Mandelate salts of palmitoyl lysyl valyl-lysine

Abstract

The present invention relates to mandelic acid addition salts of palmitoyl lysyl valyl-lysine and cosmetic formulations comprising said salts. In addition, the present invention relates to the use of mandelic acid for the preparation of mandelic acid addition salts of palmitoyl-lysyl-valyl-lysine in order to increase the storage stability of palmitoyl-lysyl-valyl-lysine.

Description

[0001] The present invention relates to the mandelic acid addition salt of palmitoyl lysyl valyl - lysine and to cosmetic preparations comprising said salt. Furthermore, the present invention relates to the use of mandelic acid for the preparation of the mandelic acid addition salt of palmitoyl lysyl valyl - lysine to increase the storage stability of palmitoyl lysyl valyl - lysine.

[0002] The prominent role of peptides in nature makes them valuable cosmetic ingredients. Beauty peptides are involved in many physiological processes (such as an increase in collagen production) and have various benefits (such as anti - wrinkle, reduction of pigmentation, firming).

[0003] Palmitoyl - lysyl valyl - lysine bis(trifluoroacetate) can be obtained commercially from DSM Nutritional Products Ltd as -COLL, which is the bis(trifluoroacetate) addition salt of the synthetic tripeptide Pal - KVK and is widely used in cosmetic applications.

[0004] Trifluoroacetic acid (TFA) is typically used in peptide synthesis, during the cleavage of peptides from their respective resins, and as an ion - pairing agent in HPLC purification. Thus, synthetic peptides are usually in the form of TFA salts (up to 45% TFA content). Furthermore, TFA salts generally exhibit good solubility, which is a prerequisite for cosmetic applications.

[0005] However, cosmetic compositions containing TFA and its salts are no longer popular with all consumers.

[0006] Therefore, there has been a continuing need for alternative peptide salts that do not contain TFA but still exhibit sufficient solubility while also providing good storage stability.

[0007] It has now surprisingly been found that the mandelic acid addition salt of palmitoyl lysyl valyl - lysine overcomes the disadvantages of the prior art.

[0008] Accordingly, in a first embodiment, the present invention relates to the mandelic acid addition salt of palmitoyl lysyl valyl - lysine (Pal - KVK).

[0009] The term "palmitoyl lysyl valyl - lysine" includes all possible isomeric forms and mixtures thereof, such as racemic mixtures and mixtures of rotamers.

[0010] In all embodiments of the present invention, palmitoyl lysyl valyl - lysine is preferably palmitoyl - L - lysyl - L - valyl - L - lysine (Cas No.: 623172 - 55 - 4; also known as N 2 -(1 - oxohexadecyl)-L - lysyl - L - valyl - L - lysine).

[0011] It is well understood that in all embodiments of the present invention, 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, D,L-mandelic acid is used in all embodiments of the present invention.

[0012] Preferably, based on palmitoyllysylvalyl-lysine, the molar equivalent of mandelic acid relative to palmitoyllysylvalyl-lysine is selected in the range of 0.5 to 3 molar equivalents, preferably in the range of 0.75 to 2.5 molar equivalents, most preferably in the range of 0.8 to 2.25 molar equivalents, for example in the range of 1.75 to 2.25 molar equivalents. Other suitable ranges are 0.75 to 1.5 molar equivalents or 1 to 1.25 molar equivalents.

[0013] Preferably, in all embodiments of the present invention, the mandelic acid addition salt of palmitoyllysylvalyl-lysine is N 2 -(1-oxohexadecyl)-lysyl-valyl-lysine mandelate (molar equivalent of peptide / acid is about 1:2), and most preferably N 2 -(1-oxohexadecyl)-L-lysyl-L-valyl-L-lysine D,L-mandelate (molar equivalent of peptide / acid is about 1:2).

