Novel peptide compositions

Abstract

The present invention relates to a composition comprising a water-soluble polyol and an acetic acid and / or a mandelic acid addition salt of at least one peptide selected from the group of palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH. Furthermore, the invention relates to the peptides as such as well as to the use of an acetic acid and / or a mandelic acid to prepare the respective acid addition salt of the peptide(s) to increase the solubility and / or storage stability thereof.

Description

[0001] NOVEL PEPTIDE COMPOSITIONS

[0002] The present invention relates to a composition comprising a water-soluble polyol and an acetic acid and / or a mandelic acid addition salt of at least one peptide selected from palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH. Furthermore, the invention relates to the use of an acetic acid and / or a mandelic acid to prepare the respective acid addition salt of the peptide(s) to increase the solubility thereof.

[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] A peptide blend comprising palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH is commercially available as SYN®-TACKS from DSM Nutritional Products Ltd. The peptides comprised therein are in the form of their bistrifluoroacetic acid addition salts. SYN®-TACKS 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.

[0008] Thus there is an ongoing need of alternative addition salts of palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH which exhibit an excellent solubility in a polyol such as in particular in glycerin, butylene glycol or 1 ,3-propanediol. In addition, such solutions should exhibit a high storage stability over a prolonged period of time. 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-p-Ala-His-OH, Oleyl-Gly-Gly-OH, Palm-His-D-Phe-Arg-NH2, Acetyl-Tyr-Arg-OCetyl, Palm-Lys-Val-Lys-OH, Elaidyl-Lys-Phe- Lys-OH, Hexanoyl-Arg-Ala-Nle-NH2, Palm-Lys-Val-Dab-OH, Palm-Lys-Val-Dab-Thr-OH, C14H29-NH-CO-Dab-Val-Dab-OH, Palm-Lys-Thr-Thr-Lys-Ser, Palm-Gly-His-Lys-OH, Palm- Gly-Lys-His-OH, Palm-Gly-GIn-Pro-Arg-OH, Palm-Val-Gly-Val-Ala-Pro-Gly-OH or Palm-Ala- Glu-Asp-Glu-Pro-Leu-Leu-Met-Glu-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 the respective acetic acid or the mandelic acid addition salts of palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH overcome the drawbacks of the prior art.

[0013] Advantageously and surprisingly, it has for example now been found that the specific combination of ingredients as claimed herein allows for an increase in storage stability.

[0014] Thus, in a first embodiment the invention relates to a composition comprising a water-soluble polyol and an acid addition salt of at least one peptide selected from palmitoyl-Lys-Val-Dab- OH and palmitoyl-Lys-Val-Dab-Thr-OH, wherein the acid is selected from acetic acid and mandelic acid as well as mixtures thereof.

[0015] The acetic acid and the mandelic acid addition salts of palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH are still novel. Thus, in a second embodiment, the invention relates to the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH.

[0016] It is well understood by a person skilled in the art, that the term ‘palmitoyl-Lys-Val-Dab-OH and ‘palmitoyl-Lys-Val-Dab-Thr-OH’ as used herein includes all possible isomeric forms as well as mixtures thereof, e.g. racemic mixtures and mixtures of rotamers.

[0017] It is well understood, in all embodiments of the present invention that mandelic acid can be used as D-(-)-mandelic acid (CAS No 611-71-2), L-(+)-mandelic acid (CAS No. 17199-29-0) or D,L-mandelic acid (CAS No 611-72-3). Preferably in all embodiments of the present invention is the use of L(+) mandelic acid and D,L-mandelic acid, most preferred is the use of D,L-mandelic acid.

[0018] In all embodiments of the present invention, palmitoyl-Lys-Val-Dab-OH is preferably palmitoyl-L-Lys-L-Val-L-Dab-OH.

[0019] In all embodiments of the present invention, palmitoyl-Lys-Val-Dab-Thr-OH is preferably palmitoyl-L-Lys-L-Val-L-Dab-L-Thr-OH.

