Topical formulations for improving skin conditions

Abstract

The present invention relates to topical formulations comprising a combination of antimicrobial peptides (AMP), in particular synthetic cyclic peptide compounds based on thiazolidine and # imgabs0 # oxazolidine components, and a skin soothing substance, such as menthoxypropanediol, a substance that enhances the skin barrier, such as omega-6 fatty acids, and / or a flavonoid, such as licochalcone, for example licochalcone, for example licochalcone, for example licochalcone, for example licochalcone, for example licochalcone, for example licochalcone, for example licochalcone, for example licochalcone, for example licochalcone, for example licochalcone, for example licochalcone. In particular, the present invention relates to compounds that synergistically and selectively fight against pathogenic bacteria, such as Staphylococcus aureus (S. aureus) and Propionibacterium acnes (C. acnes), but not fight against skin symbiotic bacteria, such as Staphylococcus epidermidis (S. epidermidis). The formulations can be advantageously used in the treatment of acne or atopic dermatitis, as well as in the care of skin that has been impaired by acne or atopic dermatitis.

Description

Technical Field

[0001] The present invention relates to topical preparations, in particular cosmetic or dermatological preparations, comprising antimicrobial peptides (AMPs), in particular thiazolidine- and The invention relates to a synthetic cyclic peptide compound based on an oxazolidine building block, in combination with a skin soothing compound such as menthoxypropanediol, a skin barrier enhancing compound such as omega-6 fatty acids, and / or a flavonoid such as licorice chalcone. Background Art

[0002] The pursuit of beauty and attractiveness is human nature. Even though the ideal of beauty has undergone changes over time, the pursuit of a flawless appearance has always been a goal of people because a pleasing appearance increases their self-esteem and attractiveness to other people. The condition and appearance of the skin plays an important role in a beautiful and attractive appearance.

[0003] In the case of grease-oily and blemished skin (it is a transitional state between healthy normal skin and pathologically altered acne skin), skin produces an increased amount of sebum (seborrhea). This provides an ideal breeding place for many microorganisms, particularly Propionibacterium acnes (Propionibacterium acnes, P. acnes, Cutibacterium acnes, C. acnes) and Pityrosporum species. Microorganisms decompose sebum into glycerol and fatty acids, stimulate sebaceous glands to increase production and attack and destroy the hair follicle wall in the skin. This causes skin inflammation (papule, pustule, nodule, cyst), which can only heal after leaving scars usually, and permanently damages the appearance of people with blemished skin (W. Umbach [ed.], Kosmetik, Entwicklung, Herstellung und Anwendung kosmetischer Mittel, 2nd ed. Thieme Verlag, Stuttgart, 1995).

[0004] Conventional products for treating oily and / or blemished skin and acne prone skin often have the disadvantage of stressing the skin, drying it out and having little nourishing effect.

[0005] A disadvantage of known acne preparations is that, in order to be effective against Propionibacterium acnes, the proportion of antimicrobial active ingredients is usually very high, making the preparations irritating to the skin.

[0006] In the treatment of acne, highly acidic (pH values ​​below pH 4.0) and highly oxidizing agents (eg, benzoyl peroxide) are also used, which damage the skin's protective acid mantle and erode or corrode the skin.

[0007] Therefore, one of the tasks of the present invention is to develop a significantly milder and better care cosmetic and / or dermatological preparation for improving skin conditions and treating acne than those known in the prior art. In addition, these preparations should also significantly reduce the concentration of acne-causing bacteria in the skin and sebaceous glands.

[0008] The causes of a large number of skin diseases, especially those of the atopic type, are unknown in detail. What these diseases have in common is an inflammatory response in the dermis and the dermal-epithelial transition zone.

[0009] Atopic dermatitis (commonly known as eczema) is a chronic inflammatory skin disease with a complex pathogenesis involving genetic susceptibility, immunological and epidermal barrier disorders, and environmental factors. Treatment generally involves the application of moisturizers, avoidance of allergenic and irritating compounds, and usually topical corticosteroids or immunomodulators.

[0010] In addition to the treatment of skin diseases such as atopic dermatitis, skin care is an essential preventive method. Today, a wide range of cosmetic preparations are offered to consumers for skin care, mainly in the form of creams and lotions, i.e. as emulsions. Products that temporarily or permanently delay or eliminate the signs of skin aging, negative environmental influences and skin diseases are becoming increasingly important. In addition to oils and lipids for moisturizing the skin and replenishing skin lipids, these skin care products contain various active ingredients and additives.

[0011] Numerous studies have been conducted on active ingredients that can be used to combat skin diseases, eczema and atopic dermatitis. However, these active ingredients are often associated with side effects, as in the case of corticosteroids, so that the advantage of alleviating the disease is accompanied by the disadvantage of damaging other areas.

[0012] Therefore, improving human skin conditions, in particular, providing preparations suitable for treating atopic dermatitis and / or acne and caring for skin damaged by atopic dermatitis or acne, is one of the necessary tasks.

[0013] Many antimicrobial peptides (AMPs) are known. They are particularly effective against Gram-negative and Gram-positive bacteria, viruses and fungi. In contrast to some antibiotics, the effect on bacteria is bactericidal, not bacteriostatic.

[0014] WO2022106667 A1 describes a novel thiazolidine-based Synthetic novel cyclic peptide compounds based on oxazolidine building blocks. These cyclic compounds are suitable for cosmetic formulations as they exhibit antimicrobial, antiviral, antibacterial and / or antifungal activity.

[0015] Flavonoids are natural compounds and belong to the group of polyphenols. They are derived formally from the basic compound flavonoids (2-phenylchroman). There are about 8000 compounds in nature.

[0016] Flavonoids are commonly found in plants as secondary plant compounds and therefore also in human food. They are said to have particularly antioxidant properties, which is why they are used in cosmetics, both as plant extracts (e.g. Glycyrrhiza inflata) and as pure substances, such as Licoricechalcone A.

[0017] For example, EP 1 839 645 A1 describes licochalcone A in cosmetic preparations.

[0018] It is desirable to provide a formulation that can be used for skin care and treatment of inflammatory skin diseases and indications such as acne, rosacea and / or atopic dermatitis. It is also desirable to provide a formulation that is suitable for wound healing and care of allergic skin. Summary of the invention

[0019] The present invention is a topical formulation comprising one or more antimicrobial peptides (AMPs) and one or more compounds selected from skin soothing compounds, skin barrier enhancing compounds and / or flavonoids. Thus, the topical formulation comprises one or more antimicrobial peptides and a compound combination of one or more compounds selected from the group of skin soothing compounds, selected from compounds that enhance the skin barrier and / or selected from flavonoids. In the context of the present invention, skin soothing compounds, compounds that enhance the skin barrier and / or flavonoids are also referred to as "combination partners", "combination compounds" or "combination partner compounds".

[0020] As described in WO2022106667 A1, it is preferred to select a thiazolidine-based According to the present invention, the term "thiazolidine-based cyclic peptide compounds" refers to "Synthetic peptide compounds containing thiazolidine building blocks" refers in particular to compounds containing at least one thiazolidine or Those peptide compounds that are based on oxazolidine building blocks.

