducing the carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin, LAMP2a and / or filaggrin-2.

[0033] The present invention therefore further relates to ectoine and / or hydroxyectoine for use in preventing and / or reducing keratinization disorders of the skin and / or keratinizing skin appendages in mammals, characterized in that they involve the upregulation of one or more proteins selected from the group consisting of filaggrin, hornerin, and LAMP2a.

[0034] In a further aspect, the present invention relates to a formulation comprising ectoine / hydroxyectoine for use in the treatment of keratinization disorders. Such formulations can be prepared within the common knowledge of a person skilled in the art.

[0035] In a further aspect, the present invention relates to a formulation comprising ectoine / hydroxyectoine for use in the treatment of keratinization disorders, characterized in that the keratinization disorders are manifested in ichthyosis and / or atopic skin. Similarly, cosmetic formulations containing the active ingredient may be prepared.

[0036] In a further aspect, the present invention relates to a cosmetic formulation comprising ectoine and / or hydroxyectoine as a cosmetic agent that reduces the carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin, LAMP2a and / or filaggrin-2 in the skin and / or keratinized skin appendages in a mammal.

[0037] In a further aspect, the present invention relates to a cosmetic formulation comprising ectoine and / or hydroxyectoine as a cosmetic agent that upregulates one or more proteins selected from the group consisting of filaggrin, hornerin, and LAMP2a in the skin and / or keratinized skin appendages in a mammal.

[0038] For the purposes of the present invention, the terms "composition" or "formulation" are also used synonymously alongside the term "preparation." Here, the preparation is usually a topically applicable preparation, such as a cosmetic or dermatological preparation or a pharmaceutical product.In the sense of the present invention, "topically applicable" means that the preparation is applied externally and locally, that is, the preparation should be suitable for application to, for example, skin or hair.In this case, the preparation comprises a cosmetically, pharmaceutical or dermatologically suitable vehicle, and optionally further suitable components according to the desired property profile.Topical preparations are preferably used as cosmetic or dermatological preparations, particularly preferably as cosmetic preparations.Suitable vehicles and adjuvants or fillers will be described in detail in the following sections.

[0039] The preparations may include, comprise, consist essentially of, or consist of the necessary or optional constituents mentioned above and / or below. All compounds or components that may be used in the preparations are known and commercially available or can be synthesized by known processes.

[0040] As indicated above and preferably described, ectoine or hydroxyectoine is typically present in the preparations of the invention in an amount of 0.001 to 50% by weight, preferably 0.01 to 10% by weight, based on the total weight of the preparation, and particularly preferably 0.1 to 10% by weight, based on the entire composition. The proportion of said compound in the composition is very particularly preferably 0.1 to 5% by weight, based on the entire composition. A person skilled in the art will have no difficulty in appropriately selecting the amount depending on the intended effect of the preparation.

[0041] Besides ectoine and / or hydroxyectoine, the composition may also contain further cosmetic, dermatological or pharmaceutical active ingredients. The further active compounds are preferably selected from the group of UV filters, pore-refining agents, antioxidants, vitamins, skin-lightening active compounds, anti-aging active compounds, anti-inflammatory active compounds, antimicrobial active compounds, active compounds for improving the moisture content of the skin (skin moisture regulators), anti-cellulite active compounds, anti-wrinkle active compounds, anti-dandruff active compounds, anti-acne active compounds, deodorant substances, pigments and self-tanning substances; particularly preferably from the group of UV filters, pore-refining agents, antioxidants, vitamins, skin-lightening active compounds, self-tanning substances, anti-aging active compounds and anti-cellulite active compounds.

[0042] In a preferred embodiment, the preparation further comprises a UV filter.In principle, all UV filters are suitable for combination in the preparation according to the present invention.Particularly preferred are UV filters whose physiological tolerance has already been demonstrated.For both UVA and UVB filters, there are many proven substances known from specialized literature.The compounds shown in the following list should only be considered as examples.Of course, other UV filters can also be used.

[0043] Preferred preparations may contain organic UV filters, so-called hydrophilic or lipophilic sun protection filters (absorbers), which are effective in the UVA and / or UVB and / or IR and / or VIS regions.These substances may be selected from, inter alia, dibenzoylmethane derivatives, p-aminobenzoic acid derivatives, salicylic acid derivatives, β,β-diphenylacrylate derivatives, camphor derivatives, triazine derivatives, cinnamic acid derivatives, and polymeric and silicone filters, as described in application WO93 / 04665.Further examples of organic filters are given in patent application EP-A 0 487 404.These UV filters are usually named according to the INCI nomenclature.

[0044] Particularly suitable combinations are: Dibenzoylmethane derivatives: 4-isopropyl-dibenzoyl-methane and 4,4'-methoxy-tert-butyl-dibenzoylmethane, which are described in FR-A-2326405, FR-A-2440933 and EP-A-0114607. 4,4'-Methoxy-tert-butyl-dibenzoylmethane is commercially available, for example, from Merck under the name "Eusolex 9020".

[0045] Para-aminobenzoic acid and its derivatives: PABA, ethyl PABA, ethyldihydroxypropyl PABA, ethylhexyldimethyl PABA (sold, for example, under the name "Escalol 507" by ISP), glyceryl PABA, PEG-25 PABA (sold, for example, under the name "Uvinul P25" by BASF).

[0046] Salicylates: homosalate (sold by Merck under the name "Eusolex HMS"); ethylhexyl salicylate (sold, for example, by Symrise under the name "Neo Heliopan OS"); dipropylene glycol salicylate (sold, for example, by Scher under the name "Dipsal"); TEA salicylate (sold, for example, by Symrise under the name "Neo Heliopan TS").

[0047] β,β-Diphenylacrylate derivatives: octocrylene (sold, for example, under the name "Eusolex® OCR" by Merck); "Uvinul N539" from BASF; etocrylene (sold, for example, under the name "Uvinul N35" by BASF).

[0048] Benzophenone derivatives: benzophenone-1 (commercially available, for example, under the name "Uvinul 400"); benzophenone-2 (commercially available, for example, under the name "Uvinul D50"); benzophenone-3 or oxybenzone (commercially available, for example, under the name "Uvinul M40"); benzophenone-4 (commercially available, for example, under the name "Uvinul MS40"); benzophenone-9 (commercially available, for example, under the name "Uvinul DS-49" by BASF); benzophenone-5, benzophenone-6 (commercially available, for example, under the name "Helisorb 11" by Norquay); benzophenone-8 (commercially available, for example, under the name "Spectra-Sorb UV-24" by American Cyanamid); benzophenone-12 n-hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate or 2-hydroxy-4-methoxybenzophenone (commercially available, for example, under the name Eusolex® 4360 by Merck, (Commercially available from Darmstadt).

[0049] Benzylidene camphor derivatives: 3-benzylidene camphor (commercially available, for example, under the name "Mexoryl SD" from Chimex); 4-methylbenzylidene camphor (commercially available, for example, under the name "Eusolex 6300" from Merck); benzylidene camphorsulfonic acid (commercially available, for example, under the name "Mexoryl SL" from Chimex); camphor benzalkonium methosulfate (commercially available, for example, under the name "Mexoryl SO" from Chimex); terephthalylidene dicamphorsulfonic acid (commercially available, for example, under the name "Mexoryl SX" from Chimex); polyacrylamidomethyl benzylidene camphor (commercially available, for example, under the name "Mexoryl SW" from Chimex).

[0050] Phenylbenzimidazole derivatives: phenylbenzimidazole sulfonic acid (commercially available, for example, under the name "Eusolex 232" from Merck); disodium phenyldibenzimidazole tetrasulfonate (commercially available, for example, under the name "Neo Heliopan AP" from Symrise).

[0051] Phenylbenzotriazole derivatives: drometrizole trisiloxane (commercially available, for example, from Rhodia Chimie under the name "Silatrizole"); methylenebis(benzotriazolyl)tetramethylbutylphenol in solid form (commercially available, for example, from Fairmount Chemical under the name "MIXXIM BB / 100") or in micronized form as an aqueous dispersion (commercially available, for example, from BASF under the name "Tinosorb M").

[0052] Triazine derivatives: ethylhexyltriazone (commercially available, for example, under the name "Uvinul T150" from BASF); diethylhexylbutamidotriazone (commercially available, for example, under the name "Uvasorb HEB" from Sigma 3V); 2,4,6-tris-(diisobutyl 4'-aminobenzalmalonate)-s-triazine or 2,4,6-tris(biphenyl)-1,3,5-triazine (commercially available, for example, as Tinosorb A2B from BASF); 2,2'-[6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diyl]bis[5-(2-ethylhexyl)oxy]phenol; Tinosorb S from BASF; N2,N4-bis[4-[5-(1,1-dimethylpropyl)-2-benzoxazolyl]phenyl]-N6-(2-ethylhexyl)-1,3,5-triazine-2,4,6-triamine (commercially available as Uvasorb K 2A from Sigma 3V), or trisbiphenyltriazine (commercially available as Tinosorb® A2B from BASF).