[0014] In all embodiments of the present invention, the mandelate salt of palmitoyllysylvalyl-lysine is preferably prepared as follows: Dissolve the corresponding acetate salt of palmitoyllysylvalyl-lysine (for example, prepared as outlined in Example 6 of US2007 / 0099842) in a suitable solvent to form a peptide acetate solution, combine the peptide acetate solution with a solution of mandelic acid dissolved in a solvent (by adding the peptide solution to the mandelic acid solution or vice versa), and then remove the solvent by suitable means (such as evaporation and / or lyophilization).

[0015] Suitable solvents especially include alkyl alcohols, such as C 1-6 alkyl alcohols, including methanol, ethanol, propanol, isopropanol and acetic acid, and their mixtures with methanol and acetic acid, and any mixture of them is particularly preferred.

[0016] The amount of the solvent is preferably selected such that the palmitoyllysylvalyl lysine acetate and mandelic acid are completely dissolved.

[0017] Therefore, in a particularly preferred embodiment, the mandelate salt of palmitoyllysylvalyl-lysine having all the definitions and preferred modes given herein is prepared by the following method:

[0018] (i) Dissolve the corresponding palmitoyl - lysyl - valyl - lysine acetate in a solvent with all the definitions and preferred embodiments given herein to form a peptide acetate solution.

[0019] (ii) Combine the peptide acetate solution with a solution of the corresponding mandelic acid dissolved in a solvent with all the definitions and preferred embodiments given herein.

[0020] (iii) Remove the solvent by evaporation, optionally and preferably followed by lyophilization.

[0021] In a preferred embodiment, the mandelic acid addition salt of palmitoyl - lysyl - valyl - lysine with all the definitions and preferred embodiments given herein is included in a composition (also referred to herein as a peptide composition), which further comprises at least one water - soluble polyol having 2 to 10 carbon atoms and 2 to 7 hydroxyl groups and optionally water.

[0022] In a particularly advantageous embodiment, the peptide composition according to the invention comprises:

[0023] (i) 0.001 - 12.5% by weight, especially 0.01 - 2% by weight, most especially 0.1 - 0.5% by weight of the mandelic acid addition salt of palmitoyl - lysyl - valyl - lysine, which has all the definitions and preferred embodiments given herein.

[0024] (ii) Up to 99.999% by weight, especially 40 - 80% by weight, most especially 60 - 75% by weight of at least one water - soluble polyol having 2 - 10 carbon atoms and 2 - 7 hydroxyl groups, and optionally

[0025] (iii) Up to 90% by weight, especially up to 50% by weight, most especially 0 - 35% by weight of water.

[0026] Even more preferably, the peptide composition according to the invention comprises:

[0027] (i) About 1000 to about 2000 ppm of the mandelic acid addition salt of palmitoyl - lysyl - valyl - lysine, which has all the definitions and preferred embodiments given herein.

[0028] (ii) About 60 to about 75% by weight of glycerol and / or 1,3 - propanediol, and

[0029] (iii) About 24.9% to about 39.9% by weight of water.

[0030] In a particularly advantageous embodiment, the components (i) to (iii) in the peptide composition total up to 100% by weight.

[0031] The peptide composition according to the invention may further comprise a surfactant and / or a thickener. The surfactant suitable for use in the peptide composition is a surfactant suitable for cosmetic applications. The surfactants are well known to those skilled in the art and particularly include nonionic surfactants such as polysorbate-20. The thickener suitable for use in the peptide composition is also a thickener suitable for cosmetic applications, such as polyacrylic acid (carbomers).

[0032] In another embodiment, the invention relates to the use of mandelic acid for increasing the storage stability of palmitoyl lysyl valyl-lysine, which has all the definitions and preferred embodiments given herein, preferably in a water-soluble polyol containing 2 to 10 carbon atoms and 2 to 7 hydroxyl groups and optionally water and / or a topical formulation as defined herein, and the water-soluble polyol has all the definitions and preferred embodiments given herein.