[0021] It is therefore particularly preferred that the preparations according to the invention contain one or more antimicrobial peptides which are cyclic peptide compounds of formula (I):

[0022] (I)

[0023] in:

[0024] -X and Y 1 To Y 5 Each selected from: methyl, ethyl, n-propyl (having the formula CH3 -CH 2 -CH 2 -), 2-propenyl (having the formula H 2 C=CH-CH 2 -), 1-methylethyl (or isopropyl, having the formula (CH 3 ) 2 CH-), n-butyl (having the formula CH 3 -CH 2 -CH 2 -CH 2 -), 2-methylpropyl (or isobutyl, having the formula (CH 3 ) 2 CH-CH 2 -), 1-methylpropyl (or butane-2-yl or sec-butyl, having the formula CH 3 -CH 2 -CH(CH 3 )-), 1,1-dimethylethyl (or having the formula (CH 3 ) 3 CH-), n-pentyl (having the formula CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -), 3-methylbutyl (or isopentyl, having the formula (CH 3 ) 2 CH-CH 2 -CH 2 -), benzyl (or a phenyl group having the formula 2 -Bn), propargyl (or having the formula HC≡C-CH 2 -ethynylmethyl), 1H-indol-3-ylmethyl (having the formula ), 1N-methyl-1H-indol-3-ylmethyl (having the formula ), 3-benzothienylmethyl (having the formula ), 1-naphthylmethyl (having the formula ), 9-anthrylmethyl (having the formula ) and pyrenylmethyl (i.e., having the formula 1-pyrenylmethyl, having the formula 2-pyrenylmethyl);

[0025] - Z is equal to O or S;

[0026] - R and R' are each selected from H, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl (isobutyl), 1-methylpropyl (butan-2-yl or sec-butyl), benzyl and propargyl, provided that when R is H, R' is not H;

[0027] - Directly bonded to substituent Y in sequence 1 , Y 2 , Y 3 , Y 4 , Y 5 The C atoms on X and X each have an alternating absolute stereochemical configuration; and

[0028] - when Z is O, the carbon atom connected to the substituent X and the thiazolidine or The C atom at position 4 of the oxazolidine ring has the same absolute stereochemical configuration, and when Z is S, has the opposite absolute stereochemical configuration;

[0029] The condition is that if X, Y 1 , Y 4 and Y 5 is 1-methylethyl, then Y 2 is 1H-indol-3-yl, Y 3 is 2-methylpropyl, R is H and R' is methyl, Z is not O; and salts thereof, solvates thereof, and solvates of salts thereof.

[0030] The following explanations regarding the various substituents and parameters apply equally to all aspects and embodiments of the present invention.

[0031] With some exceptions, the parameters X and Y 1 To Y 5 The term "individually selected" in relation to R and R' essentially means that these substituents may in each case represent the same radical from the corresponding lists above or in each case represent different radicals from these lists. In the cyclic compounds of the formula (I) according to the invention, if X, Y 1 , Y 4 and Y 5 is 1-methylethyl, Y 2 is 1H-indol-3-ylmethyl, Y 3 is 2-methylpropyl, R is H and R' is methyl, then Z is not O. In addition, for the substituents R and R' of the present invention, when R is H, R' is not H.

[0032] Within the meaning of the present invention, the substituents X, Y 1 To Y 5 The residues listed as R, R and R' are also known to those skilled in the art as follows (wherein the "-" at the end of the corresponding simplified structural formula or the " ” indicates the position at which the residue is attached to the compound in question in each case).

[0033] For the purposes of the present invention, the radical methyl has the formula CH3 - and is also abbreviated as "Me". In the present invention, a compound having the formula CH 3 -CH 2 -The residue ethyl is also abbreviated as "Et". The residue n-propyl has the formula CH 3 -CH 2 -CH 2 -. The residue 2-propenyl has the formula H 2 C=CH-CH 2 The residue 1-methylethyl within the meaning of the present invention is also known to those skilled in the art as isopropyl and has the formula (CH 3 ) 2 CH-. The residue n-butyl has the formula CH 3 -CH 2 -CH 2 -CH 2 The residue 2-methylpropyl within the meaning of the present invention is also known to the person skilled in the art as isobutyl and has the formula (CH 3 ) 2 CH-CH 2 -. The residue 1-methylpropyl is also known to those skilled in the art as butan-2-yl or sec-butyl and has the formula CH 3 -CH 2 -CH(CH 3 The residue 1,1-dimethylethyl within the meaning of the present invention is also known to the person skilled in the art as tert-butyl and has the formula (CH 3 ) 3 The residue n-pentyl has the formula CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -. The residue 3-methylbutyl is also known to those skilled in the art as isopentyl and has the formula (CH 3 ) 2 CH-CH 2 -CH 2 -.

[0034] The radical benzyl (or 1-phenylmethyl) within the meaning of the present invention is also abbreviated to "Bn" and has the formula phenyl-CH 2 -. The residue propargyl is also known to the person skilled in the art as ethynylmethyl or 2-propynyl and has the formula HC≡C—CH 2 -. The residue 1H-indol-3-ylmethyl within the meaning of the present invention is also called indol-3-ylmethyl and has the formula The residue 1N-methyl-1H-indol-3-ylmethyl within the meaning of the present invention has the formula The residue 3-benzothienylmethyl within the meaning of the present invention has the formula The residue 1-naphthylmethyl within the meaning of the present invention has the formula The residue 9-anthrylmethyl has the formula .

[0035] As used herein, the residue pyrenylmethyl (or pyrenylmethyl) denotes a pyrene ring which is linked via one of its exocyclic carbon atoms C1 to C10 to a methyl residue which in turn serves as the point of attachment for the overall pyrenylmethyl residue, i.e. 1-pyrenylmethyl, 2-pyrenylmethyl, 3-pyrenylmethyl, 4-pyrenylmethyl, 5-pyrenylmethyl, etc. (or 1-pyrenylmethyl, 2-pyrenylmethyl, 3-pyrenylmethyl, 4-pyrenylmethyl, 5-pyrenylmethyl, etc.). The residue 1-pyrenylmethyl (or (1-pyrenyl)methyl, pyren-1-ylmethyl or (pyren-1-yl)methyl) for example has the formula The residue 2-pyrenylmethyl (or (2-pyrenyl)methyl, pyren-2-ylmethyl or (pyren-2-yl)methyl) has, for example, the formula .

[0036] The cyclic compound according to the present invention falling within the formula (I) is composed of five amino acid derivatives and a thiazolidine or The term "amino acid derivative" in the sense of the present invention is generally understood to mean the classical 20 natural L- and D-α-amino acids and their diastereoisomers, but also their modified derivatives with deviating residues (R). The cyclic compounds of formula (I) according to the present invention only contain amino acid derivatives with residues (R) corresponding to the residues for the substituent Y 1 To Y 5 Defined residues.

[0037] Thiazolidine within the meaning of the present invention or The oxazolidine building blocks contain a 1,3-thiazolidine ring or a 1,3- A thiazolidine ring which is attached at the 2-position to a carbon atom (C atom) which in turn is attached to a substituent X (also attached to an amino group). The positions in the oxazolidine ring are derived from standard nomenclature known to those skilled in the art, namely:

[0038]

[0039] wherein Z is S or O, and the numbers 1-5 define the positions in the ring.

