Novel peptide compositions

Abstract

The present invention relates to a composition comprising the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH. Furthermore, the invention relates to the use of acetic acid to prepare an acetic acid addition salt of TDAC-Dab-Val-Dab-OH to increase the storage stability of TDAC-Dab-Val-Dab-OH in a polyol solution.

Description

[0001] NOVEL PEPTIDE COMPOSITIONS

[0002] The present invention relates to a composition comprising the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH. Furthermore, the invention relates to the use of acetic acid to prepare an acetic acid addition salt of TDAC-Dab-Val-Dab-OH to increase the storage stability of TDAC-Dab-Val-Dab-OH in a polyol solution.

[0003] The prominent role of peptides in nature makes them valuable cosmetic ingredients. Cosmetic peptides are involved in many physiological processes (e.g. increase of collagen production) and have various benefits (e.g. anti-wrinkle, pigmentation reduction, firming).

[0004] TDAC-Dab-Val-Dab-OH (also referred to Tetradecylaminobutyroylvalylaminobutyric urea) is commercially available as SYN®-HYCAN from DSM Nutritional Products Ltd, which commercial form is the bistrifluoroacetic acid addition salt of the synthetic tripeptide TDAC- Dab-Val-Dab-OH. SYN®-HYCAN is widely used in cosmetic applications.

[0005] Trifluoroacetic acid (TFA) is typically used in the peptide synthesis during the process of cleaving peptides from their respective resin, as well as an ion pairing agent in HPLC purifications. Therefore synthesized peptides are usually in the form of TFA salts (up to 45% TFA content). In addition the TFA salts generally exhibit a good solubility, which is a prerequisite for cosmetic applications.

[0006] However, cosmetic preparations comprising TFA respectively salts thereof are not well appreciated anymore by all consumers.

[0007] In addition, as the peptides are highly potent ingredients, commercial product forms are generally solutions of said peptides in a suitable diluent. Such solutions should exhibit a high storage stability over a prolonged period of time.

[0008] Thus, there is an ongoing need for alternative peptide salt solution of TDAC-Dab-Val-Dab- OH which are free of TFA while exhibiting a good storage stability. EP2421886 B1 describes a composition comprising: (i) 0.001-12.5 wt.-% of a peptide with 2-12 amino acids substituted with a lipophilic moiety, (ii) 0.00001-2 wt.-% of a water soluble salt of an alkali, earth alkaline metal or transition metal, (iii) at least 10 wt.-% of at least one water-soluble polyol containing 2 to 10 carbon atoms and 2 to 7 hydroxyl groups and (iv) at least 10 wt.-% of water, whereas the total amount of ingredients sums up to 100 wt.-%.

[0009] In a first list it is mentioned that the peptide may be Palm-Lys-Val-Lys-OH, Palm-Lys-Val- Dab-OH, Palm-Lys-Val-Dab-Thr-OH and / or C14H29-NH-CO-Dab-Val-Dab-OH.

[0010] In passing, in a second list, reference is made to acid addition salts such as chloride, acetate or trifluoroacetate salts, in particular trifluoroacetate salts or salts formed by the addition of a base such as alkali or earth alkaline salts, in particular lithium, sodium, potassium, magnesium or calcium salts.

[0011] In a third list it is indicated that the least one water-soluble polyol containing 2 to 10 carbon atoms and 2 to 7 hydroxyl groups may be selected from glycerine, 1 ,2-propylene glycol and / or 1 ,4-butylene glycol.

[0012] It has now surprisingly been found that a solution comprising the acetic acid addition salt of TDAC-Dab-Val-Dab-OH in certain polyols overcomes the drawbacks of the prior art. Advantageously and surprisingly such a specific combination of ingredients as claimed herein allows for an increase in storage stability.

[0013] Thus, in a first embodiment the invention relates to a composition comprising the acetic acid addition salt of or tetradecylaminocarbonyl-Dab-Val-Dab-OH in a polyol selected from the group consisting of glycerin and / or butylene glycol. Preferably, the amount of the peptide is selected in the range from 0.0005-12.5 wt.-%, based on the total weight of the composition.

[0014] The term ‘TDAC-Dab-Val-Dab-OH’ (i.e. H29Ci4-NH-CO-Dab-Val-Dab-OH) also referred to as ‘Tetradecylaminobutyroylvalylaminobutyric urea’ or tetradecylaminocarbonyl-Dab-Val- Dab-OH includes all possible isomeric forms as well as mixtures thereof, e.g. racemic mixtures and mixtures of rotamers.

