Topically applied preparation for improving skin condition

Abstract

The invention relates to a topically applied preparation comprising a combination of substances including antimicrobial peptides (AMP), in particular cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine components, and skin-soothing substances such as menthoxypropanediol, substances to strengthen the skin barrier such as omega-6 fatty acids, and / or flavonoids such as licochalcone, which act synergetically and selectively against pathogenic bacteria, such as S. aureus and C. acnes, however not against skin-commensal bacteria, such as S. epidermidis. The preparations can be used advantageously for the treatment of acne or atopic dermatitis and to care for skin that has been damaged by acne or atopic dermatitis.

Description

[0001] Topically applicable preparation to improve skin condition

[0002] The present invention relates to topically applicable, in particular cosmetic or dermatological preparations, comprising a substance combination of antimicrobial peptides (AMP), in particular cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks, and skin-soothing substances, such as menthol propanediol, skin barrier-strengthening substances, such as omega-6 fatty acids, and / or flavonoids, such as licochalcones.

[0003] The desire to look beautiful and attractive is inherent in human nature. Although the ideal of beauty has changed over time, the pursuit of a flawless appearance has always been a goal for humans, as a pleasing appearance increases self-esteem and attraction to others. The condition and appearance of the skin plays a significant role in achieving a beautiful and attractive appearance.

[0004] In oily and blemished skin, which is the transitional state between healthy, normal skin and pathologically altered acne skin, the skin produces increased amounts of sebum (seborrhea). This serves as an ideal breeding ground for numerous microorganisms, particularly Propionibacterium acnes (P. acnes, Cutibacterium acnes, C. acnes) and Pityrosporum species. The microorganisms decompose the sebum into glycerin and fatty acids, which stimulate the sebaceous glands to produce more sebum and attack and destroy the follicle walls in the skin. This causes inflammation in the skin (pimples, pustules, nodules, cysts), which often heal only with scarring, permanently damaging the visual appearance of those suffering from blemished skin (W. Umbach [ed.], Cosmetics, Development, Production and Application of Cosmetic Products, 2nd ed. Thieme Verlag, Stuttgart, 1995).

[0005] Conventional products for treating oily and / or impure skin as well as acne-prone skin generally have the disadvantage of stressing the skin, drying it out and not providing much care.

[0006] A disadvantage of the known acne preparations is that in order to act against Propionibacterium acnes (P. acnes), the proportion of antimicrobial active ingredients is often so high that the preparations are skin irritating.

[0007] In addition, highly acidic (pH values ​​below 4.0) and highly oxidizing active ingredients (e.g., benzoyl peroxide) are used in the treatment of acne. These strain the skin's protective acid mantle and attack or burn the skin. Therefore, it is an object of the present invention to develop a significantly milder and more nourishing cosmetic and / or dermatological preparation for improving the skin's condition and treating acne than those known from the prior art. Furthermore, these preparations should significantly reduce the concentration of acne-causing bacteria on the skin and in the sebaceous glands.

[0008] A large number of skin diseases, especially those of atopic origin, have not been fully explained. Common to these diseases are inflammatory reactions in the dermis and the dermo-epithelial transition zone.

[0009] Atopic dermatitis (often referred to as eczema) is a chronic inflammatory skin disease with a complex pathogenesis involving genetic susceptibility, immunological and epidermal barrier dysfunction, and environmental factors. Treatment is often achieved by applying moisturizers, avoiding allergens and irritants, and frequently with topical corticosteroids or immunomodulators.

[0010] In addition to the treatment of skin diseases such as atopic dermatitis, skin care is an essential preventative approach. Today, consumers are offered a wide variety of cosmetic preparations for skin care, mostly in the form of creams and lotions, i.e., emulsions. Products that temporarily or permanently delay or eliminate the signs of skin aging, negative environmental influences, and even skin diseases are becoming increasingly important. In addition to water for moisturizing the skin and oils and lipids for replenishing the skin's fat, such skin care products contain a variety of active ingredients, excipients, and additives.

[0011] There are countless studies on active ingredients that can be used to treat skin diseases, eczema, and atopic dermatitis. However, these active ingredients are often associated with side effects, as is the case with corticosteroids, so the benefit of alleviating disease comes with the disadvantage of damaging other areas.

[0012] Improving the condition of human skin, in particular providing a preparation suitable for the treatment of atopic dermatitis and / or acne and caring for skin damaged by atopic dermatitis or acne, is therefore one of the essential tasks.

[0013] Numerous antimicrobial peptides (AMPs) are known. Their effectiveness extends particularly to Gram-negative and Gram-positive bacteria, viruses, and fungi. Unlike some antibiotics, their effect against bacteria is bactericidal, not bacteriostatic. WO 2022106667 A1 describes novel cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks. These cyclic compounds are suitable for use in cosmetic preparations because they exhibit antimicrobial, antiviral, antibacterial, and / or antifungal activity.

[0014] Flavonoids are natural substances and belong to the group of polyphenols. They are formally derived from the basic compound flavan (2-phenylchroman). There are approximately 8,000 compounds found in nature.

[0015] Flavonoids are universally present in plants as secondary plant substances, and thus also in human food. They are believed to have particularly strong antioxidant properties, which is why they are used in cosmetic products, both as plant extracts (e.g., Glycyrrhiza inflata) and as pure substances, such as Licochalcone A.

[0016] EP 1839645 A1, for example, describes Licochalcone A in cosmetic preparations.

[0017] It is desirable to provide a preparation that can be used for skin care as well as for the treatment of inflammatory skin diseases and indications such as acne, rosacea, and / or atopic dermatitis. It is also desirable to provide a preparation that is suitable for wound healing and the care of hypersensitive skin.

[0018] The invention is a topically applicable preparation comprising one or more antimicrobial peptides (AMPs) and one or more substances selected from the group of skin-soothing substances, skin-barrier-strengthening substances, and / or flavonoids. The topically applicable preparation thus comprises a substance combination of one or more antimicrobial peptides and, in addition, one or more substances selected from the group of skin-soothing substances, skin-barrier-strengthening substances, and / or flavonoids. Within the scope of the present invention, skin-soothing substances, skin-barrier-strengthening substances, and / or flavonoids are also referred to as "combination partners," "combination substances," or "combination partner substances."

[0019] Cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks, as described in WO 2022106667 A1, are preferably selected as antimicrobial peptides. According to the invention, the term "peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks" refers in particular to those peptide compounds that contain at least one thiazolidine or oxazolidine building block. It is therefore particularly preferred that the preparation according to the invention contains one or more antimicrobial peptides that are cyclic peptide compounds of the formula (I): where:

[0020] X and Yi to Y5 are each selected from the group consisting of: methyl, ethyl, n-propyl (with the formula CH3-CH2-CH2-), 2-propenyl (with the formula H2C=CH-CH2 _), 1-methylethyl (or isopropyl, with the formula (CHURCH-), n-butyl (with the formula CH3-CH2-CH2-CH2-), 2-methylpropyl (or isobutyl, with the formula (CH3)2CH-CH2 _ ), 1-methylpropyl (or butan-2-yl or sec-butyl, with the formula CH3-CH2-CH(CH3)-), 1,1-dimethylethyl (or tert-butyl with the formula (CH5-CH2-CH2-CH2-), n-pentyl (with the formula CH3-CH2-CH2-CH2-CH2-), 3-methylbutyl (or isopentyl, with the formula (CH3)2CH-CH2-CH2-), benzyl (or benzyl with the formula phenyl-CH2-), propargyl (or ethynylmethyl, with the formula HCHC-CH2-), 1 / 7-1 ndol-3-ylmethyl (with the formula 1 / V-Methyl-1 / 7-indol-3-ylmethyl (with the formula

[0021] Benzothienylmethyl (with the formula -Naphtylmethyl (with the formula -Anthracenylmethyl (with the formula ) and pyrenylmethyl (ie 1-pyrenylmethyl with the formula -Pyrenylmethyl with the etc.);

[0022] - Z is O or S;

[0023] - R and R' are each selected from the group consisting of H, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl (isobutyl), 1-methylpropyl (butan-2-yl or sec-butyl), benzyl and propargyl, with the proviso that when R is H, R' is not H;

[0024] - the C atoms directly linked to the substituents Y1, Y2, Y3, Y4, Y5 and X, in that order, each have an alternating absolute stereochemical configuration; and

[0025] - the C atom linked to the substituent X and the C atom in position 4 of the thiazolidine or oxazolidine ring have the same absolute stereochemical configuration when Z is O and an opposite absolute stereochemical configuration when Z is S; with the proviso that when X, Y1, Y4 and Y5 are 1-methylethyl, Y2 is 1 / 7-indol-3-yl, Y3 is 2-methylpropyl, R is H and R' is methyl, Z is not O; and the salts thereof, the solvates thereof and the solvates of the salts thereof.

