Cyclic peptides, their compositions and uses

Abstract

Cyclic peptides, their compositions and uses are disclosed, relating to the technical field of polypeptides. The cyclic peptides of the present disclosure have the structure shown in formula (I): Cyclo-[Gly-His-Lys-Lys] (I). Specifically, it relates to the use of the cyclic peptide or its salt, or their compositions, and their use in the preparation of compositions for caring for or treating the skin or mucous membranes.

Description

Technical Field

[0001] The present disclosure relates to the field of polypeptide technology, in particular to a cyclic peptide and a composition thereof, and uses thereof. Background Art

[0002] Collagen, a major component of the extracellular matrix (ECM), is produced by fibroblasts and provides the skin with strength and structural support against stretch. With aging, collagen production decreases, and existing collagen degrades, leading to sagging and wrinkling. Elastin, another important ECM component, contributes to the skin's elasticity and resilience. In normal physiology, elastase participates in ECM remodeling, helping to remove damaged elastin and promote new elastin production. However, overactive elastase can lead to excessive elastin degradation, impairing the skin's elasticity and overall structure. Hyaluronic acid, an acidic mucopolysaccharide, has a strong water-retention capacity in the skin, helping to maintain hydration and volume. Hyaluronidase is an enzyme that degrades hyaluronic acid. By regulating its degradation, it affects the skin's water balance and texture. Increased hyaluronidase activity leads to a significant decrease in hyaluronic acid, disrupting the skin's barrier function and accelerating water loss. Tyrosinase is a key enzyme involved in melanin synthesis, catalyzing the conversion of tyrosine to dopaquinone, which is then formed into melanin. Melanin protects the skin from UV damage, preventing DNA damage and skin cancer. However, excessive tyrosinase activity can lead to excessive pigmentation, resulting in pigmentary skin diseases such as freckles and melasma. Therefore, tyrosinase activity affects the evenness of skin color.

[0003] In summary, collagen, elastase, hyaluronidase and tyrosinase all play important roles in maintaining skin structure and function. Summary of the Invention

[0004] The present disclosure relates to cyclic peptides, and these cyclic peptides and compositions containing these cyclic peptides have the effects of caring for or treating skin or mucous membranes.

[0005] In one aspect, the present disclosure provides a cyclic peptide represented by formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof,

[0006] Cyclo-[Gly-His-Lys-Lys](I).

[0007] The cyclic peptide shown in formula (I) of the present disclosure can exist as a mixture of stereoisomers or stereoisomers; for example, the amino acids it contains can have L-, D- configurations, or be racemic independently of each other. Therefore, it is possible to obtain isomeric mixtures as well as racemic mixtures or diastereomeric mixtures, or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and what isomers or isomeric mixtures are present. In some embodiments, the structure of the cyclic peptide shown in formula (I) of the present disclosure is a pure isomer, that is, an enantiomer or a diastereomer. In some embodiments, the structure of the cyclic peptide shown in formula (I) of the present disclosure is an L-isomer.

[0008] The present disclosure also includes all suitable isotopic variants of the cyclic peptides represented by formula (I). Isotopic variants of these cyclic peptides disclosed herein are understood herein to refer to compounds in which at least one atom in the cyclic peptides disclosed herein is replaced by another atom of the same atomic number, but the atomic mass of the other atom is different from the atomic mass usually or predominantly present in nature. Examples of isotopes that can be incorporated into the cyclic peptides disclosed herein are those of hydrogen, carbon, nitrogen or oxygen, e.g. 2 H (deuterium), 3 H (tritium), 13 C. 14 C. 15 N. 17 O or 18 O. Certain isotopic variants of the cyclic peptides disclosed herein (particularly those into which one or more radioactive isotopes have been incorporated) may be useful, for example, for examining the mechanism of action or distribution of the active compound in vivo; due to their relative ease of preparation and detectability, particularly with 3 H or 14 Compounds labeled with a C isotope are suitable for this purpose. In addition, due to the greater metabolic stability of the compound, the incorporation of an isotope (e.g., deuterium) can produce specific therapeutic benefits, such as an extension of the half-life in vivo or a reduction in the required active dose. Isotopic variants of the cyclic peptides of the present disclosure can be prepared by methods known to those skilled in the art, such as by the methods further described below and in the examples, by using the respective reagents and / or corresponding isotopic modifications of the starting materials.