[0020] In all embodiments of the present invention, the acetic acid addition salts are preferred as they provided best results with regard to transparency (i.e. solubility) and storage stability in polyol solutions.

[0021] Preferably the compositions in the embodiments according to the invention comprise no or essentially no Trifluoroacetic acid (TFA) addition salts of the palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH. More preferably the compositions of the above aspects are free from Trifluoroacetic acid (TFA) addition salts.

[0022] In all embodiments of the present invention the water-soluble polyol is preferably a water- soluble polyol containing 2 to 10 carbon atoms and 2 to 7 hydroxyl groups, e.g. selected from the group of ethylene glycol, 1 ,2-propyleneglycol, 1 ,3-propyleneglycol, butylene glycol (1 ,3- butandiol), 1 ,4-butylene glycol, glycerin, erythrit (also referred to erythritol or meso-1 ,2,3,4- Butantetrol), sorbit, mannit, methylglucoside, diglycerine, triglycerine and / or pentaerythrit. More preferably the water-soluble polyol is a water-soluble polyol containing 3 to 8 carbon atoms and 2 to 3 hydroxyl groups, such as in particular glycerin, 1 ,3-propanediol and butylene glycol as well as any mixtures thereof. Most advantageously in all embodiments of the present invention, the polyol is glycerin as it provides excellent solubilization properties reflected by the transparency of the solutions for both peptides alone as well as mixtures thereof and an excellent storage stability.

[0023] Hence, the invention preferably provides a composition comprising:

[0024] - an acid addition salt of at least one peptide selected from Palmitoyl-Lys-Val-Dab-OH and Palmitoyl-Lys-Val-Dab-Thr-OH, wherein the acid is selected from the group of acetic acid and mandelic acid as well as mixtures thereof; and

[0025] - a polyol selected from the group of ethylene glycol, 1 ,2-propyleneglycol, 1 ,3- propyleneglycol, butylene glycol (1 ,3-butandiol), 1 ,4-butylene glycol, glycerin, erythrit (also referred to erythritol or meso-1 ,2,3,4-Butantetrol), sorbit, mannit, methylglucoside, diglycerine, triglycerine and / or pentaerythrit, more preferably selected from the group of glycerin, butylene glycol and 1 ,3-propyleneglycol as well as mixtures thereof.

[0026] Preferences for such a composition are as described above and below. Most preferably the polyol is glycerin.

[0027] Preferably in all embodiments of the present invention, the composition according to the present invention comprises only one water-soluble polyol as defined herein.

[0028] In all embodiments of the present invention, the composition according to the present invention is most advantageously a composition comprising glycerin and an acetic acid addition salt of at least one, preferably of both peptides palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH as best results are obtained in view of transparency (solubility) as well as storage stability.

[0029] If both peptides are present in the composition according to the presentation invention, preferably the ratio (weight / weight) of palmitoyl-Lys-Val-Dab-OH to palmitoyl-Lys-Val-Dab- Thr-OH is selected in the range of 0.1 :1 to 1 :0.1 , more preferably in the range of 0.5:1 to 1 :0.5, most preferably in the range of 0.75:1 to 1 :0.75, such as in the range of about 1 :1.

[0030] Preferably, in all embodiments of the present invention the mole equivalents of the respective acid to the respective peptide in the acid addition salt is selected in the range from 0.5 to 3 mole equivalents. Said mole 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 or added equivalents.

[0031] In case of the acetic acid addition salts it is further preferred, that the mole equivalents are selected in the range from 0.6 to 2.25 mole equivalents, most preferably in the range from 0.9 to 2 mole equivalents such as in the range from 0.6 to 2 or from 0.9 to 1 .6 mole equivalents, based on the respective peptide.

[0032] Most preferably, in all embodiments of the present invention, the acetic acid addition salt of the peptide is selected from the group of palmitoyl-Lys-Val-Dab-OH*(x) acetic acid and palmitoyl-Lys-Val-Dab-Thr-OH*(x) acetic acid with a mole equivalent (x) of acetic acid to the respective peptide selected in the range from about 0.6 to 2, most preferably from about 0.9 to 1.6.