[0040] Thiazolidine or The oxazolidine building block is a 1,3-thiazolidine ring or a 1,3- The oxazolidine ring is linked to the carboxyl group in the free state (i.e. not integrated into the peptide derivative) at the 4-position and in the linear peptide derivative (i.e. in the linear precursor before cyclization to the cyclic compound according to the invention) or in the cyclic peptide derivative (i.e. in the cyclic compound according to the invention) is linked via the amide group (i.e. in the thiazolidine or The C-terminus of the thiazolidine building block) is linked to the peptide derivative backbone; in linear peptide derivatives, only the thiazolidine or In the case where the oxazolidine building block is not C-terminal, a 1,3-thiazolidine ring or a 1,3 The oxazolidine ring is bound to residues R and R' at the 5-position.

[0041] In the cyclic compound of formula (I) according to the present invention, the substituent Y is directly connected to 1 , Y 2 , Y 3 , Y 4 , Y 5 The C atoms on X each have an alternating absolute and relative stereochemical configuration. This means, for example, that in the cyclic compounds of formula (I) according to the invention, each directly consecutive amino acid derivative has an alternating absolute and relative stereochemical configuration of the α-carbon (Cα).

[0042] The terms "(alternating) absolute stereochemical configuration" and "(alternating) relative stereochemical configuration" are known to those 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 does not refer to the relative D / L nomenclature). Thus, the "alternating absolute stereochemical configuration" as used in the context of the present invention refers to the absolute stereochemical configuration of the substituent Y when directly attached to the substituent Y. 1 To Y 5 or X is R-configured, the closest C atom along the chain backbone of the cyclic compound of formula (I) on either side (which is also directly connected to the substituent Y) 1 To Y 5 or X) has S configuration. For example, if in the cyclic compound of formula (I), C Y3 (i.e., directly connected to the substituent Y 3 The C atom of Y4 (and C Y2 ) has S configuration, C Y5 With R configuration, C X has S configuration, etc. On the other hand, if C Y3 With S configuration, C Y4 (and C Y2 ) has R configuration, C Y5 With S configuration, C X Has R configuration, and so on.

[0043] The term "alternating relative stereochemical configuration" used in the context of the present invention should also be understood in this sense. The term "relative stereochemical configuration" used in the context of the present invention refers to the D, L nomenclature of amino acids and their derivatives. Therefore, the "alternating relative stereochemical configuration" used in the context of the present invention refers to the relative stereochemical configuration of the amino acid when directly attached to the substituent Y. 1 To Y 5 or when the relative stereochemical configuration of the C atom of X is L configuration, the closest C atom along the chain backbone of the cyclic compound (I) on either side (which is also directly connected to the substituent Y 1 To Y 5 or X) has D configuration. For example, if in the cyclic compound of formula (I), C Y4 (i.e., directly connected to the substituent Y 4 The C atom of Y5 (and C Y3 ) has D-configuration, C X With L-configuration, C Y1 has D-configuration, etc. On the other hand, if C Y4 With D configuration, then C Y5 (and C Y3 ) has L configuration, C X With D configuration, C Y1 Has an L configuration, and so on.

[0044] Similarly, the terms "opposite absolute stereochemical configuration" and "same absolute stereochemical configuration" and "opposite relative stereochemical configuration" or "same relative stereochemical configuration" should be understood in this sense. That is, in the sense of the present invention, "opposite absolute stereochemical configuration" means that when one absolute stereochemical configuration is the R configuration, the opposite absolute stereochemical configuration is the S configuration. In the sense of the present invention, "same absolute stereochemical configuration" means that if one absolute configuration is the R configuration, the same absolute configuration is also the R configuration. This applies similarly to the relative stereochemical configuration, so that "opposite relative stereochemical configuration" in the sense of the present invention means that if one relative stereochemical configuration is the D configuration, the opposite relative stereochemical configuration is the L configuration, and so on.

[0045] For the cyclic peptide compound of formula (I) (and thiazolidine or The corresponding opposite or same absolute stereochemical configuration of the oxazolidine building block, as described below) only specifies the alternating stereochemical configuration; on the other hand no specific assignment of the absolute or relative stereochemical configuration of the individual C atoms in the cyclic peptide compounds of formula (I) according to the invention is specified.

[0046] In particular, the cyclic peptide compounds of formula (I) can therefore, for example, depending on their specific structure, exist in stereoisomeric forms (enantiomers, diastereomers). Therefore, the present invention also comprises enantiomers or diastereomers and their corresponding mixtures. The stereoisomerically single components can be separated from such mixtures of enantiomers and / or diastereomers in a known manner. When the compounds according to the invention can occur in tautomeric forms, the present invention includes all tautomeric forms.

[0047] In the thiazolidine or In the oxazolidine building block, the C atom directly connected to the substituent X is also connected to the thiazolidine or The 2-position of the oxazolidine ring.

[0048] In the cyclic compound of formula (I) according to the present invention, when Z is O (ie, if it is oxazolidine ring), directly connected to the C atom of the substituent X and in the thiazolidine or The C atom at position 4 of the oxazolidine ring has the same absolute stereochemical configuration, and when Z is S (i.e. if it is a thiazolidine ring), has the opposite absolute stereochemical configuration. The terms "opposite absolute stereochemical configuration" and "same absolute stereochemical configuration" are to be understood as defined above. This means, for example, that if the cyclic peptide compound (I) has a C atom at position 4 with an R configuration If the cyclic peptide compound (I) has a thiazolidine ring having an R configuration at the 4-position, the C atom directly connected to the substituent X also has an R configuration, or if the cyclic peptide compound (I) has a thiazolidine ring having an R configuration at the 4-position, the C atom directly connected to the substituent X has an S configuration.

[0049] Salts preferably used for the purposes of the present invention are physiologically (especially cosmetically) acceptable salts of compounds of formula (I) according to the invention. However, salts which are not suitable for cosmetic applications per se are also included, but which can be used, for example, to separate or purify compounds of formula (I) according to the invention.

[0050] Examples of cosmetically acceptable salts of cyclic compounds of formula (I) include salts with inorganic bases, such as ammonium salts, alkali metal salts, in particular sodium salts or potassium salts, alkaline earth metal salts, in particular magnesium salts or calcium salts; salts with 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.

[0051] Examples of cosmetically acceptable salts of compounds of formula (I) also include salts of inorganic acids, for example 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.

[0052] Solvates in the sense of the present invention refer to the following forms of compounds of formula (I) according to the present invention, which form solid or liquid complexes by coordination with solvent molecules. Hydrates are special forms of solvates, in which coordination with water occurs. Compounds of formula (I) according to the present invention can also be complexed, for example, with iron, calcium, etc., in which compounds of formula (I) can serve as ligands, so that corresponding complexes are also the subject of the present invention.

[0053] In a preferred embodiment of the cyclic compound of formula (I) according to the present invention, the substituent X is selected from 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-anthrylmethyl and pyrenylmethyl (wherein 1-pyrenylmethyl or 2-pyrenylmethyl, preferably 1-pyrenylmethyl is selected as pyrenylmethyl). In another preferred embodiment, X is selected from n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, benzyl, propargyl and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl). In yet another preferred embodiment, X is selected from 1-methylethyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, benzyl, propargyl and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl). In another preferred embodiment, X is selected from n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl and 3-methylbutyl.

[0054] In a preferred embodiment of the present invention, the substituent Y 1 To Y 5Each of them is selected from 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-anthrylmethyl and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl). In another preferred embodiment of the present invention, Y 1 To Y 5 Each is selected from methyl, 1-methylethyl, 2-methylpropyl, 1-methylpropyl, benzyl, 1H-indol-3-yl-methyl, propargyl and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl).