[0033] The increase in storage stability as defined herein means an increase in stability after storage at 4 °C, 22 °C (RT) and 40 °C for 3 months compared to, for example, the corresponding mesylsulfonate (preferably in glycerol) or 2-methoxy-2-phenylacetic acid addition salt (preferably in propylene glycol).

[0034] Preferably, compared to, for example, the corresponding mesylsulfonate in glycerol or 2-methoxy-2-phenylacetic acid in propylene glycol, the storage stability at room temperature (RT) after 3 months is increased by at least 10%, more preferably at least 15%, and most preferably at least 20%.

[0035] The water-soluble polyol containing 2-10 carbon atoms and 2-7 hydroxyl groups is particularly selected from ethylene glycol, 1,2-propanediol, 1,3-propanediol (also referred to as propylene glycol herein), 1,4-butanediol, glycerol, erythritol (meso-1,2,3,4-butanetetraol), sorbitol, mannitol, methyl glucoside, diglycerides, triglycerides and / or pentaerythritol. In particular, the polyol is glycerol or 1,3-propanediol, most preferably glycerol.

[0036] In a specific embodiment, the addition salt is used in the form of a blend consisting essentially of:

[0037] (a) 0.05-1% by weight, preferably 0.1-1% by weight, most preferably 0.2-0.5% by weight of the addition salt according to the invention,

[0038] (b) 15-50% by weight, preferably 20-40% by weight, most preferably 25-35% by weight of panthenol,

[0039] (c) 0.1 - 1% by weight, preferably 0.2 - 0.8% by weight, most preferably 0.25 - 0.7% by weight of sodium hyaluronate,

[0040] (d) 0.25 - 7% by weight, preferably 0.3 - 5% by weight, most preferably 0.5 - 3% by weight of at least one algal extract,

[0041] (e) 0.25 - 7% by weight, preferably 0.3 - 5% by weight, most preferably 0.5 - 3% by weight of pentylene glycol,

[0042] (f) Up to 1% by weight, preferably 0.001 - 1% by weight of citric acid, and

[0043] (g) > 50% water.

[0044] It is well understood by those skilled in the art that water is used to adjust the blend to 100% by weight.

[0045] The term "the blend consists essentially of..." as used according to the present invention means that the total amount of the listed components ideally adds up to at most 100% by weight. However, it is not excluded that there may be small amounts of impurities or additives, provided that the total amount of such impurities or additives is preferably less than 3% by weight, more preferably less than 2% by weight, most preferably less than 1% by weight, and they are introduced via the corresponding raw materials.

[0046] Furthermore, it is well understood that the amount (total amount) of water in the blend is the sum of the water added via the corresponding raw materials (such as via the aqueous algal extract) and the "free" water.

[0047] The blend is preferably a colorless to light yellow liquid and exhibits a pH value of about 4.0 - 6.0, preferably 4.5 - 5.5, and a viscosity of less than 3000 mPas, preferably less than 2000 mPas, most preferably less than 1500 mPas (measured with a Brookfield RVDV-II +, spindle 3 at a shear rate of 10 rpm at 25°C for 30 s).

[0048] The algal extract in the blend according to the present invention is preferably an extract of the microalga Dunaliella Salina produced by biotechnology.

[0049] Such extracts can be obtained by culturing the corresponding algae and then harvesting the cells. The harvested cells are then rehydrated and extracted with hot water. Subsequently, the crude extract is centrifuged and ultrafiltered. In the preparation of the blend, the algal extract can be used in dry form or in the form of a concentrated aqueous algal extract with a known solids content. Preferably, the algal extract is added to the blend in the form of a concentrated aqueous algal extract with a known algal extract content (solids content). Preferably, an aqueous algal extract having an algal extract content selected in the range of 0.5 wt% to 10 wt%, preferably in the range of 1 wt% to 5 wt% based on the total aqueous algal extract, is used for preparing the blend according to the present invention. Suitable algal extracts for preparing the blend according to the present invention are -CTIVE CB, which consists of 1 - 5% Dunaliella Salina Extract, 1 - 5% pentylene glycol, 0.01 - 0.1% citric acid and water up to 100%.