[0033] In case of the mandelic acid addition salts it is further preferred, that the mole equivalents of mandelic acid to the respective peptide is selected in the range from 0.75 to 2.5 mole equivalents, most preferably in the range from 0.8 to 2.25 mole equivalents, such as in the range from 1.75 to 2.25 mole equivalents, based on the respective peptide.

[0034] Most preferably, in all embodiments of the present invention, the mandelic acid addition salt of the peptide is selected from the group of palmitoyl-Lys-Val-Dab-OH*(x) mandelic acid and palmitoyl-Lys-Val-Dab-Thr-OH*(x) mandelic acid with a mole equivalent (x) of mandelic acid to the respective peptide selected in the range from about 0.8 to 2.25 mole equivalents, most preferably from about 1.75 to 2.25 mole equivalents.

[0035] Alternatively, the amount of acid in the 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 acid in the 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.

[0036] It is well understood by a person skilled in the art, that the total amount of acid such as the acetic acid respectively mandelic 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 the added equivalents e.g. in the case of non-volatile acids such as mandelic acid or the drying methods and times in cases of volatile acids such as acetic acid. It is also well understood that some of the acid may be present in a peptide addition salt in non-deprotonated form. Accordingly the acid content can be easily adjusted by a person skilled in the art.

[0037] In all embodiments of the present invention, the acid addition salt of the respective peptide can be prepared by treating a solution of the respective trifluoroacetate salt of the peptide (prepared according to standard methods in the art (see e.g. W02007 / 124770) with acetic or mandelic acid in the presence of an - preferably weak - anion exchange resin in the acetate or mandelate form followed by filtration and drying or by treating a solution of the respective acetate salt of the peptide (prepared according to standard methods in the art (see e.g. W02007 / 124770) with mandelic acid followed by filtration and drying. Preferably, said drying encompasses vacuum drying such as e.g. lyophilization. Suitable solvents to solubilize the peptides encompass aqueous DMF, EtOAc, DMSO and AcN as well as any mixtures thereof. 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.

[0038] Alternatively the peptides can be prepared from the respective fully protected peptide Palm- Lys(Z)-Val-Dab(Z)-OBn, respectively Palm-Lys(Z)-Val-Dab(Z)-Thr-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.

[0039] In one embodiment the production process of the acetic acid addition salt of the peptides according to the present invention comprises an additional purification step which includes (i) dissolving the acetic acid addition salt of the respective peptide(s) in acetic acid to obtain a solution, (ii) optionally filtering the obtained solution and (iii-a) precipitating the (purified) acetic acid addition salt of the respective peptide(s) 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. Advantageously in all embodiments of the present invention, the acetic acid addition salt is prepared by a process encompassing the steps of either of

[0040] (i-a) treating a solution of a trifluoro acetic acid addition salt of the respective peptide(s) with acetic acid in the presence of an anion exchange resin; or

[0041] (i-b) hydrogenating Palm-Lys(Z)-Val-Dab(Z)-OBn and / or Palm-Lys(Z)-Val-Dab(Z)-Thr- OBn in the presence of acetic acid (which process is preferred) and isolating the acetic acid addition salt by a process encompassing either of

[0042] (iii-a) precipitating the acetic acid addition salt from an acetic acid solution of the palmitoyl- Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH, preferably by using ethyl acetate followed by vacuum drying of the obtained peptide precipitate, or

[0043] (iii-b) drying the acetic acid addition salt solution of the respective peptide(s), which drying preferably encompasses vacuum such as by lyophilization.

[0044] Preferably, the acetic acid solution of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val- Dab-Thr-OH in step (iii-a) or (iii-b) consists essentially of acetic acid, water and the respective peptide(s), preferably of acetic acid 99%, the respective peptide(s) and up to 5 wt.-%, preferably up to 2 wt.-%, most preferably up to 1 .5 wt.-% of water.