[0015] Preferably the compositions in the embodiments according to the invention comprise no or essentially no Trifluoroacetic acid (TFA) addition salts of the TDAC-Dab-Val-Dab-OH peptide. More preferably the compositions and / or cosmetic preparations of the invention are free from Trifluoroacetic acid (TFA) addition salts.

[0016] In all embodiments of the present invention, TDAC-Dab-Val-Dab-OH is preferably TDAC- L-Dab-L-Val-L-Dab-OH as depicted below:

[0017] Preferably, the mol equivalents of acetic acid to TDAC-Dab-Val-Dab-OH in the acetic acid addition salt according to the present invention is selected in the range of 0.5 to 2.5 mol equivalents, preferably in the range of 0.6 to 2.25 mol equivalents, most preferably in the range of 0.9 to 2 mol equivalents such as in the range from 0.6 to 2 or from 0.9 to 1 .6 mol equivalents, based on the peptide TDAC-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 e.g. by drying times.

[0018] Preferably, in all embodiments of the present invention, the acetic acid addition salt of TDAC-Dab-Val-Dab-OH (peptide) is TDAC-Dab-Val-Dab*(x)AcOH with a mol equivalent (x) of acetic acid to the peptide selected in the range from about 0.6 to 2, most preferably in the range from about 0.9 to 1 .6.

[0019] Alternatively, the amount of acetic acid in the acetic acid addition salt can be expressed in wt.-%, 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 10 to 25 wt.-%, preferably in the range from 12.5 to 20 wt.-%, most preferably in the range from 15 to 18 wt.-%, based on the weight of the peptide TDAC-Dab-Val-Dab-OH.

[0020] It is well understood by a person skilled in the art, that the total amount of acid such as the acetic 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.

[0021] In all embodiments of the present invention, the acetic acid addition salt of TDAC-Dab- Val-Dab-OH can be prepared by treating a solution of the respective trifluoroacetate salt of TDAC-Dab-Val-Dab-OH (e.g. prepared as outlined in CN107987123) with acetic acid in the presence of an - preferably weak - anion exchange resin followed by filtration and drying. Preferably, said drying encompasses vacuum drying such as e.g. lyophilization. Suitable solvents to solubilize the trifluoroacetate salt of TDAC-Dab-Val-Dab-OH encompass DMF, EtOAc, DMSO and AcN as well as any mixtures thereof. Particular preferred solvents to be used are DMF as well as mixtures of EtOAc / DMSO and AcN / DMSO. Preferably >99% acetic acid is used in the process according to the present invention. A particularly suitable anion exchange resin is a weak anion exchange resin, preferably in its acetate form.

[0022] Alternatively the TDAC-Dab-Val-Dab-OH can be prepared from the respective fully protected peptide TDAC-Dab(Z)-Val-Dab(Z)-OBn by hydrogenation in acetic acid followed by filtration and removal of residual acetic acid. Preferably, Pd / C is used as hydrogenation catalyst. In all embodiment’s herein, said process is preferred over the process using the respective TFA addition salt.

[0023] In one embodiment the production process of the acetic acid addition salt of TDAC-Dab- Val-Dab-OH according to the present invention comprises an additional purification step which includes (i) dissolving the acetic acid addition salt of TDAC-Dab-Val-Dab-OH in acetic acid to obtain a solution, (ii) optionally filtering the obtained solution and (iii-a) precipitating the (purified) acetic acid addition salt of TDAC-Dab-Val-Dab-OH from the solution using a suitable solvent such as ethyl acetate, acetone or the like or (iii-b) drying the solution e.g. by lyophilization. The use of ethyl acetate as (precipitation) solvent is particularly preferred.

[0024] Advantageously in all embodiments of the present invention, the acetic acid addition salt is prepared by a process encompassing the steps of either of (i-a) treating a solution of a trifluoro acetic acid addition salt of TDAC-Dab-Val-Dab-OH with acetic acid in the presence of an anion exchange resin; or

[0025] (i-b) hydrogenating TDAC-Dab(Z)-Val-Dab(Z)-OBn in the presence of acetic acid (which process is preferred) and isolating the acetic acid addition salt by a process encompassing either of

[0026] (iii-a) precipitating the acetic acid addition salt from an acetic acid solution of TDAC-Dab- Val-Dab-OH, preferably by using ethyl acetate followed by vacuum drying of the obtained peptide precipitate, or

[0027] (iii-b) drying an acetic acid solution of TDAC-Dab-Val-Dab-OH, which drying preferably encompasses vacuum such as by lyophilization.

