Topically applicable preparations for improving skin conditions

Abstract

Topically applicable preparations containing antimicrobial peptides (AMPs), particularly cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine components, in combination with skin-soothing substances such as menthoxypropanediol, substances strengthening the skin barrier such as omega-6 fatty acids, and / or flavonoids such as licochalcone, act synergistically and selectively against pathogenic bacteria such as Staphylococcus aureus and C. acnes, but not against resident skin bacteria such as S. epidermidis. These preparations can be advantageously used to treat acne or atopic dermatitis and to care for skin damaged by acne or atopy.

Description

[Technical Field]

[0001] The present invention relates to topically applicable, in particular cosmetic or dermatological, preparations comprising a substance combination of antimicrobial peptides (AMPs), in particular cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks, with skin-soothing substances such as menthoxypropanediol, substances that strengthen the skin barrier, such as omega-6 fatty acids, and / or flavonoids, such as licochalcone.

[0002] Humans have an innate desire to appear beautiful and attractive. Although aesthetic ideals have changed over time, the pursuit of a flawless and perfect appearance has always been a human goal, as a pleasing appearance enhances one's self-esteem and increases one's attractiveness to others. In this regard, the condition and appearance of the skin play an important role in a beautiful and attractive appearance.

[0003] In greasy, oily, and dirty skin, which is referred to as the transitional state between healthy, normal skin and diseased, acne-prone skin, the skin produces increased amounts of sebum (seborrhea), which serves as an ideal breeding ground for numerous microorganisms, particularly Propionibacterium acnes (P. acnes, Cutibacterium acnes, C. acnes) and Pityrosporum species. The microorganisms break down sebum into glycerin and fatty acids, thereby stimulating the sebaceous glands to increase production and attacking and destroying the hair follicle walls in the skin. This leads to inflammations in the skin (pimples, pustules, nodules, cysts) which often only heal with scarring, thereby permanently impairing the visual appearance of the person suffering from the unclean skin (W. Umbach [Hrsg.], Cosmetik, Entwicklung, Herstellung und Anwendung kosmetischer Mittel, 2.Aufl. Thieme Verlag, Stuttgart, 1995).

[0004] Conventional products for treating oily and / or dirty skin, as well as acneic skin, generally have the drawback of being harsh, drying and of having insufficient care action.

[0005] A drawback of known acne preparations is that they often contain a very high proportion of antibacterial active substances to act against Propionibacterium acnes (P. acnes), which makes the preparations irritating to the skin.

[0006] Furthermore, acne treatments use highly acidic (pH values ​​below 4.0) and highly oxidizing active substances (e.g., benzoyl peroxide), which can overwork the skin's protective acid mantle and attack or corrode the skin.

[0007] The object of the present invention is therefore to develop cosmetic and / or dermatological preparations for improving skin condition and treating acne that are significantly less irritating and have a better care effect than those known in the prior art. Furthermore, these preparations should significantly reduce the concentration of bacteria on the skin and in the sebaceous glands that cause acne.

[0008] The causes of many skin diseases, especially atopic skin diseases, are not fully understood. What these diseases have in common is an inflammatory reaction in the dermis and the dermal-epidermal transition zone.

[0009] Atopic dermatitis (often referred to as eczema) is a chronic inflammatory skin disease with a complex etiology that involves genetic susceptibility, immunological and epidermal barrier disorders, and environmental factors. Treatment is often achieved by applying moisturizing creams, avoiding allergens and irritants, and often with topical corticosteroids or immunomodulators.

[0010] In addition to treating skin diseases such as atopic dermatitis, skin care is also an important preventive approach.With regard to skin care, today, many cosmetic preparations are provided to consumers in the form of cream and lotion, that is, emulsion.Here, the products that temporarily or permanently delay or eliminate skin aging, adverse environmental influences and skin diseases become increasingly important.Such skin care products contain many active substances, auxiliary substances and additional ingredients, in addition to moisture for skin moisturization and oil and lipid for skin fat supply.

[0011] There has been a great deal of research into active substances that can be used against skin diseases, eczema, and atopic dermatitis. However, these active substances, like corticoids, often have side effects, so that the benefit of alleviating the disease comes at the expense of damage to other areas.

[0012] Therefore, improving the condition of human skin, in particular providing suitable preparations for the treatment of atopic dermatitis and / or acne, as well as caring for skin damaged by atopic dermatitis or acne, is one of the important challenges.

[0013] Numerous antimicrobial peptides (AMPs) are known. Their effects extend in particular to gram-negative and gram-positive bacteria, viruses, and fungi. In contrast to some antibiotics, their effect on bacteria is bactericidal, not bacteriostatic.

[0014] WO 2022106667 describes new cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks, which are suitable for use in cosmetic preparations due to their antibacterial, antiviral, antibacterial and / or antifungal effects.

[0015] Flavonoids are natural substances that belong to the group of polyphenols. They are formally derived from the basic structure flavan (2-phenylchroman). There are approximately 8,000 different compounds found in nature.

[0016] Flavonoids are widely present in plants as secondary plant substances and therefore in human foods. They are said to have particular antioxidant properties and are therefore used in cosmetics both as plant extracts (e.g., Glycyrrhiza inflata) and as pure substances, e.g., licochalcone A.

[0017] For example, EP 1 839 645 describes licochalcone A in cosmetic preparations.

[0018] It would be desirable to provide preparations that can be used for skin care and for the treatment of inflammatory skin diseases and conditions such as acne, rosacea and / or atopic dermatitis, as well as preparations that are suitable for wound healing and the care of sensitive skin.

[0019] The present invention relates to a topically applicable preparation comprising one or more antimicrobial peptides (AMPs) and one or more substances selected from the group of skin soothing substances, substances that strengthen the skin barrier, and / or flavonoids. Thus, the topically applicable preparation comprises a substance combination of one or more antimicrobial peptides and one or more substances further selected from the group of skin soothing substances, substances that strengthen the skin barrier, and / or flavonoids. Within the scope of the present invention, the skin soothing substances, substances that strengthen the skin barrier, and / or flavonoids are also referred to as "combination partners," "combination substances," or "combination partner substances."

[0020] Preferably, the antimicrobial peptide is selected to be a cyclic peptide compound based on the synthesis of thiazolidine and oxazolidine building blocks, as described in WO 2022106667. According to the present invention, the term "peptide compound based on the synthesis of thiazolidine and oxazolidine building blocks" refers in particular to a peptide compound containing at least one thiazolidine or oxazolidine building block.

[0021] Thus, the preparation according to the invention comprises a compound of formula (I): [ka] [In the formula, X and Y1 to Y5 are methyl, ethyl, n-propyl (having the formula CH3-CH2-CH2-), 2-propenyl (having the formula H2C=CH-CH2-), 1-methylethyl (or isopropyl, having the formula (CH3)2CH-), n-butyl (having the formula CH3-CH2-CH2-CH2-), 2-methylpropyl (or isobutyl, having the formula (CH3)2CH-CH2), 1-methylpropyl (or butan-2-yl or sec-butyl, having the formula CH3-C H2-CH(CH3)-), 1,1-dimethylethyl (or tert-butyl, having the formula (CH3)3CH-), n-pentyl (having the formula CH3-CH2-CH2-CH2-CH2-CH2-), 3-methylbutyl (or isopentyl, having the formula (CH3)2CH-CH2-CH2-), benzyl (or Bn, having the formula phenyl-CH2-), propargyl (or ethynylmethyl, having the formula HC≡C-CH2-), 1H-indol-3-ylmethyl (having the formula [ka] 1N-methyl-1H-indol-3-ylmethyl (having the formula [ka] 3-benzothienylmethyl (having the formula [ka] 1-naphthylmethyl (having the formula [ka] 9-anthracenylmethyl (having the formula [ka] ), and pyrenylmethyl (i.e., having the formula [ka] 1-pyrenylmethyl having [ka] 2-pyrenylmethyl having and each is selected from the group consisting of - 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 (isobutyl), 1-methylpropyl (butan-2-yl or sec-butyl), benzyl, and propargyl, with the proviso that when R is H, R' is not H; the C atoms directly bonded to the substituents Y1, Y2, Y3, Y4, Y5 and X have, in this order, alternate absolute stereochemical configurations, the C atom bonded to the substituent X and the C atom at position 4 of the thiazolidine or oxazolidine ring have the same absolute stereochemical configuration when Z is O and the opposite absolute stereochemical configuration when Z is S, provided that when X, Y1, Y4, and Y5 are 1-methylethyl, Y2 is 1H-indol-3-yl, Y3 is 2-methylpropyl, R is H, and R' is methyl, then Z is not O. a cyclic peptide compound of the formula and salts thereof, solvates thereof, and solvates of salts thereof.

