Composition comprising an acid addition salt of tetradecylaminocarbonyl-DAB-val-DAB-oh

Abstract

A composition comprising an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH, a process for preparing a cosmetic composition comprising mixing such a composition with one or more other components and the use of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab- OH to reduce or eliminate the growth of one or more microorganisms, preferably fungi, within a composition.

Description

[0001] COMPOSITION COMPRISING AN ACID ADDITION SALT OF TETRADECYLAMINOCARBONYL-DAB-VAL-DAB-OH

[0002] Technical field of the invention

[0003]

[0001] The present invention relates to a cosmetic composition comprising an acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH.

[0004] Background of the invention

[0005]

[0002] The prominent role of peptides in nature makes them valuable cosmetic ingredients. Cosmetic peptides are involved in many physiological processes such as for example the increase of collagen production. They have various benefits such as anti-wrinkle, pigmentation reduction and / or firming activity.

[0006]

[0003] Tetradecylaminocarbonyl-Dab-Val-Dab-OH (also referred to tetradecyl aminobutyroylvalylaminobutyric urea) is a tripeptide commercially available as cosmetic ingredient composition SYN®-HYCAN from DSM Nutritional Products Ltd in the form of a trifluoroacetic acid addition salt. SYN®-HYCAN is widely used in cosmetic applications.

[0007]

[0004] Trifluoroacetic acid (TFA) can be used in the peptide synthesis during the process of cleaving peptides from their respective resin. In addition it can be used as an ion pairing agent in HPLC purifications. Therefore synthesized peptides are usually in the form of TFA salts and comprise up to 45% TFA content. In addition the TFA salts generally exhibit a good solubility, which is a prerequisite for cosmetic applications. However, cosmetic preparations comprising TFA, respectively TFA salts thereof, are not well appreciated anymore by all consumers. Amongst others, they are considered not eco-friendly and therefore less desirable.

[0008]

[0005] As peptides are highly potent ingredients, commercial product forms are generally solutions of said peptides in a suitable diluent. Typically the peptides are provided in the form of an ingredient composition, comprising the desired peptide as an active and in addition one or more cosmetically acceptable diluent(s) and optionally one or more other helper ingredients (“excipients”).

[0009]

[0006] In cosmetic industry, producers commonly apply and mix different ingredient compositions from different suppliers in their manufacturing facilities to prepare a desired cosmetic composition.

[0010]

[0007] Micro-organisms such as fungi pose several risks in the cosmetic industry, affecting both product quality and consumer safety. Fungi, such as molds and yeasts, can grow in cosmetic products at different moments in time. This growth can occur during manufacturing, storage, or after the product has been opened by consumers, wherein each stage creates separate challenges.

[0011]

[0008] In respect of the growth in a cosmetic product after the product has been opened by a customer, cross-contamination with the skin of a customer poses an important challenge. For example,

[0009] fungal contamination can cause skin infections, particularly in individuals with compromised immune systems or sensitive skin. Common fungi like Candida can lead to conditions such as candidiasis. Malassezia species are commonly found on the human skin without causing any serious problems, but can aggrevate other skin conditions. At the same time contaminated cosmetic products can spoil, leading to visible changes such as discoloration, bad odor, and texture alterations. This not only reduces the product's shelf life but also its marketability. For example, Malassezia can thrive in lipid-rich environments, making oil containing cosmetic products particularly susceptible to such contamination and spoilage. Therefore many cosmetic products comprise antifungal actives.

[0012]

[0010] The contamination with fungi during the manufacturing process poses a completely different set of challenges. Cosmetic products are required to meet strict microbial limits to ensure safety and efficacy. Fungal contamination can lead to non-compliance with regulatory standards, resulting in product recalls and damage to the brand's reputation. The above mentioned separate ingredient compositions are particularly vulnerable for fungal contamination during manufacturing of a cosmetic composition, especially at the moment in time they are not mixed yet with the antifungal ingredient in the cosmetic composition. Manufacturers of cosmetic products therefore actively try to limit the exposure time of ingredients to the factory environment. Exposure times may range from a few minutes to a few hours. This practice is crucial to prevent initial contamination with micro-organisms and maintain the quality, safety and stability of ingredients whilst being processed. Aspergillus brasiliensis (formerly known as Aspergillus niger) is a common environmental mold that can pose significant challenges during the manufacturing of cosmetic products. It is a key potential contaminant that manufacturers strive to control and prevent.

[0013]

[0011] US 2007 / 0099842 describes a lengthy list of nearly one hundred tripeptide derivatives of a formula (I). The compounds of formula (I) can form salts together with acids. A wide range of acids is mentioned for such, including inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; carboxylic acids, such as aliphatic mono- or dicarboxylic acids, such as formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, glycolic acid, succinic acid, fumaric acid, malonic acid, maleic acid, oxalic cid, phthalic acid, citric acid, lactic acid or tartaric acid; and aromatic carboxylic acids, such as benzoic acid or salicylic acid; and aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid; heteroaromatic carboxylic acids, such as nicotinic acid; or aliphatic or aromatic sulfonic acids, such as methanesulfonic acid or toluenesulfonic acid.

[0014]

[0012] In passing, US 2007 / 0099842 mentions that the compositions may also comprise antibacterial and antifungal actives: As preferred examples of actives are mentioned those selected from the group of salicylic acid, benzoyl peroxide, 3-hydroxy benzoic acid, glycolic acid, lactic acid, 4-hydroxy benzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid, 2-hydroxy- pentanoic acid, 2-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, phytic acid, N-acetyl-L-cysteine, lipoic acid, azelaic acid, arachidonic acid, benzoylperoxide, tetracycline, ibuprofen, naproxen, hydrocortisone, acetominophen, resorcinol, phenoxyethanol, phenoxypropanol, 2,4, 4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'-trichlorocarba- nilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neocycin sulfate and mixtures thereof.

[0015]

[0013] Further in passing, US 2007 / 0099842 also mentions that the compositions may contain a conditioning agent selected from humectants, moisturizers or skin conditioners. Again a long list of examples is provided.

[0016]

[0014] The antibacterial and antifungal actives in US 2007 / 0099842 are nowadays less desirable as customers increasingly demand natural and eco-friendly ingredients. In addition, as outlined above, nowadays the challenges in respect of microbial contamination, especially fungi, in the cosmetic industry are complex. This complexity is not address by US 2007 / 0099842.

[0017]

[0015] Hence, it would be an advancement in the art to provide an alternative composition of Tetradecylaminocarbonyl-Dab-Val-Dab-OH which is free of TFA and / or which can be considered more eco-friendly than the TFA. In addition or in the alternative, it would be an advancement in the art to provide an alternative composition of Tetradecylaminocarbonyl-Dab-Val-Dab-OH which can assist cosmetic industry in the complex battle against microbial contamination, especially fungal contamination.

[0018] Summary of the invention

[0019]

[0016] It has now surprisingly been found that a composition comprising the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH can perform multiple functions in a cosmetic composition. The tripeptide has cosmetic activity, including anti-wrinkle, pigmentation reduction and firming activity. In addition, surprisingly, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab- Val-Dab-OH also has antimicrobial activity, especially antifungal activity, within the cosmetic composition. Such antimicrobial, respectively antifungal, activity of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH advantageously allows one to reduce or even eliminate the need for artificial non-natural and / or eco-unfriendly antimicrobial, suitably antifungal, actives in a cosmetic composition.

[0020]

[0017] In addition, it was found that if the acetic acid addition salt of Tetradecylaminocarbonyl-Dab- Val-Dab-OH is combined with a hydroxyacetophenone, glyceryl ether or glyceryl ester, such combination surprisingly shows a synergistic effect in reducing the initial growth of Aspergillus brasiliensis. Such a combination can therefore advantageously be used to assist cosmetic industry in the complex battle against such fungi during manufacturing.

[0018] Accordingly, in one aspect, the invention provides a composition, preferably a cosmetic composition or an ingredient composition, most preferably a cosmetic composition, comprising or consisting of:

[0021] - an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0022] - oil; and

[0023] - optionally water; and

[0024] - optionally one or more cosmetically acceptable excipients

[0025] Advantageously, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH within such composition can have a cosmetic activity as well as an antimicrobial activity.

[0026]

[0019] The acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH can further advantageously be combined with one or more of a hydroxyacetophenone, a glyceryl ether and / or a glyceryl ester.

[0027]

[0020] Accordingly, in another aspect, the invention provides a composition, preferably a cosmetic composition or an ingredient composition, most preferably an ingredient composition, comprising or consisting of:

[0028] - an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH; and

[0029] - a hydroxyacetophenone, a glyceryl ether and / or a glyceryl ester;

[0030] - optionally a cosmetically acceptable carrier; and

[0031] - optionally one or more cosmetically acceptable excipients.

[0032]

[0021] Preferably the compositions of the above aspects are solutions, emulsions or dispersions. If present, the cosmetically acceptable carrier preferably comprises or consists of water, oil or a combination of water and oil.

[0033]

[0022] Preferably the compositions of the above aspects comprise no or essentially no Trifluoroacetic acid (TFA) addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH. More preferably the compositions of the above aspects are free from Trifluoroacetic acid (TFA) addition salts.

[0034]

[0023] In a further aspect, the invention provides a process for preparing a cosmetic composition comprising mixing a composition, preferably an ingredient composition as described herein, with one or more other components or compositions.

[0035]

[0024] Finally, in a last aspect, the invention provides a use of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH to reduce or eliminate the growth of one or more microorganisms, preferably fungi, within a composition. Detailed description of the invention

[0036] Definitions

[0037]

[0025] Unless defined otherwise or clearly indicated by context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0038]

[0026] The articles “a” and “an” are used herein to refer to one or to more than one (i.e. to one or at least one) of the grammatical object of the article. By way of example, “an element” may mean one element or more than one element. When referring to a noun (e.g. a compound, an additive, etc.) in the singular, the plural is meant to be included. Thus, when referring to a specific moiety, e.g. a "strain", this means "at least one" of that strain, e.g. "at least one strain", unless specified otherwise.

[0039]

[0027] Throughout the present specification and the accompanying claims, all transitional phrases such as ‘comprising,’ ‘including,’ ‘carrying,’ ‘having,’ ‘containing,’ ‘involving,’ ‘holding,’ ‘composed of, and variations such as "comprises", "comprise", "includes" and "include" are to be interpreted inclusively and to be understood to be open-ended, i.e., to mean including but not limited to. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows. Only the transitional phrases ‘consisting of and ‘consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively.

[0040]

[0028] The term 'consisting essentially of as used herein means that the total amount of the listed ingredients ideally sums upto 100 wt. % (weight percent). It is however not excluded that small amount of impurities derived from the ingredients and / or the production process may be present.

[0041]

[0029] When referring to a compound of which several isomers exist (e.g. a D and an L enantiomer), the compound in principle includes all enantiomers, diastereomers and cis / trans isomers of that compound that may be used in the particular aspect of the invention; in particular when referring to such as compound, it includes the natural isomer(s).

[0042]

[0030] Unless explicitly indicated otherwise, the various embodiments of the invention described herein can be cross-combined.

[0043]

[0031] The term ‘Tetradecylaminocarbonyl-Dab-Val-Dab-OH ’ (i.e. H2gCi4-NH-CO-Dab-Val-Dab-OH) also referred to as ‘Tetradecyl aminobutyroylvalylaminobutyric urea’ includes all possible isomeric forms as well as mixtures thereof, e.g. racemic mixtures and mixtures of rotamers.