[0028] Advantageously the invention therefore also provides a process for the preparation of an acetic acid addition salt of TDAC-Dab-Val-Dab-OH, characterized in that the process is encompassing the steps of either of:

[0029] (i-a) treating a solution of a trifluoro acetic acid addition salt of TDAC-Dab-Val-Dab-OH with acetic acid in the presence of an anion exchange resin; or

[0030] (i-b) hydrogenating TDAC-Dab(Z)-Val-Dab(Z)-OBn in the presence of acetic acid; and isolating the acetic acid addition salt by a process encompassing either of

[0031] (iii-a) precipitating the acetic acid addition salt from an acetic acid solution of TDAC-Dab- Val-Dab-OH, preferably by using ethyl acetate followed by vacuum drying of the obtained peptide precipitate, or

[0032] (iii-b) drying an acetic acid solution of TDAC-Dab-Val-Dab-OH, which drying preferably encompasses vacuum drying.

[0033] Preferably, the acetic acid solution of TDAC-Dab-Val-Dab-OH in step (iii-a) or (iii-b) consists essentially of acetic acid, water and TDAC-Dab-Val-Dab-OH, preferably of acetic acid 99%, TDAC-Dab-Val-Dab-OH and up to 5 wt.-%, preferably up to 2 wt.-%, most preferably up to 1 .5 wt.-% of water.

[0034] In all embodiments of the present invention, preferably the amount of the acetic acid addition salt of TDAC-Dab-Val-Dab-OH in the composition is selected in the range from 0.0005-12.5 wt.-%, particularly in the range from 0.001-2 wt.-%, most particularly in the range from 0.001-0.5 wt.-%, such as in particular from 0.005 to 0.2 wt.-%, such as 0.05 to 0.15 wt.-% based on the total weigh of the composition. In all embodiments of the present invention, the composition according to the present invention preferably further comprises water, even more preferably in an amount selected in the range from 10-90 wt.-%, preferably in the range from 20-50 wt.-%, most preferably in the range from 25-40 wt.-%, based on the total weight of the composition.

[0035] In all embodiments of the present invention, 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.-%.

[0036] In all embodiments of the present invention, the composition according to the present invention preferably further comprises 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 0.0001-2 wt.-%, particularly in the range from 0.001-0.5 wt.-%, most particularly in the range from 0.01-0.2 wt.-%, based on the total weight of the composition.

[0037] 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 MgCI2is used.

[0038] The compositions according to the invention may further contain tensides and / or thickeners. Suitable tensides to be used in said peptide compositions are the ones appropriate for cosmetic applications. Said tensides are well known to a person skilled in the art and include in particular non ionic tensides such as e.g. Polysorbate-20. Suitable thickeners to be used in said peptide compositions are again the ones appropriate for cosmetic applications such as e e.g. polyacrylic acids (Carbomers). Preferably said tensides and / or thickeners are present in an amount of up to 5 wt.-%, more preferably up to 3 wt.-%, such as up to 2.5 wt.-% Even more preferably, the composition according to the present invention comprises

[0039] (i) from about 750 to about 2000 ppm of the acetic acid addition salt of TDAC-Dab-Val- Dab-OH with all the definitions and preferences as given herein;

[0040] (ii) from about 60 to about 75 wt.-% of glycerin or butylene glycol, preferably butylene glycol,

[0041] (iii) optionally from 100 to about 2000 ppm of MgCI2; and

[0042] (iv) from about 25 to about 40 wt.-% of water.

[0043] Most preferably the composition of (i) to (iv) comprises MgCI2.

[0044] In a particular advantageous embodiment, the ingredients (i) to (iv) in the composition sum up to 100 wt.-% to form a pre-mix peptide blend which can be readily incorporated into cosmetic preparations, i.e. the composition is a composition consisting essentially of the ingredients (i) to (iv).

[0045] The term 'consisting essentially of as used herein means that the total amount of the listed ingredients ideally sums up to 100 wt.- percent. It is however not excluded that small amounts of impurities derived from the ingredients and / or the production process may be present.