[0053] Anthraniline derivatives: Menthyl anthranilate (for example marketed under the name "Neo Heliopan MA" by Symrise). Imidazole derivative: Ethylhexyldimethoxybenzylidene dioxoimidazoline propionate. Benzalmalonate derivatives: polyorganosiloxanes containing functional benzalmalonate groups, such as Polysilicone-15 (sold for example under the name "Parsol SLX" by Hoffmann LaRoche).

[0054] 4,4-Diarylbutadiene derivatives: 1,1-dicarboxy(2,2'-dimethylpropyl)-4,4-diphenylbutadiene. Benzoxazole derivatives: 2,4-bis[5-(1-dimethylpropyl)benzoxazol-2-yl(4-phenyl)imino]-6-(2-ethylhexyl)imino-1,3,5-triazine (commercially available, for example, under the name Uvasorb K2A from Sigma 3V), and mixtures containing same.

[0055] Piperazine derivatives, e.g., the compound [ka] or UV filters with the following structure: [ka]

[0056] It is also possible to use UV filters based on polysiloxane copolymers with a random distribution according to the following formula, for example with a=1,2, b=58, c=2,8: [ka]

[0057] This list of compounds represents examples; of course, other UV filters can also be used. Suitable organic UV protection substances can preferably be selected from the following list: ethylhexyl salicylate, phenylbenzimidazole sulfonic acid, benzophenone-3, benzophenone-4, benzophenone-5, n-hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate, 4-methylbenzylidene camphor, terephthalylidene dicamphor sulfonic acid, disodium phenyl dibenzimidazole tetrasulfonate, methylene bis(benzotriazol-4-yl)benzoate ... (zolyl)tetramethylbutylphenol, butyl methoxydibenzoylmethane, ethylhexyl triazone, diethylhexylbutamidotriazone, drometrizole trisiloxane, polysilicone-15, 1,1-dicarboxy(2,2'-dimethylpropyl)-4,4-diphenylbutadiene, 2,4-bis[5-1(dimethylpropyl)benzoxazol-2-yl(4-phenyl)imino]-6-(2-ethylhexyl)imino-1,3,5-triazine and mixtures thereof.

[0058] These organic UV filters are generally incorporated into the formulation in an amount of 0.01 to 20 weight percent, preferably 1 to 10 weight percent. The preparations may further comprise inorganic UV filters, so-called particulate UV filters. These combinations with particulate UV filters can be both as powders and also dispersions or pastes of the following types:

[0059] Preference is given here to titanium dioxide, for example coated titanium dioxide (e.g. Eusolex® T-2000, Eusolex® T-AQUA, Eusolex® T-AVO, Eusolex® T-PRO, Eusolex® T-EASY). such as zinc oxide (for example Sachtotec®), iron oxide or both selected from the group of cerium oxide and / or zirconium oxide. Furthermore, a combination with pigmentary titanium dioxide or zinc oxide is also possible, the particle size of these pigments being greater than or equal to 200 nm, for example Hombitan® FG or Hombitan® FF-Pharma.

[0060] It may be further preferred that the preparation contains an inorganic UV filter that has been post-treated by conventional methods, as described, for example, in Cosmetics & Toiletries 1990, 105, 53. Here, one or more of the following post-treatment components can be selected: amino acids, beeswax, fatty acids, fatty acid alcohols, anionic surfactants, lecithin, phospholipids, sodium, potassium, zinc, iron or aluminum salts of fatty acids, polyethylene, silicone, proteins (especially collagen or elastin), alkanolamines, silicon dioxide, aluminum oxide, further metal oxides, phosphates such as sodium hexametaphosphate, or glycerin.

[0061] Particulate UV filters preferably employed herein are: - untreated titanium dioxide, for example, the product Microtitanium Dioxide MT 500 B from Tayca; titanium dioxide P25 from Degussa; - micronized titanium dioxide post-treated with aluminum oxide and silicon dioxide post-treatment, such as the product "Microtitanium Dioxide MT 100 SA" from Tayca or the product "Tioveil Fin" from Uniqema; - micronized titanium dioxide post-treated with aluminum oxide and / or aluminum stearate / laurate post-treatment, such as the product Microtitanium Dioxide MT 100 T from Tayca; Eusolex T-2000 from Merck; - micronized titanium dioxide post-treated with iron oxide and / or iron stearate post-treatment, such as the product "Microtitanium Dioxide MT 100 F" from Tayca; - silicon dioxide, aluminum oxide and micronized titanium dioxide post-treated with silicone post-treatment, such as the product "Microtitanium Dioxide MT 100 SAS" from Tayca; - Micronized titanium dioxide post-treated with sodium hexametaphosphate, such as the product "Microtitanium Dioxide MT 150 W" from Tayca.

[0062] The treated micronized titanium dioxide employed in the combination may also be post-treated with: - octyltrimethoxysilane, such as the product Tego Sun T 805 from Degussa; - silicon dioxide; for example, the product Parsol TX from DSM; - aluminum oxide and stearic acid; for example, the product UV-Titan M160 from Sachtleben; - Aluminum and glycerin; for example, the product UV-Titan from Sachtleben; - aluminum and silicone oils, such as the product UV-Titan M262 from Sachtleben; - sodium hexametaphosphate and polyvinylpyrrolidone; - polydimethylsiloxanes, such as the product 70250 Cardre UF TiO2SI3 from Cardre; - Polydimethylhydrogensiloxane, such as the product "Microtitanium Dioxide USP Grade Hydrophobic" from Color Techniques.

[0063] Combinations with the following products may also be advantageous: - untreated zinc oxide, such as the product Z Cote from BASF (Sunsmart), Nanox from Elementis, etc.; - post-treated zinc oxide, such as the following products: · "Zinc Oxide CS-5" from Toshibi (ZnO post-treated with polymethylhydrogensiloxane); · Nanogard Zinc Oxide FN from Nanophase Technologies; "SPD-Z1" from Shin-Etsu (ZnO post-treated with silicone-grafted acrylic polymer, dispersed in cyclodimethylsiloxane); · "Escalol Z100" from ISP (aluminum oxide post-treated ZnO, dispersed in an ethylhexyl methoxycinnamate / PVP-hexadecene / methicone copolymer blend); · "Fuji ZNO-SMS-10" from Fuji Pigment (ZnO post-treated with silicon dioxide and polymethylsilsesquioxane); · Untreated cerium oxide micropigments, such as those under the name "Colloidal Cerium Oxide" from Rhone Poulenc; Iron oxide untreated and / or post-treated with Nanogar, a name from Arnaud.

[0064] By way of example, post-treated and non-post-treated mixtures of various metal oxides, such as titanium dioxide and cerium oxide, can also be employed, such as the product Sunveil A from Ikeda. Additionally, aluminum oxide-, silicon dioxide-, and silicone-post-treated titanium dioxide / zinc oxide mixtures can also be employed, such as the product UV-Titan M261 from Sachtleben.

[0065] These inorganic UV filters are generally incorporated into the formulations in an amount of 0.1 to 25 percent by weight, preferably 2 to 10% by weight. A combination of one or more of the above compounds with UV filtering action can optimize protection against the harmful effects of UV radiation.

[0066] All of the above UV filters can also be used in encapsulated form.It is particularly advantageous to use organic UV filters in encapsulated form.The capsules in the preparations used according to the present invention are preferably present in the amount that ensures that the encapsulated UV filters are present in the preparation in the weight percentage ratio indicated above.

[0067] According to the invention, the formulation may preferably further comprise a pore-refining agent, such as retinol (vitamin A), 5,7-dihydroxy-2-methylchromone (marketed under the trade name RonaCare® Luremine), nicotinamide or isoquercetin. In a further preferred embodiment of the invention, the formulation further comprises at least one skin-lightening active compound (or equivalently a depigmenting active compound) or extract with skin-lightening activity.