[0044]

[0032] An “acid addition salt” of Tetradecylaminocarbonyl-Dab-Val-Dab-OH is herein also sometimes referred to as simply the “acid salt” of Tetradecylaminocarbonyl-Dab-Val-Dab-OH. Without wishing to be bound by any kind of theory an “acid addition salt” is preferably understood to be a salt composition of a weak base with a strong(er) acid forming a salt by an acid-base reaction, that is, it may involve the transfer of a proton (H+) from the acid to the base, resulting in a positively charged ion (cation) and a negatively charged ion (anion).

[0033] The term "cosmetic composition " or “cosmetic preparation” refers in the present document to a composition suitable for cosmetic purposes. More preferably the term "cosmetic composition " or “cosmetic preparation” refers in the present document to a composition which is applied to the surface of a mammalian keratinous tissue. The terms "cosmetic composition " or “cosmetic preparation” can comprise or consist of those cosmetic compositions as defined under the heading "Kosmetika" in Rompp Lexikon Chemie, 10th edition 1997, Georg Thieme Verlag Stuttgart, New York as well as to cosmetic compositions as disclosed in A. Domsch, "Cosmetic Compositions", Verlag fur chemische Industrie (ed. H. Ziolkowsky), 4thedition, 1992. More preferably the "cosmetic composition " or “cosmetic preparation” is a cosmetic preparation, respectively a cosmetic composition, that can be topically applied to mammalian keratinous tissue such as e.g. human skin or hair (including eyelashes, the eyebrows, the nails or the lips), particularly human skin. Hence, the cosmetic composition is preferably a topical composition.

[0045]

[0034] By a topical composition is herein understood a composition for, preferably external, use on keratinous tissue such as the skin.

[0046]

[0035] The term “keratinous tissue" as used in this document refers to tissue containing keratine, more preferably it means the skin (body, face, contour of the eyes, scalp), head hair, eyelashes, eyebrows, bodily hairs, nails and / or lips. Preferably, the keratinous tissue is the skin and hair.

[0047]

[0036] The term “cosmetic ingredient composition” or “ingredient composition” is preferably understood to comprise or consist of one or more ingredient(s) suitable for use in the formulation of a cosmetic product. Preferably such ingredient composition comprises one or more active ingredients and optionally one or more cosmetically acceptable excipients and / or one or more cosmetically acceptable carriers. The ingredient composition may for example be a pre-mix blend which can be readily incorporated into cosmetic compositions. Preferably the ingredient composition comprises equal to or less than 9 ingredients, most preferably in the range from equal to or more than 1 to equal to or less than 6 ingredients. Preferably the ingredient composition is an active ingredient composition comprising one or two active ingredients.

[0048]

[0037] The term cosmetically acceptable carrier herein refers to all carriers and / or diluents conventionally used in cosmetic preparations. Preferably the cosmetically acceptable carrier comprises or consists of water, oil or a combination of water and oil.

[0049]

[0038] The term "antimicrobial effect" or “antimicrobial activity” is used in this document to describe that a substance reduces the growth of one or more microorganisms when said microorganisms are brought in contact with said substance. The term "antifungal effect" or “antifungal activity” is used in this document to describe that a substance reduces the growth of one or more fungi when said fungi are brought in contact with said substance.

[0039] By an “active ingredient”, “active compound”, “active component”, “active agent” or simply “active” is herein understood a substance that has a certain activity. So-called “primary substances” are substances designed to achieve a specific intended effect in a cosmetic product.

[0050]

[0040] An “antimicrobial component”, “antimicrobial ingredient”, “antimicrobial agent”, “antimicrobial active” or simply “antimicrobial” is understood to be a substance which has an antimicrobial activity. An “antifungal component”, “antifungal ingredient”, “antifungal agent”, “antifungal active” or simply “antifungal” is a substance which has an antifungal activity.

[0051]

[0041] By an “excipient” is herein understood an inactive substance formulated alongside the active ingredient in a composition. Whilst the active ingredient provides the primary cosmetic effect or desired outcome, the excipient helps deliver, protect, and stabilize the active ingredient and / or improves the product's usability and acceptability.

[0052]

[0042] By a “lipid” is herein preferably understood an organic compound that is hydrophobic.

[0053]

[0043] In the present document, a “Cx-y-alkyl” group is an alkyl group comprising in the range from x to y carbon atoms. For example, a Ci-3-alky I group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CH(CH3)-CH2-CH3 is considered as a C4-alkyl group.

[0054]

[0044] In case identical labels for symbols or groups are present in several formulae, in the present document, the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises the same said label.

[0055]

[0045] In this application the following abbreviations are used: AcOH = Acetic acid; AcN = Acetonitrile; BG= Butyleneglycol; Dab=1 .4-Diaminobutyric acid (building block in the tripeptide); TDAC=Tetradecyl- NH-CO; Z = Benzyl oxy carbonyl; Bn=benzyl; and Val= Valine.

[0056] Acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH

[0057]

[0046] In all embodiments of the present invention, Tetradecylaminocarbonyl-Dab-Val-Dab-OH is preferably Tetradecylaminocarbonyl-L-Dab-L-Val-L-Dab-OH as depicted in formula (I) below:

[0058]

[0047] The ratio of mol equivalents of acetic acid to mol equivalents Tetradecylaminocarbonyl-Dab- Val-Dab-OH in the acetic acid addition salt of the present invention is preferably selected in the range from equal to or more than 0.5, more preferably from equal to or more than 0.6, even more preferably from equal to or more than 0.7, still more preferably from equal to or more than 0.8, yet even more preferably from equal to or more than 0.9, to equal to or less than 3, more preferably to equal to or less than 2.5, even more preferably to equal to or less than 2.25, still more preferably to equal to or less than 2.0, yet even more preferably to equal to or less than 1 .6, mol equivalents of acetic acid per mol equivalents of Tetradecylaminocarbonyl-Dab-Val-Dab-OH. Preferably the ratio of mol equivalents of acetic acid to mol equivalents Tetradecylaminocarbonyl-Dab-Val-Dab-OH is selected in the range from equal to or more than than 0.6 to equal to or less than 2.0 mol equivalents, most preferably in the range from equal to or more than than 0.9 to equal to or less than 1 .6 mol equivalents of acetic acid per mol equivalents of Tetradecylaminocarbonyl-Dab-Val-Dab-OH. Said mol equivalents can be easily determined by standard methods in the art such as by ion chromatography or quantitative-NMR and can be adjusted for example by drying times.

[0059]

[0048] Preferably, in all embodiments of the present invention, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (peptide) is Tetradecylaminocarbonyl-Dab-Val- Dab*(x)AcOH with a mol equivalent (x) of acetic acid to the peptide selected in the range from equal to or more than 0.6 to equal to or less than 2.0, most preferably in the range from equal to or more than 0.9 to equal to or less than 1 .6.

[0060]

[0049] Alternatively, the amount of acetic acid in the acetic acid addition salt can be expressed in wt.% (weight percent), based on the weight of the peptide. Thus alternatively, it is preferred in all embodiments of the present invention, that the amount of acetic acid in the acetic acid addition salt is selected in the range from equal to or more than 10 wt.%, more preferably from equal to or more than 12.5 wt.%, even more preferably from equal to or more than 15 wt.%, to equal to or less than 25 wt.%, more preferably to equal to or less than 20 wt.%, even more preferably to equal to or less than 18 wt.%, based on the weight of the peptide Tetradecylaminocarbonyl-Dab-Val-Dab-OH. Most preferably the amount of acetic acid in the acetic acid addition salt is selected in the range from equal to or more than 15 wt.% to equal to or less than 18 wt.%, based on the weight of the peptide Tetradecylaminocarbonyl- Dab-Val-Dab-OH.

[0061]

[0050] It is well understood by a person skilled in the art, that the total amount of acid in peptide addition salts depends on the preparation process such as e.g. the amount of acid used, as well as the basicity of the respective peptide and the acidity of the respective acid and may further be influenced e.g. by drying methods and times. It is also well understood that some of the acid may be present in a peptide addition salt in non-deprotonated form.

[0062]

[0051] In all embodiments of the present invention, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH can be prepared by treating a solution of the respective trifluoroacetate salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (for example prepared as outlined in CN107987123) with acetic acid in the presence of an anion exchange resin, preferably a weak anion exchange resin, in a suitable solvent, followed by filtration and / or drying. Preferably, said drying encompasses vacuum drying and / or lyophilization. Suitable solvents to solubilize the trifluoroacetate salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH include Dimethylformamide (DMF), Ethyl acetate (EtOAc), Dimethyl sulfoxide (DMSO) and Acetonitrile (can) as well as any mixtures thereof. Preferred solvents are DMF as well as mixtures of EtOAc / DMSO and AcN / DMSO. Preferably >99 wt% acetic acid is used in the process according to the present invention. A particularly preferred anion exchange resin is a weak anion exchange resin, preferably in its acetate form.

[0063]

[0052] Alternatively the Tetradecylaminocarbonyl-Dab-Val-Dab-OH can be prepared from the respective peptide Tetradecylaminocarbonyl-Dab-(Z)-Val-Dab-(Z)-OBn (sometimes also referred to as a fully protected Tetradecylaminocarbonyl-Dab-(Z)-Val-Dab-(Z)-OBn peptide) by hydrogenation in acetic acid, preferably followed by filtration and removal of residual acetic acid. Suitable hydrogenation catalysts include palladim and platinum. Preferably palladium is used as a hydrogenation catalyst. The hydrogenation catalyst more preferably comprises palladium or platinum, most preferably palladium, on a carrier. Most preferably palladium on carbon (Pd / C) is used as hydrogenation catalyst. In all embodiments herein, this hydrogenation process is the preferred process for the preparation of Tetradecylaminocarbonyl-Dab-Val-Dab-OH.

[0064]

[0053] Preferably the preparation process of the acetic acid addition salt of Tetradecylaminocarbonyl- Dab-Val-Dab-OH according to the present invention further comprises an additional purification step. Such additional purification step preferably includes:

[0065] (i) dissolving the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH in acetic acid to obtain a solution;

[0066] (ii) optionally filtering the obtained solution; and

[0067] (iii) (a) precipitating the (purified) acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab- OH from the solution using a suitable solvent such as ethyl acetate, acetone or the like and / or (b) drying the solution, for example by lyophilization. The use of ethyl acetate as (precipitation) solvent is especially preferred. In all embodiments, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab- Val-Dab-OH according to the present invention is preferably an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH prepared by a process encompassing the step of redissolving the obtained acetic acid addition salt in acetic acid followed by evaporation and / or lyophilization and / or any other drying method.

[0068]

[0054] Thus, advantageously in all embodiments of the present invention, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH is an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH prepared by a process including: a first step comprising: (i-a) treating a solution of a trifluoro acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val- Dab-OH with acetic acid in the presence of an anion exchange resin; or

[0069] (i-b) hydrogenating Tetradecylaminocarbonyl-Dab(Z)-Val-Dab(Z)-OBn in the presence of acetic acid; and a second step comprising:

[0070] (ii) dissolving the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH obtained in the first step in acetic acid to obtain an acetic acid addition salt solution; and a third step, comprising isolating the acetic acid addition salt of Tetradecylaminocarbonyl-Dab- Val-Dab-OH from the acetic acid addition salt solution, comprising:

[0071] (iii-a) precipitating the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH from the acetic acid addition salt solution, preferably by using ethyl acetate; and / or

[0072] (iii-b) drying said acetic acid addition salt solution, wherein the drying preferably includes vacuum drying and / or lyophilization.