[0046] It is well understood that the compositions according to the present inventions are preferably solutions.

[0047] Preferably in all embodiments of the present invention, the composition comprises next to glycerin and / or butylene glycol no further polyols such in particular no 1 ,3-propanediol.

[0048] The invention further relates to a container comprising the composition according to 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. In another embodiment the invention relates to the use of acetic acid to increase the storage stability of TDAC-Dab-Val-Dab-OH with all the definitions and preferences as given herein in a composition comprising at least one polyol selected from the group consisting of glycerin and / or butylene glycol.

[0049] Preferably the invention thus provides a use of acetic acid to increase the storage stability of TDAC-Dab-Val-Dab-OH peptide, more preferably TDAC-L-Dab-L-Val-L-Dab-OH peptide, in a composition comprising at least one polyol selected from the group of glycerin and / or butylene glycol, wherein preferably the polyol is butylene glycol; and wherein preferably the total amount of polyol in the composition 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; and wherein preferably the amount of the peptide is selected in the range from 0.0005-12.5 wt.-%, based on the total weight of the composition; and wherein preferably the amount of acetic acid in a formed acetic acid addition salt of the peptide is selected in the range from 10 to 25 wt.-%, preferably in the range from 12.5 to 20 wt.-%, most preferably in the range from 15 to 18 wt.-%, based on the weight of the peptide TDAC-Dab-Val-Dab-OH.

[0050] Further preferences for the composition, including the preference of any UV filters therein, are as described herein above and below.

[0051] The increase in storage stability as defined herein refers to an increased stability after 3 months storage at 4°C, 22 °C (RT) and 40°C, compared e.g. to the respective mandelic acid salt or in another polyol such as 1 ,3-propanediol.

[0052] Preferably, the increase in the storage stability @ 40°C after 2 weeks compared e.g. to the respective solution in 1 ,3-propandiol is at least 10%, more preferably at least 15 %, most preferably at least 20%.

[0053] The composition as defined herein can 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. Thus, the invention also relates to a cosmetic preparation comprising a composition as defined herein and a cosmetically acceptable carrier. Such preparations are prepared by admixing the composition according to the present invention with the other ingredients of the preparation according to standard methods in the art.

[0054] Thus, the present invention also concerns a method of preparing a cosmetic preparation, said method comprising the step of adding the composition according to the present to a cosmetically acceptable carrier, e.g. by adding the composition according to the present into a vessel used to prepare the cosmetic preparation and admixing said composition with the further ingredients used to prepare the cosmetic preparation such as e.g. adding the composition according to the present invention to the oil or water phase of the cosmetic preparation before emulsification.

[0055] The amount of the composition according to the present invention to be used in such cosmetic preparations is preferably selected in the range 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 preparation.

[0056] The amount of the acetic acid addition salt of TDAC-Dab-Val-Dab-OH in the cosmetic preparation is preferably selected in the range from in the range from 5 to 200 ppm, more preferably from 10 to 100 ppm, most preferably from 20 to 75 ppm, based on the total weigh of the composition preparation.

[0057] The term cosmetic preparation as defined herein refers in particular to cosmetic preparations that can be topically applied to mammalian keratinous tissue such as e.g. human skin or hair (including eyelashes, the eyebrows) or the nails, particularly human skin. Thus in a preferred embodiment, the cosmetic preparations according to the present invention are topical cosmetic compositions.

[0058] The term "cosmetic preparation" as used in the present application refers to cosmetic compositions as defined under the heading "Kosmetika" in Rdmpp 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. The term cosmetically acceptable carrier refers to all carriers and / or excipients and / or diluents conventionally used in cosmetic preparations.

[0059] In an advantageous embodiment, the cosmetic preparations 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, based on the total weight of the composition.

[0060] 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.

[0061] Preferably, the cosmetic preparations 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 preparation is or comprises an emulsion it can also contain one or more anionic, nonionic, cationic or amphoteric surfactant(s).

[0062] Preferred cosmetic preparations are skin care compositions, and functional compositions.

[0063] Cosmetic preparation 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.

[0064] The cosmetic preparation according to the invention are preferably 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). In another preferred embodiment, the cosmetic preparations according to the present invention are in the form of an aqueous gel and / or a clear gel.

[0065] The cosmetic preparation 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.