[0055] For example, Y 2 Preferred residues are 1H-indol-3-ylmethyl, 1N-methyl-1H-indol-3-ylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl, 9-anthrylmethyl and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl), more preferably 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl), in which case Y 5 Preferably, it is not an aromatic residue (especially not 1H-indol-3-ylmethyl or pyrenylmethyl). 3 Preferred residues of are, for example, n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl and 1,1-dimethylethyl, with 2-methylpropyl being particularly preferred. 4 , preferably the residue is, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, particularly preferably 1-methylethyl. 5 Preferred residues are, for example, 1H-indol-3-ylmethyl, 1N-methyl-1H-indol-3-ylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl, 9-anthrylmethyl and pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl), more preferably 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl), more preferably, for example, 1H-indol-3-ylmethyl, in which case Y 2 It is preferably not an aromatic residue (especially not 1H-indol-3-ylmethyl or pyrenylmethyl).

[0056] In another preferred embodiment of the present invention, if Y 5 is 1-methylethyl, then Y 2is 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl), or if Y 5 is 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl), then Y 2 In another preferred embodiment of the present invention, Y 2 is 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl), and Y 5 is 1-methylethyl, or Y 2 is 1-methylethyl, and Y 5 It is 1H-indol-3-ylmethyl or pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl).

[0057] In a particularly preferred embodiment of the cyclic compound of formula (I) according to the invention, Z is S. In another preferred embodiment of the cyclic compound of formula (I) according to the invention, Z is O.

[0058] In a preferred embodiment of the cyclic compound of formula (I) according to the present invention, R and R' are each selected from H, methyl, ethyl, n-propyl, 1-methylethyl, benzyl and propargyl. In another preferred embodiment of the cyclic compound of formula (I) according to the present invention, R and R' are each selected from H, methyl, ethyl and propargyl. In another preferred embodiment of the cyclic compound of formula (I), R and R' are both methyl. In another preferred embodiment of the cyclic compound of formula (I), R is H; and R' is methyl, ethyl, n-propyl, 1-methylethyl, benzyl or propargyl.

[0059] In a specific preferred embodiment of the cyclic compound of formula (I) according to the present invention, X is selected from 1-methylethyl, 2-methylpropyl, 1-methylpropyl, benzyl, propargyl, pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl); Y 1 To Y 5 are each selected from methyl, ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 1-methylpropyl, benzyl, 1H-indol-3-ylmethyl, propargyl, pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl); Z is O or S; and / or R and R' are each selected from H, methyl, ethyl and propargyl, with the proviso that when R is H, R' is not H.

[0060] With the substituent Y 2 or substituent Y 5Compared to the cyclic compound of formula (I) wherein the substituent Y is 1H-indol-3-ylmethyl 2 or substituent Y 5 (But preferably not at position Y at the same time 2 and Y 5 The cyclic compound of formula (I) wherein the substituent Y is pyrenylmethyl has high non-selective antimicrobial activity, especially non-selective antibacterial activity. In a preferred embodiment of the cyclic compound of formula (I), the substituent Y is 2 or substituent Y 5 is pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl). In another preferred embodiment of the cyclic compound of formula (I), the substituent Y 2 or substituent Y 5 is pyrenylmethyl (preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl), preferably without other substituents X and Y 1 To Y 5 It is pyrenylmethyl.

[0061] In another preferred embodiment of the cyclic peptide compound of formula (I), R and R' are both methyl; if Y 5 is 1-methylethyl, then Y 2 is 1H-indol-3-ylmethyl or pyrenylmethyl, or if Y 5 is 1H-indol-3-ylmethyl or pyrenylmethyl, then Y 2 is 1-methylethyl; and X is 1-methylethyl. In another preferred embodiment of the cyclic compound of formula (I), R and R' are both methyl; Y 2 is 1H-indol-3-ylmethyl or pyrenylmethyl, and Y 5 is 1-methylethyl, or Y 2 is 1-methylethyl, and Y 5 is 1H-indol-3-ylmethyl or pyrenylmethyl; X is 1-methylethyl; and Z is preferably S. The pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl.

[0062] In another preferred embodiment of the cyclic compound of formula (I), R is H; R' is methyl, ethyl, n-propyl, 1-methylethyl, benzyl or propargyl; if Y 5 is 1-methylethyl, then Y 2 is 1H-indol-3-ylmethyl or pyrenylmethyl, or if Y 5 is 1H-indol-3-ylmethyl or pyrenylmethyl, then Y 2is 1-methylethyl; 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; Y 2 is 1H-indol-3-ylmethyl or pyrenylmethyl, and Y 5 is 1-methylethyl, or Y 2 is 1-methylethyl, and Y 5 is 1H-indol-3-ylmethyl or pyrenylmethyl; X is 1-methylethyl; and Z is preferably S. The pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl.

[0063] In another preferred embodiment of the cyclic compound of formula (I), R is H; R' is methyl, n-propyl, 1-methylethyl, benzyl or propargyl; if Y 5 is 1-methylethyl, then Y 2 is 1H-indol-3-ylmethyl or pyrenylmethyl, or if Y 5 is 1H-indol-3-ylmethyl or pyrenylmethyl, then Y 2 is 1-methylethyl; X is 1-methylethyl or 2-methylpropyl. In another preferred embodiment of the cyclic compound of formula (I), R is H; R' is methyl, n-propyl, 1-methylethyl, benzyl or propargyl; Y 2 is 1H-indol-3-ylmethyl or pyrenylmethyl, and Y 5 is 1-methylethyl, or Y 2 is 1-methylethyl, and Y 5 is 1H-indol-3-ylmethyl or pyrenylmethyl; X is 1-methylethyl or 2-methylpropyl. The pyrenylmethyl is preferably 1-pyrenylmethyl or 2-pyrenylmethyl, more preferably 1-pyrenylmethyl.

[0064] In another preferred embodiment of the cyclic compound of formula (I), R and R' are both 1-methylethyl; Y 2 In another preferred embodiment of the cyclic compound of formula (I), R and R' are each H or methyl; Y 2 is 1H-indol-3-yl; and X is 1-methylethyl.

[0065] In another preferred embodiment, if Y 5 is pyrenylmethyl, then directly connected to the substituent Y 5 The C atom of is present in the cyclic compound (I) according to the invention in the (absolute) S-configuration (ie L-configuration).

[0066] In a specific preferred embodiment, the cyclic compound of formula (I) is characterized by one of the following formulae I.1a to I.24a:

[0067]

[0068]

[0069]

[0070] .

[0071] In further specific preferred embodiments, the cyclic compound of formula (I) is characterized by one of the following formulae I.1 to I.25:

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] .

[0078] Particularly preferred are cyclic compounds of the formulae I.1a to I.4a and I.1 to I.4, and cyclic compounds of the formulae I.19a to I.24a and I.19 to I.25. In a further preferred embodiment, the presence of Oxazolidine ring instead of thiazolidine ring.

[0079] According to the present invention, it is particularly preferred to select an antimicrobial peptide having the following structure

[0080]

[0081] , which in particular has the formula C 48 H 67 N 9 O 6 S.

[0082] This preferred selected peptide is referred to as ISW1-2 according to the invention. Surprisingly, it exhibits a beneficial antibacterial effect.

[0083] ISW1-2 is a peptide of D- and L-amino acids produced completely synthetically by cyclization of the thiazolidine ring. It is a derivative of the natural compound lugdunin, which is formed by the skin commensal bacterium Staphylococcus lugdunensis, which is naturally present in the human nose, among other things.