[0026] The following explanations regarding the different substituents and parameters apply equally to all aspects and embodiments of the present invention.

[0027] The term "each selected" with respect to the parameters X and Y1 to Y5, as well as R and R', apart from certain exceptions, basically means that these substituents can each represent identical radicals from the corresponding lists above or different radicals from these lists. In the cyclic compound of the formula (I) according to the invention, Z is not O if, in sum, X, Y1, Y4 and Y5 are 1-methylethyl, Y2 is 1-ndol-3-ylmethyl, Y3 is 2-methylpropyl, R is H and R' is methyl. Furthermore, for the substituents R and R', with regard to the present invention, if R is H, R' is not H. The radicals listed with respect to the substituents X, Y1 to Y5, R and R', within the meaning of the present invention, are also known to the person skilled in the art as follows (where at the end of the respective simplified structural formulas, respectively " at the end of the respective structural formulas, indicating where the residue is connected to the compound in question).

[0028] For the purposes of the present invention, the methyl radical has the formula CH3- and is also abbreviated as "Me." The ethyl radical, with the formula CH3-CH2-, is also abbreviated as "Et." The n-propyl radical has the formula CH3-CH2-CH2-. The 2-propenyl radical has the formula H2C=CH-CH2-. The 1-methylethyl radical in the sense of the present invention is also known to the person skilled in the art as isopropyl and has the formula (CHs^CH-). The n-butyl radical has the formula CH3-CH2-CH2-CH2-. The 2-methylpropyl radical in the sense of the present invention is also known to the person skilled in the art as isobutyl and has the formula (CH3)2CH-CH2-. The 1-methylpropyl radical is also known to the person skilled in the art as butan-2-yl or sec-butyl and has the formula CH3-CH2-CH(CH3)-. The 1,1-dimethylethyl radical in the sense of the present invention is also known to the person skilled in the art as tert-butyl and has the formula (CHs^CH-). The n-pentyl radical has the formula CH3-CH2-CH2-CH2-CH2-.The residue 3-methylbutyl is also known to the person skilled in the art as isopentyl and has the formula (CH3)2CH-CH2-CH2-.

[0029] The benzyl (or (1-phenyl)methyl) radical in the sense of the present invention is also abbreviated as "Bn" and has the formula phenyl-CH2-. The propargyl radical is also known to the person skilled in the art as ethynylmethyl or 2-propynyl and has the formula HCHC-CH2-. The 1 / 7-1-ndol-3-ylmethyl radical in the sense of the present invention, also known as indol-3-ylmethyl, has the formula The residue 1 / V-methyl-1 / 7-indol-3-ylmethyl, in the sense of the present

[0030] Invention, the formula The radical 3-benzothienylmethyl, in the sense of the present invention, has the formula The radical 1-naphthylmethyl, in the sense of the present invention, has the formula The residue 9-anthracenylmethyl has the formula on.

[0031] The radical pyrenylmethyl (or pyrenylmethyl), as used herein, stands for a pyrene ring which is connected via one of its outer ring carbon atoms C1 to C10 to a methyl radical, which in turn serves as a linkage for the overall pyrenylmethyl radical, ie 1-pyrenylmethyl, 2-pyrenylmethyl, 3-pyrenylmethyl, 4-pyrenylmethyl, 5-pyrenylmethyl, etc. (or 1-pyrenylmethyl, 2-pyrenylmethyl, 3-pyrenylmethyl, 4-pyrenylmethyl, 5-pyrenylmethyl, etc.). The radical 1-pyrenylmethyl (or (I-pyrenyl)methyl, pyren-

[0032] 1-ylmethyl, or (pyren-l-yl)methyl) for example has the formula on.

[0033] The residue 2-pyrenylmethyl (or (2-pyrenyl)methyl, pyren-2-ylmethyl, or (pyren-2-yl)methyl), for example, has the formula on, etc.

[0034] The cyclic compounds of the invention falling under formula (I) are composed of five amino acid derivatives and one thiazolidine or oxazolidine building block. An "amino acid derivative" within the meaning of the present invention is generally understood to mean the classic 20 natural L- and D-amino acids and their diastereomers, but also modified derivatives thereof with different (R) radicals. The cyclic compound of the invention of formula (I) comprises only amino acid derivatives with (R) radicals that correspond to the radicals defined for the substituents Yi to Ys.

[0035] A thiazolidine or oxazolidine building block within the meaning of the present invention comprises a 1,3-thiazolidine ring or a 1,3-oxazolidine ring, which is bonded in position 2 to a carbon atom (C atom), which in turn is bonded to the substituent X (and also to an amino group). The positions in the thiazolidine or oxazolidine ring are derived from the standard nomenclature known to the person skilled in the art, i.e.: where Z is S or O and the numbers 1-5 define the positions in the ring.

[0036] The 1,3-thiazolidine ring or 1,3-oxazolidine ring of the thiazolidine or oxazolidine building block is linked to a carboxyl group in position 4 in the free state (i.e., not integrated into a peptide derivative), and is linked to the peptide derivative backbone via an amide group (i.e., in the C-terminus of the thiazolidine or oxazolidine building block) in the linear peptide derivative (i.e., in the linear precursor prior to cyclization to the cyclic compound of the invention) or in the cyclic peptide derivative (i.e., in the cyclic compound of the invention); in the linear peptide derivative, of course, only if the thiazolidine or oxazolidine building block is not C-terminal. The 1,3-thiazolidine ring or 1,3-oxazolidine ring is linked to the residues R and R' in position 5.

[0037] In the cyclic compound of formula (I) according to the invention, the C atoms directly bonded to the substituents Y1, Y2, Y3, Y4, Y5, and X, in this order, each exhibit an alternating absolute and relative stereochemical configuration. This means, for example, that in the cyclic compound of formula (I) according to the invention, directly consecutive amino acid derivatives each exhibit an alternating absolute and relative stereochemical configuration of the α-carbon (Ca).