[0050] Panthenol [CAS 81 - 13 - 0] can be commercially obtained, for example, from DSM Nutritional Products Ltd as D-panthenol or D-panthenol 75L.

[0051] When used herein, the term sodium hyaluronate [CAS 9067 - 32 - 7] refers to the sodium salt of hyaluronic acid. Preferably, low molecular weight sodium hyaluronate is used in the blend according to the present invention, for example, sodium hyaluronate having a molecular weight (MW) in the range of 10 - 800 kDa, preferably MW in the range of 200 - 600 kDa, and most preferably MW in the range of 200 - 400 kDa. Such sodium hyaluronate can be obtained, for example, from DSM Nutritional products Ltd under the trade name HYA-ACT TM S and from Soliance under BasHyal (MW 100 - 300 kDa) or Renovhyal (MW 15 - 50 kDa). Most preferably in all embodiments is the use of HYA-ACT TM S, with a small molecular weight hyaluronic acid of 200 - 400 kDa.

[0052] The addition salts, correspondingly peptide compositions, and blends as defined herein can be incorporated into cosmetic formulations for improving the appearance and physiology of the skin, such as reducing fine lines, wrinkles, and other symptoms associated with aging or photo-damaged skin, treating stretch marks, or skin tightening, skin firming, and / or skin moisturization.

[0053] Accordingly, the present invention also relates to a cosmetic preparation which comprises an addition salt or the corresponding peptide composition as defined herein, and a cosmetically acceptable carrier.

[0054] The term "cosmetic preparation" as defined herein particularly refers to a cosmetic preparation which can be topically applied to mammalian keratinous tissue, such as human skin or hair (including eyelashes, eyebrows) or nails, especially human skin.

[0055] The term "cosmetic preparation" used in this application refers to a cosmetic composition as defined under the title "Kosmetika" in the 10th edition of Georg Thieme Verlag Stuttgart, New York in 1997, and a cosmetic composition as disclosed in the 4th edition in 1992 of A. Domsch, "Cosmetic Compositions", Verlag für chemische Industrie (edited by H. Ziolkowsky).

[0056] The term "cosmetically acceptable carrier" refers to all carriers and / or excipients and / or diluents conventionally used in cosmetic preparations.

[0057] In a preferred embodiment, based on the total weight of the composition, the cosmetic preparation according to the present invention comprises 50% to 99%, preferably 60% to 98%, more preferably 70% to 98%, for example especially 80% to 95% of a carrier.

[0058] In a particularly preferred embodiment, the carrier in all embodiments of the present invention also consists of at least 30% by weight, preferably at least 40% by weight, more preferably at least 45% by weight, most preferably at least 50% by weight of water, for example especially 50 to 95% by weight, 50 to 80% by weight, 50 to 70% by weight or 50 to 60% by weight of water.

[0059] Preferably, the cosmetic preparation is in the form of a suspension or dispersion in a solvent or fatty substance, or in the form of an emulsion (including microemulsion, PIT emulsion, pickering emulsion and multiple emulsion), for example especially of the O / W type or W / O type, a gel such as a hydrogel, an alcohol gel, a lipid gel, a single-phase or multi-phase solution or a vesicle dispersion or other common forms, which can also be applied by pen, as a mask or as a spray. If the cosmetic preparation is or contains an emulsion, it may also contain one or more anionic, non-ionic, cationic or amphoteric surfactants.

[0060] Preferred cosmetic preparations are skin care compositions and functional compositions.

[0061] The cosmetic preparation according to the invention can be in the form of a liquid, a lotion, a thickened lotion, a gel, a cream, a milk, an ointment, a paste, a powder, a make-up or a solid stick, and can 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 lyophilisate.