[0084] The mode of action of this peptide is particularly noteworthy. The antibacterial effect is closely related to the decrease in bacterial membrane potential. Because the enantiomers of this peptide have the same antimicrobial activity, which excludes stereospecific interactions with the target molecule, no specific target is directed. Its mechanism of action is based on proton transport while maintaining membrane integrity.

[0085] The peptides are known to support the innate immune response of the skin, acting in synergy with factors derived from the host and the microbiome, so that pathogenic bacteria are combated at different levels and recolonization with, for example, Staphylococcus aureus (S. aureus) can be counteracted.

[0086] In combination with one or more compounds selected from skin soothing compounds, skin barrier enhancing compounds and / or flavonoids, the antimicrobial peptides, in particular ISW1-2, exhibit a synergistic antimicrobial effect.

[0087] Flavonoids are advantageously selected as combination partners for AMP.

[0088] Licoricealcone A, Licoricealcone C, Licoricealcone E and / or glabripenol (especially Licoricealcone A) are advantageously selected as flavonoids.

[0089] In addition to the direct use of flavonoids, extracts, solutions and mixtures containing these flavonoids may also be used, for example the plant extract Glycyrrhiza inflata.

[0090] Licoricechalcone A has the following structure:

[0091] .

[0092] Other preferred flavonoids are, for example, Licoricechalcone C

[0093]

[0094] Licorice Chalcone E

[0095]

[0096] Wako Glycyrrhizin

[0097] .

[0098] Therefore, the topical preparation according to the invention preferably contains flavonoids, extracts containing flavonoids, solutions containing flavonoids and / or mixtures containing flavonoids, wherein the flavonoids are in particular licochalcone, and preferably licochalcone A, licochalcone C, licochalcone E and / or glabridol.

[0099] In a particularly preferred embodiment, the formulation comprises The peptide, namely peptide ISW1-2, and one or more licorice chalcone selected from licorice chalcone A, licorice chalcone C, licorice chalcone E and / or licorice alcohol.

[0100] In a preferred embodiment of the present invention, the formulation comprises peptide ISW1-2 and licoricechalcone A. In another preferred embodiment of the present invention, the formulation comprises peptide ISW1-2 and licoricechalcone C. In another preferred embodiment of the present invention, the formulation comprises peptide ISW1-2 and licoricechalcone E. In another preferred embodiment of the present invention, the formulation comprises peptide ISW1-2 and glabriquitin.

[0101] ISW1-2 has antimicrobial activity against Gram-positive bacteria in vitro already at very low concentrations (3.1 μg / ml against Staphylococcus aureus). Surprisingly, skin pathogens such as S. aureus (the increase of which is associated with the severity of atopy and has also been shown to be associated with P. acnes in acne) are particularly sensitive to this active ingredient.

[0102] ISW1-2 has an antimicrobial effect even in the micromolar range. The minimum inhibitory concentration (MIC) of ISW1-2 against Staphylococcus aureus is 3.1 μg / ml (0.00031%).

[0103] Preferably, in the cosmetic formulation, the proportion of one or more AMPs, in particular ISW1-2, is advantageously 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.

[0104] However, these small ratios are highly effective, primarily because of the unexpected reinforcement that occurs due to the presence of at least one combination partner.

[0105] Surprisingly, the synergistic effects found in combination partner compounds that strengthen the skin barrier (eg omega-6 fatty acids) and / or soothe the skin (eg licoricechalcone A, menthoxypropanediol) were also found in flavonoids.

[0106] Another advantage is that by reducing the effective amount, the cost of producing and incorporating these active ingredients can also be reduced. Furthermore, the resulting cost reduction means that they can be more widely used in cosmetic applications.

[0107] The combination partners selected from the group consisting of skin-soothing compounds, skin barrier-enhancing compounds and / or flavonoids are advantageously used in a proportion within the range of 0.0001% to 5% by weight, based on the total mass of the preparation, wherein the figures in % by weight relate in particular to the sum of the combination partners in the total mass of the preparation.

[0108] Advantageously, in particular when using emulsions, 0.0001 to 5% by weight, in particular 0.001 to 1% by weight, in particular 0.005 to 0.15% by weight of these combination compounds, in particular licochalcone, preferably licochalcone A or an extract containing licochalcone, is selected, in each case based on the total weight of the preparation. The figures in % by weight refer in particular to the sum of the combination compounds in the total weight of the preparation.

[0109] 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 mass of the preparation, and one or more flavonoids selected from licochalcone A, licochalcone C, licochalcone E and glabripenol in an amount of 0.0001 to 5% by weight, in particular 0.001 to 1% by weight, in particular 0.005 to 0.15% by weight, based on the total mass of the preparation.

[0110] In another 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 mass of the preparation, and a flavonoid selected from licochalcone A, licochalcone C, licochalcone E and glabridol in an amount of 0.0001% to 5% by weight, in particular 0.001% to 1% by weight, in particular 0.005% to 0.15% by weight, based on the total mass of the preparation.

[0111] In another particularly preferred embodiment, the preparation according to the invention comprises the 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 mass of the preparation, and licochalcone A in an amount of 0.0001% to 5% by weight, in particular 0.001% to 1% by weight, in particular 0.005% to 0.15% by weight, based on the total mass of the preparation.

[0112] In another particularly preferred embodiment, the preparation according to the invention comprises the 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 mass of the preparation, and licochalcone C in an amount of 0.0001% to 5% by weight, in particular 0.001% to 1% by weight, in particular 0.005% to 0.15% by weight, based on the total mass of the preparation.

[0113] In another particularly preferred embodiment, the preparation according to the invention comprises the 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 mass of the preparation, and licochalcone E in an amount of 0.0001% to 5% by weight, in particular 0.001% to 1% by weight, in particular 0.005% to 0.15% by weight, based on the total mass of the preparation.

[0114] In another particularly preferred embodiment, the preparation according to the invention comprises the 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 mass of the preparation, and glabridol in an amount of 0.0001% to 5% by weight, in particular 0.001% to 1% by weight, in particular 0.005% to 0.15% by weight, based on the total mass of the preparation.

[0115] The formulations of the present invention show a synergistic effect, so that even at low applied concentrations of antimicrobial peptides, in particular ISW1-2, antimicrobial efficacy against atopic dermatitis and / or acne-associated skin pathogens (Staphylococcus aureus, Propionibacterium acnes) is ensured. Surprisingly, this synergistic effect occurs in pathogenic bacteria S. aureus and Propionibacterium acnes, but not in skin commensal bacteria S. epidermidis.

[0116] This selective effect is surprising and offers a huge advantage over conventional treatments, which often affect the skin's entire microbiome.

[0117] Dysbiosis with increased bacterial load of S. aureus and decreased commensal skin bacteria is associated with worsening of the skin condition in atopic patients. Using the combination according to the invention, in particular ISW1-2 and a flavonoid, advantageously Licoricechalcone A, it was found that an antimicrobial composition that minimizes colonization of exuded S. aureus has no cytotoxic effect on skin cells (keratinocytes) and proves stable to proteolytic degradation by the skin's own enzymes.

[0118] Specifically, soothing refers to reducing or completely preventing skin irritation, itching, tightness and / or redness.

[0119] Strengthening the skin barrier means building a protective skin membrane, promoting skin cohesion and / or minimizing or reducing harmful external influences.