[0073]

[0055] Hence, the invention also provides a process for the preparation of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH comprising: a first step comprising:

[0074] (i-a) treating a solution of a trifluoro acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val- Dab-OH with acetic acid in the presence of an anion exchange resin; or

[0075] (i-b) hydrogenating Tetradecylaminocarbonyl-Dab(Z)-Val-Dab(Z)-OBn in the presence of acetic acid; and a second step comprising:

[0076] (ii) dissolving the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH obtained in the first step in acetic acid to obtain an acetic acid addition salt solution; and a third step, comprising isolating the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val- Dab-OH from the acetic acid addition salt solution, comprising:

[0077] (iii-a) precipitating the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH from the acetic acid addition salt solution, preferably by using ethyl acetate; and / or

[0078] (iii-b) drying the acetic acid addition salt solution or precipitated acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH, wherein the drying preferably includes vacuum drying and / or lyophilization.

[0079] Preferably, the acetic acid addition salt solution in the second and / or third step comprises or consists essentially of acetic acid, water and Tetradecylaminocarbonyl-Dab-Val-Dab-OH, preferably of acetic acid in a weight percentage of 99 wt.%, Tetradecylaminocarbonyl-Dab-Val-Dab-OH and up to 5 wt.%, preferably up to 2 wt.%, most preferably up to 1 .5 wt.% of water.

[0056] More preferably such a process for the preparation of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH comprises the steps of:

[0080] (i) hydrogenating an ether or ester derivative of Tetradecylaminocarbonyl-Dab(Z)-Val-Dab(Z)-OH, preferably Tetradecylaminocarbonyl-Dab(Z)-Val-Dab(Z)-OBn, in the presence of acetic acid to generate a crude acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH ; followed by

[0081] (ii) dissolving said crude acetic acid addition salt in acetic acid to obtain an acetic acid addition salt solution; followed by

[0082] (iii) precipitating of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH from said acetic acid addition salt solution and / or drying said acetic acid addition salt solution.

[0083]

[0057] In all aspects of the present invention, the amount of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH in the composition is preferably equal to or more than 0.0005 wt.%, more preferably equal to or more than 0.001 wt.%, even more preferably equal to or more than 0.005 wt.%, still more preferably equal to or more than 0.01 wt.%, yet even more preferably equal to or more than 0.05 wt.% and / or preferably equal to or less than 12.5 wt%, more preferably equal to or less than 5.0 wt%, even more preferably equal to or less than 2.0 wt%, still more preferably equal to or less than 0.5 wt.%, even still more preferably equal to or less than 0.2 wt.%, yet even more preferably equal to or less than 0.15 wt.%, based on the total weight of the composition. More preferably the amount of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH in the composition is selected in the range from 0.0005-12.5 wt.%, preferably in the range from 0.001-5 wt.%, more preferably in the range from 0.001-2 wt.%, yet more preferably in the range from 0.001-0.5 wt.%, such as in particular from 0.005 to 0.2 wt.%, such as 0.01 to 0.15 wt.% based on the total weigh of the composition. In an especially preferred embodiment the amount of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH in the composition is selected in the range from 0.01-12.5 wt.%, based on the total weight of the composition.

[0084]

[0058] Preferably the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH is multifunctional within the composition. That is, preferably the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH can perform multiple functions within the composition. As indicated above, preferably the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH has both a cosmetic activity as well as an antimicrobial activity, preferably an antifungal activity.

[0085]

[0059] The cosmetic activity preferably comprises the reduction of fine lines, wrinkles and other symptoms associated with aged or photodamaged skin, treatment of stretch marks or tightening, firming and / or moisturizing skin. The antimicrobial activity preferably comprises an antifungal activity. The compositions of the first and / or second aspect as defined herein can therefore advantageously be incorporated into cosmetic preparations useful for improving skin appearance and physiology such as e.g. reducing fine lines, wrinkles and other symptoms associated with aged or photodamaged skin, treatment of stretch marks or tightening, firming and / or moisturizing skin. At the same time, the compositions of the first and / or second aspect as defined herein can advantageously be incorporated into cosmetic preparations to reduce growth of undesired microorganisms, preferably to reduce growth of the fungi Candida and / or Malessezia and / or the bacterium Cyrynebacterium. As mentioned above, the fungi Candida and / or Malessezia and the bacterium Cyrynebacterium can be abundant on human skin, and a reduction in their growth is advantageous when the product is in use by a customer. In addition, the composition of the second aspect as defined herein can advantageously be applied during the manufacturing process of a cosmetic product as this compositions is less vulnerable for initial growth of Aspergillus brasiliensis. As mentioned above, the fungus Aspergillus brasiliensis can be abundant in a factory environment. When combined with a hydroxyacetophenone, a glyceryl ether and / or a glyceryl ester as described herein, advantageously the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH can have a synergistic effect in the reduction of the initial growth of Aspergillus brasiliensis.

[0086] Water

[0087]

[0060] In all aspects of the present invention, the composition preferably comprises water.

[0088]

[0061] If the composition comprises water, the water is preferably present in a weight percentage selected in the range from equal to or more than 1 wt.% to equal to or less than 99 wt.%, more preferably in the range from equal to or more than 5 wt.% to equal to or less than 95 wt.%, even more preferably in the range from equal to or more than 10 wt.% to equal to or less than 90 wt.%, still more preferably in the range from equal to or more than 5 wt.% to equal to or less than 60 wt.%, yet even more preferably in the range from equal to or more than 10 wt.% to equal to or less than 50 wt.%, based on the total weight of the composition.

[0089]

[0062] The skilled person will understand that the weight percentage of water present in a cosmetic composition can vary widely depending on the type of cosmetic product, its intended use, and the desired characteristics.

[0090]

[0063] In one embodiment, where the composition is a moisturizer or lotion, the composition preferably comprises in the range from equal to or more than 50 wt.% to equal to or less than 90 wt.%, more preferably equal to or less than 80 wt.% of water, based on the total weight of the composition.

[0064] In other compositions, where the composition is for example a cream, the weight percentage of water present is preferably selected in the range from equal to or more than 10 to equal to or less than 90 wt.%, more preferably in the range from equal to or more than 20 to equal to or less than 50 wt.%, even more preferably in the range from equal to or more than 25 to equal to or less than 40 wt.% of water, based on the total weight of the composition.

[0065] In the compositions according to this invention, the water may have a hydrating function but may also function as the carrier for delivery of one or more active ingredient(s), such as the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH -Dab-Val-Dab-OH.

[0091] Oil

[0092]

[0066] If the composition comprises an oil, the oil is preferably present in a weight percentage selected in the range from equal to or more than 1 wt.% to equal to or less than 99 wt.%, more preferably in the range from equal to or more than 5 wt.% to equal to or less than 95 wt.%, even more preferably in the range from equal to or more than 10 wt.% to equal to or less than 90 wt.%, still more preferably in the range from equal to or more than 5 wt.% to equal to or less than 60 wt.%, yet even more preferably in the range from equal to or more than 10 wt.% to equal to or less than 50 wt.%, based on the total weight of the composition.

[0093]

[0067] In a preferred embodiment, the composition according to the invention is a cosmetic composition. More preferably the composition according to the invention is a topical composition. The skilled person will understand that the weight percentage of oil present in a cosmetic composition can vary widely depending on the type of cosmetic product, its intended use, and the desired characteristics.

[0094]

[0068] In one embodiment, where the composition is a moisturizer or lotion, the composition preferably comprises in the range from equal to or more than 5 wt.% to equal to or less than 25 wt.%, more preferably equal to or less than 20 wt.% of oil, based on the total weight of the composition. For example a facial lotion, which may be applied to the sensitive skin of the face, may comprise in the range from equal to or more than 5 wt.% to equal to or less than 10 wt% of oil, based on the total weight of the composition. In another example a body cream, which may be applied to the hands, arms or legs, may may comprise in the range from equal to or more than 15 wt.% to equal to or less than 20 wt% of oil, based on the total weight of the composition.

[0095]

[0069] In another embodiment, where the composition is a cream or balm, the composition preferably comprises in the range from equal to or more than 20 wt.% to equal to or less 90 wt.%, more preferably equal to or less than 60 wt.% of oil, based on the total weight of the composition. For example a facial cream, which may be applied to the sensitive skin of the face, may comprise in the range from equal to or more than 20 wt.% to equal to or less than 30 wt% of oil, based on the total weight of the composition. In another example a body butter, which may be applied to the hands, arms or legs, may may comprise in the range from equal to or more than 30 wt.% to equal to or less than 60 wt% of oil, based on the total weight of the composition.

[0096]

[0070] In yet another embodiment, where the composition is a facial or hair oil treatment, the composition preferably comprises in the range from equal to or more than 50 wt.% to equal to or less 95 wt.%, more preferably equal to or less than 90 wt.% of oil, based on the total weight of the composition.

[0097]

[0071] Preferably an oil is herein understood to be a substance that is hydrophobic, more preferably the oil is furthermore in a liquid state at room temperature.

[0098]

[0072] Suitable oils in the aspects of the invention include plant-based, animal-based, mineral oils, and synthetic oils. For the purposes of this invention, the term “oil” is also understood to include ingredients such as fatty substances, lipids, di-n-alkyl esters, fatty acids or fatty alcohols. Preferably these di-n-alkyl esters, fatty acids or fatty alcohols may comprise one or more hydrocarbon chains, which hydrocarbon chains may comprise in the range from equal to or more than 10 to equal to or less than 60 carbon atoms, more preferably in the range from equal to or more than 11 to equal to or less than 30 carbon atoms. Examples of such compounds include lauryl (C12H25) alcohol, stearyl (CiaHaa) alcohol and oleyl (CisHse) alcohol.

[0099]

[0073] In one embodiment, the oil comprises or consists of hydrocarbons, more preferably alkanes comprising in the range from equal to or more than 8, more preferably equal to or more than 10, even more preferably equal to or more than 11 , to equal to or less than 30, more preferably equal to or less than 28 carbon atoms. Such alkanes can be branched or linear (no-branched). Such alkanes are preferably non-cyclic and non-aromatic. Preferred alkanes are alkanes selected from the group consisting of octane, decane, dodecane, tetradecane, hexadecane and octadecane.

[0100]

[0074] In another embodiment, the oil comprises or consists of fatty acids, more preferably fatty acids comprising in the range from equal to or more than 8, more preferably equal to or more than 10, even more preferably equal to or more than 11 , to equal to or less than 30, more preferably equal to or less than 28 carbon atoms. Most preferred are one or more fatty acids selected from the group consisting of caprylic acid (C8H16O2), capric acid (C10H20O2), lauric acid (C12H24O2) , myristic acid (C14H28O2), palmitic acid (C16H32O2), stearic acid (C18H36O2), and arachidic acid (C20H40O2).