[0022] The following explanations of different substituents and parameters apply equally to all aspects and embodiments of the present invention.

[0023] The term "respectively selected" with respect to the parameters X and Y1 to Y5 as well as R and R' basically means that, with certain exceptions, these substituents can each represent the same residue from the corresponding previous list or each represent different residues from these lists. In the cyclic compounds according to the invention of formula (I), if X, Y1, Y4, and Y5 are collectively 1-methylethyl, Y2 is 1H-indol-3-ylmethyl, Y3 is 2-methylpropyl, R is H, and R' is methyl, then Z is not O. Furthermore, for the substituents R and R' in the context of the present invention, it can be said that if R is H, then R' is not H.

[0024] The residues listed for the substituents X, Y1 to Y5, R and R' in the sense of the present invention are also known to those skilled in the art as follows ("-" at the end of the respective simplified structural formula or "-" at the end of the respective structural formula): [ka] indicates where the residue is attached to the compound in question).

[0025] In the sense of the present invention, the residue methyl has the formula CH3- and is also abbreviated as "Me". Here, the residue ethyl has the formula CH3-CH2- and is also abbreviated as "Et". The residue n-propyl has the formula CH3-CH2-CH2-. The residue 2-propenyl has the formula H2C=CH-CH2-. The residue 1-methylethyl in the sense of the present invention is also known to those skilled in the art as isopropyl and has the formula (CH3)2CH-. The residue n-butyl has the formula CH3-CH2-CH2-CH2-. The residue 2-methylpropyl in the sense of the present invention is also known to those skilled in the art as isobutyl and has the formula (CH3)2CH-CH2-. The residue 1-methylpropyl is also known to those skilled in the art as butan-2-yl or sec-butyl and has the formula CH3-CH2-CH(CH3)-. The residue 1,1-dimethylethyl in the sense of the present invention is also known to those skilled in the art as tert-butyl and has the formula (CH3)3CH-. The residue n-pentyl has the formula CH3-CH2-CH2-CH2-CH2-. The residue 3-methylbutyl, also known to those skilled in the art as isopentyl, has the formula (CH3)2CH-CH2-CH2-.

[0026] The residue benzyl (or (1-phenylmethyl) in the sense of the present invention, also abbreviated as "Bn", has the formula phenyl-CH2-. The residue propargyl is also known to those skilled in the art as ethynylmethyl or 2-propynyl and has the formula HC≡C-CH2-. The residue 1H-indol-3-ylmethyl in the sense of the present invention, also known as indol-3-ylmethyl, has the formula [ka] The residue 1N-methyl-1H-indol-3-ylmethyl in the sense of the present invention has the formula [ka] The residue 3-benzothienylmethyl in the sense of the present invention has the formula [ka] The residue 1-naphthylmethyl in the sense of the present invention has the formula [ka] The residue 9-anthracenylmethyl has the formula [ka] It has.

[0027] The residue pyrenylmethyl (or pyrenylmethyl) as used herein refers to a pyrene ring bonded to a methyl residue via one of the outer ring carbon atoms (C1-C10) of the pyrene ring, and this methyl residue also serves as the attachment point for the entire pyrenylmethyl residue, i.e., 1-pyrenylmethyl, 2-pyrenylmethyl, 3-pyrenylmethyl, 4-pyrenylmethyl, 5-pyrenylmethyl, etc. (or 1-pyren-ylmethyl, 2-pyren-ylmethyl, 3-pyren-ylmethyl, 4-pyren-ylmethyl, 5-pyren-ylmethyl, etc.). The residue 1-pyrenylmethyl (or (1-pyrenyl)methyl, pyren-1-ylmethyl, or (pyren-1-yl)methyl can be, for example, a pyrene ring of the formula [ka] The residue 2-pyrenylmethyl (or (2-pyrenyl)methyl, pyren-2-ylmethyl, or (pyren-2-yl)methyl) has, for example, the formula [ka] etc.

[0028] The cyclic compounds according to the invention according to formula (I) are composed of five amino acid derivatives and one thiazolidine or oxazolidine component. "Amino acid derivatives" in the sense of the invention are understood to essentially mean the 20 classical naturally occurring L- and D-α-amino acids and their diastereomers, as well as their modified derivatives with different residues (R). Here, the cyclic compounds according to the invention according to formula (I) include only amino acid derivatives with residues (R) corresponding to those defined for the substituents Y1 to Y5.

[0029] A thiazolidine or oxazolidine moiety in the sense of the present invention comprises a 1,3-thiazolidine or 1,3-oxazolidine ring which is bonded in position 2 to a carbon atom (C atom) which is also bonded to the substituent X (and also to the amino group). The positions within the thiazolidine or oxazolidine ring are taken from the standard nomenclature as known to the skilled person, i.e. [ka] wherein Z is S or O, and the numbers 1-5 define positions within the ring. is.

[0030] The 1,3-thiazolidine or 1,3-oxazolidine ring of the thiazolidine or oxazolidine component is attached at position 4 to a carboxyl group in a free state (i.e., not incorporated into a peptide derivative) and is attached to the peptide derivative backbone via an amide group (i.e., at the C-terminus of the thiazolidine or oxazolidine component) in linear peptide derivatives (i.e., in linear precursors before cyclization to cyclic compounds according to the invention) or in cyclic peptide derivatives (i.e., in cyclic compounds according to the invention), provided, of course, that the thiazolidine or oxazolidine component is not C-terminal. The 1,3-thiazolidine or 1,3-oxazolidine ring is attached at position 5 to residues R and R'.

[0031] In the cyclic compounds of the invention of formula (I), the C atoms directly bonded to the substituents Y, Y, Y, Y, Y, Y, and X have, in this order, alternate absolute and likewise relative stereochemical configurations. This means, for example, that in the cyclic compounds of the invention of formula (I), directly successive amino acid derivatives each have alternate absolute and likewise relative stereochemical configurations of the α-carbon (Cα).

[0032] The terms "(alternating) absolute stereochemical configuration" and "(alternating) relative stereochemical configuration" are known to those skilled in the art. The term "absolute stereochemical configuration" in the context of the present invention relates to the R / S nomenclature (not to the relative D / L nomenclature). Therefore, "alternating absolute stereochemical configuration" in the sense of the present invention means that if the absolute stereochemical configuration of the carbon atom (C atom) directly bonded to the substituents Y1 to Y5 or X is the R configuration, then the C atoms that are closest on both sides along the chain backbone of the cyclic compound of formula (I) and that are also directly bonded to the substituents Y1 to Y5 or X have the S configuration. For example, in the cyclic compound of formula (I), C Y3 (i.e., the C atom directly bonded to the substituent Y3) has the R configuration, Y4 (and similarly C Y2 ) has the S configuration, and C Y5 has the R configuration, and C X has S configuration, and there are others. Y3 If has S configuration, then C Y4 (and similarly C Y2 ) has the R configuration, and C Y5 has S configuration, and C X has the R configuration, etc.