[0120] The barrier is the outermost layer of the skin, which provides protection, retains moisture and protects against external irritants such as bacteria, allergens and environmental influences.

[0121] According to the invention, compounds having these properties are compounds which soothe the skin or strengthen the skin barrier.

[0122] As skin soothing combination compounds that can be combined with the AMP according to the present invention, one or more compounds are preferably selected from:

[0123] ▪Menthoxypropanediol

[0124] ▪Poldocanol

[0125] ▪Allantoin

[0126] ▪Vitamins, especially vitamins A, B5, and E

[0127] ▪Hyaluronic acid or its salts

[0128] ▪ Plant extracts, such as calendula, witch hazel, oatmeal

[0129] ▪Jojoba oil

[0130] The combination compounds that strengthen the skin barrier and can be combined with the AMP according to the invention are preferably selected from:

[0131] Omega-6 fatty acids

[0132] ▪Ceramide

[0133] ▪Shea butter

[0134] ▪Argan oil

[0135] According to the present invention, a preparation is advantageously provided, which, in addition to the antimicrobial peptide, in particular ISW1-2, further comprises licochalcones, in particular licochalcones A, C and / or E, glabridol or extracts, solutions or mixtures thereof. Advantageously, it further comprises one or more compounds selected from skin soothing compounds and / or compounds that enhance the skin barrier.

[0136] If the active ingredient belongs to both the group of skin soothing compounds and the group of skin barrier enhancing compounds, two or more different compounds from both groups are also included in the embodiments intended to include compounds from both groups.

[0137] According to the invention, destructive bacteria (Propionibacterium acnes, Staphylococcus aureus) are significantly inhibited in their growth, while beneficial bacteria (Staphylococcus epidermidis) stabilizing the skin microbiome are not disturbed.

[0138] This enables the selective enhancement of the healthy skin microbiome.

[0139] In a preferred embodiment, the topical preparations according to the invention are cosmetic and / or dermatological preparations, preferably based on emulsions.

[0140] In view of the advantageous properties, there are various possible uses for the topical preparations according to the invention. Thus, the non-therapeutic use of the preparations 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.

[0141] Likewise, the preparations according to the invention can be advantageously used for skin care, in particular for the care, prevention and treatment of skin damaged by atopic dermatitis or acne.

[0142] Likewise advantageously, the preparations according to the invention can be used to treat atopic dermatitis, acne and / or allergic contact dermatitis.

[0143] The preparations according to the invention can also be used advantageously for wound healing and for the care of allergic skin.

[0144] The present invention therefore also relates to a non-therapeutic method for treating the skin, in particular a cosmetic method, in which the topical preparation according to the invention is applied to the skin.

[0145] In this method, the non-therapeutic skin treatment is preferably used for caring for the skin, for supporting wound healing of the skin and / or for treating skin damaged by atopic dermatitis or acne. In this method, the non-therapeutic skin treatment for caring for the skin is preferably used for caring for allergic skin.

[0146] The preparations according to the invention and the combinations of compounds contained therein can also be used for medical administration. Therefore, in another aspect, the invention relates to a combination of compounds comprising one or more antimicrobial peptides and one or more compounds selected from skin soothing compounds, compounds that enhance the skin barrier and / or flavonoids, said combination being used for the treatment of inflammatory skin diseases and / or indications, in particular acne, rosacea and / or atopic dermatitis.

[0147] Suitable and preferred embodiments described in conjunction with the definition of the topical preparation according to the invention are correspondingly also preferred or suitable for this aspect of the invention.

[0148] Preferably, a thiazolidine-based The synthesis of cyclic peptide compounds based on oxazolidine building blocks as combination peptides.

[0149] In a particularly preferred embodiment, among the combinations of compounds according to the invention, a compound having the structure

[0150] of peptides.

[0151] In another preferred embodiment, the topical preparations according to the invention contain 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 glabridol.

[0152] It is also preferred that the combinations of compounds according to the invention are used in cosmetic and / or dermatological preparations.

[0153] Although the individual compounds of the combination according to the invention are known per se to the cosmetician, it was not known or possible to use this combination effectively, in particular in low concentrations.

[0154] Topically applicable preparations are now available which in particular lead to a reduction in the pathogenic bacteria Staphylococcus aureus and Propionibacterium acnes and at the same time achieve a balance in the skin commensal Staphylococcus epidermidis.

[0155] This leads to an improvement in skin conditions, especially in cases of acne or atopic dermatitis.

[0156] Unpleasant bacteria, such as Propionibacterium acnes, decreased on the skin, and pleasant bacteria, such as Staphylococcus epidermidis, remained the same.

[0157] 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.

[0158] The preparation of the present invention can be used in various application forms. Preferred application forms are gel, spray, serum, impregnation medium for soaking patches, wet wipes or masks.

[0159] The complex cosmetic compositions according to the invention may optionally comprise further customary auxiliaries and additives, such as thickeners, fillers, fragrances, colorants, active ingredients, vitamins, proteins, light stabilizers, stabilizers, insect repellents, salts, EDTA, other antimicrobial, proteolytic or keratolytic active substances, etc., provided that they are not excluded according to the invention.

[0160] According to the invention, one or more active ingredients selected from the following are preferably added to the formulation in order to be able to ensure the widest possible form of administration and individual care and treatment.

[0161] Advantageously, further active ingredients can be added to the preparations or application forms according to the invention, provided that they are not mentioned in the group of compounds according to the invention, such as preferably sebum-reducing active ingredients, itch-reducing active ingredients, anti-inflammatory, irritation-repairing, pain-reducing or antimicrobial active ingredients, such as dexpanthenol or natural additives, natural compounds, such as honey, chamomile or aloe vera.

[0162] Besides 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.

[0163] According to the invention, it is also preferred to add active ingredients directed against cell membranes, such as quaternary ammonium, octenidine or decanediol.

[0164] In particular, natural compounds such as cyclic and acyclic peptides of ribosomal and non-ribosomal (NRPS-derived) origin and cyclic and acyclic polyketides (PKS-derived) can be advantageously added according to the invention.

[0165] Other preferred active ingredients are enzymes, in particular cell wall hydrolases, such as lysozymes, lysozymes and chitinases, provided that they are compatible with the peptide and do not attack it.

[0166] It is particularly preferred to add one or more active ingredients selected from hydroxyacetophenone, salicylic acid, Q10 and / or thiamidol.

[0167] Other preferred additives may be selected from Ca, Mg, Al and / or Zn salts.

[0168] 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, tocopherol, carnitine, Garcinia cambogia, guarana C22, butyric acid, dibasic acid, ethylhexylglycerin, methylphenylbutanol, polyglyceryl-2 caprate, Polysaf 5600 polymer, silver citrate, zinc citrate, betaine, sea salt, taurine, SymSave H, DHA, resol, panthenol / dexpanthenol. DETAILED DESCRIPTION

[0169] Example

[0170] The antimicrobial and skin care effects of the combinations according to the invention and of the individual substances were examined in various tests.

[0171] a) In vitro studies

[0172] The effect of the preparations according to the invention on the growth of Propionibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis was investigated in an in vitro study.