[0038] The terms "(alternating) absolute stereochemical configuration" and "(alternating) relative stereochemical configuration" are known to the person skilled in the art. The term "absolute stereochemical configuration," as used in the context of the present invention, refers to the R / S nomenclature (but not to the relative D / L nomenclature). An "alternating absolute stereochemical configuration" within the meaning of the present invention thus means that if the absolute stereochemical configuration of a carbon atom (C atom) directly bonded to a substituent Y1 to Y5 or X is an R configuration, the C atoms closest to both sides along the chain backbone of the cyclic compound of formula (I) that are also directly bonded to a substituent Y1 to Y5 or X have an S configuration.For example, if in the cyclic compound of formula (I), CYS (i.e., the C atom directly linked to substituent Y3) has an R configuration, CY4 (and also CY2) has an S configuration, CYS an R configuration, Cx an S configuration, etc. In contrast, if CYS has an S configuration, CY4 (and also CY2) has an R configuration, CYS an S configuration, Cx an R configuration, etc. The term "alternating relative stereochemical configuration" within the meaning of the present invention is also to be understood in this sense. The term "relative stereochemical configuration," as used in the context of the present invention, refers to the D,L nomenclature for amino acids and their derivatives.An "alternating stereochemical relative configuration" within the meaning of the present invention thus means that if the relative stereochemical configuration of a C atom directly bonded to a substituent Y1 to Y5 or X is an L configuration, the C atoms closest to either side of the chain backbone of the cyclic compound (I) that are also directly bonded to a substituent Y1 to Y5 or X have a D configuration. For example, if in the cyclic compound of formula (I), CY4 (i.e., the C atom directly bonded to substituent Y4) has an L configuration, CYS (and also CYS) has a D configuration, Cx has an L configuration, CYI has a D configuration, etc. In contrast, if CY4 has a D configuration, CYS (and also CYS) has an L configuration, Cx has a D configuration, CYI has an L configuration, etc.

[0039] Likewise, the terms "opposite absolute stereochemical configuration" and "same absolute stereochemical configuration" and "opposite relative stereochemical configuration" and "same relative stereochemical configuration" are to be understood in this sense. That is, an "opposite absolute stereochemical configuration" within the meaning of the present invention means that when one absolute stereochemical configuration is an R configuration, the opposite absolute stereochemical configuration is an S configuration. And a "same absolute stereochemical configuration" within the meaning of the present invention means that when one absolute configuration is an R configuration, the same absolute configuration is also an R configuration.This applies analogously to the relative stereochemical configuration, so that an "opposite relative stereochemical configuration" in the sense of the present invention means that if one relative stereochemical configuration is a D-configuration, the opposite relative stereochemical configuration is an L-configuration, etc.

[0040] For the cyclic peptide compound of formula (I), only the alternating stereochemical configuration is specified (as well as the corresponding opposite or identical absolute stereochemical configuration for the thiazolidine or oxazolidine building block, as described below); however, a concrete assignment of the absolute or relative stereochemical configuration of individual C atoms in the cyclic peptide compound of formula (I) according to the invention is not specified. In particular, the cyclic peptide compound of formula (I) can therefore exist in stereoisomeric forms (enantiomers, diastereomers), for example, depending on its specific structure. The invention therefore also encompasses the enantiomers or diastereomers and corresponding mixtures thereof. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.If the compound of the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

[0041] In the thiazolidine or oxazolidine building block of the cyclic compound of formula (I) according to the invention, the C atom which is directly connected to the substituent X is also connected via a direct bond to a thiazolidine or oxazolidine ring in position 2.

[0042] In the cyclic compound of formula (I) according to the invention, the C atom directly bonded to the substituent X and the C atom in position 4 of the thiazolidine or oxazolidine ring have the same absolute stereochemical configuration when Z is O (i.e., if it is an oxazolidine ring), and an opposite absolute stereochemical configuration when Z is S (i.e., if it is a thiazolidine ring). The terms "opposite absolute stereochemical configuration" and "same absolute stereochemical configuration" are to be understood as defined above. This means, for example, if a cyclic peptide compound (I) has an oxazolidine ring and this ring has an R configuration in position 4, the C atom directly bonded to the substituent X also has an R configuration.if a cyclic peptide compound (I) has a thiazolidine ring and this has an R configuration in position 4, the C atom which is directly connected to the substituent X has an S configuration.

[0043] Preferred salts for the purposes of the present invention are physiologically (especially cosmetically) acceptable salts of the compound of formula (I) according to the invention. However, they also include salts that are not themselves suitable for cosmetic applications but can be used, for example, for isolating or purifying the compound of formula (I) according to the invention.

[0044] Examples of cosmetically acceptable salts of the cyclic compound of formula (I) include salts of inorganic bases such as ammonium salts, alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, in particular magnesium or calcium salts; salts of organic bases, in particular salts derived from cyclohexylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, ethylenediamine, procaine, morpholine, pyrroline, piperidine, N-ethylpiperidine, N-methylmorpholine, piperazine as organic base; or salts with basic amino acids, in particular lysine, arginine, ornithine and histidine.

[0045] Examples of cosmetically acceptable salts of the compound of formula (I) also include salts of inorganic acids such as hydrochlorides, hydrobromides, sulfates, phosphates or phosphonates; salts of organic acids, in particular acetates, formates, propionates, lactates, citrates, fumarates, maleates, benzoates, tartrates, malates, methanesulfonates, ethanesulfonates, toluenesulfonates or benzenesulfonates; or salts with acidic amino acids, in particular aspartate or glutamate.

[0046] Solvates, within the meaning of the invention, refer to those forms of the compound of formula (I) according to the invention that form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water. The compound of formula (I) according to the invention can also be complexed, e.g., with iron, calcium, etc., in which case the compound of formula (I) can act as a ligand, so that corresponding complexes are also subject of the present invention.

[0047] In a preferred embodiment of the cyclic compound of formula (I) according to the invention, the substituent X is selected from the group consisting of ethyl, n-propyl, 2-propenyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, benzyl, propargyl, 1N-methyl-1 / 7-indol-3-ylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl, 9-anthracenylmethyl and pyrenylmethyl (where pyrenylmethyl is preferably selected as 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl). In a further preferred embodiment, X is selected from the group consisting of n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, benzyl, propargyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl).In yet another preferred embodiment, X is selected from the group consisting of 1-methylethyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, benzyl, propargyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl). In an alternatively preferred embodiment, X is selected from the group consisting of n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl, and 3-methylbutyl.In a preferred embodiment of the present invention, the substituents Y1 to Y5 are each selected from the group consisting of methyl, ethyl, n-propyl, 2-propenyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, benzyl, propargyl, 1 / 7-indol-3-ylmethyl, 1 / V-methyl-1 / 7-indol-3-ylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl, 9-anthracenylmethyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl). In a further preferred embodiment of the present invention, Y1 to Y5 are each selected from the group consisting of methyl, 1-methylethyl, 2-methylpropyl, 1-methylpropyl, benzyl, 1 / 7-indol-3-yl-methyl, propargyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl).

[0048] For example, preferred radicals for Y2 are 1 / 7-1ndol-3-ylmethyl, 1 / V-methyl-1 / 7-indol-3-ylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl, 9-anthracenylmethyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), more preferably 1 / 7-1ndol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), in which case Y5 is preferably not an aromatic radical (in particular not 1 / 7-1ndol-3-ylmethyl or pyrenylmethyl). For example, preferred radicals for Y3 are n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, and 1,1-dimethylethyl, particularly preferred is 2-methylpropyl. For example, preferred radicals for Y4 are methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, and 1,1-dimethylethyl, particularly preferred is 1-methylethyl.For example, preferred radicals for Y5 are 1 / 7-1ndol-3-ylmethyl, 1 / V-methyl-1 / 7-indol-3-ylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl, 9-anthracenylmethyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), more preferably 1 / 7-1ndol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), for example particularly preferably 1 / 7-indol-3-ylmethyl, in which case Y2 is preferably not an aromatic radical (in particular not 1 / 7-1ndol-3-ylmethyl or pyrenylmethyl).

[0049] In a further preferred embodiment of the present invention, Y2 is 1 / 7-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl) if Y5 ​​is 1-methylethyl, or Y2 is 1-methylethyl if Y5 ​​is 1 / 7-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl). In yet another preferred embodiment of the present invention, Y2 is 1 / 7-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), and Y5 is 1-methylethyl, or Y2 is 1-methylethyl, and Y5 is 1 / 7-1 indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl).