[0101]

[0075] In a further embodiment, the oil comprises or consists of fatty alcohols, more preferably fatty alcohols comprising in the range from equal to or more than 8, more preferably equal to or more than 10, even more preferably equal to or more than 11 , to equal to or less than 30, more preferably equal to or less than 28 carbon atoms. Such a fatty alcohol can be a mono-alkanol, di-alkanol or tri-alkanol. An especially preferred fatty alcohol is caprylyl glycol. 1 ,2-Octanediol, also known as caprylyl glycol, is a diol with the molecular formula CH3(CH2)sCHOHCH2OH. Caprylyl glycol can be derived from caprylic acid, a fatty acid that is present in palm oil and coconut oil. 1 ,2-octanediol is thus an especially preferred fatty alcohol as it can be obtained from a natural source.

[0102] The invention thus also provides a composition comprising or consisting of:

[0103] - an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0104] - 1 ,2-Octanediol; and - optionally water; and

[0105] - optionally one or more cosmetically acceptable excipients.

[0106] Further preferences for such are as described herein above and below.

[0107]

[0076] In still another embodiment, the oil comprises or consists of fatty ethers and / or fatty esters, more preferably fatty ethers and / or fatty esters comprising in the range from equal to or more than 8, more preferably equal to or more than 10, even more preferably equal to or more than 11 , to equal to or less than 30, more preferably equal to or less than 28 carbon atoms.

[0108]

[0077] In addition, all the embodiments herein can be combined. That is, the oil may also suitably comprise mixtures of hydrocarbons, fatty acids, fatty alcohols, fatty ethers and / or fatty esters, preferably the hydrocarbons, fatty acids, fatty alcohols, fatty ethers and / or fatty esters as described herein.

[0109]

[0078] More preferably the oil in all aspects of the invention comprises or consists of so-called “ester oils”. By an ester oil is preferably understood an ester of a fatty acid. The esters include mono-esters as well as di-esters and tri-esters. More preferably the oil comprises or consists of:

[0110] - esters of saturated and / or unsaturated, linear or branched alkyl carboxylic acids with equal to or more than 3, more preferably with equal to or more than 8 to equal to or less than 30 carbon atoms, more preferably equal to or more than 10 to equal to or less than 30 carbon atoms, and of saturated and / or unsaturated, linear and / or branched alcohols with equal to or more than 3, more preferably with equal to or more than 8 to equal to or less than 30 carbon atoms, more preferably equal to or more than 10 to equal to or less than 30 carbon atoms; and / or

[0111] - esters of aromatic carboxylic acids with equal to or more than 3, more preferably with equal to or more than 8 to equal to or less than 30 carbon atoms, more preferably equal to or more than 10 to equal to or less than 30 carbon atoms, and of saturated and / or unsaturated, linear or branched alcohols with equal to or more than 3, more preferably with equal to or more than 8 to equal to or less than 30 carbon atoms, more preferably equal to or more than 10 to equal to or less than 30 carbon atoms, more preferably C12-15 alkyl benzoate.

[0112] Preferably the oil comprises or consists of one or more esters derived from glycerol and fatty acids (also sometimes referred to as “triglycerides”). Preferences for such fatty acids in such triglycerides are as mentioned above.

[0113] Most preferably the oil in all aspects of the invention comprises or consists of one or more ester oils selected from the group consisting of diethyl hexyl sebacate, dicaprylyl carbonate, octylpalmitate, octylcocoate, octylisostearate, octyldodecylmyristate, cetearylisononanoate, isopropylmyristate, isopropylpalmitate, isopropylstearate, isopropyloleate, n-butylstearate, n-hexyllaurate, n- decyloleate, isooctylstearate, isononylstearate, isononylisononanoate, 2-ethyl hexylpalmitate, 2- ethylhexyllaurate, 2-hexyldecylstearate, 2-octyldodecylpalmitate, stearylheptanoate, oleyloleate, oleylerucate, erucyloleate, erucylerucate, tridecylstearate, tridecyltrimellitate, as well as synthetic, half-synthetic or natural mixtures of such esters such as for example jojoba oil, and combinations of one or more of these. Other preferred ester oils include a mixture of C12-15 alkyl benzoates.

[0114] Advantageously such ester oils can nowadays be produced from natural sources.

[0115]

[0079] Oils with a good spreading value of higher than 600 mm2 / 10 min are preferred. Exemplary oils of this group are Isopropyl Palmitate, Isopropyl Myristate, Coco-Caprylate / Caprate, Isopropyl Isostearate, Cyclomethicone, Butylene Glycol Dicaprylate / Dicaprate, Dicaprylyl Carbonate, Isopropyl Stearate, Ethylhexyl Cocoate, Dibutyl Adipate, Isodecyl Neopentanoate, Isohexadecane, C13-16 Isoparaffin and / or Dicaprylyl Ether and combinations of one or more of these.

[0116]

[0080] In another preferred embodiment the the oil in all aspects of the invention comprises or consists of one or more polar oils. Polar oils according to the present invention are well known to a person in the art and encompass in particular esters such as e.g. cocoglycerides (Myritol 331), di-C12-13 alkyl tartrate (Cosmacol ETI), di-C12-13 alkyl lactate (Cosmacol ELI), caprylic / capric triglycerides (Miglyol 812), isopropyl lauroyl sarcosinate (Eldew SL-205), pentaerytrityl tetraisostearate (Crodamol PTIS), PEG-2 diethylene hexanoate (Dermol 488), isostearyl isostearate (Prisorine 2039), dibutyl adipate (Cetiol B), stearyl heptanoate (Tegosoft SH), diisopropyl sebacate (DUB DIS), phenethyl benzoate (X- Tend 226), propylene glycol dicaprylate / dicaprate (Miglyol 840), tricaprylin (Trivent OCG), butylene glycol dicaprylate / dicaprate (Dermofeel BGC), isopropyl stearate, triheptanoin (Dermofeel TC-7), octyldodecyl myristate (Gatteefosse M.O.D.), isodecyl salicylate (Dermol IDSA), ethylhexyl palmitate (Tegosoft OP), diethylhexyl succinate (Crodamol OSU), dicaprylyl ether (Cetiol OE), isopropyl myristate, ethylhexyl benzoate (Finsolv EB), tridecyl isononanoate (Dermol 139), ethylhexyl isononanoate (Dermol 98), cetearyl isononanoate (Cetiol SN), isopropyl palmitate, diethylhexyl carbonate (Tegosoft DEC), isohexyl decanoate (Dermol IHD), isodecyl neopentanoate (DUB VCI 10), dicaprylyl carbonate (Crodamol DA), and diethyl adipate (DUB DEA) as well as mixtures thereof.

[0117]

[0081] Such polar oils encompass as well alcohols such as e.g. diethylene glycol (Dermol 489), isostearyl alcohol (Prisorine 3531), butyloctanol (Isofol 12), butyldodecanol (Eutanol G), as well as in particular natural oils such as e.g. avocado oil, castor oil, macadamia nut oil, jojoba oil, as well as in particular polar silicone oils such as e.g. phenyl trimethicone (Dow Corning 558 Fluid), dimethicone (Wacker AK 100), cyclomethicone (Dow Corning Fluid 345), cyclopolydimethylsiloxane (Dow Corning Fluid 244), and Cyclopentasiloxane (Xiameter PMX-0245) as well as in particular alkanes such as isohexadecane, isododecane as well as mixtures thereof.

[0118]

[0082] Suitably the oil in the aspects of the invention is a plant-based oil. Preferably the oil comprises or consists of one or more oils, preferably ester oils, chosen from the group consisting of or based on argan oil, jojoba oil, olive oil, coconut oil, almond oil, avocado oil, grapeseed oil, rosehip oil, chamomile oil, lavender oil, tea tree oil, peppermint oil or menthol oil, eucalyptus oil, rapeseed oil, sunflower oil, soybean oil, castor oil, palm oil, groundnut oil, clove oil, camphor oil, eugenol, cinnamon oil, hazel oil and / or combinations thereof. Especially preferred are argan oil, jojoba oil, olive oil, coconut oil, almond oil, avocado oil, grapeseed oil, rosehip oil, chamomile oil, lavender oil, tea tree oil and combinations of one or more of these.

[0119]

[0083] In a special embodiment the oil may be a so-called “fragrance oil” or “perfume oil”. Hence, in another aspect, the oil may comprise or consist of one or more fragrances selected from limonene, citral, linalool, alpha-isomethylionone, geraniol, citronellol, 2-isobutyl-4-hydroxy-4- methyltetrahydropyran, 2-tert-pentylcyclohexyl acetate, 3-methyl-5-phenyl-1 -pentanol, 7-acetyl- 1 ,1 ,3,4,4, 6-hexamethyltetralin, adipic diester, cinnamal, amyl salicylate, alpha-amylcinnamaldehyde, alpha-methylionone, butylphenylmethylpropional, cinnamal, amylcinnamyl alcohol, anise alcohol, benzoin, benzyl alcohol, benzyl benzoate, benzyl cinnamate, benzyl salicylate, bergamot oil, bitter orange oil, butylphenylmethylpropional, cardamom oil, cedrol, cinnamal, cinnamyl alcohol, citronellyl methylcrotonate, citrus oil, coumarin, diethyl succinate, ethyllinalool, eugenol, Evernia furfuracea extract, Evernia prunastri extract, farnesol, guaiacwood oil, hexylcinnamal, hexyl salicylate, hydroxycitronellal, lavender oil, lemon oil, linalyl acetate, mandarin oil, menthyl PCA, methyl hexadecan, nutmeg oil, rosemary oil, sweet orange oil, terpineol, tonkabean oil, triethyl citrate, vanillin.

[0084] All different types of oils described in the above embodiments may suitably be combined in a mixture or a blend. That is, the oil in the aspects of the invention may also comprise a mixture or blend of the different types of oil described in the above embodiments.

[0120]

[0085] As described in the article by Biobelemonye et al, titled “Dandruff aetiology and the effects of edible lipids on the growth of isolates”, published in the European Journal of Pharmaceutical and medical research in September 2016, vol. 3(9), pages 71-76, growth of Malassezia furfuris especially explicit in oils. The combination of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val- Dab-OH with the oils, preferably ester oils, as described above is therefore especially advantageous. It can help to reduce abundant growth of Malassezia furfur.

[0121]

[0086] The composition of the first and / or second aspect of the invention can be especially advantageous when the oil is selected from the group of natural oils consisting of groundnut oil, coconut oil, olive oil and castor oil or from the group of ester oils based on an oil selected from this group consisting of groundnut oil, coconut oil, olive oil and castor oil.

[0122] Hydroxyacetophenone, glyceryl ether or glyceryl ester

[0123]

[0087] In all aspects according to the invention, the composition preferably comprises a hydroxyacetophenone, a glyceryl ether and / or a glyceryl ester. As illustrated by the examples, when the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH is combined with a hydroxyacetophenone, a glyceryl ether and / or a glyceryl ester a synergistic anti-fungal effect is obtained in reducing initial growth and / or contamination with Aspergillus brasiliensis, a key potential contaminant in an industrial manufacturing environment. The synergistic antifungal effect can be beneficial both before as well as after the mixing with other ingredients during the manufacturing process.

[0124]

[0088] In one embodiment, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH is combined with a hydroxyacetophenone. The invention thus also provides a composition, preferably a cosmetic composition or an ingredient composition, most preferably an ingredient composition, comprising:

[0125] - an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH; and

[0126] - a hydroxyacetophenone.