[0173] Propionibacterium acnes DSM1897 was incubated under anaerobic conditions at 37°C. Overnight cultures were diluted 1:1000 in Caso medium (casein peptone 17 g / l; soy peptone 3 g / l; sodium chloride 5 g / l; glucose 2.5 g / l; potassium dihydrogen phosphate 2.5 g / l; pH 7.3 ± 0.2) and inoculated in microtiter plates. Different concentrations of plant extracts Glycyrrhiza inflata and Licorice Chalcone 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 non-inhibitory ISW1-2 concentration (0.00001% ISW1-2). The optical density (OD) was measured photometrically at a wavelength of 600 nm (OD600) to estimate the growth of the bacteria. Increasing values ​​indicate bacterial growth.

[0174] Unless otherwise stated, amounts refer to weight of compound per volume of medium, eg 1 μg / ml refers to 1 μg of Licoricechalcone A in 1 ml of medium. Percent amounts of ISW1-2 refer to the weight of ISW1-2 relative to the total weight of the corresponding test formulation.

[0175] Propionibacterium acnes 1897 was isolated from the presence of ISW1-2 ( Figure 1 shaded) and a non-inhibitory concentration of 0.00001% ISW1-2 ( Figure 1 , black) to which different concentrations of Licorice Chalcone A extract were added (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 culture medium.

[0176] The extract of Glycyrrhiza inflata was used as the licorice chalcone A extract, which contained 21% by weight of licorice chalcone A.

[0177] Figure 1 The results are shown.

[0178] By adding 1 μg / ml of licorice chalcone A extract to 0.00001% ISW1-2 in the culture medium, Propionibacterium acnes ( Figure 1 , middle column) no growth inhibition was observed.

[0179] Addition of 2 μg / ml of Licoricechalcone A extract to 0.00001% ISW1-2 in the culture medium resulted in significant inhibition of the growth of P. acnes.

[0180] Addition of Licoricechalcone A was tested in the same way (0 μg / ml = control; 1 μg / ml; 2 μg / ml).

[0181] Figure 2 These results are shown.

[0182] By adding 1 μg / ml licoricechalcone A to 0.00001% ISW1-2 in the culture medium, Propionibacterium acnes ( Figure 2 , middle column) no growth inhibition was observed.

[0183] Addition of 2 μg / ml licoricechalcone A to 0.00001% ISW1-2 in the culture medium resulted in significant inhibition of the growth of P. acnes ( Figure 2 right column, black).

[0184] Surprisingly, when licochalcone A was added, non-inhibitory amounts of antimicrobial peptides (ISW1-2) were able to exert an inhibitory effect on P. acnes ( Figure 1 and 2 In contrast, pure extracts or pure licoricechalcone A had only a minor inhibitory effect ( Figure 1 and Figure 2 left column, hatched).

[0185] In further studies the inhibition of Staphylococcus aureus was investigated.

[0186] Staphylococcus aureus DSM20231 and Staphylococcus epidermidis ATTC12228 were incubated at 37°C under aerobic conditions with constant shaking. Overnight cultures were diluted 1:10000 in MHB (Müller Hinton Broth: starch 1.5 g / l; meat extract 2.0 g / l; casein hydrolyzed peptone 17.5 g / l; pH: 7.4±0.2) and inoculated in microtiter plates. Different concentrations of the plant extract Glycyrrhiza inflata and flavonoids Licorice chalcone A, C and E (1 μg / ml, 2 μg / ml) were added, mixed and bacterial growth was observed over a period of 24 hours at 37°C. 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) was measured photometrically at a wavelength of 600 nm (OD600). Increased values ​​indicate bacterial growth (mean from three independent experiments).

[0187] Staphylococcus aureus DSM20231 was isolated from the culture medium without ISW1-2 ( Figure 3 , 5 , 7, 9) and 0.00002% of the non-inhibitory concentration of ISW1-2 ( Figure 4 , 6 , 8, 10) in the presence of different concentrations of licorice chalcone extracts; licorice chalcone A; licorice chalcone C and licorice chalcone E (0 μg / ml = control; 1 μg / ml; 2 μg / ml). Figures 3 to 10 Shown are bacterial growth over 24 h under different conditions (mean values ​​from three independent experiments).

[0188] Bacterial growth was measured by an increase in turbidity (OD600) in the culture medium, ie an increase in OD over time indicated bacterial growth.

[0189] The results are Figures 3 to 10 They show that the licorice chalcone extract and licorice chalcone act synergistically with ISW1-2. No growth of Staphylococcus aureus was observed with the addition of the combination of compounds according to the invention.

[0190] Figure 3 Bacterial growth with addition of Licorice Chalcone A extract (0%, control) and relatively low growth delay with addition of 1 μg or 2 μg are shown.

[0191] Figure 4 Shown are bacterial growth with addition of pure non-inhibitory ISW1-2 (0.00002%, control), and growth with addition of Licoricechalcone A extract (1 μg / ml, 2 μg / ml) to ISW1-2.

[0192] Figure 3 and4 The overall view makes it impressive that only the combination of compounds according to the invention leads to a significant inhibition of bacterial growth.

[0193] Similarly, ISW1-2 and licochalcone A ( Figure 5 and 6 ) showed that only the combination of the antimicrobial peptide according to the invention and the flavonoid (licochalcone A) resulted in a significant inhibition of bacterial growth.

[0194] Figure 7 and 8 Studies using ISW1-2 and Licorice Chalcone C are shown. Four different amounts of Licorice Chalcone 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 ).

[0195] Here, it can also be seen that only the compound combination according to the present invention ( Figure 8 ) resulted in significant inhibition of bacterial growth.

[0196] Although licochalcone C was less synergistic with ISW1-2 than licochalcone A, the synergistic effect was present and sufficient to affect bacterial growth ( Figure 8 ). Advantageously and according to the invention, the concentration of the partner (in this case Licoricechalcone C) can be increased (for example to 4 μg / ml) to completely inhibit the growth of S. aureus.

[0197] Fig. 9 and 10 Studies using ISW1-2 and licochalcone E are shown. Three different amounts of licochalcone E (0%, control; 1 μg / ml; 2 μg / ml) were used, either alone ( Fig. 9 ) and together with 0.00002% ISW1-2 ( Fig.10 ).

[0198] Licorice chalcone E again had a better synergistic effect with ISW1-2, similar to Licorice chalcone A, and there was no growth of S. aureus in the combination of compounds according to the invention ( Fig.10 ).

[0199] In a further comparative study, the effects of the combination of compounds according to the invention were also observed on skin commensal bacteria such as Staphylococcus epidermidis ( Figures 11 to 18 ) to confirm.

[0200] For this purpose, Staphylococcus epidermidis 12228 was cultured in the absence of ISW1-2 ( Fig.11 , 13, 15, 17) and 0.00002% of the non-inhibitory concentration of ISW1-2 ( Fig.12 , 14 , 16, 18) incubated with different concentrations of licorice chalcone extracts; licorice chalcone A; licorice chalcone C and licorice chalcone E (0 μg / ml = control; 1 μg / ml; 2 μg / ml). Shown are bacterial growth within 24 h under different conditions (mean values ​​from three independent experiments).

[0201] Bacterial growth was measured by an increase in turbidity (OD600) in the culture medium, ie an increase in OD over time indicated bacterial growth.

[0202] Neither the licorice chalcone extract nor licorice chalcone A, C, E or their combination with ISW1-2 showed any effect on bacterial growth of skin commensal bacteria. No effect of the combination according to the invention on the growth of Staphylococcus epidermidis was observed ( Figures 11 to 18 ).