[0050] In a particularly preferred embodiment of the cyclic compound of formula (I) according to the invention, Z is S. In an alternative preferred embodiment of the cyclic compound of formula (I) according to the invention, Z is O.

[0051] In a preferred embodiment of the cyclic compound of formula (I) according to the invention, R and R' are each selected from the group consisting of H, methyl, ethyl, n-propyl, 1-methylethyl, benzyl and propargyl. In a further preferred embodiment of the cyclic compound of formula (I) according to the invention, R and R' are each selected from the group consisting of H, methyl, ethyl and propargyl. In a further preferred embodiment of the cyclic compound of formula (I), R and R' are both methyl. In a further preferred embodiment of the cyclic compound of formula (I), R is H; and R' is methyl, ethyl, n-propyl, 1-methylethyl, benzyl or propargyl.

[0052] In a specific preferred embodiment of the cyclic compound of the formula (I) according to the invention, X is selected from the group consisting of 1-methylethyl, 2-methylpropyl, 1-methylpropyl, benzyl, propargyl, pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl); Yi to Ys are each selected from the group consisting of methyl, ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 1-methylpropyl, benzyl, 1 / 7-indol-3-yl-methyl, propargyl, pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl); Z is O or S; and / or R and R' are each selected from the group consisting of H, methyl, ethyl, and propargyl, with the proviso that when R is H, R' is not H.

[0053] The cyclic compound of formula (I), wherein either substituent Y2 or substituent Y5, but preferably not in positions Y2 and Y5 simultaneously, is pyrenylmethyl, exhibits high non-selective antimicrobial, in particular non-selective antibacterial, activity compared to a cyclic compound of formula (I) wherein substituent Y2 or substituent Y5 is 1 / 7-indol-3-ylmethyl. In a preferred embodiment of the cyclic compound of formula (I), substituent Y2 or substituent Y5 is pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl).In a further preferred embodiment of the cyclic compound of formula (I), either the substituent Y2 or the substituent Y5 is pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), and preferably no other substituent X and Y1 to Y5 is a pyrenylmethyl.

[0054] In a further preferred embodiment of the cyclic peptide compound of formula (I), R and R' are both methyl; Y2 is 1-methylethyl or pyrenylmethyl if Y5 ​​is 1-methylethyl, or Y2 is 1-methylethyl if Y5 ​​is 1-methylethyl or pyrenylmethyl; and X is 1-methylethyl. In a further preferred embodiment of the cyclic compound of formula (I), R and R' are both methyl; Y2 is 1-methylethyl or pyrenylmethyl, and Y5 is 1-methylethyl, or Y2 is 1-methylethyl and Y5 is 1-methylethyl or pyrenylmethyl; X is 1-methylethyl; and Z is preferably S. The pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl.

[0055] In a further preferred embodiment of the cyclic compound of formula (I), R is H; R' is methyl, ethyl, n-propyl, 1-methylethyl, benzyl or propargyl; Y2 is 1-methylethyl if Y5 ​​is 1-methylethyl, or Y2 is 1-methylethyl if Y5 ​​is 1-methylethyl or pyrenylmethyl; X is 1-methylethyl; and Z is preferably S. In yet another preferred embodiment of the cyclic compound of formula (I), R is H; R' is methyl, ethyl, n-propyl, 1-methylethyl, benzyl or propargyl; Y2 is 1-methylethyl and Y5 is 1-methylethyl, or Y2 is 1-methylethyl and Y5 is 1-methylethyl or pyrenylmethyl; X is 1-methylethyl; and Z is preferably S. The pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, in particular 1-pyrenylmethyl.

[0056] In yet another preferred embodiment of the cyclic compound of formula (I), R is H; R' is methyl, n-propyl, 1-methylethyl, benzyl or propargyl; Y2 is 1-methylethyl or pyrenylmethyl if Y5 ​​is 1-methylethyl, or Y2 is 1-methylethyl if Y5 ​​is 1-methylethyl or pyrenylmethyl; X is 1-methylethyl or 2-methylpropyl. In yet another preferred embodiment of the cyclic compound of formula (I), R is H; R' is methyl, n-propyl, 1-methylethyl, benzyl or propargyl; Y2 is 1-methylethyl and Y5 is 1-methylethyl, or Y2 is 1-methylethyl and Y5 is 1-methylethyl or pyrenylmethyl; X is 1-methylethyl or 2-methylpropyl. The pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl.In yet another preferred embodiment of the cyclic compound of formula (I), R and R' are both 1-methylethyl; and Y2 is 1 / 7-indol-3-ylmethyl. In yet another preferred embodiment of the cyclic compound of formula (I), R and R' are each H or methyl; Y2 is 1 / 7-indol-3-yl; and X is 1-methylethyl.

[0057] In an alternatively preferred embodiment, if Y5 ​​is pyrenylmethyl, the C atom which is directly bonded to the substituent Y5 in the cyclic compound (I) according to the invention is in an (absolute) S configuration (ie L configuration).

[0058] In specific preferred embodiments, the cyclic compound of formula (I) is characterized by one of the following formulas 1.1a to 1.24a:

[0059]

[0060]

[0061] In further specific preferred embodiments, the cyclic compound of the

[0062] Formula (I) characterized by one of the following formulas 1.1 to I.25:

[0063]

[0064] Particularly preferred are the cyclic compounds of formulas 1.1a to 1.4a and 1.1 to 1.4, respectively, as well as the cyclic compounds of formulas 1.19a to 1.24a and 1.19 to 1.25. In yet further specific preferred embodiments, an oxazolidine ring is present in formulas 1.14a to 1.18a and 1.14 to 1.18 instead of a thiazolidine ring.

[0065] According to the invention, the antimicrobial peptide having the structure

[0066] cyclo[N-DVal-LT rp-DLeu-LVal-DT rp-LMe2Thz(i_Val)-C], which in particular has the formula C48H67N9O6S.

[0067] This preferably selected peptide is designated ISW1-2 according to the invention. It surprisingly exhibits beneficial antibacterial effects.

[0068] ISW1-2 is a fully synthetic peptide composed of D- and L-amino acids that cyclize via a thiazolidine ring. It is a derivative of the natural product lugdunin, which is produced by the skin-commensal bacterium Staphylococcus lugdunensis, which occurs naturally in the human nose, among other places.

[0069] Of particular note is the mode of action of this peptide. The antibacterial effect strongly correlates with the disruption of the membrane potential of the bacteria. No specific target is addressed, as the enantiomer of the peptide possesses the same antimicrobial efficacy, thus precluding a stereospecific interaction with a target molecule. The mechanism of action is based on proton translocation, while maintaining membrane integrity.

[0070] It is known that the peptide supports the innate immune response of the skin, in synergy with the factors derived from the host and microbiome, so that pathogens are combated at different levels and recolonization, for example with S. aureus, can be counteracted.

[0071] In combination with one or more substances selected from the group of skin-soothing substances, the group of skin-barrier-strengthening substances, and / or the group of flavonoids, the antimicrobial peptides, especially ISW1-2, exhibit a synergistic antimicrobial effect. Flavonoids are advantageously chosen as combination partners for the AMPs.

[0072] Licochalcone A, Licochalcone C, Licochalcone E and / or Glabrol, in particular Licochalcone A, are advantageously chosen as flavonoids.

[0073] Instead of the flavonoids directly, extracts, solutions, mixtures containing these flavonoids can also be used, such as the plant extract Glycyrrhiza inflata.

[0074] Licochalcone A has the structure:

[0075] Other preferred flavonoids include Licochalcone C and Glabrol.