[0066] In accordance with the present invention, the cosmetic preparation 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. 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 e.g. described in the CTFA Cosmetic Ingredient Handbook, Second Edition (1992) without being limited thereto.

[0067] Preferably the compositions according to the invention and / or the cosmetic preparations according to the invention also comprise one or more UV filters.

[0068] 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, titanium dioxide, Butyl methoxydibenzoylmethane (also referred to as “BMDBM” or “Avobenzone”) and Bis- Ethylhexyloxyphenol Methoxyphenyl Triazine (also referred to as Bemotrizinol or “BEMT”) are especially preferred.

[0069] Preferably the composition, respectively the cosmetic preparation, comprises one or more of such UV filters, more preferably one or more organic UV filters, optionally in combination with one or more inorganic UV filters.

[0070] If an inorganic UV filter is present in the composition and / or preparation, preferably such inorganic UV filter is present in a weight amount in the range from equal to or more than 0.01 wt. % to equal to or less than 20. wt. %, more preferably in the range from equal to or more than 0.1 wt. % to equal to or less than 5 wt. %, most preferably in the range from equal to or more than 0.5 wt. % to equal to or less than 2 wt. %, based on the total weight of the composition, respectively the preparation. If an inorganic UV filter is present, such inorganic UV filter is preferably titanium dioxide.

[0071] If an organic UV filter is present in the composition and / or preparation, preferably the organic UV filter is present in a weight amount in the range from equal to or more than 0.01 wt. % to equal to or less than 10.0 wt. %, more preferably in the range from equal to or more than 0.1 wt. % to equal to or less than 5.0 wt. %, most preferably in the range from equal to or more than 0.1 wt. % to equal to or less than 2.0 wt. %, based on the total weight of the composition, respectively preparation. If an organic UV filter is present, such organic UV filter is preferably Butyl methoxydibenzoylmethane and / or Bis- Ethylhexyloxyphenol Methoxyphenyl Triazine.

[0072] In an especially preferred embodiment, the composition, respectively the preparation, comprises Butyl methoxydibenzoylmethane in a weight amount in the range from equal to or more than 1 wt % to equal to or less than 3 wt%, based on the total weight of the composition, respectively preparation.

[0073] In another especially preferred embodiment the composition, respectively the preparation, comprises Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine in a weight amount in the range from equal to or more than 1 .5 wt% to equal to or less than 2 wt%, based on the total weight of the composition, respectively preparation.

[0074] In another especially preferred embodiment the composition, respectively the preparation, comprises Methylene Bis-Benzotriazolyl Tetramethylbutylphenol in a weight amount in the range from equal to or more than 0.5 wt% to equal to or less than 6 wt%, based on the total weight of the composition, respectively preparation.

[0075] Without wishing to be bound by any kind of theory it is believed that the presence of one or more UV filters may be advantageous to further improve the stability of the composition, respectively of the cosmetic preparation.

[0076] Without wishing to be bound by any kind of theory, the combination of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH and UV filters, preferably organic UV filters, is believed to allow for a synergistic effect in stability and / or efficacy of sunscreen products, which may in turn advantageously allow for an improvement of the overall Sun Protection Factor (SPF). The UV filter is believed to allow for a better stability of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH whilst the presence of the acetic acid addition salt of Tetradecylaminocarbonyl-Dab-Val-Dab-OH is believed to allow for a better stability of the UV filter.

[0077] In addition, or alternatively, the composition and / or cosmetic preparaiton may advantageously comprise one more photostabilizers. Preferably the composition, in each aspect of the invention, may therefore comprise one or more photostabilizers selected from the group consisting of butyloctyl salicylate, benzotriazolyl dodecyl p cresol, ethylhexyl methoxycrylene, polyester-8, trimethoxybenzylidene pentanedione, diethylhexyl 2,6-naphthalate, polyester-25, diethylhexyl syringylidenemalonate and combinations of one or more thereof.

[0078] The usual cosmetic adjuvants and additives such as e.g. emulsifiers, thickeners, surface active ingredients and film formers can show synergistic effects which can be determined by the expert in the field with normal trials, or with the usual considerations regarding the formulation of cosmetic preparation. The necessary amounts can, based on the desired product, easily be determined by the skilled person. The cosmetically active ingredients useful herein can in some instances provide more than one benefit or operate via more than one mode of action.