[0068] The skin-lightening active compound can in principle be any active compound known to those skilled in the art.Suitable for combination are commercially available melanogenesis inhibitors, such as ascorbic acid and its derivatives, aloesin, niacinamide, emblica, ellagic acid, licorice extract, mulberry extract, kojic acid, licorice extract, rucinol, hydroquinone, azelaic acid, arbutin, magnesium ascorbyl phosphate, lactic acid, butylphenyl methoxyphenyl propanediol (available from Merck as RonaCare® PristineBright®) or the like.Preferred examples of compounds with skin-lightening activity are hydroquinone, niacinamide, ascorbic acid and their physiologically acceptable salts, kojic acid, arbutin, aloesin, azelaic acid, ellagic acid, lactic acid, butylphenyl methoxyphenyl propanediol or rucinol.Preferred examples of extracts with skin-lightening activity are licorice extract, mulberry extract or emblica.

[0069] The preparations described above may further comprise one or more self-tanning substances. This type of preparation generally has the effect of reducing contrast, allowing for the achievement of a uniform skin shade. The present invention also relates to the use of the compatible solutes described above in combination with one or more self-tanning substances to achieve contrast reduction and a uniform skin shade. Consequently, a contrast-reducing agent is a substance that reduces uneven skin color by reducing the contrast between more and less pigmented skin areas. This type of uneven skin color may be caused by uneven pigmentation and / or different distribution of keratinized skin. Uneven pigmentation is by no means normal in the population and is due to different levels of melanin production by melanocytes or the irregular distribution of melanocytes in the skin.

[0070] A reduction in contrast can be achieved, inter alia, by preparations in which self-tanning substances are additionally present, which may be self-tanning substances that react with amino acids of the skin based on the Maillard or Michael addition reaction, or so-called melanogenesis promoters or pigmentation promoters that stimulate the natural pigmentation of the skin.

[0071] Preferred self-tanning substances are, for example: 1,3-dihydroxyacetone (DHA) and derivatives derived therefrom, glycerol aldehyde, hydroxymethylglyoxal, γ-dialdehyde, erythrulose, 6-aldo-D-fructose, ninhydrin, 5-hydroxy-1,4-naphthoquinone (juglone) or 2-hydroxy-1,4-naphthoquinone (lawsone) or mixtures of said compounds. Particularly preferred are 1,3-dihydroxyacetone, erythrulose and mixtures thereof.

[0072] Pigmentation-promoting substances are known to those skilled in the art. Examples include glyceric acid, melanocyte-activating hormone (alpha-MSH), peptide analogs, thymidine dinucleotide, L-tyrosine and their esters, bicyclic monoterpene diols (described in Brown et al., Photochemistry and Photobiology B: Biology 63 (2001) 148-161) or 7-acyloxy-chromen-4-one derivatives (described in WO2012 / 097857A1), especially hexadecanoic acid 5-hydroxy-2-methyl-4-oxo-4H-chromen-7-yl ester (Ronacare® Bronzyl). TM available from Merck KGaA, Darmstadt, Germany).

[0073] Preferably, the self-tanning substance is present in the composition in an amount of from 0.01 to 20% by weight, more preferably from 0.5 to 15% by weight, and most preferably from 1 to 8% by weight, relative to the total weight of the preparation. In the described preparation, colored pigments can also be present, and the layer structure of the pigments is not limited. When used in an amount of 0.5-5% by weight, the colored pigments should preferably be skin-colored or brown. The selection of the corresponding pigments is well known to those skilled in the art.

[0074] In a further preferred embodiment of the formulation, the preparation comprises one or more antioxidants and / or one or more vitamins. The use of antioxidants generally allows for a protective effect against oxidative stress or against the effects of free radicals, and those skilled in the art will have no difficulty in selecting an antioxidant that acts appropriately quickly or with a delayed action. There are many proven substances known from the specialist literature that can be used as antioxidants, such as amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g. urocanic acid) and their derivatives, peptides such as D,L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g. anserine), carotenoids, carotenes (e.g. α-carotene, β-carotene, lycopene) and their derivatives, chlorogenic acid and their derivatives, lipoic acid and its derivatives (e.g. dihydrolipoic acid), gold thioglucose, propylthiouracil and other thiols (e.g. thioredoxin, glutathione, cysteine, cystine, cystamine and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, γ-linoleyl, cholesteryl and their glyceryl esters), and and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (e.g., esters, ethers, peptides, lipids, nucleotides, nucleosides and salts, etc.), and sulfoximine compounds with extremely low tolerated doses (e.g., pmol to μmol / kg, etc.) (e.g., buthionine sulfoximine, homocystasulfoximine, buthionine sulfone, penta-, hexa- and heptathionine sulfoximine, etc.), and also (metal) chelating agents (e.g., α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin, etc.), α-hydroxy acids (e.g., citric acid, lactic acid, malic acid, etc.), humic acid, bile acids, bile extracts, bilirubin, biliverdin, EDTA, EGTA, pentasodium ethylenediaminetetramethylenephosphonate and their derivatives, unsaturated fatty acids and their derivatives, vitamin C and derivatives (e.g.,Examples of suitable antioxidants include ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate, tocopherols and derivatives (e.g., vitamin E acetate), vitamin A and derivatives (e.g., vitamin A palmitate), and coniferyl benzoate of benzoin resin, rutinic acid and derivatives thereof, α-glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, quercetin, uric acid and derivatives thereof, mannose and derivatives thereof, zinc and derivatives thereof (e.g., ZnO, ZnSO, etc.), selenium and derivatives thereof (e.g., selenomethionine, etc.), stilbenes and derivatives thereof (e.g., stilbene oxide, trans-stilbene oxide, etc.). Further suitable antioxidants are also described in WO2006 / 111233 and WO2006 / 111234.

[0075] Suitable antioxidants are also compounds of general formula A or B [ka] During the ceremony R 1 is -C(O)CH3, -CO2R 3 , -C(O)NH2 and -C(O)N(R 4 )2, X represents O or NH; R 2 represents a linear or branched alkyl having 1 to 30 C atoms, R 3 represents a linear or branched alkyl having 1 to 20 C atoms, R 4 in each case independently of one another, represent H or linear or branched alkyl having 1 to 8 C atoms, R 5 represents H, linear or branched alkyl having 1 to 8 C atoms or linear or branched alkoxy having 1 to 8 C atoms, and R6 represents a linear or branched alkyl having 1 to 8 C atoms.

[0076] Preference is given to derivatives of 2-(4-hydroxy-3,5-dimethoxybenzylidene)malonic acid and / or 2-(4-hydroxy-3,5-dimethoxybenzyl)malonic acid, particularly preferred are bis(2-ethylhexyl) 2-(4-hydroxy-3,5-dimethoxybenzylidene)malonate (e.g. Oxynex® ST Liquid) and / or bis(2-ethylhexyl) 2-(4-hydroxy-3,5-dimethoxybenzyl)malonate (e.g. RonaCare® AP).

[0077] Mixtures of antioxidants are likewise suitable for use in the preparations according to the invention. Known and commercially available mixtures are, for example, mixtures which contain as active ingredients lecithin, L-(+)-ascorbyl palmitate and citric acid, natural tocopherol, L-(+)-ascorbyl palmitate, L-(+)-ascorbic acid and citric acid (such as, for example, Oxynex® K LIQUID), tocopherol extract from natural sources, L-(+)-ascorbyl palmitate, L-(+)-ascorbic acid and citric acid (such as, for example, Oxynex® L LIQUID), DL-α-tocopherol, L-(+)-ascorbyl palmitate, citric acid and lecithin (such as, for example, Oxynex® LM) or butylhydroxytoluene (BHT), L-(+)-ascorbyl palmitate and citric acid (such as, for example, Oxynex® 2004). Antioxidants of this type are typically employed in such compositions with compounds of formula (I) or part-formulas thereof in a weight percent ratio ranging from 1000:1 to 1:1000, preferably from 100:1 to 1:100.

[0078] Among phenols with antioxidant properties, polyphenols, some of which occur naturally, are particularly interesting for applications in pharmaceuticals, cosmetics, or nutrition. For example, flavonoids or bioflavonoids, primarily known as plant pigments, often have antioxidant potential. Lemanska et al., Current Topics in Biophysics 2000, 24(2), 101-108, related the effects of the substitution patterns of mono- and dihydroxyflavones. It was observed that dihydroxyflavones containing OH groups near the keto functional group or at the 3',4'-, 6,7-, or 7,8-positions possess antioxidant properties, while in some cases other mono- and dihydroxyflavones lack such properties.

[0079] Quercetin (cyanidanol, cyanidenolone 1522, meletin, sophoretin, erythrin, 3,3',4',5,7-pentahydroxyflavone) is often cited as a particularly effective antioxidant (e.g., Rice-Evans et al., Trends in Plant Science 1997, 2(4), 152-159). Lemanska et al., Free Radical Biology & Medicine 2001, 31(7), 869-881, investigated the pH dependence of the antioxidant activity of hydroxyflavones. Quercetin exhibited the highest activity of the structures investigated across the entire pH range.