[0045] In all embodiments of the present invention, the mandelic acid salt of palmitoyl-Lys-Val-Dab- OH and / or palmitoyl-Lys-Val-Dab-Thr-OH is preferably prepared by dissolving the respective acetate salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH in a suitable solvent forming a peptide acetate solution, combining said peptide acetate solution with mandelic acid or a solution of mandelic acid dissolved in a solvent (either by addition of said peptide solution to the mandelic acid / mandelic acid solution or the other way round), followed by removal of said solvent(s) by suitable means such as evaporation and / or lyophilization. Suitable solvents include in particular alkyl alcohols such as Ci_6alkyl alcohols e.g. including methanol, ethanol, propanol, isopropanol and acetic acid, as well as mixtures thereof with methanol and acetic acid as well as any mixtures thereof being particularly preferred. The amount of solvent is preferably selected such, that the palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH and the mandelic acid are fully dissolved.

[0046] Thus, in a particular preferred embodiment, the mandelic acid salt of palmitoyl-Lys-Val-Dab- OH and / or palmitoyl-Lys-Val-Dab-Thr-OH with all the definitions and preferences as given herein is prepared by (i) Dissolving the respective acetic acid addition salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH acetate in a solvent with all the definitions and preferences as given herein to form a peptide acetate solution,

[0047] (ii) Combining the peptide acetate solution with the respective mandelic acid / a mandelic acid solution with all the definitions and preferences as given herein,

[0048] (iii) Removing said solvent(s) by evaporation, optionally and preferably followed by lyophilization.

[0049] In all embodiments of the present invention, preferably the (total) amount of the acid addition salt(s) of the peptide(s) in the composition is selected in the range from 0.0005-12 wt.-%, preferably from 0.001-4 wt.-%, more preferably from 0.001-1 wt.-%, most preferably from 0.005 to 0.4 wt.-%, based on the total weigh of the composition.

[0050] 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.-%, most preferably in the range from 20-50 wt.-%, such as in the range from 25-40 wt.-%, based on the total weight of the composition.

[0051] 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.-%.

[0052] 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 tensideas 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.-%.

[0053] Even more preferably, the composition according to the present invention comprises (i) from about 2000 to about 6000 ppm of the acid addition salt of Palmitoyl-Lys-Val-Dab- OH and / or Palmitoyl-Lys-Val-Dab-Thr-OH with all the definitions and preferences as given herein;

[0054] (ii) from about 60 to about 75 wt.-% of polyol, preferably glycerin,

[0055] (iii) optionally from 100 to about 2000 ppm of MgCI2; and

[0056] (iv) from about 25 to about 40 wt.-% of water.

[0057] Preferably, the composition comprises both peptides (i), even more preferably in the form of the acetic acid addition salts, most preferably each of them independently from each other selected in an amount in the range from 1000 to 3000 ppm.

[0058] Preferably, in all embodiments of the present invention, the composition comprises no MgCI2.

[0059] 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), preferably said composition does not comprise MgCI2(i.e. no component (iii).

[0060] 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.

[0061] It is well understood that the compositions according to the present inventions are solutions.

[0062] 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 or mandelic acid to increase the transparency (i.e. solubility) and / or the storage stability of at least one peptide selected from palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val-Dab-Thr-OH with all the definitions and preferences as given herein in a composition comprising at least one water- soluble polyol, preferably selected from the group of glycerin, butylene glycol and / or 1 ,3- propanediol, most preferably glycerin.

[0063] In one embodiment, the composition according to the present invention, respectively the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and palmitoyl-Lys-Val- Dab-Thr-OH as such, both with all the definitions and preferences as given 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.

[0064] Thus, the invention also relates to a cosmetic preparation comprising the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr- OH respectively the composition as defined herein and a cosmetically acceptable carrier. Such preparations are prepared by either admixing the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH or the composition according to the present invention comprising the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH in a water-soluble polyol with the other ingredients of the preparation according to standard methods in the art.