[0062] The cosmetic preparation according to the invention is preferably formulated as an oil-in-water or water-in-oil emulsion, a silicone-in-water or water-in-silicone emulsion or an aqueous serum or an aqueous gel, in particular an oil-in-water emulsion (O / W emulsion).

[0063] In another preferred embodiment, the cosmetic preparation according to the invention is in the form of an aqueous gel and / or a transparent gel.

[0064] The cosmetic preparation according to the invention has a pH in the range of 3 - 10, preferably a pH in the range of 4 to 8, and most preferably a pH in the range of 4 - 6.

[0065] According to the invention, the topical preparation can optionally contain additional ingredients, such as ingredients for: skin brightening; sun protection; treatment of hyperpigmentation; prevention or reduction of acne, wrinkles, fine lines, atrophy and / or inflammation; and local anesthetics; antimicrobial and / or antifungal agents; chelating agents and / or sequestrants; anti-cellulite and weight loss (such as phytanic acid), firming, moisturizing and revitalizing, self-tanning, soothing, and reagents for improving elasticity and the skin barrier and / or ultraviolet filtering substances. The topical cosmetic preparation can also contain common cosmetic adjuvants and additives, such as preservatives / antioxidants, fatty substances / oils, water, organic solvents, silicones, thickeners, softeners, emulsifiers, defoamers, humectants, cosmetic components such as fragrances, surfactants, fillers, sequestering agents, anionic polymers, cationic polymers, nonionic polymers or amphoteric polymers or mixtures thereof, propellants, acidifying or alkalizing agents, dyes, colorants / coloring agents, abrasives, absorbents, essential oils, skin sensates, astringents, defoamers, pigments or nanopigments, such as those suitable for providing a photoprotective effect by physically blocking ultraviolet radiation, or any other ingredients commonly formulated into cosmetic preparations. Such cosmetic ingredients commonly used in the skin care industry and suitable for use in the cosmetic preparation according to the invention are described, for example, in the second edition (1992) of the CTFA Cosmetic Ingredient Handbook, but are not limited thereto.

[0066] Conventional cosmetic adjuvants and additives (such as emulsifiers, thickeners, surface-active ingredients, and film-forming agents) can exhibit synergistic effects, which can be determined by those skilled in the art using normal tests or by using the usual considerations related to the formulation of cosmetic preparations.

[0067] Based on the desired product, those skilled in the art can readily determine the necessary amounts. In some cases, the cosmetic active ingredients available herein can provide more than one benefit or act via more than one mode of action.

[0068] Unless otherwise stated, the carriers, excipients, additives, diluents, adjuvants, and additives, etc. mentioned below are particularly suitable for the cosmetic preparations according to the present invention.

[0069] The following examples are provided to further illustrate the present invention. These examples are illustrative only and are not intended to limit the scope of the present invention in any way. Examples

[0070] Abbreviations: MA = mandelic acid (hydroxyphenylacetic acid)

[0071] MSA = methanesulfonic acid

[0072] MPAA = 2-methoxy-2-phenylacetic acid

[0073] DAB: 1,4-diaminobutyric acid (structural unit in the tripeptide)

[0074] Example 1: Preparation of various Palm-Lys-Val-Lys-OH addition salts

[0075] 1.1 Palm-Lys-Val-Lys-OH*2MA

[0076] To a solution of 2 g (2.73 mmol) of Palm-Lys-Val-Lys-OH·2AcOH in an aqueous 90% MeOH solution, 0.852 g (5.60 mmol, 2.05 equivalents) of mandelic acid dissolved in 20 mL of MeOH was added. The mixture was stirred until a homogeneous solution was obtained. Then, MeOH was removed first under reduced pressure and then by lyophilization.

[0077] 1.2 Palm-Lys-Val-Lys-OH*2MPAA (reference)

[0078] To a solution of 500 mg (0.68 mmol) of Palm-Lys-Val-Lys-OH·2AcOH in an aqueous 90% MeOH solution, 233 mg (1.40 mmol, 2.05 equivalents) of methoxyphenylacetic acid in was added. The mixture was stirred until a homogeneous solution was obtained. Subsequently, MeOH was removed first under reduced pressure and then by lyophilization.