[0080] The preparation according to the invention may contain vitamins as further components: vitamin A, vitamin A propionate, vitamin A palmitate, vitamin A acetate, retinol, vitamin B, thiamine chloride hydrochloride (vitamin B1), riboflavin (vitamin B2), nicotinamide, vitamin C (ascorbic acid), vitamin D, ergocalciferol (vitamin D2), vitamin E, DL-α-tocopherol, tocopherol E acetate, tocopherol hydrogen succinate, vitamin K1, esculin (vitamin P active compound), thiamine (vitamin B1), nicotinic acid (niacin), pyridoxine, pyridoxal, pyridoxamine, (vitamin B6), pantothenic acid, biotin, folic acid and cobalamin (vitamin B 12 Vitamins and vitamin derivatives selected from the group consisting of: vitamin A palmitate, vitamin C and its derivatives, DL-α-tocopherol, tocopherol E acetate, nicotinic acid, pantothenic acid and biotin are preferably present in the preparations according to the invention. In the case of cosmetic applications, vitamins are usually added with the preparation in the range of 0.01 to 5% by weight, based on the total weight. Nutritional-physiological applications are guided by the respective recommended vitamin requirements.

[0081] The preparations according to the invention may further comprise at least one substance that serves to maintain and / or improve the moisture content of the skin, which may, without this being intended to be limiting, be, inter alia, substances belonging to the so-called natural moisturizing factors, such as, for example, 2-oxopyrrolidine 5-carboxylic acid.

[0082] The preparations according to the invention may further comprise an anti-aging active compound, an anti-cellulite active compound or a conventional skin-protecting or skin-care active compound. The skin-protecting or skin-care active compound may in principle be any active compound known to those skilled in the art. Particularly preferred anti-aging active compounds are pyrimidinecarboxylic acids, aryloximes, bioflavonoids, bioflavonoid-containing extracts, chromones or retinoids.

[0083] Additionally, anti-aging active compounds that can be used are products from Merck, such as 5,7-dihydroxy-2-methylchromone, which are sold under the trade names RonaCare® Luremine, Ronacare® Isoquercetin, Ronacare® Tilirosid or Ronacare® Cyclopeptide 5.

[0084] Known anti-aging substances are also chromones or retinoids, such as retinol (vitamin A), retinoic acid, retinaldehyde or synthetically modified compounds of vitamin A, as described, for example, in EP 1508327. At the same time, the described chromones and retinoids are also effective anti-cellulite active compounds. A similarly known anti-cellulite active compound is caffeine.

[0085] In the above-mentioned formulations, compatible solutes include, for example, anisic acid, alcohol, ammonium benzoate, ammonium propionate, benzoic acid, bronopol, butylparaben, benzethonium chloride, benzalkonium chloride, 5-bromo-5-nitro-1,3-dioxane, benzyl alcohol, boric acid, benzisothiazolinone, benzotriazole, benzyl hemiformate, benzylparaben, 2-bromo-2-nitropropane-1,3-diol, butyl benzoate, chlorphenesin, caprylic / capric acid glyceride, caprylyl glycol, tea leaf (Camellia sinensis) extract, Candida bombicola (Candida Bombicola) / Glucose / Rapeseed Oil Fatty Acid Methyl, Chloroxylenoic Acid, Chloroacetamide, Chlorhexidine, Chlorobutanol, Calcium Benzoate, Calcium Paraben, Calcium Propionate, Calcium Salicylate, Calcium Sorbate, Captan, Chloramine T, Chlorhexidine Diacetate, Chlorhexidine Digluconate, Chlorhexidine Dihydrochloride, Chloracetamine, p-Chloro-m-Cresol, Chlorophene, p-Chlorophenol, Chlorothymol, Grapefruit (Citrus Grandis) (Grapefruit) Fruit Extract, Grapefruit (Citrus Grandis) Fruit Extract, Grandis (Grapefruit) Seed Extract, m-Cresol, o-Cresol, p-Cresol, Mixed Cresols, 1,2-Decanediol (INCI Decylene Glycol), Diazolidinyl Urea, Dichlorobenzyl Alcohol, Dimethyloxazolidine, DMDM ​​Hydantoin, Dimethylhydroxymethylpyrazole, Dehydroacetic Acid, Diazolidinyl Urea, DEDM Hydantoin, DEDM Hydantoin Dilaurate, Dibromopropamidine Diisothionate, Dimethylolethylenethiourea, Dithiomethylbenzamide, DMHF, Domiphen Bromide, 7-Ethylbicyclooxazolidine, Ethylparaben, Ethylhexylglycerol, Ethanol, Ethyl Ferulate, Formaldehyde, Ferulic Acid, Glyceryl Caprate, Glutaral

[0086] Glycerol formate, glyoxal, hexamidine diisethionate, hexanediol, hexetidine, hexamidine, hexamidine diparaben, hexamidine paraben, 4-hydroxybenzoic acid, hydroxymethyldioxazabicyclooctane, imidazolidinyl urea, imidazolidinyl urea NF, isobutylparaben, isothiazolinone, iodopropynyl butylcarbamate, isodecylparaben, isopropyl cresol, isopropylparaben, isopropyl sorbate, potassium sorbate NF FCC, copper usnate, potassium benzoate, potassium ethylparaben, potassium methylparaben, potassium paraben, potassium phenoxide, potassium o-phenylphenate, potassium propionate, potassium propylparaben, potassium salicylate, potassium sorbate, methylparaben, methylisothiazolinone, methylbenzethonium chloride phenol, methyldibromoglutaronitrile, methaneammonium chloride, methylbromoglutaronitrile, magnesium benzoate, magnesium propionate, magnesium salicylate, MDM hydantoin, MEA benzoate, MEA o-phenylphenate, MEA salicylate, methylchloroisothiazolinone, sodium benzoate NF FCC, sodium caprylate, sodium dehydroacetate, sodium dehydroacetate FCC, sodium hydroxymethylglycinate, sodium methylparaben, sodium propylparaben, sodium iodate, neem tree seed oil,

[0087] Nisin, Sodium Benzoate, Sodium Butylparaben, Sodium p-Chloro-m-Cresol, Sodium Ethylparaben, Sodium Formate, Sodium Hydroxymethanesulfonate, Sodium Isobutylparaben, Sodium Paraben, Sodium Phenolsulfonate, Sodium Phenoxide, Sodium o-Phenylphenate, Sodium Propionate, Sodium Propylparaben, Sodium Pyrithione, Sodium Salicylate, Sodium Sorbate, Ortho-Phenylphenol, Phenoxyethanol, Propylparaben, Polymethoxy Bicyclic Oxazolidine, Pinus Pinaster Bark Extract, Poloxamer 188, PVP Iodine, Parabens, Piroctone Olamine, Phenethyl Alcohol, Polyaminopropyl Biguanide, Polyquaternium-42, PEG-5 DEDM Hydantoin, PEG-15 DEDM Hydantoin, PEG-5 Hydantoin Oleate, PEG-15 DEDM Hydantoin Stearate, Phenethyl Alcohol, Phenol, Phenoxyethylparaben, Phenoxyisopropanol, Phenyl Benzoate, Phenylmercury Acetate, Phenylmercury Benzoate, Phenylmercury Borate, Phenylmercury Bromide, Phenylmercury Chloride, Phenylparaben, o-Phenylphenol, Polyaminopropyl Biguanide Stearate, Propionic Acid, Propyl Benzoate, Quaternium-15, Quaternium-8, Quaternium-14, Rosemary Leaf Extract, Sorbic Acid NF FCC, Selenium Disulfine, Sorbic Acid, Salicylic Acid, Silver Borosilicate, Silver Magnesium Aluminum Phosphate, Triclosan, Di-alpha-Tocopherol, Tocopheryl Acetate, Thimerosal, Triclocarban, TEA Sorbate, Thimerosal, Usnic Acid, Undecylenoyl PEG-5 Paraben, Vitis Vinifera (Vitis) Seed Oil The active ingredients may be advantageously combined with any known preservative or antimicrobial active compound, such as (Vitamin C) vinifera seed extract, tea tree oil, hydrogen peroxide, zinc pyrithione, zinc oxide, zinc phenolsulfonate or combinations thereof.

[0088] In this respect, the formulation may comprise an antimicrobially active compound as described in WO2013 / 091775A2, WO2013 / 159865A1 or WO2013 / 167220A1, in particular 4-hydroxy-cyclohexanecarboxylic acid butyl ester (available as RonaCare® SereneShield from Merck KGaA, Darmstadt, Germany).