[0033] The term "alternating relative stereochemical configuration" in the sense of the present invention should also be understood in this sense. The term "relative stereochemical configuration" as used in the context of the present invention relates to the D,L nomenclature of amino acids and their derivatives. Therefore, "alternating relative stereochemical configuration" in the sense of the present invention means that when the relative stereochemical configuration of the C atom directly bonded to the substituents Y1 to Y5 or X is L-configuration, the C atom closest on both sides along the chain backbone of the cyclic compound (I) and also directly bonded to the substituents Y1 to Y5 or X has the D-configuration. For example, in the cyclic compound of formula (I), C Y4 (i.e., the C atom directly bonded to the substituent Y4) has an L configuration, Y5 (and similarly C Y3 ) has the D configuration, and C X has the L configuration, and C Y1 has the D configuration, and there are others. Y4 If has D configuration, then C Y5 (and similarly C Y3 ) has the L configuration, and C X has the D configuration, and C Y1 has an L configuration, among others.

[0034] Similarly, the terms "opposite absolute stereochemical configuration" and "same absolute stereochemical configuration", as well as "opposite relative stereochemical configuration" or "same relative stereochemical configuration" should also be understood in this sense. That is, "opposite absolute stereochemical configuration" in the sense of the present invention means that when one absolute stereochemical configuration is the R configuration, the opposite absolute stereochemical configuration is the S configuration. Also, "same absolute stereochemical configuration" in the sense of the present invention means that when one absolute configuration is the R configuration, the same absolute configuration is also the R configuration. This also applies to relative stereochemical configurations, and therefore "opposite relative stereochemical configuration" in the sense of the present invention means that when one relative stereochemical configuration is the D configuration, the opposite relative stereochemical configuration is the L configuration, etc.

[0035] Here, for the cyclic peptide compounds of formula (I), only the alternate stereochemical configurations (and the corresponding opposite or same absolute stereochemical configurations for the thiazolidine or oxazolidine components as described below) are specified; in contrast, the specific assignment of the absolute or relative stereochemical configurations of individual C atoms in the cyclic peptide compounds according to the invention of formula (I) is not specified.

[0036] That is, in particular, the cyclic peptide compound of formula (I) can exist in stereoisomeric forms (enantiomers, diastereomers), for example, depending on its specific structure.Therefore, the present invention also includes enantiomers or diastereomers and their corresponding mixtures.Single components of stereoisomers can be isolated from such mixtures of enantiomers and / or diastereomers by known methods.When the compounds of the present invention can occur in tautomeric forms, the present invention includes all tautomeric forms.

[0037] In the thiazolidine or oxazolidine component of the cyclic compounds according to the invention of formula (I), the C atom directly bonded to the substituent X is also bonded to the thiazolidine or oxazolidine ring in the 2-position via a direct bond.

[0038] In the cyclic compound of formula (I) according to the present invention, when Z is O (i.e., when it is an oxazolidine ring), the C atom directly bonded to the substituent X and the C atom at the 4th position of the thiazolidine ring or oxazolidine ring have the same absolute stereochemical configuration, and when Z is S (i.e., when it is a thiazolidine ring), they have the opposite absolute stereochemical configuration. Here, the terms "opposite absolute stereochemical configuration" and "same absolute stereochemical configuration" should be understood as defined above. This means, for example, that when the cyclic peptide compound (I) has an oxazolidine ring and has R configuration at the 4th position, the C atom directly bonded to the substituent X also has R configuration, or when the cyclic peptide compound (I) has a thiazolidine ring and has R configuration at the 4th position, the C atom directly bonded to the substituent X has S configuration.

[0039] Preferred salts for the purposes of the present invention are physiologically (especially cosmetically) acceptable salts of the compounds according to the invention of formula (I). However, salts which are not themselves suitable for cosmetic applications but which can be used, for example, to isolate or purify the compounds according to the invention of formula (I) are also included.

[0040] Examples of cosmetically acceptable salts of the cyclic compounds 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 bases; or salts with basic amino acids, in particular lysine, arginine, ornithine and histidine.

[0041] Examples of cosmetically acceptable salts of the compounds of formula (I) 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 aspartates or glutamates.

[0042] Solvates in the sense of the present invention refer to the form of the compound of formula (I) according to the present invention, which forms a complex in solid or liquid state by coordination with solvent molecules.Hydrate is a special form of solvate, in which coordination with water occurs.The compound of formula (I) according to the present invention can be complexed with, for example, iron, calcium, etc., and the compound of formula (I) can act as a ligand, and therefore the corresponding complexes are also subject of the present invention.

[0043] 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-1H-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, 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 another further 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.

[0044] 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, 1H-indol-3-ylmethyl, 1N-methyl-1H-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, 1H-indol-3-ylmethyl, propargyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl).

[0045] For example, preferred groups for Y2 are 1H-indol-3-ylmethyl, 1N-methyl-1H-indol-3-ylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl, 9-anthracenylmethyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), more preferably 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), and Y5 is preferably not an aromatic residue (especially not 1H-indol-3-ylmethyl or pyrenylmethyl).For example, preferred residues for Y3 are n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, and 1,1-dimethylethyl, and 2-methylpropyl is particularly preferred. For example, preferred groups for Y4 are methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, and 1,1-dimethylethyl, with 1-methylethyl being particularly preferred. For example, preferred groups for Y5 are 1H-indol-3-ylmethyl, 1N-methyl-1H-indol-3-ylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl, 9-anthracenylmethyl, and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), more preferably 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl), for example, particularly preferably 1H-indol-3-ylmethyl, and Y2 is preferably not an aromatic residue (particularly not 1H-indol-3-ylmethyl or pyrenylmethyl).

[0046] In a further preferred embodiment of the invention, Y2 is 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl) when Y5 is 1-methylethyl, or Y2 is 1-methylethyl when Y5 is 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl). In another further preferred embodiment of the invention, Y2 is 1H-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 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl).

[0047] In a particularly preferred embodiment of the cyclic compounds according to the invention of formula (I), Z is S. In an alternative preferred embodiment of the cyclic compounds according to the invention of formula (I), Z is O.

[0048] In a preferred embodiment of the cyclic compound according to the present invention of formula (I), 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 according to the present invention of formula (I), 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 according to formula (I), R and R' are both methyl. In a further preferred embodiment of the cyclic compound according to formula (I), R is H and R' is methyl, ethyl, n-propyl, 1-methylethyl, benzyl, or propargyl.

[0049] In certain preferred embodiments of the cyclic compounds according to the invention of formula (I), 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), Y1 to Y5 are each selected from the group consisting of methyl, ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 1-methylpropyl, benzyl, 1H-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 if R is H, then R' is not H.

[0050] Cyclic compounds of formula (I) in which either the substituent Y2 or the substituent Y5 is pyrenylmethyl, preferably not simultaneously at positions Y2 and Y5, have enhanced non-selective antibacterial activity, particularly non-selective antibacterial activity, compared to cyclic compounds of formula (I) in which the substituent Y2 or the substituent Y5 is 1H-indol-3-ylmethyl. In a preferred embodiment of the cyclic compound of formula (I), the substituent Y2 or the 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 the other substituents X and Y1 to Y5 are not pyrenylmethyl.