[0079] Unless explicitly indicated otherwise, the various embodiments of the invention described herein can be cross-combined.

[0080] If nothing else is stated, the carrier, excipients, additives, diluents, adjuvant and additives etc. mentioned in the following are in particular suitable for cosmetic preparation according to the present invention.

[0081] The following examples are provided to further illustrate the invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

[0082] Abbreviation: AcOH = Acetic acid

[0083] AcN = Acetonitrile

[0084] BG: Butylene glycol (1 ,3-butanediol)

[0085] Bn: Benzyl

[0086] DAB: 1.4-Diaminobutyric acid (building block in the tripeptide) Gly: Glycerin

[0087] MA-DL = DL-Mandelic acid

[0088] MA-L = L(+)-Mandelic acid

[0089] 1 ,3-PDO: 1 ,3-Propanediol TDAC: Tetradecyl-NH-CO Z = Benzyl oxy carbonyl

[0090] Example 1 : Preparation of TDAC-Dab-Val-Dab-OH addition salts

[0091] 1 . Acetic acid addition salts of TDAC-Dab-Val-Dab-OH a) To a warm solution (30-40°C) of 7.5 g (9.6 mmol) of the trifluoro acetic acid addition salt of TDAC-Dab-Val-Dab-OH in 400ml 99% AcOH, 80g Bio-Rad AG® 1-X8 Anion Exchange Resin acetate form is added, 150ml DMF are added and the mixture is agitated for 2h. The resulting mixture is filtered via G1 frit, washed with AcN and DMF. Solvents are removed in vacuum; residue is redissolved in AcOH and lyophilized (62h @RT). Yield: 4.85g. b) 21g (0.68mmol) TDAC-Dab(Z)-Val-Dab(Z)-OBn is dissolved in 99% AcOH. The solution is hydrogenated using Pd / C as hydrogenation catalyst. Once the reaction is completed, the reaction mixture is filtered, all solvents are removed in vacuum, the residue redissolved in 250ml AcOH, stirred for 1 h and filtered. The product is precipitated by adding 1 L of EtOAc, stirred for 1 h and filtered. Product is washed with EtOAc and MTBE and dried in a vacuum drying oven at 30-40°C @1 mbar until constant weight. Yield: 13.64g. . Mandelic acid addition salts of TDAC-Dab-Val-Dab-OH a) 1.2g (1.773mmol) of the acetic acid addition salt of TDAC-Dab-Val-Dab-OH is dissolved in MeOH and water. Then, 553mg (2.05 eq, 3.634mmol) DL-mandelic acid is added, volatile solvents are removed in vacuum, remaining solution is lyophilized. Yield: 1.57g. b) 1.2g (1.773mmol) of the acetic acid addition salt of TDAC-Dab-Val-Dab-OH is dissolved in MeOH and water. Then, 553mg (2.05 eq, 3.634 mmol) L-(+)-mandelic acid is added, volatile solvents are removed in vacuum, remaining solution is lyophilized. Yield: 1 ,63g.

[0092] Example 2: Preparation of peptide compositions

[0093] 2. 1 Compositions comprising the acetic acid addition salt of TDAC-Dab-Val-Dab-OH a) qlycerin / water composition (AcOH-Gly)

[0094] 100.4mg of the acetic acid addition salt of example 1 b) 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 / MqCI2composition (AcOH-Gly-MqCI2)

[0095] 150mg of the acetic acid addition salt of example 1 b) 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. 100mg MgCI2*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)

[0096] 100.7mg of the acetic acid addition salt of example 1b) 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. d) 1 ,3-propanediol / water composition (AcOH-PDO)

[0097] 100.1 mg of the acetic acid addition salt of example 1 b) 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 1 ,3-propanediol glycol is added followed by the addition of 0.9 g of water.