[0089] The formulations may further comprise, and are contemplated to be, anti-acne active compounds, for example, those of WO 2009 / 098139, page 47, line 2 to page 48, line 27, and DE 10324567. Exemplary additional anti-acne active compounds are silver particles and silver salts, such as silver lactate and silver citrate, azelaic acid, ellagic acid, lactic acid, glycolic acid, salicylic acid, glycyrrhizic acid, triclosan, phenoxyethanol, hexamidine diisethionate, ketoconazole, peroxides, such as hydrogen peroxide or benzoyl peroxide, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, phytic acid, arachidonic acid, capryl glycol, ethylhexylglycerol, farnesol, cetylpyridinium salts, 6-trimethylpentyl-2-pyridone (piroctone olamine), and lipohydroxy acid (LHA).

[0090] Antidandruff active compounds are, for example, zinc pyrithione, piroctone olamine, selenium disulfide, climbazole, triclosan, butylparaben, 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDM hydantoin), fumaric acid, methylchloroisothiazolinone or methylisothiazolinone (MIT).

[0091] The following may be mentioned as examples of the use forms of the preparations according to the present invention: solutions, suspensions, emulsions, PIT emulsions, pastes, ointments, gels, creams, lotions, foams, masks, powders, soaps, surfactant-containing cleansing preparations, oils, aerosols, plasters, compresses, adhesive bandages and sprays, especially for external use.Other application forms are, for example, sticks, shampoos and shower baths.Typical cosmetic use forms are also lipsticks, lip care sticks, powders, emulsions and wax makeups, and sun protection, pre-sun and after-sun preparations.

[0092] The cosmetic and dermatological preparations according to the invention may in particular be water-free preparations, lotions or emulsions, such as creams or milks, or microemulsions, in each case of the water-in-oil (W / O) or oil-in-water (O / W) type, such as multiple emulsions of the water-in-oil-in-water (W / O / W) type or vice versa (O / W / O), gels or solutions (in particular oil-alcoholic, oil-aqueous or aqueous-alcoholic gels or solutions), solid sticks, ointments or aerosols. For application, the cosmetic and dermatological preparations according to the invention are applied to the skin in the appropriate amount in the usual manner for cosmetics.

[0093] Any desired conventional vehicles, adjuvants and, if desired, further active compounds may be added to the preparations. Preferred adjuvants are from the group of preservatives, stabilizers, solubilizers, colorants, i.e., pigments, dyes, emulsifiers or odor improvers.

[0094] The ointments, pastes, creams and gels may contain customary vehicles suitable for topical application, such as animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silica, talc and titanium dioxide, or mixtures of these substances.

[0095] Powders and sprays may contain conventional vehicles such as lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may also contain conventional, readily volatile, liquefied propellants such as chlorofluorocarbons, propane / butane or dimethyl ether. Compressed air can also be used advantageously. However, air can also be used in pressureless metering devices such as pump sprays.

[0096] The solutions and emulsions may contain customary vehicles, such as solvents, solubilizers and emulsifiers, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, in particular cottonseed oil, peanut oil, wheat germ oil, olive oil, castor oil and sesame oil, glycerol fatty acid esters, polyethylene glycol and fatty acid esters of sorbitan, or mixtures of these substances. A preferred solubilizer is generally 2-isopropyl-5-methylcyclohexane-carbonyl-D-alanine methyl ester.

[0097] Suspensions may contain customary vehicles, such as liquid diluents, for example, water, ethanol or propylene glycol, suspension media, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

[0098] The soaps may contain customary vehicles, such as alkali metal salts of fatty acids, salts of fatty acid monoesters, fatty acid protein hydrolysates, isothionates, lanolin, fatty alcohols, vegetable oils, vegetable extracts, glycerol, sugars, etc., or mixtures of these substances.

[0099] Cleansing products containing surfactants may contain customary vehicles such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic acid monoesters, fatty acid protein hydrolysates, isothionates, imidazolinium derivatives, methyl taurate, sarcosinates, fatty acid amide ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable and synthetic oils, lanolin derivatives, ethoxylated glycerol fatty acid esters, and the like, or mixtures of these substances.

[0100] Facial and body oils may contain conventional vehicles such as synthetic oils, e.g., fatty acid esters, fatty alcohols, silicone oils, etc., natural oils, e.g., vegetable oils and oily plant extracts, paraffin oil, lanolin oil, etc., or mixtures of these substances. Further suitable vehicles are liposomes, cyclodextrins or other sugars such as sorbitol.

[0101] A preferred embodiment of the present invention is an emulsion in the form of a cream or milk, comprising, for example, the above-mentioned fats, oils, waxes and other fatty substances, and water or an aqueous phase containing, for example, a solvent or hydrophilic surfactant, and an emulsifier normally used for this type of preparation.

[0102] The lipid phase can advantageously be chosen from the following groups of substances: - Mineral oil, mineral wax; oils, such as capric or caprylic triglycerides, and also natural oils, such as castor oil; fats, waxes and other natural and synthetic fatty substances, preferably esters of fatty acids with alcohols having a low carbon number, such as isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids or fatty acids having a low carbon number; Silicone oils, such as in the form of dimethylpolysiloxane, diethylpolysiloxane, diphenylpolysiloxane, and mixtures thereof.

[0103] For the purposes of the present invention, the oily phase of the emulsion, oleogel or hydrodispersion or lipodispersion 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. Ester oils of this type can then advantageously be selected from the group of 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-hexaldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate and synthetic, semi-synthetic and natural mixtures of esters of this type, such as, for example, jojoba oil.

[0104] Furthermore, the oil phase can be advantageously selected from the group of branched and unbranched hydrocarbons and hydrocarbon waxes, silicone oils, dialkyl ethers, saturated and unsaturated, branched and unbranched alcohols, and fatty acid triglycerides, in particular the group of triglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 8 to 24, especially 12 to 18 carbon atoms. The fatty acid triglycerides can be advantageously selected, for example, from the group of synthetic, semi-synthetic and natural oils, such as olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, etc. Any desired mixture of oil and wax components of this type may also be advantageously employed for the purposes of the present invention, which may also advantageously employ a wax, such as cetyl palmitate, as the sole lipid component of the oil phase.

[0105] The aqueous phase of the preparation according to the invention may optionally advantageously contain one or more thickeners, either individually or in combination, which may be selected from the group consisting of alcohols, diols or polyols with a low carbon number and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and similar products, as well as alcohols with a low carbon number, such as ethanol, isopropanol, 1,2-propanediol, glycerol, and in particular silicon dioxide, aluminum silicate, polysaccharides or derivatives thereof, such as hyaluronic acid, xanthan gum, hydroxypropylmethylcellulose, particularly preferably polyacrylates, preferably those from the group of so-called Carbopols, such as Carbopol grades 980, 981, 1382, 2984, 5984. In particular, mixtures of the above-mentioned solvents are used. In the case of alcohol solvents, water may be an additional constituent.

[0106] In a preferred embodiment, the preparation according to the invention comprises a hydrophilic surfactant, preferably selected from the group of alkylglucosides, acyl lactylates, betaines and coconut amphoacetates. Emulsifiers that can be used are, for example, the known W / O and O / W emulsifiers. It may be advantageous to use additional conventional co-emulsifiers in the preferred O / W emulsions according to the invention.

[0107] The co-emulsifiers selected according to the invention are advantageously O / W emulsifiers from the group of substances having predominantly an HLB value of 11 to 16, very particularly advantageously 14.5 to 15.5, provided that the O / W emulsifier has saturated radicals R and R'. If the O / W emulsifier has unsaturated radicals R and / or R' or if isoalkyl derivatives are present, the preferred HLB value of such emulsifiers may be higher or lower. It is advantageous to select fatty alcohol ethoxylates from the group of ethoxylated stearyl alcohols, cetyl alcohols, cetylstearyl alcohols (cetearyl alcohols).

[0108] It is further advantageous to select the fatty acid ethoxylates from the following group: Polyethylene glycol (20) stearate, polyethylene glycol (21) stearate, polyethylene glycol (22) stearate, polyethylene glycol (23) stearate, polyethylene glycol (24) stearate, polyethylene glycol (25) stearate, polyethylene glycol (12) isostearate, polyethylene glycol (13) isostearate, polyethylene glycol (14) isostearate, polyethylene glycol (15) isostearate, polyethylene glycol (16) isostearate, polyethylene glycol (17) isostearate, polyethylene glycol (18) isostearate, polyethylene glycol (19) isostearate, polyethylene polyethylene glycol (20) isostearate, polyethylene glycol (21) isostearate, polyethylene glycol (22) isostearate, polyethylene glycol (23) isostearate, polyethylene glycol (24) isostearate, polyethylene glycol (25) isostearate, polyethylene glycol (12) oleate, polyethylene glycol (13) oleate, polyethylene glycol (14) oleate, polyethylene glycol (15) oleate, polyethylene glycol (16) oleate, polyethylene glycol (17) oleate, polyethylene glycol (18) oleate, polyethylene glycol (19) oleate, polyethylene glycol (20) oleate.