[0051] In a further preferred embodiment of the cyclic peptide compound of formula (I), R and R' are both methyl, Y2 is 1H-indol-3-ylmethyl or pyrenylmethyl when Y5 is 1-methylethyl, or Y2 is 1-methylethyl when Y5 is 1H-indol-3-ylmethyl 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 1H-indol-3-ylmethyl or pyrenylmethyl, and Y5 is 1-methylethyl, or Y2 is 1-methylethyl and Y5 is 1H-indol-3-ylmethyl or pyrenylmethyl, X is 1-methylethyl, and Z is preferably S. Here, pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl.

[0052] 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 1H-indol-3-ylmethyl or pyrenylmethyl when Y5 is 1-methylethyl, or Y2 is 1-methylethyl when Y5 is 1H-indol-3-ylmethyl or pyrenylmethyl, X is 1-methylethyl, and Z is preferably S. In another 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 1H-indol-3-ylmethyl or pyrenylmethyl, Y5 is 1-methylethyl, or Y2 is 1-methylethyl and Y5 is 1H-indol-3-ylmethyl or pyrenylmethyl, X is 1-methylethyl, and Z is preferably S. Here, pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, in particular 1-pyrenylmethyl.

[0053] In another further preferred embodiment of the cyclic compound of formula (I), R is H, R' is methyl, n-propyl, 1-methylethyl, benzyl, or propargyl, Y2 is 1H-indol-3-ylmethyl or pyrenylmethyl when Y5 is 1-methylethyl, or Y2 is 1-methylethyl when Y5 is 1H-indol-3-ylmethyl or pyrenylmethyl, and X is 1-methylethyl or 2-methylpropyl. In another further preferred embodiment of the cyclic compound of formula (I), R is H, R' is methyl, n-propyl, 1-methylethyl, benzyl, or propargyl, Y2 is 1H-indol-3-ylmethyl or pyrenylmethyl, Y5 is 1-methylethyl, or Y2 is 1-methylethyl, Y5 is 1H-indol-3-ylmethyl or pyrenylmethyl, and X is 1-methylethyl or 2-methylpropyl. Here, pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, particularly preferably 1-pyrenylmethyl.

[0054] In another further preferred embodiment of the cyclic compound of formula (I), R and R' are both 1-methylethyl and Y2 is 1H-indol-3-ylmethyl. In another further preferred embodiment of the cyclic compound of formula (I), R and R' are each H or methyl, Y2 is 1H-indol-3-yl, and X is 1-methylethyl.

[0055] In an alternatively preferred embodiment, in the cyclic compound (I) according to the present invention, when Y5 is pyrenylmethyl, the C atom directly bonded to the substituent Y5 is in the (absolute) S-configuration (i.e., L-configuration).

[0056] In certain preferred embodiments, the cyclic compounds of formula (I) have the following formulae I.1a to I.24a: [ka] [ka] [ka] The present invention is characterized by any one of the following:

[0057] In further particularly preferred embodiments, the cyclic compounds of formula (I) have the following formulae I.1 to I.25: [ka] [ka] [ka] The present invention is characterized by any one of the following:

[0058] Particularly preferred are the cyclic compounds of formulae I.1a to I.4a and I.1 to I.4, respectively, and I.19a to I.24a and I.19 to I.25, respectively. In another further particularly preferred embodiment, an oxazolidine ring is present instead of the thiazolidine ring in formulae I.14a to I.18a and I.14 to I.18, respectively.

[0059] According to the invention, particular preference is given to compounds of the formula C 48 H 67 Structure with N9O6S: [ka] Cyclo[N- D Val- L Trp- D Leu- L Val- D Trp- L Me2Thz( L Val)-C] The antimicrobial peptide having the formula:

[0060] This preferably selected peptide is, according to the present invention, designated ISW1-2. Surprisingly, it has advantageous antibacterial effects.

[0061] ISW1-2 are synthetically produced peptides composed of D- and L-amino acids cyclized via a thiazolidine ring. They are derivatives of lugdunin, a natural substance formed by Staphylococcus lugdunensis, a naturally occurring skin bacterium, particularly in the human nose.

[0062] Of particular note is the mode of action of this peptide. The antibacterial effect is strongly correlated with a decrease in bacterial membrane potential. Here, no specific target is targeted, as peptide enantiomers have the same antibacterial effect, thereby eliminating stereospecific interactions with target molecules. The mode of action is based on proton translocation while maintaining membrane integrity.

[0063] This peptide is known to synergize with host- and microbiota-derived factors to support the skin's innate immune response, thereby combating pathogens at various levels and inhibiting recolonization by bacteria such as Staphylococcus aureus.

[0064] Antimicrobial peptides, particularly ISW1-2, exhibit synergistic antimicrobial effects in combination with one or more substances selected from the group of skin-soothing substances, the group of substances that strengthen the skin barrier, and / or the group of flavonoids.

[0065] Advantageously, a flavonoid is chosen as the combination partner of the AMP.

[0066] Advantageously, as flavonoids, licochalcone A, licochalcone C, licochalcone E and / or glabrol, and in particular licochalcone A, are chosen.

[0067] Instead of flavonoids directly, extracts, solutions and mixtures containing these flavonoids can also be used, such as the plant extract Glycyrrhiza inflata.

[0068] Licochalcone A has the following structure: [ka] It has.

[0069] Further preferred flavonoids include, for example, licochalcone C: [ka] Licochalcone E: [ka] and Grab Roll: [ka] is.

[0070] Thus, the topical preparation according to the invention preferably contains a flavonoid, a flavonoid-containing extract, a flavonoid-containing solution, and / or a flavonoid-containing mixture, the flavonoid being in particular a licochalcone, preferably licochalcone A, licochalcone C, licochalcone E, and / or glabrol.

[0071] In a particularly preferred embodiment, the preparation is cyclo[N- D Val- L Trp- D Leu- L Val- D Trp- L Me2Thz( L The peptides contain peptides having the structure [(Val)-C], i.e., peptides ISW1-2, and one or more licochalcones from the group licochalcone A, licochalcone C, licochalcone E, and / or glabrol.

[0072] In a preferred embodiment of the invention, the preparation contains peptide ISW1-2 and licochalcone A. In a further preferred embodiment of the invention, the preparation contains peptide ISW1-2 and licochalcone C. In a further preferred embodiment of the invention, the preparation contains peptide ISW1-2 and licochalcone E. In a further preferred embodiment of the invention, the preparation contains peptide ISW1-2 and glabrol.

[0073] ISW1-2 already has antibacterial activity against Gram-positive bacteria in vitro at very low concentrations used (3.1 μg / ml against Staphylococcus aureus).

[0074] Surprisingly, skin pathogens such as Staphylococcus aureus, whose increase correlates with the severity of atopy and which has also been linked to the acne bacterium Cutibacterium acnes, showed particular sensitivity to this active substance.

[0075] ISW1-2 has an antibacterial effect already in the micromolar range: the minimum inhibitory concentration (MIC) of ISW1-2 for Staphylococcus aureus is 3.1 μg / ml (0.00031%).

[0076] Preferably, the proportion range of one or more AMPs, in particular ISW1-2, is advantageously chosen in cosmetic formulations in the range of 0.00001% to 1.0% by weight, preferably 0.0001% to 0.5% by weight, in particular 0.0003% to 0.3% by weight, based on the total weight of the preparation.

[0077] However, even these small percentage amounts are highly effective, especially due to the unexpected enhancement that occurs due to at least one combination partner.

[0078] Surprisingly, synergistic effects were shown with combination partners 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.