[0127] Other preferences for such a composition are as described herein above and below.

[0128]

[0089] In another embodiment, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab- OH is combined with a glyceryl ether. The invention thus also provides a composition, preferably a cosmetic composition or an ingredient composition, most preferably an ingredient composition, comprising:

[0129] - an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0130] - a glyceryl ether.

[0131] Other preferences for such a composition are as described herein above and below.

[0132]

[0090] In another embodiment, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab- OH is combined with a glyceryl ester. The invention thus also provides a composition, preferably a cosmetic composition or an ingredient composition, most preferably an ingredient composition, comprising:

[0133] - an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0134] - a glyceryl ester.

[0135] Other preferences for such a composition are as described herein above and below.

[0136]

[0091] In yet another embodiment, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val- Dab-OH is combined with a combination of at least two compounds selected from the group of hydroxyacetophenones, glyceryl ethers, and glyceryl esters. The invention thus also provides a composition, preferably a cosmetic composition or an ingredient composition, most preferably an ingredient composition, comprising:

[0137] - an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0138] - one or more hydroxyacetophenones and / or one or more glyceryl ethers and / or one or more glyceryl esters.

[0139] Other preferences for such a composition are as described herein above and below.

[0140]

[0092] Antimicrobials commonly used in the cosmetic industry are mainly not natural occurring compounds and often derived from a fossil source. As indicated above, it is desirable to reduce said fossil derived antimicrobials by using more natural, eco-friendly or biologically derived antimicrobials. The hydroxyacetophenone(s), glyceryl ether(s) and / or glyceryl ester(s) are therefore preferably obtained from, produced in and / or derived from a natural, eco-friendly, biological or biotechnical source. For example, they may be produced fermentatively.

[0141]

[0093] The hydroxyacetophenone compound can suitably be 2-hydroxyacetophenone (also referred to as ortho-hydroxyacetophenone or o-hydroxyacetophenone), 3-hydroxyacetophenone (also referred to as meta-hydroxyacetophenone or m-hydroxyacetophenone), 4-hydroxyacetophenone (also referred to as para-hydroxyacetophenone or p-hydroxyacetophenone or piceol) or a mixture of one or more of these. If present, the hydroxyacetophenone is preferably para-hydroxyacetophenone. Para- hydroxyacetophenone is commercially available, for example from the company Symrise under the trade name "Symsave® H” or in the form of "Symsave® 5E”.

[0142]

[0094] The hydroxyacetophenone in this invention can suitably be a hydroxyacetophenone that is not chemically produced. For example it can be produced via extraction from a plant or via production in a micro-organism. For example Wu et al describe, in their article titled “Production of p- Hydroxyacetophenone by Engineered Escherichia coli; Heterologously Expressing 1-(4-Hydroxyphenyl)- Ethanol Dehydrogenase”, published in J Microbiol Biotechnol. 2024 Feb 28; 34(2): 467-475, the microbial production of hydroxyacetophenone in Escherichia coli .

[0143]

[0095] Advantageously the Symsave® H product is a "natural identical”.

[0144]

[0096] If present, the hydroxyacetophenone is preferably present in a weight percentage in the range from equal to or more than 0.005 wt. %, more preferably from equal to or more than 0.010 wt. %, even more preferably from equal to or more than 0.05 wt. %, still more preferably from equal to or more than 0.1 wt. %, to equal to or less than 20 wt. %, more preferably to equal to or less than 10 wt. %, even more preferably to equal to or less than 5 wt. %, yet more preferably to equal to or less than 3 wt. %, most preferably to equal to or less than 2 wt. %, based on the total weight of the composition. As illustrated by the examples a low dosage can already be very effective. For practical purposes, in a cosmetic composition, the hydroxyacetophenone can even be present in a weight percentage in the range from equal to or more than 0.1 wt. % to 1.0 wt%, based on the total weight of a cosmetic composition.

[0145]

[0097] By a glyceryl ether is herein understood an ether of propane-1 ,2,3-triol (propane-1 ,2,3-triol is also referred to herein as glycerol or glycerin). One, two or all three hydroxyl groups of the glycerol can be etherified. Preferably the one, two or three ether groups are alkyl-ether groups. That is, the glyceryl ether is preferably a mono-, di- or tri-alkyl ether of propane-1 ,2,3-triol. It is preferred that not all the hydroxyl groups are etherified. Preferably the glyceryl ether is a mono-ether of propane-1 ,2,3-triol, more preferably a mono-alkyl-ether of propane-1 ,2,3-triol. By a mono-alkyl-ether of propane-1 ,2,3-triol is herein understood that merely one of the hydroxy groups in the propane-1 ,2,3-triol was etherified, that is, merely one of the hydroxy groups was replaced with an alkyl ether group. Preferably one of the primary hydroxyl groups of glycerol are etherified. That is, the glyceryl ether is preferably a terminal mono-alkyl-ether of propane-1 ,2,3-triol.

[0146]

[0098] Most preferably the glyceryl ether is a glyceryl ether of the formula (II) CH2(OH)-CH(OH)-CH2-O-R1(II), wherein R1is a non-cyclic alkyl group, more preferably a non-cyclic C1-18 alkyl group.

[0147] More preferably R1comprises from equal to or more than 2 carbon atoms, more preferably from equal to or more than 4 carbon atoms, still more preferably equal to or more than 6 carbon atoms and most preferably from equal to or more than 8 carbon atoms. Preferably R1comprises equal to or less than 18 carbon atoms, more preferably to equal to or less than 12 carbon atoms. Even more preferably R1is a non-cyclic C2-12 alkyl group, yet even more preferably a non-cyclic Ce-i2alkyl group R1can be a branched or linear (i.e. non-branched) non-cyclic alkyl group .

[0148]

[0099] Preferred glyceryl ethers include 3-(octyloxy)-propane-1 ,2-diol (also referred to as caprylyl glyceryl ether), 3-(dodecyloxy)-propane-1 ,2-diol (also referred to as lauryl glyceryl ether), 3- (octadecyloxy)propane-l ,2-diol (also referred to as stearyl glyceryl ether), 3-(16- methylheptadecyloxy)propane-1 ,2-diol (also referred to as isostearyl glyceryl ether) and 3-(2- ethylhexoxy)propane-1 ,2-diol (also referred to as ethylhexylglycerin). A most preferred glyceryl ether is 3-(2-ethylhexoxy)propane-1 ,2-diol (ethylhexylglycerin).

[0149]

[0100] If present, the glyceryl ether, preferably ethylhexylglycerin, is preferably present in a weight percentage in the range from equal to or more than 0.005 wt. %, more preferably from equal to or more than 0.010 wt. %, even more preferably from equal to or more than 0.05 wt. %, still more preferably from equal to or more than 0.1 wt. %, to equal to or less than 20 wt. %, more preferably to equal to or less than 10 wt. %, even more preferably to equal to or less than 5 wt. %, most preferably to equal to or less than 3 wt. %, most preferably to equal to or less than 2 wt. %, based on the total weight of the composition. As illustrated by the examples a low dosage can already be very effective. For practical purposes, in a cosmetic composition, the glyceryl ether, preferably ethylhexylglycerin, can even be present in a weight percentage in the range from equal to or more than 0.1 wt. % to 1 .0 wt%, based on the total weight of a cosmetic composition.

[0150]

[0101] By a glyceryl ester is herein understood an ester of propane-1 ,2,3-triol (propane-1 ,2,3-triol is also referred to herein as glycerol or glycerin). One, two or all three hydroxyl groups of the glycerol can be esterified. Preferably the one, two or three ester groups are alkyl-ester groups. That is, the glyceryl ester is preferably a mono-, di- or tri-alkyl ester of propane-1 ,2,3-triol. It is preferred that not all the hydroxyl groups are esterified. Preferably the glyceryl ester is a mono-ester of propane-1 ,2,3-triol, more preferably a mono-alkyl-ester of propane-1 ,2,3-triol. By a mono-alkyl-ester of propane-1 ,2,3-triol is herein understood that merely one of the hydroxy groups in the propane-1 ,2,3-triol was esterified, that is, merely one of the hydroxy groups was replaced with an alkyl ester group. Preferably one of the primary hydroxyl groups of glycerol are esterified. That is, the glyceryl ester is preferably a terminal mono-alkyl-ester of propane-1 ,2 ,3-triol .

[0151]

[0102] Most preferably the glyceryl ester is a glyceryl ester of the formula (III) CH2(OH)-CH(OH)-CH2-O-C(O)-R2(III), wherein R2is a non-cyclic alkyl group, more preferably a non-cyclic C1-18 alkyl group.

[0152] More preferably R2comprises from equal to or more than 2 carbon atoms, more preferably from equal to or more than 4 carbon atoms, still more preferably equal to or more than 6 carbon atoms and most preferably from equal to or more than 8 carbon atoms. Preferably R2comprises to equal to or less than 18 carbon atoms, more preferably to equal to or less than 12 carbon atoms. Even more preferably R2is a non-cyclic C2-18 alkyl group, yet even more preferably a non-cyclic Ce-is alkyl group R2can be a branched or linear (i.e. non-branched) non-cyclic alkyl group .

[0153]

[0103] Preferred glyceryl esters include 11-(2,3-dihydroxypropoxycarbonyl)heptadecanoate, 2,3- dihydroxypropyl octanoate (also referred to as glyceryl caprylate), 2,3-dihydroxypropyl dodecanoate (also referred to as glyceryl mono-laurate) and 2,3-dihydroxypropyl octadecenoate (also referred to as glyceryl mono-stearate). A most preferred glyceryl ester is 2,3-dihydroxypropyl octanoate (glyceryl caprylate), Glyceryl caprylate may also be referred to as a monoester of octanoic acid with glycerol.

[0154]

[0104] If present, the glyceryl ester, preferably glyceryl caprylate, is preferably present in a weight percentage in the range from equal to or more than 0.005 wt. %, more preferably from equal to or more than 0.010 wt. %, even more preferably from equal to or more than 0.05 wt. %, still more preferably from equal to or more than 0.1 wt. %, to equal to or less than 20 wt. %, more preferably to equal to or less than 10 wt. %, most preferably to equal to or less than 5 wt. %, based on the total weight of the composition. For practical purposes, in a cosmetic composition, the glyceryl ester, preferably glyceryl caprylate, can even be present in a weight percentage in the range from equal to or more than 0.1 wt. % to 1 .0 wt%, based on the total weight of a cosmetic composition.

[0155]

[0105] In a preferred embodiment, the glyceryl ether and / or glyceryl ester may or may not comprise or consist of glyceryl glucoside, glyceryl stearate citrate, caprylic / capric triglyceride, and / or glyceryl stearate.

[0156] Other components

[0157]

[0106] As indicated above, the compositions according to the first and second aspect of the invention preferably comprise a cosmetically acceptable carrier. Preferably the compositions comprise water, oil and / or another suitable carrier, such as glycerol. If present, the cosmetically acceptable carrier more preferably comprises or consists of water, oil or a combination of water and oil. Preferably the compositions of the first and second aspect are solutions, emulsions or dispersions.

[0107] In all embodiments of the present invention, the compositions according to the first and second aspect of the invention preferably further comprise at least one water soluble salt of an alkali, earth alkaline metal or transition metal, even more preferably in an amount selected in the range from 0.00001-2 wt.%, particularly in the range from 0.01-0.5 wt.%, most particularly in the range from 0.02- 0.01 wt.%, based on the total weight of the composition.