[0109] An ethoxylated alkyl ether carboxylic acid or salt thereof that can be advantageously used is sodium laureth-11 carboxylate. An alkyl ether sulfate that can be advantageously used is sodium laureth 1-4 sulfate. An ethoxylated cholesterol derivative that can be advantageously used is polyethylene glycol (30) cholesteryl ether. Polyethylene glycol (25) soy sterol that can be advantageously used has also proven successful. An ethoxylated triglyceride that can be advantageously used is polyethylene glycol (60) evening primrose glyceride.

[0110] It is furthermore advantageous to select the polyethylene glycol glycerol fatty acid esters from the group polyethylene glycol (20) glyceryl laurate, polyethylene glycol (21) glyceryl laurate, polyethylene glycol (22) glyceryl laurate, polyethylene glycol (23) glyceryl laurate, polyethylene glycol (6) glyceryl caprate / caprinate, polyethylene glycol (20) glyceryl oleate, polyethylene glycol (20) glyceryl isostearate, polyethylene glycol (18) glyceryl oleate (cocoate).

[0111] It is also preferred to select the sorbitan ester from the group polyethylene glycol (20) sorbitan monolaurate, polyethylene glycol (20) sorbitan monostearate, polyethylene glycol (20) sorbitan monoisostearate, polyethylene glycol (20) sorbitan monopalmitate and polyethylene glycol (20) sorbitan monooleate.

[0112] The following may be employed as optional W / O emulsifiers, which may nevertheless be advantageous in accordance with the present invention: fatty alcohols having 8 to 30 carbon atoms, monoglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 C atoms, diglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 C atoms, monoglycerol esters of saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 8 to 24, in particular 12 to 18 C atoms Glycerol ethers, diglycerol ethers of saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 8 to 24, in particular 12 to 18 C atoms, propylene glycol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 C atoms, sorbitan esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 C atoms.

[0113] Particularly advantageous W / O emulsifiers are glyceryl monostearate, glyceryl monoisostearate, glyceryl monomyristate, glyceryl monooleate, diglyceryl monostearate, diglyceryl monoisostearate, propylene glycol monostearate, propylene glycol monoisostearate, propylene glycol monocaprylate, propylene glycol monolaurate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monocaprylate, sorbitan monoisooleate, sucrose distearate, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, isobehenyl alcohol, selachyl alcohol, thymyl alcohol, polyethylene glycol (2) stearyl ether (steareth-2), glyceryl monolaurate, glyceryl monocaprylate, glyceryl monocaprylate or PEG-30 dipolyhydroxystearate.

[0114] The preparations may contain cosmetic adjuvants typically used in preparations of this type, such as thickeners, emollients, moisturizers, surfactants, emulsifiers, preservatives, anti-foaming agents, fragrances, waxes, lanolin, propellants, dyes and / or pigments for coloring the composition itself or the skin, and other ingredients typically used in cosmetics.

[0115] The dispersant or solubilizer used may be an oil, wax or other fatty substance, a lower monoalcohol or lower polyol or a mixture thereof. Particularly preferred monoalcohols or polyols include ethanol, i-propanol, propylene glycol, glycerol and sorbitol.

[0116] Further preferred embodiments are oily lotions based on natural or synthetic oils and waxes, lanolin, fatty acid esters, especially triglycerides of fatty acids, or oily-alcoholic lotions based on lower alcohols, such as ethanol, or glycerol, such as propylene glycol, and / or polyols, such as glycerol, and oils, waxes and fatty acid esters, such as triglycerides of fatty acids.

[0117] Preparations according to the invention may also be in the form of alcoholic gels, which contain one or more lower alcohols or polyols, such as ethanol, propylene glycol or glycerol, and a thickener, such as diatomaceous earth. Oily alcoholic gels further contain natural or synthetic oils or waxes.

[0118] The solid sticks preferably consist of natural or synthetic waxes and oils, fatty alcohols, fatty acids, fatty acid esters, lanolin and other fatty substances. If the preparation is formulated as an aerosol, the customary propellants are preferably used, such as alkanes, air, nitrogen, nitrous oxide, etc., particularly preferably alkanes or air.

[0119] A further aspect of the present invention is a preparation as described above, characterized in that a vehicle suitable for topical application and, optionally, physiologically acceptable adjuvants and / or fillers may be present, such vehicles, adjuvants and fillers being as defined above.

[0120] Another aspect of the present invention is directed to a process for the preparation of a preparation as described above, characterized in that at least one compatible solute is mixed with at least one further skin pore lightening active and, optionally, with further ingredients. These compounds can be incorporated in the usual manner into cosmetic or dermatological preparations.

[0121] The preparation process typically includes the following steps: (a) mixing at least one compatible solute with at least one additional pore-lightening active compound and at least one vehicle suitable for topical application, and optionally with physiologically acceptable adjuvants and / or fillers, and optionally (b) making the compatible solute into an apparent ready state. Preparations according to the present invention can be prepared with the aid of techniques well known to those skilled in the art. Mixing can result in dissolution, emulsification or dispersion of at least one compatible solute as described above in the vehicle. The previous teachings of the present invention and their embodiments regarding compatible solutes and preparations containing them can be applied, where valid and appropriate, to the preparation of the preparation without limitation.

[0122] Obviously, the preparation is directed to a use within the meaning of the present invention, i.e., to prevent and reduce keratinization disorders in the skin or keratinizing skin appendages. A clear or appropriate preparation can consist, for example, of a) a specific arrangement of the substance or object, i.e., when it is individualized in such a way that its suitability for use in accordance with the patent is clearly demonstrated; b) the inclusion of instructions for use (e.g., a pack leaflet) in the sale; c) formulation, assembly, dispensing, and ready-to-use packaging; d) treatment regimes, dosage recommendations; e) the use of a trade name specific to the use (Schulte / Kuehnen, German Patents Act, 8th Edition, §14 marginal note 101).

[0123] The composition as described above is applied to the skin or keratinized skin appendages, such as hair or nails. Without further comment, it is assumed that those skilled in the art can utilize the above description to the fullest extent. Therefore, the preferred embodiments should be regarded as merely an illustrative disclosure and in any way not limiting.

[0124] The complete disclosures of all applications and publications, mentioned above and below, are hereby incorporated by reference into this application. The following examples are intended to illustrate the invention, however, they should not be construed as limiting. [Example]

[0125] example Example 1: Proteomics approach Sample illumination and 2D gel electrophoresis: material and method: Protein oxidation (carbonylation) is assessed and quantified by a difference gel electrophoresis proteomics approach demonstrating distinct oxidized protein spots upon UV-A (365 nm) irradiation of skin explants in the presence or absence of ectoine (0.2%) (source Merck KGaA, Darmstadt, Germany). During the study, human explants are irradiated under UVA (LED light source; UWAVE; light source and chamber manufactured for custom needs by France, peak 365 nm, 480 J / cm). 2 , 40 min). A solution of N-acetyl-cysteine ​​(Reference A7250, Sigma-Aldrich) is used as a positive control for protection. Immediately after irradiation, the explants are snap-frozen and proteins are extracted for analysis.

[0126] Protein extraction from explants was performed using a commercially available kit (Total Protein Extraction Kit, Merck KGaA) protocol for skin explants. The extracted proteins were quantified by the Bradford method and divided into equal amounts for analysis. The samples were labeled with a fluorescent probe functionalized to selectively react with carbonyl groups, and then analyzed for carbonylated proteins. Fluorescent labeling of carbonyls was achieved by reaction with an amine-N-oxyl functionalized fluorophore (custom synthesized) and the formation of a stable covalent bond.

[0127] Thus, a sample is labeled with two different fluorescent dyes characterized by different excitation and emission wavelength peaks. CF® 555 (supplied by Biotium) is a red fluorescent dye spectrally similar to Cy3® and Alexa Fluor® 555 (λex 547 nm / λem 572 nm), while CF® 647 (supplied by Biotium) is a far-red fluorescent dye spectrally similar to Cy® 5 and Alexa Fluor® 647 (λex 639 nm / λem 668 nm). This approach allows two distinct labeled samples to be loaded onto the same two-dimensional electrophoresis gel and analyzed independently.