[0065] Thus, the present invention also concerns a method of preparing a cosmetic preparation, said method comprising the step of adding the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH or the composition according to the present to a cosmetically acceptable carrier, e.g. by adding the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr- OH or the composition according to the present in a vessel used to prepare the cosmetic preparation and admixing said composition with further ingredients used to prepare the cosmetic preparation such as e.g. adding the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr-OH or the composition according to the present invention into the oil or water phase of the cosmetic preparation before emulsification. The amount of the composition according to the present invention to be used in such cosmetic preparations is preferably selected in the range from 0.1 to 5wt.-%, preferably from 0.25 to 4 wt.-%, most preferably from 0.5 to 3 wt.-%, such as in the range of 0.5 to 1 .5-% wt.-%, based on the total weight of the cosmetic preparation.

[0066] In all embodiments of the present invention preferably, the (total) amount of the acetic acid or mandelic acid addition salt of palmitoyl-Lys-Val-Dab-OH and / or palmitoyl-Lys-Val-Dab-Thr- OH in the cosmetic preparation is selected 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 cosmetic preparation.

[0067] 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 particularly the cosmetic preparations according to the present invention are topical cosmetic preparations.

[0068] 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.

[0069] The term cosmetically acceptable carrier refers to all carriers and / or excipients and / or diluents conventionally used in cosmetic preparations.

[0070] 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.

[0071] 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.

[0072] 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).

[0073] Preferred cosmetic preparations are skin care compositions, and functional compositions.

[0074] 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.

[0075] 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).

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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 Hydroxy benzoyl 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.

[0080] 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 photo- protective 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. 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] Abbreviation: AcOH = Acetic acid

[0085] AcN = Acetonitrile

[0086] BG: Butylene glycol

[0087] Bn: Benzyl

[0088] Dab: 1 ,4-Diaminobutyric acid (building block in the tripeptide)

[0089] Gly: Glycerin

[0090] MA-DL = DL-Mandelic acid

[0091] MA-L = L(+)-Mandelic acid PDO: 1 ,3-Propanediol TDAC: Tetradecyl-NH-CO Z = Benzyl oxy carbonyl

[0092] Example 1 : Preparation of Palmitoyl-Lys-Val-Dab-OH addition salts a) Acetic acid addition salts of Palmitoyl-Lys-Val-Dab-OH

[0093] • Ion Exchange: 1 mmol of the trifluoracetic acid addition salt of Palmitoyl-Lys-Val- Dab-OH is dissolved in aqueous acetonitrile. 10g Bio-Rad AG® 1-X8 Anion Exchange Resin acetate form is added, and the mixture is agitated for 2h. Mixture is filtered via G1 frit, washed with AcN and water. Main part of AcN was removed in vacuum; residual solution is lyophilized for 60h.

[0094] • Hydrogenation: 20g Palmitoyl-Lys(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, solvent is 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 1h and filtered. Product is washed with EtOAc and dried in a vacuum drying oven at 30-40°C @1mbar until constant weight. b) Mandelic acid addition salts of Palmitoyl-Lys-Val-Dab-OH

[0095] • 1 .70 mmol of the acetic acid addition salt of Palmitoyl-Lys-Val-Dab-OH is dissolved in aqueous methanol. 3.49 mmol of L(+) or DL mandelic acid is added and well stirred. Methanol is removed in vacuum (rotatory evaporator. The residual solutions is lyophilized for 60 hours to obtain the respective mandelic acid addition salts. c) HOI addition salt of Palmitoyl-Lys-Val-Dab-OH

[0096] 1 .70 mmol of the acetic acid addition salt of Palmitoyl-Lys-Val-Dab-OH is dissolved in warm (50-80°C) aqueous Acetonitrile. 3.75 mmol of 1 N hydrochloric acid is added and well stirred. The residual is lyophilized for 60 hours.