[0076] The topical preparation according to the invention thus preferably contains flavonoids, flavonoid-containing extracts, flavonoid-containing solutions and / or flavonoid-containing mixtures, wherein the flavonoids are in particular licochalcones, and preferably licochalcone A, licochalcone C, licochalcone E and / or glabrol.

[0077] In a particularly preferred embodiment, the preparation contains the peptide with the structure cyclo[N-DVal-LTrp-DLeu-LVal-DTrp-LMe2Thz(LVal)-C], ie the peptide ISW1-2, and one or more licochalcones from the group Licochalcone A, Licochalcone C, Licochalcone E and / or Glabrol.

[0078] In a preferred embodiment of the invention, the preparation contains the peptide ISW1-2 and licochalcone A. In a further preferred embodiment of the invention, the preparation contains the peptide ISW1-2 and licochalcone C. In a further preferred embodiment of the invention, the preparation contains the peptide ISW1-2 and licochalcone E. In a further preferred embodiment of the invention, the preparation contains the peptide ISW1-2 and glabrol.

[0079] ISW1-2 exhibits antimicrobial activity against Gram-positive bacteria even at very low concentrations in vitro (3.1 g / ml against Staphylococcus aureus). Surprisingly, skin pathogens such as Staphylococcus aureus, whose increase correlates with the severity of atopy and is also demonstrably associated with Cutibacterium acnes in acne, were particularly sensitive to this active ingredient.

[0080] ISW1-2 exhibits antimicrobial activity even in the micromolar range. The minimum inhibitory concentration (MIC) of ISW1-2 for Staphylococcus aureus is 3.1 g / ml (0.00031%).

[0081] Preferably, proportions of one or more AMPs, in particular ISW1-2, are selected in the range from 0.00001 wt.% to 1.0 wt.%, preferably 0.0001 wt.% to 0.5 wt.%, in particular 0.0003 wt.% to 0.3 wt.%, based on the total mass of the preparation, advantageously in cosmetic formulations. These small proportions nevertheless demonstrate high efficacy, especially because an unexpected boost occurs due to the at least one combination partner.

[0082] Surprisingly, synergistic effects were observed with the combination partner substances that strengthen the skin barrier (e.g. omega-6 fatty acids) and / or soothe the skin (e.g. licochalcone A, menthoxypropanediol) and also with flavonoids.

[0083] A further advantage is that by reducing the effective amounts, the costs of manufacturing and introducing these active ingredients can also be reduced. Furthermore, the resulting cost reduction allows for a broader range of cosmetic applications.

[0084] The combination partners, selected from skin-soothing substances, skin-barrier-strengthening substances and / or flavonoids, are advantageously used in a proportion in the range of 0.0001 wt% to 5 wt%, based on the total mass of the preparation, whereby the information in wt% refers in particular to the sum of the combination partners in the total mass of the preparation.

[0085] It is advantageous, particularly for emulsions, to select 0.0001 to 5 wt.%, especially 0.001 to 1 wt.%, and very particularly 0.005 to 0.15 wt.% of these combined substances, based in each case on the total weight of the preparation, especially licochalcones, preferably licochalcone A or extracts containing licochalcones. The data in wt.% refer in particular to the sum of the combined substances in the total weight of the preparation.

[0086] In a particularly preferred embodiment, the preparation according to the invention comprises one or more AMPs in an amount of 0.00001 wt.% to 1.0 wt.%, preferably 0.0001 wt.% to 0.5 wt.%, in particular 0.0003 wt.% to 0.3 wt.%, based on the total mass of the preparation, and one or more flavonoids selected from the group consisting of licochalcone A, licochalcone C, licochalcone E and glabrol in an amount of 0.0001 to 5 wt.%, in particular 0.001 to 1 wt.%, very particularly 0.005 to 0.15 wt.%, based on the total mass of the preparation.

[0087] In a further particularly preferred embodiment, the preparation according to the invention comprises an AMP in an amount of 0.00001 wt.% to 1.0 wt.%, preferably 0.0001 wt.% to 0.5 wt.%, in particular 0.0003 wt.% to 0.3 wt.%, based on the total mass of the preparation, and a flavonoid selected from the group consisting of licochalcone A, licochalcone C, licochalcone E and glabrol in an amount of 0.0001 to 5 wt.%, in particular 0.001 to 1 wt.%, very particularly 0.005 to 0.15 wt.%, based on the total mass of the preparation. In a further particularly preferred embodiment, the preparation according to the invention comprises the peptide ISW1-2 in an amount of 0.00001 wt.% to 1.0 wt.%, preferably 0.0001 wt.% to 0.5 wt.%, in particular 0.0003 wt.% to 0.3 wt.%, based on the total mass of the preparation, and Licochalcone A in an amount of 0.0001 to 5 wt.%, in particular 0.001 to 1 wt.%, very particularly 0.005 to 0.15 wt.-%, based on the total mass of the preparation.

[0088] In a further particularly preferred embodiment, the preparation according to the invention comprises the peptide ISW1-2 in an amount of 0.00001 wt.% to 1.0 wt.%, preferably 0.0001 wt.% to 0.5 wt.%, in particular 0.0003 wt.% to 0.3 wt.%, based on the total mass of the preparation, and Licochalcone C in an amount of 0.0001 to 5 wt.%, in particular 0.001 to 1 wt.%, very particularly 0.005 to 0.15 wt.%, based on the total mass of the preparation.

[0089] In a further particularly preferred embodiment, the preparation according to the invention comprises the peptide ISW1-2 in an amount of 0.00001 wt.% to 1.0 wt.%, preferably 0.0001 wt.% to 0.5 wt.%, in particular 0.0003 wt.% to 0.3 wt.%, based on the total mass of the preparation, and Licochalcone E in an amount of 0.0001 to 5 wt.%, in particular 0.001 to 1 wt.%, very particularly 0.005 to 0.15 wt.%, based on the total mass of the preparation.

[0090] In a further particularly preferred embodiment, the preparation according to the invention comprises the peptide ISW1-2 in an amount of 0.00001 wt.% to 1.0 wt.%, preferably 0.0001 wt.% to 0.5 wt.%, in particular 0.0003 wt.% to 0.3 wt.%, based on the total mass of the preparation, and Glabrol in an amount of 0.0001 to 5 wt.%, in particular 0.001 to 1 wt.%, very particularly 0.005 to 0.15 wt.%, based on the total mass of the preparation.

[0091] The inventive preparations exhibit synergistic effects, ensuring antimicrobial efficacy against atopic dermatitis and / or acne-associated skin germs (Staphylococcus aureus, Cutibacterium acnes) even at low concentrations of antimicrobial peptides, particularly ISW1-2. Surprisingly, this synergistic effect occurs with the pathogenic germs S. aureus and C. acnes, but not with the skin-commensal germ S. epidermidis.

[0092] This selective effect is surprising and offers a huge advantage over conventional treatment methods, which often compromise the entire skin microbiome.

[0093] Dysbiosis with increased bacterial load of S. aureus and a reduction in commensal skin bacteria correlates with a deterioration of the skin condition in atopic patients. With the inventive combination, particularly ISW1-2 and flavonoids, advantageously licochalcone A, an antimicrobial combination was found that minimizes excessive S. aureus colonization, is non-cytotoxic to skin cells (keratinocytes), and is resistant to proteolytic degradation of the skin's own enzymes.

[0094] Skin soothing means reducing or completely avoiding skin irritation, itching, tightness and / or redness.

[0095] Strengthening the skin barrier means building up a protective skin film, promoting skin cohesion and / or minimizing or preventing harmful external influences.

[0096] The barrier is the outermost layer of the skin that provides protection, retains moisture, and protects against external irritants such as bacteria, allergens, and environmental influences.

[0097] According to the invention, substances that have these properties are skin-soothing or skin barrier-strengthening substances.