[0098] 2.2. Compositions comprising the mandelic acid addition salt of TDAC-Dab-Val-Dab-OH a) qlycerin / water composition (MADL-Gly)

[0099] 100.3mg of the mandelic acid addition salt of example 2a) was charged into a 100ml round bottom necked flask. 15.0g water is added and the peptide is dissolved at 85°C using short time (approx. 30 sec) ultrasonic bath. 67.44g glycerin is added (pH is adjusted from 3.48 to 4.68, using 0.41 ml 1 % NaOH) followed by the addition of 0.5g of water. b) butylene qlycol / water composition (MADL-BG)

[0100] 100.6 of the mandelic acid addition salt of example 2a) is charged into a 100ml round bottom necked flask. 24g water is added and the peptide is dissolved at approx. 85°C using short time (approx. 30 sec) ultrasonic bath. 58.39g Butylene glycol is added followed by the addition of 0.94g of water. c) qlycerin / water composition (MAL-Gly)

[0101] 100.5mg of the mandelic acid addition salt of example 2b) was charged into a 100ml round bottom necked flask. 15.0g water is added and the peptide is dissolved at 85°C using short time (approx. 5-15 sec) ultrasonic bath. 67.44g glycerin is added (pH is adjusted from 3.55 to 4.55, using 0.3 ml 1 % NaOH) followed by the addition of 0.5g of water. d) butylene qlycol / water composition (MAL-BG)

[0102] 100.3 mg of the mandelic acid addition salt of example 2b) is charged into a 100ml round bottom necked flask. 24g water is added and the peptide is dissolved at approx. 85°C using short time (approx. 30 sec) ultrasonic bath. 58.39g Butylene glycol is added followed by the addition of 0.94g of water.

[0103] Example 3: Storage stability

[0104] The solutions of the various acid addition salts of TDAC-Dab-Val-Dab-OH in glycerin (Gly), 1 ,3-propanediol (1 ,3-PDO) respectively butylene glycol (BG) prepared as outlined above with an initial peptide content of approx. 1200ppm were stored at 4 °C. After 1 day, samples were analyzed for their remaining peptide content with analytical HPLC. The results are depicted in Table 1-a.

[0105] Table 1-a: peptide content after 1 day storage at 4°C

[0106] As can be retrieved from Table 1-a, the AcOH salt according to the present invention exhibits a significantly better storage stability compared to the respective mandelic acid addition salts.

[0107] Samples were also analyzed for their peptide content after 2 weeks storage at 40°C with analytical HPLC. The results are depicted in Table 1-b. Table 1-b: peptide content after 2 weeks storage at 40°C

[0108] As can be retrieved from Table 1-b, the use of glycerin or butylene glycol as diluent leads to an improved stability of the acetic acid addition salt in the final formulation compared to the use of the 1 ,3-propanediol, butylene glycol being particular suitable.

[0109] In addition, peptide compositions of the acetic acid addition salt of TDAC Dab-Val-Dab- OH in glycerin were prepared with or without MgCI2as outlined above. Samples were analyzed for their peptide content after 8 weeks and after 3 months storage at 4°C, 22°C (RT) and 40°C with analytical HPLC. The results are depicted in Table 1-c.

[0110] Table 1-c: peptide content after storage at different temperatures

[0111] As can be retrieved from Table 1-c, the addition of MgCI2leads to a significantly improved stability of the Acetate salt in the final formulation. Example 4: Exemplary cosmetic preparations

[0112] Table 2 outlines exemplary O / W emulsions, comprising peptide compositions according to the present invention.

[0113] Table 2: Formulation (O / W emulsions)

[0114] In the formulations as exemplified in example 4 advantageously a synergy can be obtained as on the one hand the UV filters can increase the stability of the acetic acid addition salt of tetradecylaminocarbonyl-Dab-Val-Dab-OH (TDAC-Dab-Val-Dab-OH) and on the other hand the acetic acid addition salt of tetradecylaminocarbonyl-Dab-Val-Dab-OH (TDAC- Dab-Val-Dab-OH) can increase the stability of one or more UV filters, such as for example Butyl methoxydibenzoylmethane, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine and / or titanium dioxide.

Claims

Claims1. A composition comprising an acetic acid addition salt of tetradecylaminocarbonyl-Dab- Val-Dab-OH (TDAC-Dab-Val-Dab-OH) and a polyol selected from the group of glycerin and / or butylene glycol, characterized in that the amount of the acid addition salt in said composition is selected in the range from 0.0005-12.5 wt.-%, based on the total weight of the composition.

2. The composition of claim 1 , characterized in that the TDAC-Dab-Val-Dab-OH is TDAC- L-Dab-L-Val-L-Dab-OH.

3. The composition according to anyone of the preceding claims, characterized in that the polyol is butylene glycol.

4. The composition according to anyone of the preceding claims, characterized in that the amount of the acid addition salt in the composition is selected in the range from 0.001- 2 wt.-%, preferably from 0.001-0.5 wt.-%, most preferably from 0.005 to 0.2 wt.-%, based on the total weigh of the composition.