[0079] 1.3Palm-Lys-Val-Lys-OH*2MSA (reference)

[0080] To a solution of 200 mg (0.273 mmol) of Palm-Lys-Val-Lys-OH·2AcOH in 90% aqueous MeOH, 53.8 mg (0.56 mmol, 2.05 eq) of methanesulfonic acid (MSA) was added. The mixture was stirred until a homogeneous solution was obtained. Subsequently, MeOH was removed under reduced pressure and then lyophilized.

[0081] Example 2: Preparation of Peptide Composition

[0082] 2.1 Palm-Lys-Val-Lys-OH*2MA–glycerol / water composition

[0083] (MA-Gly)

[0084] 100 mg of Palm-Lys-Val-Lys-OH·2MA prepared as described above was charged into a 100 ml round-bottom neck flask. 21.0 g (from a total of 24.9 g) of water was added, and the peptide was dissolved using a short-time (about 5 - 15 seconds) ultrasonic bath at 85 °C. Then 58.1 g of glycerol (99.9%) (pH adjusted to about 4.5 with aqueous NaOH solution (about 0.05 M)) was added, followed by 3.36 g of water.

[0085] 2.2 Palm-Lys-Val-Lys-OH*2MA–1,3-propanediol (PDO) / water composition

[0086] (MA-PDO)

[0087] 100 mg of Palm-Lys-Val-Lys-OH·2 mandelate prepared as described above was charged into a 100 ml round-bottom neck flask. 21.4 g (from a total of 24.9 g) of water was added, and the peptide was dissolved using a short-time (about 5 - 15 seconds) ultrasonic bath at 85 °C. Then 58.1 g of PDO (99.9%) (pH about 4.5) was added, followed by 3.5 g of water.

[0088] 2.3 Palm-Lys-Val-Lys-OH*2MSA–glycerol / water composition

[0089] (MSA-Gly)

[0090] 200 mg of Palm-Lys-Val-Lys-OH·2MSA prepared as described above was charged into a 250 ml round-bottom neck flask. 33.2 g of water was added, and the peptide dissolved at about 80 °C. Then 132.3 g of glycerol (86.5%) (pH adjusted to about 4.5 with aqueous NaOH solution (about 0.05 M)) was added.

[0091] 2.4Palm-Lys-Val-Lys-OH*2MPAA–1,3-propanediol (PDO) / water composition

[0092] (MPAA-PDO)

[0093] 100 mg of Palm-Lys-Val-Lys-OH*2MPPA prepared as described above was charged into a 100 ml round-bottom neck flask. 21.7 g of water was added, and the peptide was dissolved using a short-time (about 5 - 15 seconds) ultrasonic bath at 85 °C. Then 58.1 g of PDO (99.9%) (pH about 4.5) was added, and then 3.2 g of water was added.

[0094] Example 3: Storage Stability

[0095] Colorless solutions of various salts of the tripeptide palmitoyl lysyl valyl-lysine prepared as described above in glycerol or 1,3-propanediol (target initial peptide content: about 1200 ppm) were stored at 4 °C, 22 °C (RT), and 40 °C. After 3 months of storage, the peptide content of the samples was analyzed by analytical HPLC. In addition, the color was evaluated, i.e., whether it remained colorless or turned yellow (or light yellow). The results are plotted in Table 1.

[0096] Table 1-a: Peptide content after storage at different temperatures

[0097] Composition MA-Gly MA-PDO MSA-Gly MPAA-PDO Salt MA MA MSA MPAA Solvent Glycerol Propylene glycol Glycerol Propylene glycol 4℃ 1018 1027 939 778 RT 1047 1001 816 320 40℃ 992 1003 527 53 Color Colorless Colorless Yellow Yellow

[0098] It can be seen from Table 1-a that the MA salt according to the present invention exhibits good stability during storage, while the corresponding MSA or MPAA salts exhibit significant loss of activity during storage.