[0009] The term "salt" refers to a salt that is approved for use in animals, and more specifically in humans, and includes metal salts of the cyclic peptide represented by formula (I), where the metal includes, but is not limited to: lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc, or aluminum, etc.; includes salts formed by the cyclic peptide represented by formula (I) and an organic base, where the organic base includes, but is not limited to: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine, or piperazine, etc.; includes salts formed by the cyclic peptide represented by formula (I) and an inorganic acid or an organic acid, where the organic acid includes, but is not limited to: acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoate, or gluconic acid, etc.; the inorganic acid includes, but is not limited to: hydrochloric acid, sulfuric acid, boric acid, or carbonic acid.

[0010] The synthesis of the cyclic peptide represented by formula (I) of the present disclosure or its salt can be carried out according to conventional methods known in the prior art, such as solid-phase synthesis, liquid-phase synthesis, or a method combining solid-phase and liquid-phase, and can also be prepared by a biotechnological method aimed at generating the desired sequence, or by controlled hydrolysis of proteins of animal, fungal, or plant origin.

[0011] For example, a method for obtaining the cyclic peptide represented by formula (I) includes the following steps:

[0012] - Coupling an amino acid with a protected N-terminus and a free C-terminus to an amino acid with a free N-terminus and a protected or solid-support-bound C-terminus;

[0013] - Removing the group protecting the N-terminus;

[0014] - Repeating this coupling sequence and removing the group protecting the N-terminus until the desired peptide sequence is obtained;

[0015] - Removing the group protecting the C-terminus or cleaving from the solid support;

[0016] - Performing a condensation reaction between the free amino group at the N-terminus and the free carboxyl group at the C-terminus of the peptide sequence to effect head-to-tail cyclization;

[0017] - Removing the groups protecting the side chains.

[0018] In some embodiments, the C-terminus is bound to a solid support and the method is carried out on the solid phase, including coupling an amino acid with a protected N-terminus and a free C-terminus to an amino acid with a free N-terminus and a C-terminus bound to a polymer support; removing the group protecting the N-terminus; and repeating this sequence the required number of times so as to thereby obtain a peptide of the desired length, followed by cleaving the synthesized peptide from the original polymer support.

[0019] During the entire synthesis, the functional groups of the side chains of these amino acids are kept sufficiently protected with temporary or permanent protecting groups.

[0020] In some embodiments, solid-phase synthesis can be carried out by a convergent strategy of coupling a dipeptide or tripeptide to a polymer support or to a dipeptide or amino acid previously bound to the polymer support.

[0021] Another aspect of the present disclosure provides a composition comprising an effective amount of the cyclic peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, and at least one excipient and an optional adjuvant.