[0158]

[0108] Any water-soluble salt of an alkali, earth alkaline metal or transition metal or mixtures thereof with cosmetically acceptable anions can be used in the compositions according to the invention such as the chlorides, bromides, acetates, trifluoroacetates, sulfates, lactates, succinates or phosphates. Preferably the alkali, earth alkaline metal or transition metal is selected from Mg, Ca, Zn, Li and / or Na salts. Particularly MgCh, CaCh, ZnCh, LiCI and / or NaCI, more in particular MgCh is used. Further preferences in this respect are as described in WO2010122423A2, hereby incorporated by reference.

[0159]

[0109] In all embodiments of the present invention, the compositions according to the first and second aspect of the invention further may or may not comprise one or more polyols, such as propane-1 ,2,3- triol (also referred to as glycerol or glycerin), propane-1 ,2-diol, propane-1 ,3-diol, butane-1 ,2-diol, butane-1 ,3-diol, butane-1 ,4-diol, pentane-1 ,2-diol, hexane-1 ,2-diol and / or heptane-1 ,2-diol. In one embodiment the composition does not comprise propane-1 ,2, 3-triol (glycerol) and in another embodiment the composition does not comprise any one of the butane-diols, more preferably the composition does not comprise butylene glycol (butane-1 ,3-diol).

[0160]

[0110] In one embodiment, the composition comprises no or essentially no polyols other than the hydroxyacetophenone, glyceryl ether or glyceryl ester.

[0161]

[0111] In another embodiment, the composition does comprise hexane-1 ,2-diol and / or heptane-1 ,2- diol. Without wishing to be bound by any kind of theory it is believed that such alkanediols may blend well with the above oil components due to their longer chain length.

[0162]

[0112] Hence, the invention also provides a composition, preferably a cosmetic composition or an ingredient composition, comprising or consisting of:

[0163] - an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0164] - an oil;

[0165] - hexane-1 ,2-diol and / or heptane-1 ,2-diol; and

[0166] - optionally water; and

[0167] - optionally one or more cosmetically acceptable excipients.

[0168] Further preferences for such a composition are as described herein above and herein below.

[0169]

[0113] In another embodiment, if present , the (total) amount of polyol in the composition according to the present invention is preferably selected in the range from 10-90 wt.%, preferably in the range from 25 to 80 wt.%, most preferably in the range from 60-75 wt.%, based on the total weight of the composition. Further suitable ranges are selected in the range from 30 to 80 wt.%, 40 to 80 wt.% or 50 to 80 wt.%.

[0170] Cosmetic compositions and process for their preparation

[0171]

[0114] In one embodiment according to the invention, the compositions according to the invention are cosmetic compositions, more preferably topical compositions. Cosmetic compositions preferably comprise equal to or more than 10 ingredients, more preferably in the range from equal to or more than 10 to equal to or less than 60 ingredients, suitably in the range from equal to or more than 10 to equal to or less than 40 ingredients. In accordance with the present invention, the composition, especially wherein the composition is a cosmetic composition, may optionally comprise further ingredients such as ingredients for skin lightening; tanning prevention; treatment of hyperpigmentation; preventing or reducing acne, wrinkles, lines, atrophy and / or inflammation; as well as topical anesthetics; antimicrobial and / or antifungal agents; chelators and / or sequestrants; anti-cellulites and slimming (e.g. phytanic acid), firming, moisturizing and energizing, self-tanning, soothing, as well as agents to improve elasticity and skin barrier and / or UV-filter substances. In one embodiment the composition is preferably a topical cosmetic composition. The topical cosmetic preparations can also contain usual cosmetic adjuvants and additives, such as preservatives / antioxidants, fatty substances / oils, water, organic solvents, silicones, thickeners, softeners, emulsifiers, antifoaming agents, moisturizers, aesthetic components such as fragrances, surfactants, fillers, sequestering agents, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or basifying agents, dyes, colorings / colorants, abrasives, absorbents, essential oils, skin sensates, astringents, antifoaming agents, pigments or nanopigments, e.g. those suited for providing a photoprotective effect by physically blocking out ultraviolet radiation, or any other ingredients usually formulated into cosmetic preparations. Such cosmetic ingredients commonly used in the skin care industry, which are suitable for use in the cosmetic preparation of the present invention are for example described in the CTFA Cosmetic Ingredient Handbook, Second Edition (1992) without being limited thereto.

[0172]

[0115] If nothing else is stated, the carrier, excipients, additives, diluents, adjuvant and additives etc. mentioned herein are in particular suitable for cosmetic preparation according to the present invention.

[0173]

[0116] In one embodiment the composition, preferably a cosmetic composition, comprises, based on the total weight of the composition:

[0174] (i) from equal to or more than 0.001 wt.%, more preferably equal to or more than 0.01 wt.% to preferably equal to or less than 0.5 wt.-%, more preferably equal to or less than 0.2 wt.%, of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0175] (ii) from equal to or more than 5 wt.% to equal to or less than 95 wt.%, even more preferably in the range from equal to or more than 10 wt.% to equal to or less than 90 wt.%, still more preferably in the range from equal to or more than 5 wt.% to equal to or less than 60 wt.%, of an oil, more preferably an oil chosen from the group consisting of argan oil, jojoba oil, olive oil, coconut oil, almond oil, avocado oil, grapeseed oil, rosehip oil, chamomile oil, lavender oil, tea tree oil, peppermint oil or menthol oil, eucalyptus oil, rapeseed oil, sunflower oil, soybean oil, castor oil, palm oil, groundnut oil, clove oil, camphor oil, eugenol, cinnamon oil, hazel oil and / or combinations thereof;

[0176] (iii) optionally in the range from equal to or more than 0.005 wt. %, more preferably from equal to or more than 0.010 wt. %, even more preferably from equal to or more than 0.05 wt. %, to equal to or less than 20 wt. %, more preferably to equal to or less than 10 wt. %, even more preferably to equal to or less than 5 wt. %, most preferably to equal to or less than 3 wt. %, each individually, of one or more of a hydroxyacetophenone, glyceryl ether and / or glyceryl ester, more preferably p- hydroxyacetophenone, ethylhexylglycerin and / or glyceryl caprylate;

[0177] (iv) optionally in the range from equal to or more than 0.00001 to equal to or less than 2 wt.% of a water soluble salt of an alkali, earth alkaline metal or transition metal, preferably MgCh;

[0178] (v) optionally equal to or more than 0.01 wt.% to equal to or less than 60 wt.%, even more preferably in the range from equal to or more than 0.1 wt.% to equal to or less than 50 wt.%, still more preferably in the range from equal to or more than 0.1 wt.% to equal to or less than 30 wt.%, each individually, of one or more other active ingredients and / or cosmetic adjuvants and / or additives, as exemplified above; and

[0179] (vi) water to sum up to 100 wt.%.

[0180]

[0117] In another embodiment the composition, preferably a cosmetic composition, comprises, based on the total weight of the composition:

[0181] (i) from equal to or more than 0.001 wt.%, more preferably equal to or more than 0.01 wt.% to preferably equal to or less than 0.5 wt.-%, more preferably equal to or less than 0.2 wt.%, of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0182] (ii) optionally from equal to or more than 5 wt.% to equal to or less than 95 wt.%, even more preferably in the range from equal to or more than 10 wt.% to equal to or less than 90 wt.%, still more preferably in the range from equal to or more than 5 wt.% to equal to or less than 60 wt.%, of an oil;

[0183] (iii) in the range from equal to or more than 0.005 wt. %, more preferably from equal to or more than 0.010 wt. %, even more preferably from equal to or more than 0.05 wt. %, to equal to or less than 20 wt. %, more preferably to equal to or less than 10 wt. %, even more preferably to equal to or less than 5 wt. %, most preferably to equal to or less than 3 wt. %, each individually, of one or more of a hydroxyacetophenone, glyceryl ether and / or glyceryl ester, more preferably p- hydroxyacetophenone, ethylhexylglycerin and / or glyceryl caprylate;

[0184] (iv) optionally in the range from equal to or more than 0.00001 to equal to or less than 2 wt.% of a water soluble salt of an alkali, earth alkaline metal or transition metal, preferably MgCh; (v) optionally equal to or more than 0.01 wt.% to equal to or less than 60 wt.%, even more preferably in the range from equal to or more than 0.1 wt.% to equal to or less than 50 wt.%, still more preferably in the range from equal to or more than 0.1 wt.% to equal to or less than 30 wt.%, each individually, of one or more other active ingredients and / or cosmetic adjuvants and / or additives, as exemplified above; and

[0185] (vi) water to sum up to 100 wt.%.

[0186]

[0118] The invention further provides a process for preparing a cosmetic composition comprising mixing one or more of the components (i) to (vi) as mentioned above in respect of such cosmetic composition. More preferably the invention further provides a process for preparing a composition comprising mixing components (i), (iii) and optionally one or more of components (ii), (iv), (v) and / or (vi) as mentioned above.

[0187]

[0119] Preferably, the cosmetic compositions are in the form of a suspension or dispersion in solvents or fatty substances, or alternatively in the form of an emulsion (including micro, PIT, pickering and multiple emulsion), such as in particular of O / W- or W / O-type, gels such as hydrogels, alcoholic gels, lipogels, one- or multiphase solution or vesicular dispersion or other usual forms, which can also be applied by pens, as masks or as sprays. If the cosmetic composition is or comprises an emulsion it can also contain one or more anionic, nonionic, cationic or amphoteric surfactant(s). More preferably the cosmetic composition according to the invention are formulated as an oil-in-water or water-in-oil emulsion, water-in-silicone or silicone-in-water emulsion or as an aqueous serum or aqueous gel in particular as an oil-in water emulsion (O / W emulsion). Preferably the cosmetic compositions according to the invention have a pH in the range of 3-10, preferably in the range of pH of 4-8, most preferred in the range of pH 4-6.

[0188]

[0120] The oil in the aspects of the invention can suitable be incorporated in the oil phase of an emulsion, microemulsion, oleo gel, hydrodispersion or lipodispersion

[0189]

[0121] In an advantageous embodiment, the cosmetic compostions according to the present invention comprise from 50% to 99%, preferably from 60% to 98%, more preferably from 70% to 98%, such as in particular from 80% to 95% of a carrier, suitably a cosmetically acceptable carrier, based on the total weight of the composition. In a particular advantageous embodiment, the carrier in all embodiments of the present invention consists furthermore of at least 30 wt. %, preferably of at least 40 wt.-%, more preferably of at least 45 wt.-%, most preferably of at least 50 wt.-% of water, such as in particular of 50 to 95 wt.-%, from 50 to 80 wt.-%, from 50 to 70 wt.-% or from 50 to 60 wt.-% of water.

[0190]

[0122] Preferred cosmetic compositions are skin care compositions, and functional compositions.

[0191]

[0123] Cosmetic compositions in accordance with the invention can be in the form of a liquid, lotion, a thickened lotion, a gel, a cream, a milk, an ointment, a paste, a powder, a make-up, or a solid tube stick and can be optionally be packaged as an aerosol and can be provided in the form of a mousse such as an aerosol mousse, a foam or a spray foam, a spray, a stick, a plaster, a cleanser, a soap, a wipe or a lyophilizate.