[0099] As comparative data, the mandelate salt of tetradecyl Dab-Val-Dab-OH (also known as tetradecyl aminobutyryl valyl aminobutyric acid urea mandelate) and the corresponding peptide compositions in glycerol and propylene glycol (referred to as TDVD-MA-Gly and TDVD-MA-PDO) were prepared as described above. After storage at 40 °C for 2 weeks, the peptide content of the samples was analyzed by analytical HPLC. The results are plotted in Table 1-b.

[0100] Table 1-b: Peptide content after storage at 40 °C for 2 weeks

[0101] Tripeptide MA-gly MA-PDO TDVD-MA-Gly TDVD-MA-PDO Salt MA MA MA MA Solvent Glycerol Propylene glycol Glycerol Propylene glycol 40 °C / 2 weeks 1033 1036 660 225

[0102] It can be seen from Tables 1-a and 1-b that the MA salt according to the present invention exhibits good storage stability, while the mandelate salt of tetradecyl Dab-Val-Dab-OH has already exhibited a significant loss of activity after 2 weeks.

[0103] Example 4: Stability in cosmetic formulations

[0104] Table 2: Preparation (transparent gel)

[0105]

[0106] Table 3: Peptide content after storage at different temperatures after 3 months

[0107] (Theoretical initial content in the gel: 21.0 ppm for MA-Gly and 20.7 ppm for MA-PDO)

[0108] Composition MA-Gly MA-PDO Salt MA MA Solvent Glycerol Propylene glycol 4℃ 20.1 19 RT 19 18.1 40℃ 16.3 12.7

[0109] It can be concluded from Table 3 that compared with using a 1,3-propanediol composition, using a glycerol composition results in improved stability in the final formulation.

[0110] Table 4: Peptide content after storage at different temperatures after 4 weeks (theoretical initial content: 19.3 ppm)

[0111] Composition MPAA-Gly Salt MPAA Solvent Glycerol 4℃ 20.8 40℃ 9.8

[0112] It can be concluded from Table 3 and Table 4 that compared with the corresponding MPAA salts, the MA salts according to the present invention exhibit significantly better stability upon storage. The corresponding MPAA salts already exhibit a 52% loss of activity after 1 month (at 40 °C), while the corresponding MA salts only exhibit a -19% loss after storage at 40 °C for 3 months.

[0113] Example 5: Blend

[0114] Prepare a blend consisting essentially of 1.25 g of the mandelate salt of palmitoyl lysyl valyl-lysine (D / L form), 150 g of D-panthenol (DSM Nutritional Products Ltd), 2.5 g of hyaluronic acid (HYA-ACT S, DSM Nutritional Products Ltd), 288 g of PEPHA-CTIVE CB (obtained from DSM Nutritional Products Ltd), 25 g of pentylene glycol (Hydrolite 5 green) and 55 g of Milli Q water. The blend shows excellent storage stability and peptide recovery after storage (2256 ppm after storage at 40 °C for 3 months).

[0115] Example 5: Exemplary cosmetic formulation

[0116] Table 5 outlines exemplary O / W emulsions containing the peptide composition according to the present invention.

[0117] Table 5: Formulation (O / W emulsion)

[0118]

[0119]

[0120]

Claims

1. The mandelic acid addition salt of palmitoyl lysyl valyl-lysine.

2. The mandelic acid addition salt according to claim 1, wherein the palmitoyl lysyl valyl-lysine is N 2 -(1-oxohexadecyl)-L-lysyl-L-valyl-L-lysine.

3. The mandelic acid addition salt according to claim 1 and / or 2, wherein the mandelic acid is D-(-)-mandelic acid, L-(+)-mandelic acid or D,L-mandelic acid, preferably D,L-mandelic acid.