[0128] Additionally, 50 μg of protein from each sample is pooled and labeled with a third fluorescent probe, CF® 488 (supplied by Biotium) (λex 483 nm / λem 508 nm). CF® 488 is a green fluorescent dye that is spectrally similar to AlexaFluor® 488. CF® 488 is used as an internal standard (IS) for normalization between gels. After specific fluorescent labeling, carbonylated proteins are separated by two-dimensional electrophoresis, and a fluorescent image of each specifically labeled sample is obtained.

[0129] The first dimension of protein separation (focusing on the isoelectric point) is performed using nonlinear pH 3-11 gel strips, while the second step of electrophoretic separation is performed by SDS-PAGE using 4%-20% w / v gradient polyacrylamide gels. Digital acquisition of gel images is performed using an "Ettan DIGE imager" system (GE Healthcare). Data processing is performed using the software "Progenesis SameSpots" (Nonlinear Dynamics, UK).

[0130] Carbonylated proteins are represented as an overlay image of two independent fluorescent signals (green or red), and matched proteins with comparable intensities result in yellow spots due to the overlay of the two dyes used to label them (green and red). Carbonylated proteins present at different levels in two samples on the gel are visualized as red or green spots depending on the experimental group, as independent labels for each sample.

[0131] result: More than 200 spots were detected per sample, with the number and intensity increasing in the UV-A irradiated samples. These spots were located between 37 kDa and 75 kDa. The fluorescence signal of each spot was normalized to the internal standard spot signal of each gel. The alignment of spots from different gels and the analysis of the variance of their carbonylation levels in different samples and groups were performed using the software Progenesis Samespots.

[0132] The oxidation level of eight protein spots was detected to be statistically significantly increased in the irradiated (UV-A) group compared to the control (non-irradiated) group (p<0.05). In this group of eight spots, five spots were detected as being protected by the action of 0.2% ectoine (spots 186, 133, 184, 185, 206). In the absence of irradiation, ectoine also reduces the level of oxidation of 10 protein spots that differ from the spots protected from UV-A stress (except spot 100). These results show that ectoine protects distinct protein spots under basal conditions or upon irradiation, suggesting a strong detoxification effect mediated by ectoine.

[0133] These results are shown in Figure 1: 8 proteins showing upregulated protein carbonylation by UV-A irradiation were identified in 2D-gel electrophoresis. Five proteins showed reduced protein carbonylation by 0.2% ectoine treatment (spots 186, 133, 184, 185, 206). For three proteins (spots 100, 230, 203), carbonylation was not reduced after ectoine treatment (n=4).

[0134] Table 1 shows the resulting data: Data have been processed from the different stainings: CTRL: Spot intensity without any treatment / irradiation UV-A: Spot intensity after irradiation compared to CTRL UV-A + Ectoine 0.2%: Spot intensity after ectoine treatment before UV-A irradiation (n=4).

[0135] [Table 1]

[0136] Protein Identification: material and method: The two-dimensional electrophoresis gel was fixed and the proteins were stained using Coomassie Blue (G-250, Reference 27815 (Sigma-Aldrich)). Selected spots were excised, and after reduction and alkylation of the gel fragments, they were digested with LysC / trypsin (Mass Spec grade (Promega)) according to a commercially available digestion kit (Trypsin / Lys-C; ix, Mass Spec grade (Promega)). Mass spectral signals of the peptides were collected using a nanoLC RSLC / ESI QExactive (Thermo Scientific, Orbitrap). The list of peptide peak intensities and mass-to-charge (m / z) values ​​will be analyzed with Mascot (Matrice Science Ltd, London, UK) and SEQUEST HT (Thermo Scientific, 2013) according to the following parameters:

[0137] Software: Mascot v2.5 and SEQUEST HT via Proteome Discoverer v2.2 Search Type MS / MS Ion Search Database SwissProt 03 / 2018 (554,241 sequences; 198,410,167 residues) Classification criteria Homo sapiens (humans) Enzyme Trypsin Transformation Modification Digestion - Desalination Carbamidomethyl (C), deamidation (NQ), oxidation (M) LysC / Trypsin - Zip-tip, eluted with 50% ACN / 0.1% TFA Liquid chromatography: 60 min gradient 2-40% B phase (A phase: 98% H2O, 0.1% formic acid, 2% ACN; B phase: 90% ACN, 10% H2O, 0.1% formic acid), 6 μL injection, column: Acclaim PepMap100 C18, 50 cm, 75 μm

[0138] Mass value Monoisotopic Protein mass unrestricted Peptide mass tolerance 5 ppm Fragment mass tolerance 0.5Da Peptide charge 2+ et 3+ Max uncut 2 Instrument type: RSLC / ESI QExactive (Orbitrap) Significance threshold p<0.05 MS / MS DDA top 10, resolution MS 70 000, resolution MSMS 17 500 The UniProt database (03 / 2018), restricted by the classification "human", is searched using the search engine Masco et SEQUEST with the software Protein Discoverer 2.2.

[0139] result: The results are shown in Table 2: [Table 2] In this example, differential protein analysis shows that ectoine prevents significant protein carbonylation of proteins with known functions in the skin barrier function of the stratum corneum.

[0140] Example 2: Fluorescence imaging To demonstrate changes in the expression levels of selected pools of proteins on skin explants (ex vivo) treated or not with ectoine 0.2% (supplied by Merck KGaA. Darmstadt, Germany) and exposed or not to UV-A radiation: On day 0 (D0), skin explants from a female donor (34 years old, phototype III, Ref. EXP001100F022) are kept alive in calcium-free DMEM (Dulbecco's modified Eagle's medium) containing 10% FCS (fetal calf serum) at 37 °C in a humid atmosphere supplemented with 5% CO2. On day 1 (D1), ectoine 0.2% w / v is obtained by dilution in HO. Experimental groups are incubated in the active state for 24 h prior to irradiation. Day 2 (D2), UV-A (LED light source, peak 365nm, 480J / cm 2 Stress induced by irradiation at 1000 rpm for 40 min is applied to the explants.

[0141] material and method: Skin explants were pretreated with or without ectoine and UV-A irradiation, cryopreserved in OCT (embedding resin (Shandon Cryomatrix; Thermo Scientific, Reference 6769006)), flash-frozen in isopentane / liquid nitrogen, and stored at -80°C. Five-micrometer tissue sections were cut using a cryotome, air-dried at room temperature (RT) for 15 minutes, and fixed in a mixture of 95% ethanol / 5% acetic acid for 5 minutes. The fixed tissue was then saturated with 5% BSA (bovine serum albumin) in PBS (phosphate-buffered saline; 1X, pH 7.4) at RT.

[0142] Primary antibodies (filaggrin 2, polyclonal, Invitrogen™ rabbit polyclonal antibody, Ref: Thermo Scientific PA555951 diluted 1 / 100; LAMP-2A, polyclonal, Invitrogen™ rabbit polyclonal antibody Ref: Invitrogen 512200 diluted 1 / 200; filaggrin, santa cruz biotechnology mouse antibody SC-66192 diluted 1 / 50) were diluted in PBS / 5% BSA and applied onto the tissue for 1 hour at RT, followed by three washes of 5 minutes each with PBS pH 7.4.

[0143] Appropriate secondary antibodies (goat anti-mouse IgG (H+L) cross-adsorbed, Alexa Fluor 488, polyclonal, secondary antibody, Invitrogen™ goat polyclonal secondary antibody Ref: Invitrogen R37120 dilution: 1 / 1000; goat anti-rabbit IgG (H+L) cross-adsorbed, Alexa Fluor 488, polyclonal, secondary antibody, Invitrogen™ goat polyclonal secondary antibody Ref: Invitrogen A11008) diluted in PBS and DAPI (dilution 1:3000) are applied onto the tissue sections for 1 hour at RT, followed by three washes with PBS pH 7.4 for 5 minutes each.

[0144] Fluorescence images were collected using an epifluorescence microscope (DMi8, Leica) and processed with ImageJ software (Schneider, CA, Rasband, WS, Eliceiri, KW "NIH Image to ImageJ: 25 years of image analysis" Nature Methods 9, 671-675, 2012). Image comparison between different conditions was achieved using identical exposures (100ms and 630X).

[0145] result: The results are shown in Figures 2 and 3: Figure 2 shows that filaggrin expression levels were reduced in UV-A irradiated explants compared to non-irradiated explants, however, ectoine ("active") treatment prevented this reduction in filaggrin in UV-A irradiated explants. Figure 3 shows that ectoine ("active") treatment under basal conditions (without UV-A) increases LAMP2A expression, which contributes to the activity of the chaperone-mediated autophagy (CMA) detoxification function in the skin.