[0192] UV filters

[0193] In a preferred embodiment the compositions of the invention comprise one or more UV filters. Without wishing to be bound by any kind of theory it is believed that such may be advantageous to further improve the stability of the composition. Preferred UV filters include Titanium Dioxide, Zinc Oxide, Benzophenone-3 (also referred to as Oxybenzone), Benzophenone-4 (also referred to as Sulisobenzone), Benzophenone-5, Butyl methoxydibenzoylmethane (also referred to as “BMDBM” or “Avobenzone”), Ethylhexyl Methoxycinnamate (also referred to as Octinoxate), Ethylhexyl Salicylate (also referred to as Octisalate), Homosalate, Octocrylene, Terephthalylidene Dicamphor Sulfonic Acid, Drometrizole Trisiloxane, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (also referred to as Bemotrizinol or “BEMT”), Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (also referred to as Bisoctrizole, “MBBT”” ), Diethylamino Hydroxybenzoyl Hexyl Benzoate (also referred to as “DHHB”), Ethylhexyl Triazone (also referred to as “EHT”), Polysilicone-15, Isoamyl p-Methoxycinnamate, Phenylbenzimidazole Sulfonic Acid, Bisdisulizole Disodium, Tris-Biphenyl Triazine and / or combinations of one or more of these. Of these Butyl methoxydibenzoylmethane (also referred to as “BMDBM” or “Avobenzone”) is especially preferred.

[0194] Ingredient compositions and process for their preparation

[0195]

[0124] Cosmetic compositions can be prepared by mixing a number of ingredient compositions. In another embodiment according to the invention, the compositions according to the invention are ingredient compositions. Ingredients compositions are preferably less complex than cosmetic compositions. Preferably the ingredient composition comprises less than 10 ingredients, more preferably in the range from equal to or more than 1 to equal to or less than 9 ingredients, suitably in the range from equal to or more than 2 to equal to or less than 7 ingredients. Advantageously the invention thus also provides a pre-mix peptide blend which can be readily incorporated into cosmetic compositions. Preferably the ingredient composition comprises merely one, two or three active ingredients, optionally in combination with a cosmetically acceptable carrier and / or optionally in combination with one or more additive compounds such as stabilizers or other helper ingredients. In the preparation of a cosmetic composition, multiple ingredient compositions by different suppliers can be combined.

[0196]

[0125] In an ingredient composition, a certain volume of acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH can be desirable. More preferably the amount of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH in an ingredient composition, is selected in the range from 0.0005-12.5 wt.%, preferably in the range from 0.001-2 wt.%, more preferably in the range from 0.001-0.5 wt.%, such as in particular from 0.005 to 0.2 wt.%, such as 0.01 to 0.15 wt.% based on the total weigh of the composition.

[0197]

[0126] Hence, in one embodiment the composition, preferably an ingredient composition (such as for example a pre-mix blend supplied by an ingredient supplier to a cosmetic product manufacturer), consists essentially of or consists of, based on the total weight of the composition:

[0198] (i) from equal to or more than 0.01 wt.%, more preferably equal to or more than 0.05 wt.% to preferably equal to or less than 0.5 wt.-%, more preferably equal to or less than 0.2 wt.%, of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0199] (ii) from equal to or more than 5 wt.% to equal to or less than 95 wt.%, even more preferably in the range from equal to or more than 10 wt.% to equal to or less than 90 wt.%, still more preferably in the range from equal to or more than 5 wt.% to equal to or less than 60 wt.%, of an oil, more preferably an oil chosen from the group consisting of argan oil, jojoba oil, olive oil, coconut oil, almond oil, avocado oil, grapeseed oil, rosehip oil, chamomile oil, lavender oil, tea tree oil, peppermint oil or menthol oil, eucalyptus oil, rapeseed oil, sunflower oil, soybean oil, castor oil, palm oil, groundnut oil, clove oil, camphor oil, eugenol, cinnamon oil, hazel oil and / or combinations thereof;

[0200] (iii) optionally in the range from equal to or more than 0.005 wt. %, more preferably from equal to or more than 0.010 wt. %, even more preferably from equal to or more than 0.05 wt. %, to equal to or less than 20 wt. %, more preferably to equal to or less than 10 wt. %, even more preferably to equal to or less than 5 wt. %, most preferably to equal to or less than 3 wt. %, each individually, of one or more of a hydroxyacetophenone, glyceryl ether and / or glyceryl ester, more preferably p- hydroxyacetophenone, ethylhexylglycerin and / or glyceryl caprylate;

[0201] (iv) optionally in the range from equal to or more than 0.00001 to equal to or less than 2 wt.% of a water soluble salt of an alkali, earth alkaline metal or transition metal, preferably MgCh;

[0202] (v) water to sum up to 100 wt.%.

[0203]

[0127] In another embodiment the composition, preferably an ingredient composition, consists essentially of or consists of, based on the total weight of the composition:

[0204] (i) from equal to or more than 0.01 wt.%, more preferably equal to or more than 0.05 wt.% to preferably equal to or less than 0.5 wt.-%, more preferably equal to or less than 0.2 wt.%, of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH;

[0205] (ii) optionally from equal to or more than 5 wt.% to equal to or less than 95 wt.%, even more preferably in the range from equal to or more than 10 wt.% to equal to or less than 90 wt.%, still more preferably in the range from equal to or more than 5 wt.% to equal to or less than 60 wt.%, of an oil, more preferably an oil chosen from the group consisting of argan oil, jojoba oil, olive oil, coconut oil, almond oil, avocado oil, grapeseed oil, rosehip oil, chamomile oil, lavender oil, tea tree oil, peppermint oil or menthol oil, eucalyptus oil, rapeseed oil, sunflower oil, soybean oil, castor oil, palm oil, groundnut oil, clove oil, camphor oil, eugenol, cinnamon oil, hazel oil and / or combinations thereof;

[0206] (iii) in the range from equal to or more than 0.005 wt. %, more preferably from equal to or more than 0.010 wt. %, even more preferably from equal to or more than 0.05 wt. %, to equal to or less than 20 wt. %, more preferably to equal to or less than 10 wt. %, even more preferably to equal to or less than 5 wt. %, most preferably to equal to or less than 3 wt. %, each individually, of one or more of a hydroxyacetophenone, glyceryl ether and / or glyceryl ester, more preferably p- hydroxyacetophenone, ethylhexylglycerin and / or glyceryl caprylate;

[0207] (iv) optionally in the range from equal to or more than 0.00001 to equal to or less than 2 wt.% of a water soluble salt of an alkali, earth alkaline metal or transition metal, preferably MgCh;

[0208] (v) water to sum up to 100 wt.%.

[0209]

[0128] Preferably the above compositions comprise equal to or less than 1 wt% glycerin or butylene glycol, more preferably no glycerin or butylene glycol.

[0210]

[0129] The invention further provides a process for preparing an ingredient composition comprising mixing one or more of the components (i) to (v) as mentioned above in respect of such ingredient composition. More preferably the invention further provides a process for preparing a composition comprising mixing components (i), (iii) and optionally one or more of components (ii), (iv) and / or (v) as mentioned above.

[0211]

[0130] The above ingredient composition, respectively premix-peptide blend, can advantageously be incorporated into cosmetic compositions useful for improving skin appearance and physiology such as e.g. reducing fine lines, wrinkles and other symptoms associated with aged or photodamaged skin, treatment of stretch marks or tightening, firming and / or moisturizing skin. Examples of such cosmetic compositions are mentioned above.

[0212]

[0131] Thus, the invention also relates to a cosmetic composition comprising an ingredient composition as defined above and a cosmetically acceptable carrier. Such preparations are prepared by incorporating an ingredient composition as described above with the other ingredients of the cosmetic composition according to standard methods in the art.

[0213]

[0132] The amount of the ingredient composition according to the present invention to be used in such cosmetic compositions is preferably selected in the range from from 0.5 to 5wt.-%, preferably from 0.75 to 4 wt.-%, most preferably in the range from 1 to 3 wt.-%, based on the total weight of the cosmetic composition.

[0214] Use and packaging of the composition

[0215]

[0133] In line with the above, the invention also provides the use of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH to reduce or eliminate the growth of one or more microorganisms, preferably fungi, within a composition, preferably within a cosmetic composition or an ingredient composition. More preferably the invention also provide the use of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH as a cosmetic active and / or an antimicrobial, preferably antifungal, active within a composition. Preferences for such use are as outlined above. Suitably the invention provides a use of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab- Val-Dab-OH to reduce or eliminate growth of and / or contamination with one or more of the microbial species chosen from the group consisting of Candida, Malessezia, Cyrynebacterium, Aspergillus and / or combinations thereof, more preferably the group consisting of Candida albicans, Malassezia furfur, Cyrynebacterium xerosis, Aspergillus brasiliensis and / or combinations thereof.

[0216]

[0134] The invention further relates to a container comprising a composition according to the first or second aspect of the invention. Suitable containers include any containers suitable for packaging and transport of the compositions according to the invention. Such container can be made of glass, polyethylene, polystyrene, polylactic acid, polyethyleneterephthalat or polypropylene without being limited thereto. Suitable containers are well known and can easily be chosen by a person skilled in the art such as polyethylene canisters with a volume of e.g. 1 kg or 10kg, glass container with a volume of e.g. 50ml, 11, 2.51 or polyethylene canister with a volume of e.g. 100ml. The compositions according to the invention advantageously assist in the reduction and / or elimination of growth of and / or contamination with one or more micro-organisms as above within the container.

[0217]

[0135] The invention is illustrated by the following non-limiting examples. If nothing else is stated, the carrier, excipients, additives, diluents, adjuvant and additives etc. mentioned in the following are in particular suitable for the compositions according to the present invention.

[0218] Examples

[0219] Sample preparation and method

[0220]

[0136] For all tests, the different products were prepared at three concentrations in H2O (final volume 2 mL) in deep well plates (n=3 for each concentration).

[0221]

[0137] Analysis controls were prepared and used identically to samples :

[0222] - A growth control of microorganisms in the corresponding culture medium (T1);

[0223] - A negative control consisting of Phenoxyethanol prepared at 1 % (v / v) directly in H2O (T2);

[0224] - A growth control of microorganisms in H2O (T3).

[0225]

[0138] Samples were contaminated with respectively Candida albicans, Corynebacterium xerosis and Malassezia furfur for example 1 and Aspergillus brasiliensis for example 2, at a final concentration of 1.106 colony forming units per milliliter (cfu / mL) for bacteria and at a final concentration of 1.105 cfu / mL for fungi, and incubated at a temperature of 37 °C ± 2,5 °C during 4 hours, taking care to respect the respiratory type of the strain. After the time periods as listed in the examples, a pick-up of the contaminated samples was performed (20 pL) after gentle agitation.

[0226]

[0139] Tests were carried out on the contaminated samples using an acetic acid addition salt of

[0227] Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”) respectively an Trifluoroacetic acid (TFA) addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“TFA salt”). Additional tests were carried out in the presence of 4’-hydroxyacetophenone (p-hydroxyacetophenone, abbreviated as “HAP”), 3-(2- ethylhexoxy)propane-1 ,2-diol (ethylhexylglycerin, abbreviated as “EHG”), (2,3- dihydroxypropoxycarbonyl)heptadecanoate (glyceryl caprylate, abbreviated as “GC”), in each case alone and in combination with the AcOH salt respectively the TFA salt. Further comparative tests were carried out in respect of combinations with hexane-1 ,2-diol and heptane-1 ,2-diol, in each case alone and in combination with the AcOH salt respectively the TFA salt. All the amounts were as indicated in the tables below. The percentages as indicated are weight percentages (w / w).