4. The mandelic acid addition salt according to any one of the preceding claims, wherein based on palmitoyl lysyl valyl-lysine, the molar equivalent of mandelic acid in the mandelic acid addition salt is selected from 0.5 to 3 molar equivalents.

5. The mandelic acid addition salt according to any one of the preceding claims, wherein the salt is prepared by the following steps: dissolving palmitoyl lysyl valyl-lysine acetate in 1-6 an alkyl alcohol and / or acetic acid to form a peptide acetate solution, combining the peptide acetate solution with a solution of mandelic acid in 1-6 an alkyl alcohol and / or acetic acid, and then removing 1-6 the alkyl alcohol and / or acetic acid by evaporation and / or lyophilization.

6. The mandelic acid addition salt according to claim 5, wherein the C 1-6 alkyl alcohol is methanol.

7. The mandelic acid addition salt according to any one of the preceding claims, wherein the addition salt is contained in a composition which further comprises at least one water-soluble polyol having 2 to 10 carbon atoms and 2 to 7 hydroxyl groups and water.

8. The mandelic acid addition salt according to claim 7, wherein the composition comprises: (i) 0.001-12.5% by weight, especially 0.01-2% by weight, most especially 0.1-0.5% by weight of the mandelic acid addition salt of palmitoyl lysyl valyl-lysine, (ii) up to 99.999% by weight, especially 40-80% by weight, most especially 60-75% by weight of at least one water-soluble polyol having 2-10 carbon atoms and 2-7 hydroxyl groups, and (iv) up to 90% by weight, especially up to 50% by weight, most especially 0-35% by weight of water.

9. The mandelic acid addition salt according to claim 8, wherein the components (i) to (iii) of the composition in total are at most 100% by weight.

10. The mandelic acid addition salt according to any one of claims 7 to 9, wherein the at least one water-soluble polyol having 2 to 10 carbon atoms and 2 to 7 hydroxyl groups is selected from the group consisting of glycerol, 1,2-propanediol, 1,3-propanediol and / or 1,4-butanediol, preferably selected from glycerol and 1,3-propanediol, most preferably glycerol.

11. The mandelic acid addition salt according to any one of the preceding claims, wherein the addition salt is contained in a blend consisting essentially of: (a) 0.05-1% by weight, preferably 0.1-1% by weight, most preferably 0.2-0.5% by weight of the mandelic acid addition salt, (b) 15-50% by weight, preferably 20-40% by weight, most preferably 25-35% by weight of panthenol, (c) 0.1-1% by weight, preferably 0.2-0.8% by weight, most preferably 0.25-0.7% by weight of sodium hyaluronate, (d) 0.25-7% by weight, preferably 0.3-5% by weight, most preferably 0.5-3% by weight of at least one algal extract, preferably Dunaliella salina extract, (e) 0.25-7% by weight, preferably 0.3-5% by weight, most preferably 0.5-3% by weight of pentylene glycol, (f) up to 1% by weight, preferably 0.001-1% by weight, most preferably 0.001-0.1% by weight of citric acid, and (g) at least 50% by weight of water.

12. A cosmetic preparation comprising a mandelic acid addition salt of palmitoyl lysyl valyl - lysine according to any one of claims 1 to 11 and a cosmetically acceptable carrier.

13. The cosmetic composition according to claim 12, wherein the carrier consists of at least 50% by weight of water.

14. The cosmetic composition according to claims 12 to 13, wherein the composition is in the form of a gel or an emulsion.

15. Use of mandelic acid for increasing the storage stability of palmitoyl lysyl valyl - lysine, preferably in a composition comprising at least one water - soluble polyol having 2 - 10 carbon atoms and 2 - 7 hydroxyl groups and / or in a cosmetic preparation comprising a cosmetically acceptable carrier.

16. The use according to claim 15, wherein the at least one water - soluble polyol is glycerol or 1,3 - propanediol.

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