[0098] As skin-soothing combination substances that can be combined with the AMPs according to the invention, one or more substances are preferably selected from the group comprising

[0099] • Menthoxypropanediol

[0100] • Polidocanol

[0101] • Allantoin

[0102] • Vitamins, especially vitamins A, B5, E

[0103] • Hyaluronic acid or its salts

[0104] • Plant extracts such as calendula, witch hazel, oats

[0105] • Jojoba oil

[0106] As combination substances that strengthen the skin barrier and that can be combined with the AMPs according to the invention, preferably selected from the group

[0107] • Omega-6 fatty acids

[0108] • Ceramide

[0109] • Shea butter

[0110] • Argan oil

[0111] According to the invention, preparations are advantageously provided which, in addition to antimicrobial peptides, in particular ISW1-2, comprise licochalcones, in particular licochalcones A, C and / or E, glabrol, or extracts, solutions, or mixtures containing them. It is advantageous if one or more substances from the group of skin-soothing substances and / or substances that strengthen the skin barrier are also additionally included. If an active ingredient belongs to both the skin-soothing substance group and the group of substances that strengthen the skin barrier, then in an embodiment intended to comprise substances from both groups, two or more different substances from both groups are also included.

[0112] According to the invention, the growth of disruptive bacteria (C. acnes, S. aureus) is significantly inhibited and at the same time beneficial bacteria (S. epidermides), which stabilize the skin microbiome, are left unaffected.

[0113] This enables a selective strengthening of the healthy skin microbiome.

[0114] In a preferred embodiment, the topically applicable preparation according to the invention is a cosmetic and / or dermatological preparation, preferably based on an emulsion.

[0115] Given the advantageous properties, various possible uses arise for the topically applicable preparations according to the invention. Therefore, the non-therapeutic use of the preparation according to the invention for the treatment of inflammatory skin diseases and / or indications, in particular acne, rosacea, and / or atopic dermatitis, is particularly advantageous.

[0116] Likewise, the preparation according to the invention can advantageously be used for skin care, in particular for the care, prophylaxis and treatment of skin damaged by atopic dermatitis or acne.

[0117] The preparation according to the invention can also be used advantageously in the treatment of atopic dermatitis, acne and / or allergic contact dermatitis.

[0118] The preparation according to the invention can also be used advantageously in wound healing and for the care of hypersensitive skin.

[0119] The invention therefore also relates to a non-therapeutic, in particular cosmetic, method for skin treatment, in which the topically applicable preparation according to the invention is applied to the skin.

[0120] In this procedure, the non-therapeutic skin treatment is primarily for skin care, to support skin wound healing, and / or to treat skin damaged by atopic dermatitis or acne. This non-therapeutic skin treatment is particularly suitable for the care of hypersensitive skin.

[0121] The preparations according to the invention and the substance combinations contained therein can also be used in medical applications. Therefore, in a further aspect, the invention relates to a substance combination comprising one or more antimicrobial peptides and one or more substances selected from the group of skin-soothing substances, skin barrier-strengthening substances, and / or flavonoids for use in the treatment of inflammatory skin diseases and / or indications, in particular acne, rosacea, and / or atopic dermatitis.

[0122] The suitable and preferred embodiments described in connection with the definition of the topically applicable preparation according to the invention are also correspondingly preferred or suitable in this aspect of the invention.

[0123] Cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks are preferably selected as peptides in the substance combination.

[0124] In a particularly preferred embodiment, the peptide having the structure cyclo[N-DVal-LTrp-Dl_eu-LVal-DTrp- LMe2Thz(LVal)-C] chosen.

[0125] In a further preferred embodiment, the topical preparation according to the invention contains flavonoids, flavonoid-containing extracts, flavonoid-containing solutions and / or flavonoid-containing mixtures, wherein the flavonoids are in particular licochalcones, particularly preferably licochalcone A, licochalcone C, licochalcone E and / or glabrol.

[0126] It is also preferred that the substance combination according to the invention is used in a cosmetic and / or dermatological preparation.

[0127] Although the individual substances of the combination according to the invention are known to the cosmetics expert, it has not yet been known or succeeded in using the combination effectively, particularly at low concentrations.

[0128] A topically applicable preparation can now be provided that leads, in particular, to a reduction in the pathogenic bacteria S. aureus and C. acnes, while simultaneously balancing the skin commensal bacteria S. epidermidis. This leads to an improvement in the skin condition, especially in cases of acne or atopic dermatitis-damaged skin.

[0129] The unpleasant bacteria, such as Propionibacterium acnes, are reduced on the skin and the pleasant bacteria, such as Staphylococcus epidermidis, remain untouched.

[0130] According to the invention, "selective" means a reduction in anaerobic bacteria and a slight (preferably no) reduction in aerobic bacteria. According to the invention, the combination is advantageously used in cosmetic or dermatological preparations.

[0131] The preparations according to the invention can be used in a variety of application forms. Preferred application forms are gels, sprays, serums, impregnation media for impregnated patches, wipes, or masks.

[0132] The sophisticated cosmetic compositions according to the invention may optionally comprise further customary auxiliaries and additives, such as, for example, consistency regulators, fillers, perfume, dyes, active ingredients, vitamins, proteins, light stabilizers, stabilizers, insect repellents, salts, EDTA, further antimicrobial, proteolytic or keratolytic active substances, etc., unless they are excluded by the invention.

[0133] According to the invention, one or more active ingredients from the following groups are preferably added to the preparations in order to ensure the widest possible range of applications and individual care and treatments.

[0134] Advantageously, further active ingredients can be added to the preparations or application forms according to the invention, provided they are not mentioned in the substance groups according to the invention, such as preferably sebum-reducing active ingredients, itching-relieving active ingredients, anti-inflammatory, healing-stimulating, pain-relieving or antimicrobial active ingredients, such as dexpanthenol, or natural additives, natural substances, such as honey, chamomile or aloe vera.

[0135] In addition to vitamins such as vitamin A, C or E, other possible additional active ingredients include growth factors such as PDGF, sugars or polysaccharides such as glucose, minerals such as zinc, amino acids and their derivatives such as arginine or creatine.

[0136] Also preferred according to the invention is the addition of cell membrane-addressing active ingredients, such as quats, octenidines or decanediol.

[0137] In particular, natural substances such as cyclic and non-cyclic peptides of ribosomal and non-ribosomal (NRPS-derived) origin, as well as cyclic and non-cyclic polyketides (PKS-derived) are advantageously added according to the invention. Other preferred active ingredients are enzymes, especially cell wall hydrolytic enzymes such as endolysins, lysozyme, and chitinases, provided they are compatible with the peptide and do not attack it.

[0138] The addition of one or more active ingredients selected from the group of hydroxyacetophenones, salicylic acid, Q10 and / or thiamidol is particularly preferred.

[0139] Further preferred additives can be selected from Ca, Mg, Al, and / or Zn salts.

[0140] Other preferred active ingredients can be selected from Magnolia, Arctiin, Bioxilift, Creatine, Isoflavones, Laminaria, NAHP, Phloridzin, Vitamin C, Lotus Extract, Myriceline, White Tea, AGR, Glycyrrhetinic Acid, Silymarin S, Tocopheryl, Carnitine, Garcinia Cambogia, Guarana C22, Butyloctanoic Acid, Dioic, Ethylhexylglycerin, Methyl Phenylbutanol, Polyglyceryl-2 Caprate, Polysaf 5600 Polymer, Silver Citrate, Zinc Citrate, Betaine, Sea Salt, Taurine, SymSave H, DHA, Rucinol, Panthenol / Dexpanthenol.