[0022] In some embodiments,The adjuvant is selected from: analgesics, agents that inhibit PAR-2 activity, collagen synthesis stimulants, agents that regulate PGC-1α synthesis, agents that regulate the activity of PPARγ, agents that increase or decrease the triglyceride content of adipocytes, agents that stimulate or delay adipocyte differentiation, lipolytic agents or agents that stimulate lipolysis, lipolytic solvents, lipogenic agents, inhibitors of acetylcholine receptor aggregation, agents that inhibit muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloproteinase inhibitors, melanin synthesis stimulants or inhibitors, whitening agents or depigmenting agents, pigmentation promoters, self-tanning agents, anti-aging agents, NO-synthase inhibitors, 5α-reductase inhibitors, inhibitors of lysyl hydroxylase and / or prolyl hydroxylase, antioxidants, free radical scavengers and / or agents against air pollution, reactive carbonyl species scavengers, antiglycation agents, antihistamines, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, moisture-retaining substances, α-hydroxy acids, β-hydroxy acids, humectants, epidermal hydrolases, vitamins, amino acids, proteins, pigments, dyes, biopolymers, gum polymers, thickeners, surfactants, softeners, adhesives, preservatives, anti-wrinkle agents, agents capable of reducing or treating lower eyelid bags, keratolytic agents, antimicrobial agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and / or are capable of inhibiting or preventing their degradation, agents that stimulate elastin synthesis, agents that stimulate the synthesis of decorin, agents that stimulate the synthesis of laminin, agents that stimulate the synthesis of defensins, agents that stimulate the synthesis of chaperone proteins, agents that stimulate cAMP synthesis, agents that stimulate hyaluronic acid synthesis, agents that stimulate fibronectin synthesis, agents that stimulate deacetylase synthesis, agents that stimulate the synthesis of lipids and stratum corneum components, ceramides, fatty acids, agents that inhibit collagen degradation, agents that inhibit elastin degradation, agents that inhibit serine proteases, agents that stimulate fibroblast proliferation, agents that stimulate keratinocyte proliferation, agents that stimulate adipocyte proliferation, agents that stimulate melanocyte proliferation, agents that stimulate keratinocyte differentiation, agents that inhibit acetylcholinesterase, skin relaxants, agents that stimulate glycosaminoglycan synthesis, antihyperkeratotic agents, comedolytic agents, antipsoriatic agents, anti-eczema agents, DNA repair agents, DNA protectants, stabilizers, antipruritic agents, agents for treating and / or caring for sensitive skin, curing agents, firming agents, restructuring agents, anti-stretch mark agents, agents that regulate sebum production, antiperspirants, agents that stimulate healing, agents that assist healing, agents that stimulate re-epithelialization, agents that assist re-epithelialization, cytokines, sedatives, anti-inflammatory agents, agents acting on capillary circulation and / or microcirculation, angiogenesis stimulants, agents that inhibit vascular permeability, venotonic agents, agents acting on cell metabolism, agents for improving the dermal-epidermal junction, hair growth inducers, hair growth inhibitors or retardants, fragrances, chelating agents, plant extracts, essential oils, marine extracts, agents obtained from biological fermentation processes, inorganic salts, cell extracts, sunscreens, and organic or inorganic light protectants that are effectively resistant to UVA and / or UVB or mixtures thereof.

[0023] The effective amount of the cyclic peptides of the present disclosure to be administered and their dosages will depend on a number of factors, including age, the condition of the user, the severity of the condition, the route and frequency of administration, and the specific nature of the cyclic peptides to be used.

[0024] "Effective amount" means an amount of one or more cyclic peptides of the present disclosure that is non-toxic but sufficient to provide the desired effect. The cyclic peptides of the present disclosure are used at an effective concentration in the composition to obtain the desired effect. In some embodiments, the concentration is between 0.00000001% (by weight) and 20% (by weight) relative to the total weight of the composition; in some embodiments, the concentration is between 0.000001% (by weight) and 15% (by weight) relative to the total weight of the composition; in some embodiments, the concentration is between 0.0001% (by weight) and 10% (by weight) relative to the total weight of the composition; in some embodiments, the concentration is between 0.0001% (by weight) and 5% (by weight) relative to the total weight of the composition.

[0025] Another aspect of the present disclosure provides a delivery system or sustained release system for better penetration of the active ingredient, which comprises an effective amount of the cyclic peptide represented by the above formula (I), or its stereoisomer, or a mixture of its stereoisomers, or its salt, or the above composition.