[0079] A further advantage is that by reducing the amount of active ingredient, the costs of manufacturing and application of these active ingredients can also be reduced, and the resulting cost savings can lead to a wider range of cosmetic uses.

[0080] The combination partners chosen from skin-soothing substances, substances strengthening the skin barrier and / or flavonoids are advantageously used in proportions ranging from 0.0001% to 5% by weight, based on the total weight of the preparation, the percentages by weight referring in particular to the sum of the combination partners in the total weight of the preparation.

[0081] In particular in the case of emulsions, it is advantageous to select 0.0001 to 5% by weight, in particular 0.001 to 1% by weight, and very particularly 0.005 to 0.15% by weight of these co-substances, in particular licochalcone, preferably licochalcone A, or extracts containing licochalcone, in each case based on the total weight of the preparation, where the percentages by weight refer in particular to the sum of the co-substances in each case relative to the total weight of the preparation.

[0082] In a particularly preferred embodiment, the preparation according to the invention comprises one or more AMPs in an amount of 0.00001 to 1.0% by weight, preferably 0.0001 to 0.5% by weight, in particular 0.0003 to 0.3% by weight, based on the total weight 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% by weight, in particular 0.001 to 1% by weight, and very particularly 0.005 to 0.15% by weight, based on the total weight of the preparation.

[0083] In a further particularly preferred embodiment, the preparation according to the invention comprises AMP in an amount of 0.00001 to 1.0% by weight, preferably 0.0001 to 0.5% by weight, in particular 0.0003 to 0.3% by weight, based on the total weight 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% by weight, in particular 0.001 to 1% by weight, and very particularly 0.005 to 0.15% by weight, based on the total weight of the preparation.

[0084] In a further particularly preferred embodiment, the preparation according to the invention comprises peptide ISW1-2 in an amount of 0.00001 to 1.0% by weight, preferably 0.0001 to 0.5% by weight, in particular 0.0003 to 0.3% by weight, based on the total weight of the preparation, and licochalcone A in an amount of 0.0001 to 5% by weight, in particular 0.001 to 1% by weight, and very particularly 0.005 to 0.15% by weight, based on the total weight of the preparation.

[0085] In a further particularly preferred embodiment, the preparation according to the invention comprises peptide ISW1-2 in an amount of 0.00001 to 1.0% by weight, preferably 0.0001 to 0.5% by weight, in particular 0.0003 to 0.3% by weight, based on the total weight of the preparation, and licochalcone C in an amount of 0.0001 to 5% by weight, in particular 0.001 to 1% by weight, and very particularly 0.005 to 0.15% by weight, based on the total weight of the preparation.

[0086] In a further particularly preferred embodiment, the preparation according to the invention comprises peptide ISW1-2 in an amount of 0.00001 to 1.0% by weight, preferably 0.0001 to 0.5% by weight, in particular 0.0003 to 0.3% by weight, based on the total weight of the preparation, and licochalcone E in an amount of 0.0001 to 5% by weight, in particular 0.001 to 1% by weight, and very particularly 0.005 to 0.15% by weight, based on the total weight of the preparation.

[0087] In a further particularly preferred embodiment, the preparation according to the invention comprises peptide ISW1-2 in an amount of 0.00001% to 1.0% by weight, preferably 0.0001% to 0.5% by weight, in particular 0.0003% to 0.3% by weight, based on the total weight of the preparation, and glabrol in an amount of 0.0001 to 5% by weight, in particular 0.001 to 1% by weight, very in particular 0.005 to 0.15% by weight, based on the total weight of the preparation.

[0088] The preparations according to the invention exhibit a synergistic effect, so that even low application concentrations of the antimicrobial peptides, especially ISW1-2, guarantee an antimicrobial effect against atopic dermatitis and / or acne-associated skin bacteria (Staphylococcus aureus, Cutibacterium acnes). Surprisingly, this synergistic effect occurs with the pathogenic bacteria S. aureus and C. acnes, but not with the normal skin flora S. epidermidis.

[0089] This selective effect is surprising and represents a major advantage over conventional treatments, which often inhibit the entire skin microflora.

[0090] Dysbiosis, accompanied by an increase in the bacterial load of Staphylococcus aureus (S. aureus) and a decrease in the normal skin bacteria, correlates with a worsening of the skin condition in atopic patients. The combination according to the invention, in particular ISW1-2 and a flavonoid, advantageously licochalcone A, has made it possible to find an antibacterial combination that minimizes excessive colonization by Staphylococcus aureus (S. aureus), is not cytotoxic to skin cells (keratinocytes), and is proven to be stable against proteolysis by the skin's own enzymes.

[0091] Skin soothing means, in particular, reducing or completely avoiding skin irritation, itching, tightness, and / or redness of the skin.

[0092] Strengthening the skin barrier means establishing a skin barrier, promoting skin adhesion, and / or minimizing or avoiding harmful external influences.

[0093] 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.

[0094] According to the present invention, substances with these properties are skin soothing substances or substances that strengthen the skin barrier.

[0095] Skin soothing combination substances that can be combined with the AMPs according to the invention preferably include: Menthoxypropanediol Polidocanol Allantoin Vitamins, especially vitamins A, B5, and E Hyaluronic acid or its salts Plant extracts such as marigold, witch hazel, and oat Jojoba oil One or more substances are selected from the group comprising:

[0096] Concomitant substances which strengthen the skin barrier and which can be combined with the AMPs according to the invention are preferably from the following group: Omega-6 fatty acids Ceramides Shea butter Argan oil is selected from.

[0097] The present invention advantageously provides a preparation comprising, in addition to an antimicrobial peptide, in particular ISW1-2, licochalcones, in particular licochalcones A, C and / or E, glabrol, or an extract, solution or mixture containing them, which advantageously also contains one or more substances from the group of skin-soothing substances and / or substances that strengthen the skin barrier.

[0098] Where an active agent belongs to both the group of skin soothing agents and the group of agents that strengthen the skin barrier, in embodiments where it is desirable to include agents from both groups, two or more different agents from both groups are also included.

[0099] Advantageously, according to the present invention, destructive bacteria (C. acnes, S. aureus) are significantly inhibited in their growth, while beneficial bacteria (S. epidermides) that stabilize the skin microflora are not disturbed.

[0100] This allows for the selective enrichment of healthy skin microbiota.

[0101] In a preferred embodiment, the topically applicable preparations according to the invention are cosmetic and / or dermatological preparations, preferably based on emulsions.

[0102] In view of the advantageous properties, various possibilities for use are conceivable for the topically applicable preparations according to the invention, thus in particular the non-therapeutic use of the preparations according to the invention for the treatment of inflammatory skin diseases and / or conditions, in particular acne, rosacea, and / or atopic dermatitis, is advantageous.

[0103] Likewise, the preparations according to the invention can advantageously be used for the care of the skin, in particular for the care, prevention and treatment of skin damaged by atopic dermatitis or acne.

[0104] Likewise, the preparations according to the invention can be advantageously used in the treatment of atopic dermatitis, acne and / or allergic contact dermatitis.

[0105] Likewise, the preparations according to the invention can be advantageously used in wound healing and in the care of sensitive skin.

[0106] The present invention therefore also relates to a non-therapeutic, in particular cosmetic, method for treating the skin, in which a topically applicable preparation according to the invention is applied to the skin.

[0107] In this method, the non-therapeutic skin treatment is preferably for skin care, for assisting skin wound healing, and / or for treating skin damaged by atopic dermatitis or acne, where the non-therapeutic skin treatment is for skin care, in particular for the care of sensitive skin.