[0097] Example 2: Preparation of Palmitoyl-Lys-Val-Dab-Thr-OH addition salts a) Acetic acid addition salts of Palmitoyl-Lys-Val-Dab-Thr-OH

[0098] • Ion Exchange: 1 mmol of the trifluoracetic acid addition salt of Palmitoyl-Lys-Val-Dab-

[0099] Thr-OH is dissolved in aqueous acetonitrile. 10g Bio-Rad AG® 1-X8 Anion Exchange Resin acetate form is added, and the mixture is agitated for 2h. Mixture is filtered via G1 frit, washed with AcN and water. Main part of AcN was removed in vacuum; residual solution is lyophilized for 60h.

[0100] • Hydrogenation: 17g Palmitoyl-Lys(Z)-Val-Dab(Z)-Thr-OBn is dissolved in 99% AcOH.

[0101] The solution is hydrogenated using Pd / C as hydrogenation catalyst. Once the reaction is completed, the reaction mixture is filtered, solvent is 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 dried in a vacuum drying oven at 30-40°C @1 mbar until constant weight. b) Mandelic acid addition salts of Palmitoyl-Lys-Val-Dab-Thr-OH

[0102] • 1 .70 mmol of the acetic acid addition salt of Palmitoyl-Lys-Val-Dab-Thr-OH is dissolved in aqueous methanol. 3.49 mmol of L(+) or DL mandelic acid is added and well stirred. Methanol is removed in vacuum (rotatory evaporator. The residual solutions are lyophilized for 60 hours to obtain the respective mandelic acid addition salts. c) HCI addition salt of Palmitoyl-Lys-Val-Dab-Thr-OH

[0103] 1 .70 mmol of the Acetic acid addition salt of Palmitoyl-Lys-Val-Dab-Thr-OH is dissolved in warm (50-80°C) aqueous acetonitrile. 3.75 mmol of 1 N hydrochloric acid is added and well stirred. The residual is lyophilized for 60 hours.

[0104] Example 3: Preparation of peptide compositions

[0105] At least one acid addition salt (i.e. the acetic acid, L(+) or DL mandelic acid or hydrochloric acid addition salt) of Palmitoyl-Lys-Val-Dab-OH or of Palmitoyl-Lys-Val-Dab-Thr-OH to provide solutions as outlined in the tables below was dissolved in 100g of hot water (80-90°C) in amount to reach a target concentration of 2000 ppm for (each) peptide in the final composition. The concentrate is then transferred into the respective polyol (glycerin, 1-3 propanediol, butylene glycol and well stirred or the respective polyol is added to the stirred concentrate to form the peptide compositions.

[0106] Example 4: Solubility / Transparency

[0107] The transparency correlating with the respective solubility (in brackets) was assessed visually and rated as follows: 5: very light opalescent (excellent), 4: light opalescent (very good); 3: opalescent (good); 2: turbid (acceptable); 1 cloudy (not acceptable). a). Palmitoyl-Lys-Val-Dab-OH

[0108] The solutions of the various acid addition salts of Palmitoyl-Lys-Val-Dab-OH in glycerin (Gly), 1 ,3-propanediol (PDO) respectively butylene glycol (BG) prepared as outlined above (example 3) were assessed for their visual appearance (i.e. transparency), which correlates with their solubility in the respective polyol right after their preparation.

[0109] The results are depicted in Table 1-a to 1c. Table 1-a: Palmitoyl-Lys-Val-Dab-OH salts in glycerin

[0110] Table 1-b: Palmitoyl-Lys-Val-Dab-OH salts in butylene glycol Table 1-c: Palmitoyl-Lys-Val-Dab-OH salts in 1 ,3-propanediol

[0111] As can be retrieved from table 1a to 1c, the acetic acid addition salts of Palmitoyl-Lys-Val- Dab-OH generally exhibited a good or even excellent solubility in glycerin reflected by a very low opalesence in 1 ,3-propanediol or butylene glycol, compared to the respective mandelic acid addition salts. The HOI addition salt performed worst, leading to cloudy suspensions. b) Palmitoyl-Lys-Val-Dab-Thr-OH