[0026] The term "delivery system" refers to a diluent, adjuvant, excipient or carrier administered together with the cyclic peptides of the present disclosure, which are selected from: water, oils or surfactants, including those of petroleum origin, animal origin, plant origin, or synthetic origin, such as and not limited to peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glucosides, maltosides, fatty alcohols, nonoxynols, poloxamers, polyethylene oxides, polyethylene glycols, dextrans, glycerols, digitonin and the like. Diluents that can be used in different delivery systems in which the cyclic peptides of the present disclosure can be administered are known to those of ordinary skill in the art.

[0027] The term "sustained release" is used in its conventional meaning and refers to a delivery system of a compound that provides for the gradual release of the compound over a period of time. In some embodiments, the sustained release system has a relatively constant level of compound release over the entire time period.

[0028] Examples of delivery systems or sustained release systems include, but are not limited to: liposomes, oleosomes, ethosomes, millicapsules, microcapsules, nanocapsules, nanostructured lipid carriers, sponges, inclusion complexes, niosomes, micelles, millispheres, microspheres, nanospheres, lipid spheres, microemulsions, nanoemulsions, milliparticles, microparticles or nanoparticles.

[0029] On the other hand, the present disclosure provides a cosmetic comprising an effective amount of the cyclic peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or the above composition, or the above delivery system or sustained-release system.

[0030] In some embodiments, the dosage form of the cosmetic includes paste, cream, emulsion, aqueous solution, oil, gel, powder, tablet, mud, patch, film, aerosol, spray, freeze-dried preparation or nano-preparation.

[0031] On the other hand, the present disclosure provides the use of the cyclic peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or the above composition, or the above delivery system or sustained-release system in the preparation of a composition for caring for or treating the skin or mucous membrane.

[0032] On the other hand, the present disclosure provides the use of the cyclic peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or the above composition, or the above delivery system or sustained-release system in the preparation of a composition for anti-aging, repair, moisturizing or soothing.

[0033] On the other hand, the present disclosure provides the use of the cyclic peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or the above composition, or the above delivery system or sustained-release system in the preparation of a composition for whitening, brightening skin color, removing skin spots and / or eliminating uneven skin tone.

[0034] On the other hand, the present disclosure provides the use of the cyclic peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or the above composition, or the above delivery system or sustained-release system in the preparation of a composition for inhibiting elastase activity, or in the preparation of a composition for promoting collagen production, or in the preparation of a composition for increasing skin elasticity and / or improving skin firmness, or in the preparation of a composition for promoting the regeneration or healing of the skin or mucous membrane, or in the preparation of a composition for repairing the skin barrier, or in the preparation of a composition for inhibiting hyaluronidase activity, or in the preparation of a composition for inhibiting tyrosinase activity, or in the preparation of a composition for inhibiting melanin production.

[0035] On the other hand, the present disclosure provides the use of the cyclic peptide represented by the above formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a salt thereof, or the above composition, or the above delivery system or sustained-release system in the preparation of a sunscreen.

[0036] Another aspect of the present disclosure provides the use of the cyclic peptide represented by the above formula (I), or its stereoisomer, or a mixture of its stereoisomers, or its salt, or the above composition, or the above delivery system or sustained-release system in the preparation of cosmetics.

[0037] In the present disclosure, the term "skin" should be understood to refer to the multiple layers that make it up, from the outermost layer or stratum corneum to the innermost layer or subcutaneous tissue, including both endpoints. These layers are composed of different types of cells, such as keratinocytes, fibroblasts, melanocytes, and / or adipocytes, etc. In the present disclosure, the term "skin" includes the scalp.

[0038] The term "caring for the skin" refers to maintaining and nourishing the skin, improving the state of the skin, and making the skin delicate, smooth, tender, and healthy.

[0039] The present disclosure has the following advantages and effects:

[0040] 1. The cyclic peptide of the present disclosure can inhibit elastase activity, promote collagen production, increase skin elasticity, improve skin firmness, promote the regeneration or healing of the skin or mucosa, inhibit hyaluronidase activity, repair the skin barrier, and can also inhibit tyrosinase activity, inhibit melanin production, brighten skin color, fade skin spots, and eliminate uneven skin tone, having multiple effects such as anti-aging, repair, moisturizing, soothing, and whitening.