[0108] The preparations according to the invention and the substance combinations contained therein can also be used for medical purposes. Thus, in a further aspect, the invention relates to a substance combination of one or more antimicrobial peptides with one or more substances selected from the group of skin-soothing substances, substances that strengthen the skin barrier, and / or flavonoids, for application in the treatment of inflammatory skin diseases and / or conditions, in particular acne, rosacea, and / or atopic dermatitis.

[0109] The appropriate preferred embodiments mentioned in connection with the definition of the topically applicable preparation according to the invention are correspondingly preferred or appropriate in this aspect of the invention.

[0110] Preferably, in the substance combination, the peptide selected is a cyclic peptide compound based on the synthesis of thiazolidine and oxazolidine building blocks.

[0111] In a particularly preferred embodiment, in the substance combination according to the invention, cyclo[N- D Val- L Trp- D Leu- L Val- D Trp- L Me2Thz( L The structure of [Val)-C]: [ka] Peptides having the formula:

[0112] In a further preferred embodiment, the topical preparation according to the invention contains a flavonoid, a flavonoid-containing extract, a flavonoid-containing solution, and / or a flavonoid-containing mixture, in particular a licochalcone, particularly preferably licochalcone A, licochalcone C, licochalcone E, and / or glabrol.

[0113] Furthermore, it is preferred that the substance combinations according to the invention are applied in cosmetic and / or dermatological preparations.

[0114] Although the individual substances of the combination according to the invention are known per se to cosmetic experts, to date it has not been known or successful to use the combination effectively, especially at low use concentrations.

[0115] Here, a topically applicable preparation is provided that specifically results in a reduction of the pathogenic bacteria S. aureus and C. acnes, while simultaneously achieving a balance of the normal skin flora S. epidermidis.

[0116] This results in an improvement in skin condition, especially in skin damaged by acne or atopic dermatitis.

[0117] Unwanted bacteria such as Propionibacterium acnes are reduced on the skin, while beneficial bacteria such as Staphylococcus epidermidis remain intact.

[0118] According to the invention, "selective" means that anaerobic bacteria are reduced and aerobic bacteria are not reduced to a significant extent (preferably not at all). Advantageously, according to the invention, this combination is applied in cosmetic or dermatological preparations.

[0119] The preparations according to the invention can be applied in various application forms, preferred application forms being gels, sprays, serums, impregnating media for immersion patches, wipes or masks.

[0120] The sophisticated cosmetic compositions according to the invention may, if desired, contain further common auxiliary and additive substances, such as, for example, thickeners, fillers, fragrances, coloring substances, active substances, vitamins, proteins, light stabilizers, stabilizers, insect repellents, salts, EDTA, further substances with antibacterial, proteolytic or keratolytic action, etc., unless excluded by the present invention.

[0121] According to the invention, preferably one or more active substances from the following groups are added to the preparation in order to be able to ensure the widest possible range of application and individual care and treatment:

[0122] Advantageously, the preparations or application forms according to the invention can be supplemented with further active substances, for example preferably sebum-reducing active substances, itching-relieving active substances, anti-inflammatory, healing-promoting, analgesic or antibacterial active substances, such as dexpanthenol, or natural additives, natural substances, for example honey, chamomile or aloe vera, unless otherwise mentioned in the substance group according to the invention.

[0123] Further possible active substances are vitamins, such as vitamins A, C or E, as well as 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.

[0124] According to the invention, the addition of active substances that target cell membranes, such as quats, octenidine, or decanediol, is also preferred.

[0125] In particular, according to the invention, natural substances such as cyclic and acyclic peptides of ribosomal and non-ribosomal origin (NRPS-derived) and cyclic and acyclic polyketides (PKS-derived) are advantageously added.

[0126] Further preferred active substances are enzymes, here especially cell wall hydrolases such as endolysins, lysozymes, chitinases, etc., as long as these are compatible with and do not attack the peptides.

[0127] The addition of one or more active substances selected from the group hydroxyacetophenone, salicylic acid, Q10 and / or thiamidol is particularly preferred.

[0128] More preferred additives may be selected from Ca salts, Mg salts, Al salts, and / or Zn salts.

[0129] Further preferred active ingredients may be selected from magnolia, arctiin, bioxylift, creatine, isoflavones, laminaria, NAHP, phloridzin, vitamin C, lotus extract, myricerin, white tea, AGR, glycyrrhetinic acid, silymarin S, tocopheryl, carnitine, garcinia cambogia, guarana C22, butyloctanoic acid, diacid, ethylhexylglycerin, methylphenylbutanol, polyglyceryl-2 caprate, Polysaf 5600 polymer, silver citrate, zinc citrate, betaine, sea salt, taurine, SymSave H, DHA, rucinol, panthenol / dexpanthenol. [Brief explanation of the drawings]

[0130] [Figure 1] FIG. 1 shows the effect of a preparation according to the invention. [Figure 2] FIG. 1 shows the effect of a preparation according to the invention. [Figure 3] FIG. 10 is a diagram showing the effect of the substance combination according to the present invention. [Figure 4] FIG. 10 is a diagram showing the effect of the substance combination according to the present invention. [Figure 5]FIG. 10 is a diagram showing the effect of the substance combination according to the present invention. [Figure 6] FIG. 10 is a diagram showing the effect of the substance combination according to the present invention. [Figure 7] FIG. 10 is a diagram showing the effect of the substance combination according to the present invention. [Figure 8] FIG. 10 is a diagram showing the effect of the substance combination according to the present invention. [Figure 9] FIG. 10 is a diagram showing the effect of the substance combination according to the present invention. [Figure 10] FIG. 10 is a diagram showing the effect of the substance combination according to the present invention. [Figure 11] FIG. 1 shows the effect of the substance combination according to the present invention on normal skin flora. [Figure 12] FIG. 1 shows the effect of the substance combination according to the present invention on normal skin flora. [Figure 13] FIG. 1 shows the effect of the substance combination according to the present invention on normal skin flora. [Figure 14] FIG. 1 shows the effect of the substance combination according to the present invention on normal skin flora. [Figure 15] FIG. 1 shows the effect of the substance combination according to the present invention on normal skin flora. [Figure 16] FIG. 1 shows the effect of the substance combination according to the present invention on normal skin flora. [Figure 17] FIG. 1 shows the effect of the substance combination according to the present invention on normal skin flora. [Figure 18] FIG. 1 shows the effect of the substance combination according to the present invention on normal skin flora. [Figure 19] FIG. 1 illustrates the effect of a topically applicable preparation according to the present invention.

[0131] Example In various tests, the antibacterial and skin care effects of the combination according to the invention and of the individual substances were investigated.

[0132] a) In vitro studies In an in vitro study, the effect of the preparation according to the invention on the growth of C. acnes, S. aureus and S. epidermidis was investigated.

[0133] C. acnes DSM1897 was grown at 37°C under anaerobic conditions. Overnight cultures were diluted 1:1000 in Caso medium (casein peptone 17 g / L, soy flour peptone 3 g / L; sodium chloride 5 g / L; glucose 2.5 g / L; dipotassium phosphate 2.5 g / L; pH 7.3 ± 0.2) and plated onto microtiter plates. Different concentrations of the plant extracts Glycyrrhiza inflata and licochalcone A (1 μg / ml, 2 μg / ml) were added, mixed, and incubated anaerobically at 37°C for 5 days. These experiments were repeated in the presence of a noninhibitory concentration of ISW1-2 (0.00001% ISW1-2). To allow estimation of bacterial growth, optical density (OD) was measured photometrically at a wavelength of 600 nm (OD600). An increase in the value indicates bacterial growth.