[0203] b) In vivo studies

[0204] The efficacy of the topical formulations according to the invention was also tested in vivo.

[0205] To this end, three different formulations were prepared as cosmetic formulas. The first formulation was a control formulation (vehicle) containing only a carrier composition. The second formulation (+ISW1-2) contained a carrier composition and 0.015% ISW1-2. The third formulation (+ISW1-2+licochalcone extract) contained a carrier composition, 0.015% ISW1-2, and an additional 0.025% licochalcone extract (Glycyrrhiza inflata extract with 21% by weight licochalcone A).

[0206] The three formulations were tested on 6 healthy skin volunteers. Three areas (5 cm x 5 cm) were marked on the upper back of each subject, and samples were taken from each area with a flocked swab (FloqSwab®) to determine the bacterial colonization of the skin before application of the three formulations. The three formulations were then applied to all test subjects, with 75 μl (3 μl / cm 2 ) was applied to one of the three marked areas. Two applications were performed daily during the 48-hour test period, i.e. a total of 5 times. After 48 hours, the sample was taken again with a flocked swab.

[0207] To determine the bacterial count, samples before (0 h) and after (48 h) application were plated, inoculated, incubated aerobically and colonies were counted.

[0208] The results are Fig.19. When the control formulation (vehicle) was used, no change in bacterial counts on the skin was observed. By using the +ISW1-2 formulation, the bacterial counts were approximately halved. When the third formulation was used, a significantly greater reduction in bacterial counts was observed, indicating a synergistic effect of ISW1-2 and licorice chalcone extract.

[0209] c) Examples of cosmetic preparations

[0210] Examples of cosmetic preparations according to the invention are listed in the table below. The numbers refer to proportions by weight, based on the total mass of the preparation.

[0211]

Claims

1. A topical formulation comprising a combination of one or more antimicrobial peptides and a compound selected from the group consisting of a skin soothing compound, a skin barrier enhancing compound and / or a flavonoid.

2. The preparation according to claim 1, characterized in that Selection based on thiazolidine and Synthesis of Cyclic Peptide Compounds Based on Oxazolidine Building Blocks as Peptides.

3. The preparation according to claim 1 or 2, characterized in that As the peptide there is a cyclic peptide compound of formula (I): (I)， in: X and 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, n-pentyl, 3-methylbutyl, benzyl, propargyl (HC≡C-CH2-), 1H-indol-3-ylmethyl ( )、1N-methyl-1H-indol-3-ylmethyl ( )、3-Benzothienylmethyl( )、1-naphthylmethyl( ), 9-anthrylmethyl ( ) and pyrenylmethyl ( ); - Z is equal to O or S; - R and R' are independently selected from H, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl, 1-methylpropyl, benzyl and propargyl, provided that when R is H, R' is not H; - the C atoms directly bonded to the substituents Y1, Y2, Y3, Y4, Y5 and X in that order each have an alternating absolute stereochemical configuration; and - when Z is O, the carbon atom connected to the substituent X and the thiazolidine or The C atom at position 4 of the oxazolidine ring has the same absolute stereochemical configuration, and when Z is S, has the opposite absolute stereochemical configuration; Provided that if X, Y1, Y4 and Y5 are 1-methylethyl, then Y2 is 1H-indol-3-yl, Y3 is 2-methylpropyl, R is H and R' is methyl, and Z is not O; and salts thereof, solvates thereof and solvates of salts thereof.

4. 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; if Y5 ​​is 1-methylethyl, Y2 is 1H-indol-3-ylmethyl or pyrenylmethyl, or if Y5 ​​is 1H-indol-3-ylmethyl or pyrenylmethyl, Y2 is 1-methylethyl; and X is 1-methylethyl; - R is H; R′ is methyl, ethyl, n-propyl, 1-methylethyl, benzyl or propargyl; if Y5 ​​is 1-methylethyl, Y2 is 1H-indol-3-ylmethyl or pyrenylmethyl, or if Y5 ​​is 1H-indol-3-ylmethyl or pyrenylmethyl, Y2 is 1-methylethyl; and X is 1-methylethyl; - R is H; R' is methyl, n-propyl, 1-methylethyl, benzyl or propargyl; if Y5 ​​is 1-methylethyl, Y2 is 1H-indol-3-ylmethyl or pyrenylmethyl, or if Y5 ​​is 1H-indol-3-ylmethyl or pyrenylmethyl, Y2 is 1-methylethyl; and X is 1-methylethyl or 2-methylpropyl; or R and R' are both 1-methylethyl; and Y2 is 1H-indol-3-ylmethyl.

5. Preparation according to any one of the preceding claims, characterized in that The cyclic peptide compound has one of the following formulae I.1a to I.24a: 。 6. Preparation according to any one of the preceding claims, characterized in that Select the structure of peptides.

7. Preparation according to any one of the preceding claims, characterized in that Licoricealcone is selected as the flavonoid, in particular licoricealcone A, licoricealcone C, glabridol and / or licoricealcone E, and / or an extract containing licoricealcone.

8. Preparation according to any one of the preceding claims, characterized in that The structure exists The peptide and one or more licochalcones selected from licochalcone A, licochalcone C, glabridol and / or licochalcone E.

9. Preparation according to any one of the preceding claims, characterized in that The proportion of the one or more antimicrobial peptides is selected from the range of 0.00001 wt % to 1.0 wt %, preferably 0.0001 wt % to 0.5 wt %, more preferably 0.0003 wt % to 0.3 wt %, based on the total mass of the preparation.

10. Preparation according to one of the preceding claims, characterized in that As skin soothing compounds one or more compounds are selected from menthoxypropanediol, polidocanol, allantoin, vitamins, in particular vitamins A, B5, E, hyaluronic acid or its salts, plant extracts such as calendula, witch hazel, oat and / or jojoba oil.

11. The preparation according to any one of the preceding claims, characterized in that One or more compounds from the group of omega-6 fatty acids, ceramides, shea butter and / or argan oil are selected as compounds for strengthening the skin barrier.

12. Preparation according to any one of the preceding claims, characterized in that The proportion of one or more skin soothing compounds, skin barrier enhancing compounds and / or flavonoids is selected from the range of 0.0001% to 5% by weight, particularly 0.001% to 1% by weight, in particular 0.005% to 0.15% by weight, based on the total mass of the preparation.

13. Preparation according to any one of the preceding claims, characterized in that The preparations are cosmetic and / or dermatological preparations, preferably based on emulsions.

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 skin damaged by atopic dermatitis or acne.

15. A combination of compounds comprising one or more antimicrobial peptides and one or more compounds selected from skin soothing compounds, compounds that enhance the skin barrier and / or flavonoids for use in the treatment of inflammatory skin diseases and / or indications, particularly acne, rosacea and / or atopic dermatitis.

16. The combination of compounds for use according to claim 15, characterized in that Selection based on thiazolidine and Synthesis of Cyclic Peptide Compounds Based on Oxazolidine Building Blocks as Peptides.

17. A combination of compounds for use according to claim 15 or 16, characterized in that Select the structure of peptides.

18. Combination of compounds for use according to any one of claims 15 to 17, characterized in that Licoricealcones, in particular licoricealcone A, licoricealcone C, glabridol and / or licoricealcone E and / or extracts containing licoricealcones are selected as flavonoids.

19. The combination of compounds for use according to any one of claims 15 to 18, characterized in that The combination is used in cosmetic and / or dermatological preparations.

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