[0112] The solutions of the various acid addition salts of Palmitoyl-Lys-Val-Dab-Thr-OH in glycerin (Gly), 1 ,3-propanediol (PDO) respectively butylene glycol (BG) prepared as outlined above (example 3) were assessed for their visual appearance (i.e. transparency), which correlates with their solubility right after their preparation. The results are depicted in Table 2-a to 2c. Table 2-a: Palmitoyl-Lys-Val-Dab-Thr-OH salts in glycerin

[0113] Table 2-b: Palmitoyl-Lys-Val-Dab-Thr-OH salts in butylene glycol Table 2-c: Palmitoyl-Lys-Val-Dab-Thr-OH salts in 1 ,3-propanediol

[0114] As can be retrieved from table 2a to 2c, the acetic acid addition salt of Palmitoyl-Lys-Val-Dab- Thr-OH overall exhibited a good or even excellent solubility in glycerin reflected by the opalescence in 1 ,3-propanediol or butylene glycol, while the respective HOI, MA-L or MA-DL salt resulted in a turbid or even cloudy suspension, indicating a generally lower solubility, the HOI salt performing the worst. c) Palmitoyl-Lys-Val-Dab-OH and Palmitoyl-Lys-Val-Dab-Thr-OH

[0115] The solutions of mixtures of the respective acid addition salts of Palmitoyl-Lys-Val-Dab-OH and Palmitoyl-Lys-Val-Dab-Thr-OH in glycerin (Gly), 1 ,3-propanediol (PDO) respectively butylene glycol (BG) prepared as outlined above (example 3) were assessed for their visual appearance (i.e. transparency), which correlates with their solubility right after their preparation. The results are depicted in Table 3-a to 3c. Table 3-a: Palmitoyl-Lys-Val-Dab-OH / Palmitoyl-Lys-Val-Dab-Thr-OH salts in glycerin

[0116] Table 3-b: Palmitoyl-Lys-Val-Dab-OH / Palmitoyl-Lys-Val-Dab-Thr-OH salts in butylene glycol

[0117] Table 3-c: Palmitoyl-Lys-Val-Dab-OH / Palmitoyl-Lys-Val-Dab-Thr-OH salts in 1 ,3-propanediol

[0118] As can be retrieved from table 3a to 3c, the acetic acid as well as the mandelic acid of the peptide blend consisting of Palmitoyl-Lys-Val-Dab-OH and Palmitoyl-Lys-Val-Dab-Thr-OH overall exhibited a good solubility in glycerin, 1 ,3-propanediol or butylene glycol, while the respective HOI salts led to a white turbid cloudy suspension with a low solubility.

[0119] Example 5: Storage stability

[0120] The solutions identified above with a sufficient solubility were in addition assessed for their storage stability. Thus the solutions as outlined in Table 4-1 to 4-c having an initial peptide content of approx. 2000 respectively 4000 ppm were stored as outlined in Table 4-1 and 4-b. After storage the samples were analyzed for their remaining peptide content with analytical HPLC (standard deviation approx. ± 2.5%). The results are depicted in Table 4-a and 4-b.

[0121] Table 4-a: Palmitoyl-Lys-Val-Dab-OH [target concentration 2000 ppm] content after 3 month storage

[0122] *approx. 22°C

[0123] As can be retrieved from Table 4-a, the acetic acid addition salt of Palmitoyl-Lys-Val-Dab-OH overall exhibits a better storage stability compared to the mandelic acid addition salts. Table 4-b: Palmitoyl-Lys-Val-Dab-OH / Palmitoyl-Lys-Val-Dab-Thr-OH content upon storage at 4°C [target concentration 4000 ppm]

[0124] As can be retrieved from Table 4-b the acetate addition salts exhibited an increased storage stability compared to the respective mandelic acid addition salts.

[0125] Example 6: Exemplary cosmetic preparations

[0126] Table 2 outlines exemplary O / W emulsions, comprising peptide compositions according to the present invention. Table 2: Formulation (O / W emulsions)

[0127]

[0128] Water Ad 100

Claims

CLAIMS1. A composition comprising a water-soluble polyol and an acid addition salt of at least one peptide selected from Palmitoyl-Lys-Val-Dab-OH and Palmitoyl-Lys-Val-Dab-Thr-OH, wherein the acid is selected from the group of acetic acid and mandelic acid as well as mixtures thereof.