[0228]

[0140] To perform the counting of the cfu / mL, aliquots of the contaminated samples were serially diluted (decimal dilutions) in culture medium in 96-wells plates with eventually presence of triphenyltetrazolium (TTC) for bacteria which had deshydrogenase activity and incubated at a temperature of 37 °C ± 2,5 °C during 48 hours. After 48 hours at the optimal growing conditions, the last dilution showing a pink colour (triphenyltetrazolium) or turbidity indicated the contamination rate and allowed the determination of the corresponding microbial population according to the nutrient pad procedure (NPP).

[0229] Example 1 : Growth inhibition of fungi present on the skin of customers

[0230]

[0141] To illustrate the invention, tests were carried out using an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”) and comparative tests were carried out using a Trifluoroacetic acid (TFA) addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“TFA salt”). The AcOH salt and the TFA salt were tested alone and in combination with para-hydroxyacetophenone, a glyceryl ether (ethylhexylglycerin) and a glyceryl ester (glyceryl caprylate). In addition, combinations with the diols hexane-1 ,2-diol and heptane-1 ,2-diol were made, as illustrated and in the amounts in the tables below.

[0231]

[0142] The AcOH salt and the TFA salt were both tested for growth inhibition of the tested bacteria and fungi in liquid media in deepwell plates. As medium water was used. The AcOH salt and the TFA salt were applied in a concentration of 0.01 wt. %.

[0232]

[0143] The tests in this example 1 explored the inhibition of the growth of Candida albicans, Corynebacterium xerosis, and Malassezia furfur, each micro-organisms that are abundant on the human skin and pose cross-contamination challenges when a cosmetic composition is used by a customer.

[0233]

[0144] The results of the above “time to kill” study are presented in the respective Tables below. Samples were taken and results were determined after the time periods of 30 minutes, 2 hours and 4 hours. Table 1 shows the results for Candida albicans, Table 2 shows the results for Corynebacterium xerosis, and Table 3 shows the results for Malassezia furfur. The microbial population counts are expressed in colony forming unit per mililiter (CFU / mL, determined by the nutrient pad procedure (NPP).

[0234]

[0145] The results of the test show that in comparison with the prior art Trifluoroacetic acid (TFA) addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“TFA salt”), the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”) has a remarkable antimicrobial activity. From the results it can be concluded that advantageously the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH can contribute in / to the reduction of micro-organisms. The acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH can suitably be an antimicrobial active in respect of the fungi Candida and / or Malessezia and / or the bacterium Cyrynebacterium. As illustrated in Tables 1 and 3, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH has antifungal activity against Candida albicans as well as Malassezia furfur. As further illustratrated in Table 2, the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH also has antibacterial activity against Cyrynebacterium xerosis. It is especially noted that Table 3 shows that the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”) can effectively inhibit Malassezia furfur, a fungus that otherwise may thrive in cosmetic compositions comprising a substantial oil component.

[0235] Example 2 : Initial growth inhibition of fungi present in a factory environment

[0236]

[0146] To illustrate the invention, furthermore tests were carried out to mimic initial growth inhibition of fungi in ingredient compositions during manufacturing conditions. Tests were carried out using the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”) in combination with para-hydroxyacetophenone, a glyceryl ether (ethylhexylglycerin) and a glyceryl ester (glyceryl caprylate). Comparative tests were carried out with hexane-1 ,2-diol and heptane-1 ,2-diol. The tests were carried out in a similar manner as for Example 1. Samples were taken and results were determined after a time period of 30 minutes.

[0237]

[0147] The test explored the initial inhibition of the growth of Aspergillus brasiliensis, a fungus with high abundancy in factory environments. Table 4 shows the results for Aspergillus brasiliensis. The microbial population counts are expressed in colony forming unit per mililiter (CFU / mL, determined by the nutrient pad procedure (NPP).

[0148] As illustrated in Table 4, the acetic acid addition salt ofTetradecylaminocarbonyl-Dab-Val-Dab- OH (“AcOH salt”) together with a para-hydroxyacetophenone, a glyceryl ether (ethylhexylglycerin) or a glyceryl ester (glyceryl caprylate) shows a synergistic initial growth inhibition of Aspergillus brasiliensis that is highly improved over the initial growth inhibition of either of the components alone.

[0149] All percentages are in weight percent. The experiments were carried out with 0.01 wt% of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”), but based on the excellent results it is hypothesized and a skilled person can expect that the synergistic advantage can be obtained also with lower percentages, such as for example 0.001 wt% of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”).

[0238] Table 1 : Inhibition of the growth of Candida albicans (results in cfu / ml, determined by NPP)

[0239] Table 2 : Inhibition of the growth of Cyrynebacterium xerosis (results in cfu / ml, determined by NPP)

[0240] Table 3 : Inhibition of the growth of Malassezia furfur (results in cfu / ml, determined by NPP)

[0241] Table 4 : Initial inhibition (at 30 minutes) of the growth of Aspergillus brasiliensis (results in cfu / ml, determined by NPP) Example 3 : Examples of Formulations according to the invention

[0242]

[0150] In the below a number of exemplary formulations for the compositions of the invention are provided. All amounts are in weight percentage. Formulation 1 : Daycare Oil-in-Water (O / W) emulsion

[0243]

[0244] Formulation 3 : Sun Care Tanning Cream

[0245] Formulation 4 : Dav Care Oil-in-Water (O / W) emulsion

[0246]

[0247] Formulation 5 : Dav Care Oil-in-Water (O / W) emulsion

[0248] Formulation 6 : Sun Care Oil-in-Water (O / W) emulsion

[0249]

[0250] Formulation 7 : Sun Care Oil-in-Water (O / W) emulsion

[0251]

[0252] Formulation 8 : Sun Care Oil-in-Water (O / W) emulsion

[0253] Formulation 9 : Sun Care Oil-in-Water (O / W) emulsion

[0254] Example 4 : Special Formulation according to the invention

[0255] The below specific formulations of this example 4 outlines a special set of O / W emulsions, comprising an ingredient AcOH-Gly, AcOH-Gly-MgCI2 or AcOH-BG prepared as described below. a) qlycerin / water composition (AcOH-Gly)

[0256] 100.4mg of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”) was charged into a 100ml round bottom necked flask and is dissolved in 24.0 g water and dissolved at 95°C using short time (approx. 30 sec) ultrasonic bath. Afterwards 58.1g glycerin (86.5%) is added followed by the addition of 0.9ml water. b) qlycerin / water / MqCh composition (AcOH-Gly-MqCI2)

[0257] 150mg of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”) was charged into a 250ml round bottom necked flask and is dissolved in 20.2g water and dissolved at 85°C using short time (approx. 30 sec) ultrasonic bath. Afterwards 99.6g glycerin (86.5%) is added and stirred for 10 mins. 10Omg MgCh *6H2O diluted in 1 .5ml water is added, stirred for 1 h, the pH is adjusted to approx. 4.5 with 10% AcOH, followed by the addition of 1.36g of water. c) butylene qlycol / water composition (AcOH-BG)

[0258] 100.7mg of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH (“AcOH salt”) was charged into a 100ml round bottom necked flask. 24.0g water is added and the peptide is dissolved at 95°C using short time (approx. 30 sec) ultrasonic bath. 58.1g Butylene glycol is added followed by the addition of 0.9g of water.

[0259] According to one preferred embodiment of the invention, such specific formulations of this example 4 may be included in the scope of the invention. According to an alternative preferred embodiment of the invention, the invention may exclude the specific formulations of this example 4.

Claims

CLAIMS1 . A composition comprising:- an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH; and- a hydroxyacetophenone, a glyceryl ether and / or a glyceryl ester.

2. The composition according to claim 1 , wherein the composition further comprises water, oil and / or glycerol.

3. The composition according any one of the preceding claims, wherein the amount of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH in the composition is equal to or more than 0.001 wt.%, based on the total weight of the composition.

4. The composition according any one of the preceding claims, wherein the amount of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH in the composition is equal to or more than 0.01 wt.% and equal to or less than 12.5 wt%, based on the total weight of the composition.

5. The composition according any one of the preceding claims, wherein the composition comprises the hydroxyacetophenone, glyceryl ether and / or glyceryl ester in a weight percentage in the range from equal to or more than 0.005 wt. % to equal to or less than 20 wt. %, based on the total weight of the composition.

6. The composition according any one of the preceding claims, wherein the composition comprises an oil, and wherein the the oil comprises or consists of one or more ester oils selected from the group consisting of diethyl hexyl sebacate, dicaprylyl carbonate, octylpalmitate, octylcocoate, octylisostearate, octyldodecylmyristate, cetearylisononanoate, isopropylmyristate, isopropylpalmitate, isopropylstearate, isopropyloleate, n-butylstearate, n-hexyllaurate, n- decyloleate, isooctylstearate, isononylstearate, isononylisononanoate, 2-ethyl hexylpalmitate, 2- ethylhexyllaurate, 2-hexyldecylstearate, 2-octyldodecylpalmitate, stearylheptanoate, oleyloleate, oleylerucate, erucyloleate, erucylerucate, tridecylstearate, tridecyltrimellitate, as well as synthetic, half-synthetic or natural mixtures of such esters such as for example jojoba oil, and combinations of one or more of these.

7. The composition according any one of the preceding claims, wherein the composition comprises a hydroxyacetophenone and wherein the hydroxyacetophenone is para- hydroxyacetophenone.

8. The composition according any one of the preceding claims, wherein the composition comprises a a glyceryl ether and wherein the glyceryl ether is ethylhexylglycerin.

9. The composition according any one of the preceding claims, wherein the composition comprises a glyceryl ester and wherein the glyceryl ester is glyceryl caprylate.

10. The composition according any one of the preceding claims, wherein the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH has a cosmetic activity and an antimicrobial activity.11 . The composition according any one of the preceding claims, wherein the Tetradecylaminocarbonyl- Dab-Val-Dab-OH is Tetradecylaminocarbonyl-L-Dab-L-Val-L-Dab-OH.

12. The composition according any one of the preceding claims, wherein the composition further comprises a water soluble salt of an alkali, earth alkaline metal or transition metal, more preferably magnesium chloride.

13. The composition according any one of the preceding claims, wherein the mol equivalents of acetic acid in the acetic acid addition salt is selected in the range of 0.5 to 3 mol equivalents based on Tetradecylaminocarbonyl-Dab-Val-Dab-OH.

14. The composition according any one of the preceding claims, wherein the composition further comprises one or more alkanediols, preferably one or more alkanediols chosen from the group consisting of hexanediol, heptanediol, octanediol and / or mixtures thereof.

15. A process for preparing a cosmetic composition comprising mixing a composition according to any one of the preceding claims with one or more other components or compositions.

16. Use of an acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH to reduce or eliminate the growth of one or more microorganisms, more preferably fungi, most preferably Aspergillus brasiliensis, within a composition, preferably a composition according to any one of claims 1 to 14.

Images