[0141] Examples

[0142] The antimicrobial and skin-care effects of the inventive combinations and the individual substances were investigated in various tests. a) In vitro studies

[0143] In in vitro studies, the effect of the preparations according to the invention on the growth of C. acnes, S. aureus and S. epidermidis was investigated.

[0144] C. acnes DSM 1897 was incubated under anaerobic conditions at 37°C. The overnight culture was diluted 1:1000 in Caso Medium (casein peptone 17g / l; soybean meal peptone 3g / l;

[0145] Sodium chloride 5g / L; glucose 2.5g / L; dipotassium hydrogen phosphate 2.5g / L; pH 7.3 ± 0.2) and seeded into microtiter plates. Different concentrations of the plant extract Glycyrrhiza inflata and Licochalcone A (1g / ml, 2pg / ml) were added, mixed, and incubated anaerobically at 37°C for 5 days. These experiments were repeated in the presence of a non-inhibitory ISW1-2 concentration (0.00001% ISW1-2). To estimate bacterial growth, the optical density (OD) was measured photometrically at a wavelength of 600nm (GD600). Increasing values ​​indicate bacterial growth.

[0146] Unless otherwise stated, the quantities refer to the weight of the substance per volume of medium, e.g., 1 pg / ml means 1 pg of Licochalcone A in 1 ml of medium. The percentage amounts of ISW1-2 refer to the weight of ISW1-2 in relation to the total weight of the respective test mixture. C. acnesl 897 was incubated without ISW1-2 (Fig. 1 hatched) and with a non-inhibitory concentration of 0.00001% ISW1-2 (Fig. 1 black), with various concentrations of Licochalcone A extract (0 pg / ml = control; 1 pg / ml; 2 pg / ml) added. Bacterial growth or inhibition is measured by the increase / decrease in turbidity in the medium (OD600).

[0147] Glycyrrhiza inflata extract, which contains 21 wt.% Licochalcone A, was used as Licochalcone A extract.

[0148] The results are shown in Figure 1.

[0149] By adding 1 pg / ml Licochalcone A extract to 0.00001% ISW1-2 in the medium, no growth inhibition of C. acnes is observed (Fig. 1 middle bars).

[0150] The addition of 2pg / ml Licochalcone A extract to 0.00001% ISW1-2 in the medium results in a significant growth inhibition of C. acnes.

[0151] In the same way, studies were carried out with the addition of Licochalcone A (0 pg / ml = control; 1 pg / ml; 2 pg / ml).

[0152] These results are shown in Figure 2.

[0153] By adding 1 pg / ml Licochalcone A to 0.00001% ISW1-2 in the medium, no growth inhibition of C. acnes is observed (Fig. 2 middle bars).

[0154] The addition of 2pg / ml Licochalcone A to 0.00001% ISW1-2 in the medium results in a significant growth inhibition of C. acnes (Fig. 2 right bars, black).

[0155] Surprisingly, a non-inhibitory amount of an antimicrobial peptide (ISW1-2) is capable of exerting an inhibitory effect on C. acnes when added to licochalcone A (Figures 1 and 2, right bars, black). In contrast, the pure extract or pure licochalcone A exhibits only a weaker inhibitory effect (Figures 1 and 2, left bars, hatched).

[0156] Further studies investigated the inhibition of S. aureus.

[0157] S. aureus DSM20231 and S. epidermidis ATTC 12228 were incubated under aerobic conditions at 37°C with constant shaking. The overnight cultures were diluted 1:10,000 in MHB (Müller Hinton Broth: starch 1.5 g / L; meat infusion 2.0 g / L; hydrolyzed casein peptone 17.5 g / L; pH: 7.4 ± 0.2) and seeded into microtiter plates. Different concentrations of the plant extract Glycyrrhiza inflata and the flavonoids licochalcones A, C, and E (1 g / ml, 2 pg / ml) were added, mixed, and bacterial growth was observed at 37°C for 24 h. These experiments were repeated in the presence of a non-inhibitory ISW1-2 concentration (0.00002% ISW1-2). To estimate bacterial growth, the optical density (OD) at a wavelength of 600 nm (OD600) was measured photometrically. Increasing values ​​indicate bacterial growth (average of three independent experiments).

[0158] Staphylococcus aureus DSM20231 was incubated without ISW1-2 (Figures 3, 5, 7, 9) and with a non-inhibitory concentration of 0.00002% ISW1-2 (Figures 4, 6, 8, 10), spiked with various concentrations of licochalcone extract; licochalcone A; licochalcone C; and licochalcone E (opg / ml = control; 1 pg / ml; 2 pg / ml). Figures 3 to 10 show bacterial growth over 24 hours under the different conditions (mean values ​​from three independent experiments).

[0159] Bacterial growth is measured by the increase in turbidity in the medium (OD600), i.e. an increase in OD over time signals bacterial growth.

[0160] The results are presented in Figures 3 to 10. They demonstrate that licochalcone extracts and licochalcones act synergistically with ISW1-2. No growth of S. aureus was observed when the substance combinations according to the invention were added.

[0161] Figure 3 shows the bacterial growth upon addition of Licochalcone A extract (0%, control) and a relatively slight growth delay upon addition of 1 pg or 2 pg.

[0162] Figure 4 shows the bacterial growth when pure non-inhibitory ISW1-2 (0.00002%, control) was added and the growth when Licochalcone A extract was added to ISW1-2 (1 pg / ml, 2 pg / ml).

[0163] The overall view of Figures 3 and 4 clearly shows that only the substance combinations according to the invention lead to a significant inhibition of bacterial growth.

[0164] Similarly, the studies with ISW1-2 and Licochalcone A (Figures 5 and 6) show that only the inventive combination of antimicrobial peptide and flavonoids (Licochalcone A) leads to a significant inhibition of bacterial growth.

[0165] Figures 7 and 8 show the studies with ISW1-2 and Licochalcone C. Four different amounts of Licochalcone C were used (0%, control; 1 pg / ml; 2 pg / ml and 4 pg / ml), alone (Figure 7) and with 0.00002% ISW1-2 (Figure 8).

[0166] Here, too, it is evident that only the substance combinations according to the invention (Figure 8) lead to a significant inhibition of bacterial growth

[0167] Although Licochalcone C is somewhat less synergistic with ISW1-2 than Licochalcone A, the synergism is present and sufficient to influence bacterial growth (Figure 8). Advantageously and according to the invention, the concentration of the cooperating partner, in this case Licochalcone C, can be increased (e.g., to 4 pg / ml) to completely inhibit S. aureus growth.

[0168] Figures 9 and 10 show the studies with ISW1-2 and Licochalcone E. Three different amounts of Licochalcone E were used (0%, control; 1 pg / ml; 2 pg / ml), alone (Figure 9) and with 0.00002% ISW1-2 (Figure 10).

[0169] Licochalcone E, in turn, has a better synergistic effect with ISW1-2, similar to Licochalcone A, and no growth of S. aureus was observed in the substance combination according to the invention (Figure 10).

[0170] In further comparative studies, the influence of the substance combination according to the invention on skin commensal germs, such as S. epidermidis, was also determined (Figures 11 to 18).

[0171] For this purpose, Staphylococcus epidermidisl 2228 was incubated without ISW1-2 (Figures 11, 13, 15, 17) and with a non-inhibitory concentration of 0.00002% ISW1-2 (Figures 12, 14, 16, 18) using different concentrations of Licochalcone Extract;

[0172] Licochalcone A; Licochalcone C; and Licochalcone E (Opg / rnl = control; 1 pg / ml; 2 pg / ml). Bacterial growth over 24 hours under the different conditions is shown (average values ​​from three independent experiments).

[0173] Bacterial growth is measured by the increase in turbidity in the medium (OD600), i.e. an increase in OD over time signals bacterial growth.