2. The composition of claim 1 , characterized in that the water-soluble polyol is selected from the group of water-soluble polyol containing 3 to 8 carbon atoms and 2 to 3 hydroxyl groups, preferably from the group of glycerin, butylene glycol and 1 ,3-propyleneglycol as well as mixtures thereof.

3. The composition of claim 1 or 2, wherein the peptide is selected from Palmitoyl-L-Lys-L- Val-L-Dab-OH and Palmitoyl-L-Lys-L-Val-L-Dab-L-Thr-OH.

4. The composition according to anyone of the preceding claims, wherein the acid is acetic acid.

5. The composition according to anyone of the preceding claims, wherein the water-soluble polyol is glycerin or butylene glycol, preferably glycerin.

6. The composition according to anyone of the preceding claims, characterized that both of Palmitoyl-Lys-Val-Dab-OH and Palmitoyl-Lys-Val-Dab-Thr-OH are present.

7. The composition according to anyone of the preceding claims, characterized in that the total amount of the at least one acid addition salt in the composition is selected in the range from 0.0005-12 wt.-%, preferably from 0.001-4 wt.-%, more preferably from 0.001-1 wt.-%, most preferably from 0.005 to 0.4 wt.-%, based on the total weigh of the composition.

8. 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 from 20-50 wt.-%, most preferably from 25-40 wt.-%, based on the total weight of the composition.

9. 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 from 25 to 80 wt.-%, most preferably from 60-75 wt.-%, based on the total weight of the composition.

10. The composition according to anyone of the preceding claims, characterized in that the composition comprises, preferably consists essentially of(i) from about 2000 to about 6000 ppm of the acid addition salt of Palmitoyl-Lys-Val- Dab-OH and / or Palmitoyl-Lys-Val-Dab-Thr-OH;(ii) from about 60 to about 75 wt.-% of the polyol, and(iii) from about 25 to about 40 wt.-% of water.11 . The composition according to anyone of the preceding claims, characterized in that the composition comprises, preferably consists essentially of(i) from about 1000 to 3000 ppm of the acetic acid addition salt of Palmitoyl-Lys-Val- Dab-OH;(ii) from about 1000 to about 3000 ppm of the acetic acid addition salt of Palmitoyl- Lys-Val-Dab-Thr-OH;(iii) from about 60 to about 75 wt.-% of glycerin or butylene glycol, and(iv) from about 25 to about 40 wt.-% of water.

12. A cosmetic preparation comprising a composition according to any one of claims 1 to 11 and a cosmetically acceptable carrier.

13. The cosmetic preparation according to claim 12, characterized in that the amount of the composition incorporated into said cosmetic preparation is selected in the range from 0.1 to 5wt.-%, preferably from 0.25 to 4 wt.-%, most preferably from 0.5 to 3 wt.-%, based on the total weight of the cosmetic preparation.

14. An acetic acid or mandelic acid addition salt of Palmitoyl-Lys-Val-Dab-OH and Palmitoyl- Lys-Val-Dab-Thr-OH, preferably the acetic acid addition salt of Palmitoyl-Lys-Val-Dab-OH or Palmitoyl-Lys-Val-Dab-Thr-OH, most preferably the acetate addition salt of Palmitoyl-L- Lys-L-Val-L-Dab-OH and Palmitoyl-L-Lys-L-Val-L-Dab-L-Thr-OH.

15. Use of acetic or mandelic acid to increase the solubility and / or the storage stability of at least one peptide selected from Palmitoyl-Lys-Val-Dab-OH and Palmitoyl-Lys-Val-Dab-Thr-OH in a composition comprising at least one water-soluble polyol, preferably selected from the group of glycerin, butylene glycol and / or 1 ,3-propanediol.

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