[0134] Unless otherwise stated, amounts refer to the weight of a substance per volume of medium, e.g., 1 μg / ml means 1 μg of licochalcone A in 1 ml of medium. Amounts expressed as a percentage of ISW1-2 refer to the weight of ISW1-2 relative to the total weight of the respective experimental batch.

[0135] C. acnes 1897 was incubated without ISW1-2 (shaded area in Figure 1) or with a non-inhibitory concentration of 0.00001% ISW1-2 (black area in Figure 1) and doped with different concentrations of licochalcone A extract (0 μg / ml = control; 1 μg / ml; 2 μg / ml). Bacterial growth or inhibition was measured by the increase / decrease in turbidity (OD600) in the medium.

[0136] As the licochalcone A extract, a Glycyrrhiza inflata extract containing 21% by weight of licochalcone A was used.

[0137] The results are shown in Figure 1.

[0138] No growth inhibition in C. acnes was observed by adding 1 μg / ml of licochalcone A extract to 0.00001% ISW1-2 in the medium (center bar in FIG. 1).

[0139] Addition of 2 μg / ml of licochalcone A extract to 0.00001% ISW1-2 in the medium resulted in significant growth inhibition in C. acnes.

[0140] Similarly, studies were also conducted with the addition of licochalcone A (0 μg / ml = control; 1 μg / ml; 2 μg / ml).

[0141] These results are shown in Figure 2.

[0142] No growth inhibition in C. acnes was observed by adding 1 μg / ml of licochalcone A to 0.00001% ISW1-2 in the medium (center bar in FIG. 2).

[0143] Addition of 2 μg / ml of licochalcone A to 0.00001% ISW1-2 in the medium resulted in significant growth inhibition in C. acnes (right bar, black part in FIG. 2).

[0144] Surprisingly, non-inhibitory amounts of the antimicrobial peptides ISW1-2 can inhibit C. acnes by adding licochalcone A (Figs. 1 and 2, right bars, black), whereas the pure extract or pure licochalcone A alone exerts a lower inhibitory effect (Figs. 1 and 2, left bars, shaded).

[0145] Further investigations investigated the inhibition of Staphylococcus aureus (S. aureus).

[0146] S. aureus DSM20231 and S. epidermidis ATTC12228 were grown under aerobic conditions with constant shaking at 37°C. Overnight cultures were diluted 1:10000 in MHB (Mueller-Hinton Broth: starch 1.5 g / L, Fleisch-Infusion 2.0 g / L, peptone from casein (hydrolyzed) 17.5 g / L, pH 7.4 ± 0.2) and inoculated into microtiter plates.

[0147] Different concentrations of the plant extract Glycyrrhiza inflata and the flavonoids licochalcones A, C, and E (1 μg / ml, 2 μg / ml) were added and mixed, and bacterial growth was observed over a 24-h period at 37°C. These experiments were repeated in the presence of a non-inhibitory concentration of ISW1-2 (0.00002% ISW1-2). To be able to estimate bacterial growth, optical density (OD) was measured photometrically at a wavelength of 600 nm (OD600). An increase in the value indicates bacterial growth (average from three independent experiments).

[0148] Staphylococcus aureus DSM20231 was incubated without ISW1-2 (Figures 3, 5, 7, and 9) or with a non-inhibitory concentration of 0.00002% ISW1-2 (Figures 4, 6, 8, and 10) and doped with different concentrations of licochalcone extracts: licochalcone A, licochalcone C, and licochalcone E (0 μg / ml = control; 1 μg / ml; 2 μg / ml). Figures 3–10 show bacterial growth over 24 hours under different conditions (mean values ​​from three independent experiments).

[0149] Bacterial growth is measured by the increase in turbidity (OD600) in the medium, i.e., an increase in OD over time indicates bacterial growth.

[0150] The results are shown in Figures 3 to 10. These results indicate that the licochalcone extract and licochalcone act synergistically with ISW1-2. When the substance combination according to the present invention was added, no growth of Staphylococcus aureus (S. aureus) was observed.

[0151] FIG. 3 shows bacterial growth upon addition of licochalcone A extract (0%, control) and relatively little growth retardation upon addition of 1 μg or 2 μg.

[0152] FIG. 4 shows bacterial growth upon addition of pure non-inhibitory ISW1-2 (0.00002%, control) and upon addition of licochalcone A extract to ISW1-2 (1 μg / ml, 2 μg / ml).

[0153] When Figures 3 and 4 are viewed as a whole, it becomes clear that the substance combination according to the invention results for the first time in a significant inhibition of bacterial growth.

[0154] Similarly, the studies with ISW1-2 and licochalcone A (FIGS. 5 and 6) show for the first time that the substance combination according to the invention from an antimicrobial peptide and a flavonoid (licochalcone A) results in a significant inhibition of bacterial growth.

[0155] Figures 7 and 8 show studies using ISW1-2 and licochalcone C. In this case, four different amounts of licochalcone C (0%, control; 1 μg / ml; 2 μg / ml, and 4 μg / ml) were used alone (Figure 7) and together with 0.00002% ISW1-2 (Figure 8).

[0156] Here again it can be seen that the substance combination according to the invention (FIG. 8) is the first to bring about a significant inhibition of bacterial growth.

[0157] Licochalcone C synergizes somewhat less strongly with ISW1-2 than licochalcone A, but the synergistic effect is still present and sufficient to affect bacterial growth (FIG. 8). Advantageously, in this case, the concentration of the cooperating partner, here licochalcone C, can be increased (e.g., to 4 μg / ml) according to the present invention to completely inhibit the growth of S. aureus.

[0158] Figures 9 and 10 show studies using ISW1-2 and licochalcone E. In this case, three different amounts of licochalcone E (0%, control; 1 μg / ml; 2 μg / ml) were used alone (Figure 9) and together with 0.00002% ISW1-2 (Figure 10).

[0159] Furthermore, licochalcone E, like licochalcone A, acted synergistically with ISW1-2 better than ISW1-2, and the substance combination according to the present invention did not show any growth of S. aureus (FIG. 10).

[0160] In further comparative studies, the effect of the substance combination according to the invention on normal skin bacteria such as S. epidermidis was also determined (FIGS. 11-18).

[0161] To this end, Staphylococcus epidermidis 12228 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) and doped with different concentrations of licochalcone extracts: licochalcone A, licochalcone C, and licochalcone E (0 μg / ml = control; 1 μg / ml; 2 μg / ml). Bacterial growth over 24 h under different conditions is shown (mean values ​​from three independent experiments).

[0162] Bacterial growth is measured by the increase in turbidity (OD600) in the medium, i.e., an increase in OD over time indicates bacterial growth.

[0163] Licochalcone extract and their combination with licochalcones A, C, E, and ISW1-2 had no effect on the growth of normal skin flora. No effect on the growth of S. epidermidis was observed with the combination according to the present invention (Figures 11-18).

[0164] b) In vivo studies The effects of topically applicable preparations according to the invention were also tested in vivo.

[0165] For this purpose, three different preparations were prepared for cosmetic formulation. The first preparation was a control containing only the carrier composition (vehicle). The second preparation (+ISW1-2) contained the carrier composition and 0.015% ISW1-2. The third preparation (+ISW1-2+LiCo extract) contained the carrier composition, 0.015% ISW1-2, and an additional 0.025% LiCo extract (Glycyrrhiza inflata with 21% by weight of licochalcone A).

[0166] The three preparations were tested on six subjects with healthy skin. For each subject, three areas (5 cm x 5 cm) were marked on the upper back, and for each area, a sample was taken with a flocked swab (FloqSwab®) to determine the bacterial colonization of the skin before applying the three preparations. Subsequently, the three preparations were applied to all subjects, each in 75 μl (3 μl / cm 2 The preparation was applied to one of the three marked areas. The application was performed twice daily for a total of five times over the 48-hour experimental period. After 48 hours, samples were again collected using flocked swabs.