[0174] None of the licochalcone extracts and licochalcones A, C, and E, as well as their combination with ISW1-2, showed any effect on the bacterial growth of skin commensal bacteria. No effect on the growth of S. epidermidis was observed with the inventive combination (Figures 11 to 18). b) In vivo studies

[0175] The efficacy of the topically applicable preparation according to the invention was also tested in vivo.

[0176] For this purpose, three different preparations were produced as cosmetic formulations. The first preparation was a control preparation containing only the vehicle. The second preparation (+ISW1-2) contained the vehicle and 0.015% ISW1-2. The third preparation (+ISW1-2 +LicoExtr.) contained the vehicle, 0.015% ISW1-2, and an additional 0.025% LicoExtract (Glycyrrhiza inflata extract with 21% w / w Licochalcone A). The three preparations were tested on six volunteers with healthy skin. For each volunteer, three areas (5 cm x 5 cm) were marked on the upper back, and a sample was taken from each area using a stained swab (FloqSwab®) to determine the bacterial colonization of the skin prior to application of the three preparations. The three preparations were then applied to all volunteers, with 75 μl (3 μl / cm 2) of a preparation was applied to one of the three marked areas. The applications were carried out twice daily over the 48-hour test period, i.e., a total of five times. After 48 hours, samples were taken again with stained swabs.

[0177] To determine the number of microbes, the samples taken before application (0 h) and after application (48 h) were plated, incubated aerobically and the colonies were counted.

[0178] The results are shown in Figure 19. When using the control preparation (vehicle), no change in the bacterial count on the skin was observed. Using the preparation +ISW1-2, the bacterial count was approximately halved. A significantly greater reduction in the bacterial count, which suggests a synergistic effect of ISW1-2 and LicoExtract, was observed when using the third preparation. c) Examples of cosmetic preparations

[0179] Examples of cosmetic preparations according to the invention are listed in the table below. The figures refer to weight fractions based on the total mass of the preparation.

Claims

A topically applicable preparation comprising a substance combination of one or more antimicrobial peptides and one or more substances selected from the group of skin-soothing substances, skin-barrier-strengthening substances, and / or flavonoids. Preparation according to claim 1, characterized in that cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks are selected as peptides. Preparation according to claim 1 or 2, characterized in that a cyclic peptide compound of formula (I) is present as peptide: where: - X and Yi to Ys are each selected from the group consisting of: methyl, ethyl, n-propyl, 2-propenyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1- Dimethylethyl, n-Pentyl, 3-Methylbutyl, Benzyl, Propargyl (HCHC-CH2-), 1 / 7-Indol-3-ylmethyl Methyl-1 / 7-indol-3-ylmethyl Benzothieny -Naphtylmethyl -Anthracenylmethyl ( Z is O or S; - R and R' are each selected from the group consisting of H, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, benzyl and propargyl, with the proviso that when R is H, R' is not H; - the C atoms directly linked to the substituents Y1, Y2, Y3, Y4, Y5 and X, in that order, each have an alternating absolute stereochemical configuration; and - the C atom connected to the substituent X and the C atom in position 4 of the thiazolidine or oxazolidine ring have the same absolute stereochemical configuration when Z is O, and an opposite absolute stereochemical configuration when Z is S; with the proviso that when X, Y1, Y4, and Y5 are 1-methylethyl, Y2 is 1-ndol-3-yl, Y3 is 2-methylpropyl, R is H, and R' is methyl, Z is not O; and the salts thereof, the solvates thereof, and the solvates of the salts thereof. Preparation according to any one of the preceding claims, characterized in that in the cyclic peptide compound of formula (I) - R and R' are both methyl; Y2 is 1-methylethyl if Y5 ​​is 1-indol-3-ylmethyl or pyrenylmethyl, or Y2 is 1-methylethyl if Y5 ​​is 1-indol-3-ylmethyl or pyrenylmethyl; and X is 1-methylethyl; - R is H; R' is methyl, ethyl, n-propyl, 1-methylethyl, benzyl or propargyl; Y2 is 1-methylethyl or pyrenylmethyl if Y5 ​​is 1-methylethyl, or Y2 is 1-methylethyl if Y5 ​​is 1-methylethyl or pyrenylmethyl; and X is 1-methylethyl; - R is H; R' is methyl, n-propyl, 1-methylethyl, benzyl or propargyl; Y2 is 1-methylethyl or pyrenylmethyl if Y5 ​​is 1-methylethyl, or Y2 is 1-methylethyl if Y5 ​​is 1-methylethyl or pyrenylmethyl; and X is 1-methylethyl or 2-methylpropyl; or R and R' are both 1-methylethyl; and Y2 is 1-ndol-3-ylmethyl. Preparation according to one of the preceding claims, characterized in that the cyclic peptide compound has one of the following formulas 1.1a to 1.24a:

6. Preparation according to one of the preceding claims, characterized in that the peptide has the structure cyclo[n-DVal-LTrp-DLeu-LVal-DTrp-LMe2Thz(i_Val)-C] is selected. Preparation according to one of the preceding claims, characterized in that licochalcones, in particular licochalcone A, licochalcone C, glabrol and / or licochalcone E, and / or extracts containing licochalcones, are selected as flavonoids. Preparation according to one of the preceding claims, characterized in that the peptide of the structure cyclo[N-DVal-LTrp-DLeu-LVal-DTrp-LMe2Thz(LVal)-C] and one or more licochalcones from the group Licochalcone A, Licochalcone C, Glabrol and / or Licochalcone E are contained.O Preparation according to one of the preceding claims, characterized in that the proportion of one or more antimicrobial peptides is selected in the range from 0.00001% by weight to 1.0% by weight, preferably 0.0001% by weight to 0.5% by weight, in particular 0.0003% by weight to 0.3% by weight, based on the total mass of the preparation.Preparation according to one of the preceding claims, characterized in that one or more substances are selected from the group comprising menthoxypropanediol, polidocanol, allantoin, vitamins, in particular vitamins A, B5, E, hyaluronic acid or salts thereof, plant extracts, such as calendula, witch hazel, oats, and / or jojoba oil as skin-soothing substances. Preparation according to one of the preceding claims, characterized in that one or more substances from the group consisting of omega-6 fatty acids, ceramides, shea butter, and / or argan oil are selected as substances that strengthen the skin barrier. Preparation according to one of the preceding claims, characterized in that the proportion of one or more skin-soothing substances, skin-barrier-strengthening substances, and / or flavonoids is in the range from 0.0001% by weight to 5% by weight, in particular. 0.001 to 1 wt.%, very particularly 0.005 to 0.15 wt.%, based on the total mass of the preparation. Preparation according to one of the preceding claims, characterized in that the preparation is a cosmetic and / or dermatological preparation, preferably based on an emulsion. Non-therapeutic use of a preparation according to one of claims 1 to 13 for skin care, in particular for the care of skin damaged by atopic dermatitis or acne. Substance combination of one or more antimicrobial peptides and one or more substances selected from the group of skin-soothing substances, skin barrier-strengthening substances and / or flavonoids for use in the treatment of inflammatory skin diseases and / or indications, in particular acne, rosacea and / or atopic dermatitis.A substance combination for use according to claim 15, characterized in that cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks are selected as peptides. A substance combination for use according to claim 15 or 16, characterized in that the peptide has the structure cyclo[N-DVal-LTrp-Dl_eu-LVal-DTrp-LMe2Thz(LVal)-C]. is selected. A substance combination for use according to any one of claims 15 to 17, characterized in that licochalcones, in particular licochalcone A, licochalcone C, glabrol and / or licochalcone E and / or extracts containing licochalcones, are selected as flavonoids.

19. A combination of substances for use according to any one of claims 15 to 18, characterized in that the combination is used in a cosmetic and / or dermatological preparation.

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