5. The composition according to anyone of the preceding claims, characterized in that the composition further comprises water, preferably in an amount selected in the range from 10-90 wt.-%, more preferably in the range from 20-50 wt.-%, most preferably in the range from 25-40 wt.-%, based on the total weight of the composition.

6. The composition according to anyone of the preceding claims, characterized in that the (total) amount of polyol in the composition is 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.

7. The composition according to anyone of the preceding claims, characterized in that the composition further comprises a water-soluble salt of an alkali, earth alkaline metal or transition metal, preferably MgCI2.

8. The composition according to claims 7, characterized in that the amount of the water- soluble salt of an alkali, earth alkaline metal or transition metal in the composition isselected in the range from 0.00001-2 wt.-%, preferably in the range from 0.001- 0.5 wt.-%, most preferably in the range from 0.01-0.2 wt.-%, based on the total weight of the composition.

9. The composition according to anyone of the preceding claims, characterized in that the composition consists essentially of(i) from about 750 to about 2000 ppm of the acetic acid addition salt of TDAC- Dab-Val-Dab-OH, preferably TDAC-L-Dab-L-Val-L-Dab-OH;(ii) from about 60 to about 75 wt.-% of the polyol,(iii) optionally from 100 to about 2000 ppm of MgCI2, and(iv) from about 25 to about 40 wt.-% of water.

10. The composition according to anyone of claim 1 to 9, characterized in that the acetic acid addition salt is prepared by a process encompassing the steps of either of(i-a) treating a solution of a trifluoro acetic acid addition salt of TDAC-Dab-Val-Dab-OH with acetic acid in the presence of an anion exchange resin; or(i-b) hydrogenating TDAC-Dab(Z)-Val-Dab(Z)-OBn in the presence of acetic acid; and isolating the acetic acid addition salt by a process encompassing either of(iii-a) precipitating the acetic acid addition salt from an acetic acid solution of TDAC- Dab-Val-Dab-OH, preferably by using ethyl acetate followed by vacuum drying of the obtained peptide precipitate, or(iii-b) drying an acetic acid solution of TDAC-Dab-Val-Dab-OH, which drying preferably encompasses vacuum drying.11 . A cosmetic preparation comprising a composition according to any one of claims 1 to 10 and a cosmetically acceptable carrier.

12. The cosmetic preparation according to claim 11 , characterized in that the amount of the composition incorporated into said cosmetic preparation is selected in the range from 0.5 to 5wt.-%, preferably from 0.75 to 4 wt.-%, most preferably from 1 to 3 wt.-%, based on the total weight of the cosmetic preparation.

13. The cosmetic preparation according to claim 11 to 12, characterized in that the composition is in the form of a gel or an emulsion.

14. The composition according to any one of claims 1 to 10 or the cosmetic preparation according to any one of claims 11 to 13, wherein such composition, respectively such preparation further comprises a UV filter, preferably a UV filter chosen from the group consisting of Titanium Dioxide, Zinc Oxide, Benzophenone-3, Benzophenone-4, Benzophenone-5, Butyl methoxydibenzoylmethane, Ethylhexyl Methoxycinnamate, Ethylhexyl Salicylate, Homosalate, Octocrylene, Terephthalylidene Dicamphor Sulfonic Acid, Drometrizole Trisiloxane, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Methylene Bis-Benzotriazolyl Tetramethylbutylphenol, Diethylamino Hydroxybenzoyl Hexyl Benzoate, Ethylhexyl Triazone, Polysilicone-15, Isoamyl p- Methoxycinnamate, Phenylbenzimidazole Sulfonic Acid, Bisdisulizole Disodium, Tris- Biphenyl Triazine and / or combinations of one or more of these, more preferably a UV filter chosen from the group consisting of titanium dioxide, Butyl methoxydibenzoylmethane and Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine and / or combinations of one or more of these.

15. Use of acetic acid to increase the storage stability of TDAC-Dab-Val-Dab-OH in a composition comprising at least one polyol selected from the group of glycerin and / or butylene glycol, preferably the polyol is butylene glycol.

16. Use according to claim 15, characterized in that TDAC-Dab-Val-Dab-OH is TDAC-L- Dab-L-Val-L-Dab-OH.

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