[0167] To determine bacterial counts, samples taken before (0 h) and after (48 h) application were placed on plates, incubated aerobically, and colonies were counted.

[0168] The results are shown in Figure 19. When the control preparation (vehicle) was applied, no change in the number of bacteria on the skin could be observed. By applying the preparation + ISW1-2, the number of bacteria could be reduced by about half. When the third preparation was applied, a significantly stronger reduction in the number of bacteria could be observed, suggesting a synergistic effect of ISW1-2 and Lico extract.

[0169] c) Examples of cosmetic preparations Below, examples of cosmetic preparations according to the invention are listed in the table, the figures refer to percentages by weight based on the total mass of the preparation.

[0170] [Table 1]

Claims

1. 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, substances that strengthen the skin barrier and / or flavonoids.

2. 2. Preparation according to claim 1, characterized in that as peptides, cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks are selected.

3. As a peptide, a compound of formula (I): 【Chemical 1】 [In the formula, - X and Y １ ~Y ５ is methyl, ethyl, n-propyl, 2-propenyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, benzyl, propargyl (HC≡C—CH ２ -), 1H-indol-3-ylmethyl ( 【Chemistry 2】 ), 1N-methyl-1H-indol-3-ylmethyl ( 【Chemistry 3】 ), 3-benzothienylmethyl ( 【Chemistry 4】 ), 1-naphthylmethyl ( 【Chemistry 5】 ), 9-anthracenylmethyl ( 【Chemistry 6】 ), and pyrenylmethyl ( 【Chemistry 7】 ） and each selected from the group consisting of: 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; - Substituent Y １ , Y ２ , Y ３ , Y ４ , Y ５ and the C atom directly bonded to X have alternate absolute stereochemical configurations in this order, the C atom bonded to the substituent X and the C atom at position 4 of the thiazolidine or oxazolidine ring have the same absolute stereochemical configuration when Z is O and the opposite absolute stereochemical configuration when Z is S, However, X and Y １ , Y ４ , and Y ５ is 1-methylethyl, and Y ２ is 1H-indol-3-yl, and Y ３ is 2-methylpropyl, R is H, and R' is methyl, then Z is not O. a cyclic peptide compound of the formula and salts thereof, solvates thereof, and solvates of salts thereof 3. The preparation according to claim 1 or 2, characterized in that it comprises:

4. In the cyclic peptide compound of formula (I), R and R' are both methyl and Y ２ But Y ５ is 1-methylethyl, then 1H-indol-3-ylmethyl or pyrenylmethyl, or Y ２ But Y ５ is 1H-indol-3-ylmethyl or pyrenylmethyl, then it is 1-methylethyl and X is 1-methylethyl; R is H, R' is methyl, ethyl, n-propyl, 1-methylethyl, benzyl, or propargyl, and Y ２ But Y ５ is 1-methylethyl, then 1H-indol-3-ylmethyl or pyrenylmethyl, or Y ２ But Y ５ is 1H-indol-3-ylmethyl or pyrenylmethyl, then it is 1-methylethyl and X is 1-methylethyl; R is H, R' is methyl, n-propyl, 1-methylethyl, benzyl, or propargyl, and Y ２ But Y ５ is 1-methylethyl, then 1H-indol-3-ylmethyl or pyrenylmethyl, or Y ２ But Y ５ is 1H-indol-3-ylmethyl or pyrenylmethyl, then it is 1-methylethyl and X is 1-methylethyl or 2-methylpropyl; or R and R' are both 1-methylethyl, and Y ２ is 1H-indol-3-ylmethyl 4. A preparation according to any one of claims 1 to 3, characterized in that it

5. The cyclic peptide compound is represented by the following formulae I.1a to I.24a: 【Chemistry 8-1】 【Chemistry 8-2】 5. A preparation according to any one of claims 1 to 4, characterized in that it comprises one of the following:

6. Cyclo[N- Ｄ Val- Ｌ Trp- Ｄ Leu- Ｌ Val- Ｄ Trp- Ｌ Me ２ Thz ( Ｌ Structure of Benzylalanine-3-phosphate dehydrogenase (Val)-C: 【Chemistry 9】 6. A preparation according to any one of claims 1 to 5, characterized in that the peptide is selected to have the following structure:

7. 7. A preparation according to claim 1, characterized in that as flavonoids licochalcones are selected, in particular licochalcone A, licochalcone C, glabrol and / or licochalcone E, and / or an extract containing licochalcone.

8. Cyclo[N- Ｄ Val- Ｌ Trp- Ｄ Leu- Ｌ Val- Ｄ Trp- Ｌ Me ２ Thz ( Ｌ 8. The preparation according to claim 1, characterized in that it contains the peptide of the structure [(Val)-C] and one or more licochalcones from the group licochalcone A, licochalcone C, glabrol, and / or licochalcone E.

9. 9. Preparation according to any one of claims 1 to 8, characterized in that the proportion of one or more antimicrobial peptides is selected in the range of 0.00001% to 1.0% by weight, preferably 0.0001% to 0.5% by weight, in particular 0.0003% to 0.3% by weight, based on the total mass of the preparation.

10. 10. A preparation according to any one of claims 1 to 9, characterized in that the skin-soothing substances are one or more substances selected from the group comprising menthoxypropanediol, polidocanol, allantoin, vitamins, in particular vitamins A, B5, E, hyaluronic acid or its salts, plant extracts such as marigold, hamamelis, oat, and / or jojoba oil.

11. 11. Preparation according to any one of claims 1 to 10, characterized in that as substances strengthening the skin barrier, one or more substances are selected from the group of omega-6 fatty acids, ceramides, shea butter and / or argan oil.

12. 12. Preparation according to any one of claims 1 to 11, characterized in that the proportion of one or more skin-soothing substances, said substances strengthening the skin barrier and / or flavonoids is selected in the range from 0.0001% to 5% by weight, in particular from 0.001 to 1% by weight, very particularly from 0.005 to 0.15% by weight, based on the total weight of the preparation.

13. 13. Preparation according to any one of claims 1 to 12, characterized in that the preparation is a cosmetic and / or dermatological preparation, preferably based on an emulsion.

14. 14. Non-therapeutic use of a preparation according to any one of claims 1 to 13 for the care of the skin, in particular for the care of the skin damaged by atopic dermatitis or acne.

15. A substance combination of one or more antimicrobial peptides with one or more substances selected from the group of skin soothing substances, substances that strengthen the skin barrier, and / or flavonoids, for application in the treatment of inflammatory skin diseases and / or conditions, in particular acne, rosacea, and / or atopic dermatitis.

16. 16. Substance combination for the application according to claim 15, characterized in that as peptides cyclic peptide compounds based on the synthesis of thiazolidine and oxazolidine building blocks are selected.

17. Cyclo[N- Ｄ Val- Ｌ Trp- Ｄ Leu- Ｌ Val- Ｄ Trp- Ｌ Me ２ Thz ( Ｌ Structure of Benzylalanine-3-phosphate dehydrogenase (Val)-C: 【Chemistry 10】 17. The substance combination for application according to claim 15 or 16, wherein a peptide having the formula:

18. 18. A substance combination for application according to any one of claims 15 to 17, characterized in that as flavonoids licochalcones are selected, in particular licochalcone A, licochalcone C, glabrol and / or licochalcone E, and / or extracts containing licochalcone.

19. 19. Substance combination for application according to any one of claims 15 to 18, characterized in that the combination is applied in cosmetic and / or dermatological preparations.

Images