[0146] Example 3: O / W day care formulation [Table 3]

[0147] procedure: Disperse Solagum AX in water and stir until homogeneous. Add ectoine and glycerin and stir until homogeneous. Heat phases A and B separately to 80°C. Mix phase B into phase A. Stir until homogenous. Cool while stirring and add preservative (potassium sorbate dissolved in water). Adjust pH to below 6.00 with citric acid.

[0148] Supplier: [Table 4]

[0149] Example 4: W / O night care formulation [Table 5]

[0150] procedure: Heat phases A and B to 75°C. Mix phase A into phase B. Mix until homogenous. Cool while stirring. Gradually add ingredients for phase C.

[0151] Supplier: [Table 6]

[0152] Example 5: O / W formulation baby care lotion [Table 7]

[0153] procedure: Sprinkle Avicel RC-591F into a portion of the water and glycerin (7%) and stir for approximately 20 minutes. Add the pre-mixed xanthan gum and the remaining glycerin (3%) and stir until homogenous. Solubilize the RonaCare® Ectoine while stirring. Then add Montanov™ L and Montanov™ 14. Prepare phase B by heating phases A and B to 75-78°C. Add phase B to phase A and homogenize. Add phase C and stir until homogenous. Allow to cool slowly with gentle stirring. When T<35°C, add phase D and stir until homogenous. Adjust the pH to 6.8-7 with phase E.

[0154] Supplier: [Table 8]

[0155] Example 6: Day Care Gel Formulation [Table 9]

[0156] procedure: Disperse the carbomer in water, then add the rest of Phase A. Adjust the pH to approximately 5.5-6.0 with Phase B. Add the ingredients of Phase C individually and mix until uniform.

[0157] Supplier: [Table 10]

[0158] Example 7: Sun Care Gel Formulation [Table 11]

[0159] procedure: Disperse Avicel PC 591 in water, then add the remaining ingredients of Phase B. Heat Phases A and B to 80°C and disperse Keltrol in the oil phase. Mix Phase A into Phase B. Mix until homogenous. Cool with stirring. Add Phase C and adjust pH if necessary.

[0160] Supplier: [Table 12]

[0161] Example 8: W / O BB formulation with sun protection [Table 13]

[0162] procedure: Heat phase A1 to 70-80°C. Add phase A2 to phase A1 while stirring. Heat phases A and B to 70-80°C. Slowly add phase B to phase A while mixing vigorously. Cool to room temperature.

[0163] Supplier: [Table 14]

[0164] Example 9: Solution / two-phase system - face mist formulation [Table 15]

[0165] procedure: Disperse PC Avicel 611 in water and stir for at least 10 minutes. Add the remaining ingredients of phase B. To better dissolve RonaCare® Pristine Bright™, slight heating is possible. Prepare phase A. Add phase A to phase B while stirring. Homogenize. Adjust the pH to 5.5-6.5. Add the ingredients of phase C separately.

[0166] Supplier: [Table 16]

[0167] Example 10: Solution / Two-Phase System - Suncare Two-Phase Spray [Table 17]

[0168] procedure: Heat phase B to 75°C and stir until a homogeneous phase is reached. Cool to room temperature. Mix Phase A ingredients together and stir until uniform. Adjust pH to 7.2, if necessary. Add C to B, then add B+C to A and mix. Add Phase D.

[0169] Supplier: [Table 18]

[0170] Example 11: W / O soft serve ice cream containing organic / inorganic filters [Table 19-1] [Table 19-2]

[0171] procedure: Dissolve RonaCare® tromethamine in the water of phase B; add Eusolex® 232 and stir until a clear solution is obtained. Then add the remaining ingredients of phase B. Heat phases A1 and B to 65-70°C. Disperse phase A2 in phase A1. Add phase A to phase B while stirring. Homogenize. Add phase C to 50-60°C while stirring. Homogenize. Add phase D at 45°C. Adjust the pH value to 6.8-7.2 with phase E.

[0172] Supplier: [Table 20]

[0173] Example 12: Soft cream O / W lightening formulation [Table 21-1] [Table 21-2]

[0174] procedure: Disperse phase B2 into phase B1 and stir until uniform. Heat phases A and B to 80°C. Slowly add phase A to phase B while stirring. Mix until homogenous. Cool to 40°C and add phases C and D with stirring. If necessary, adjust the pH to 5.0-5.5.

[0175] Supplier: [Table 22]

[0176] Example 13: Soft cream - O / W preparation Tanning preparation [Table 23]

[0177] procedure: Phase B: Disperse Keltrol in water + glycerol. Combine Phase A. Heat Phase A and B separately to 75°C. Add Phase A to Phase B while stirring. Homogenize. Cool while stirring and add Phase C at approximately 35°C. Finally add the ingredients of Phase D.

[0178] Supplier: [Table 24]

[0179] Example 14: Soft ice cream O / W formulation containing insect repellent [Table 25]

[0180] procedure: Heat phase A to 80°C and phase B to 75°C. Add phase A to phase B while stirring. Mix until homogenized. Adjust the pH with phase C (6.0-7.0) and cool while stirring. Finally, add phase D.

[0181] Supplier: [Table 26]

[0182] Example 15: W / Si formulation with sun protection [Table 27]

[0183] procedure: COLD PROCESSING: Mix Phase A at high energy until completely incorporated into Phase B. Slowly add Phase C while stirring until dissolved. Homogenize. Add Phase D while stirring.

[0184] Supplier: [Table 28]

[0185] Example 16: Rinse-off mask [Table 29]

[0186] procedure: Place Yellow Illite Clay and Tapioca Pure in a blender and blend twice for 10 seconds. Add Jojoba Oil and blend twice for 10 seconds. Add RonaCare® Reneaumer and blend twice for 10 seconds. Add Phase C and blend twice for 10 seconds.

[0187] Supplier: [Table 30] [Brief explanation of the drawings]

[0188] [Figure 1] FIG. 1 shows the results of Example 1. [Figure 2] FIG. 2 shows the results of Example 2. [Figure 3] FIG. 3 shows the results of Example 2.

Claims

1. Non-therapeutic use of ectoine and / or hydroxyectoine for preventing and / or reducing keratinization disorders of the skin and / or keratinizing skin appendages in a mammal.

2. 1. Non-therapeutic use of ectoine and / or hydroxyectoine to improve a mammalian skin condition selected from keratosis pilaris and / or impure skin.

3. Non-therapeutic use of ectoine and / or hydroxyectoine as a cosmetic agent to reduce the carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin, LAMP2a and / or filaggrin-2 in the skin and / or keratinized skin appendages in a mammal.

4. Non-therapeutic use of ectoine and / or hydroxyectoine as a cosmetic agent that upregulates one or more proteins selected from the group consisting of filaggrin, hornerin, and LAMP2a in the skin and / or keratinized skin appendages in a mammal.

5. Use according to any one of claims 1 to 4, characterized in that the mammal is a human.

6. 1. Ectoine and / or hydroxyectoine for use in preventing and / or reducing keratinization disorders of the skin and / or keratinizing skin appendages in a mammal.

7. 7. Ectoine and / or hydroxyectoine for use according to claim 6, characterized in that the keratinization disorders are manifested in ichthyosis and / or atopic skin.

8. Ectoine and / or hydroxyectoine for use according to claim 6 or 7, characterized in that they are involved in reducing the carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin, LAMP2a and / or filaggrin-2.

9. Ectoine and / or hydroxyectoine for use according to any one of claims 6 to 8, characterized in that they are involved in the upregulation of one or more proteins selected from the group consisting of filaggrin, hornerin and LAMP2a.

10. A formulation for use in the treatment of keratinization disorders, comprising ectoine and / or hydroxyectoine.

11. 11. The preparation according to claim 10, characterized in that the keratinization disorder is manifested in ichthyosis and / or atopic skin.

12. 12. Formulation according to claim 10 or 11, characterized in that it further comprises a vehicle suitable for topical application and optionally physiologically acceptable adjuvants and / or fillers.

13. Formulation according to any one of claims 10 to 12, characterized in that the ectoine and / or hydroxyectoine are present in the formulation in an amount of 0.01 to 10% by weight of the formulation.

14. A cosmetic formulation comprising ectoine and / or hydroxyectoine as a cosmetic agent for reducing carbonylation of one or more proteins selected from the group consisting of filaggrin, hornerin, LAMP2a and / or filaggrin-2 in the skin and / or keratinized skin appendages in a mammal.

15. A cosmetic formulation comprising ectoine and / or hydroxyectoine as a cosmetic agent that upregulates one or more proteins selected from the group consisting of filaggrin, hornerin, and LAMP2a in the skin and / or keratinized skin appendages in a mammal.

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