[0041] 2. The cyclic peptide of the present disclosure is obtained by head-to-tail cyclization through a condensation reaction of the free amino group at the N-terminus and the free carboxyl group at the C-terminus of the linear peptide GHKK. However, compared with the linear peptide GHKK, the cyclic peptide of the present disclosure has achieved unexpected technical effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the technical solutions of the present disclosure, the drawings required for the description of the present disclosure will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present disclosure. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0043] Figure 1 is the mass spectrometry diagram of the cyclic peptide ACyclo-[Gly-His-Lys-Lys].

[0044] Figure 2 is the result diagram of the effect of the test sample on the content of collagen I.

[0045] Figure 3 is the result diagram of the effect of the test sample on the content of collagen III. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0046] To make the objectives, features, and advantages of the present disclosure more apparent and understandable, the present disclosure will be further described in detail below with reference to the accompanying drawings and embodiments. Obviously, the described embodiments are some, but not all, of the embodiments of the present disclosure. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present disclosure without creative efforts fall within the scope protected by the appended claims of the present disclosure.

[0047] In the present disclosure, the abbreviations for amino acids follow the rules specified by the IUPAC-IUB Commission of Biochemical Nomenclature in the European Journal of Biochemistry (Eur. J. Biochem. 1984, 138: 9-37).

[0048] Unless otherwise specified, the experimental reagents and materials used in the present disclosure can be obtained commercially. The following are the abbreviations for some reagents and materials:

[0049] 2-CTC Resin: An initial resin for polypeptide synthesis (2-chlorotrityl chloride resin); DMF: N,N-dimethylformamide; DCM: Dichloromethane; DIPEA: Diisopropylethylamine; MeOH: Methanol; piperidine: Piperidine; HOBt: 1-Hydroxybenzotriazole; DIC: Diisopropylcarbodiimide; TFA: Trifluoroacetic acid; HBTU: Benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate; TIS: Triisopropylsilane; Gly: Glycine; His: Histidine; Lys: Lysine; Fmoc: 9-Fluorenylmethoxycarbonyl; Trt: Trityl; Boc: tert-Butoxycarbonyl.

[0050] Example 1 Preparation of Cyclo-[Gly-His-Lys-Lys]

[0051] 1.1 Swelling of the resin

[0052] Weigh 10 g of 2-CTC Resin into a solid-phase synthesis reaction column, swell it with DCM, wash the resin, and draw off the solvent.

[0053] 1.2 Feeding reaction

[0054] Weigh 11 g of Fmoc-Lys(Boc)-OH and 11.2 mL of DIPEA, add them to the swollen resin, react for 3 h, draw off the reaction solution, wash the resin, and draw off the solvent. Then continue to add DCM, MeOH, and DIPEA for capping treatment for 30 min, wash the resin, and draw off the solvent. Obtain Fmoc-Lys(Boc)-2-CTC Resin.

[0055] The Fmoc group of Fmoc-Lys(Boc)-2-CTC Resin was deprotected twice with 20% piperidine / DMF for 10 minutes each time. Samples were taken for K test, and the color developed was dark blue. The resin was washed 7 times with DMF, and the solvent was removed by suction.

[0056] Weigh 11 g of Fmoc-Lys(Boc)-OH and 3.5 g of HOBt, add them to a dry Erlenmeyer flask, dissolve them with DMF, seal it and place it in a -18°C refrigerator for 30 minutes. Add 4.3 mL of DIC and activate for 7 minutes, avoiding water vapor. Add the activated amino acid to the deprotected resin and react for 3 hours. The reaction solution was removed by suction. The resin being colorless and transparent in the K test indicates that the reaction is complete.

[0057] Deprotect the N-terminal Fmoc group, and in the presence of 3.5 g of HOBt and 4.3 mL of DIC, use DMF as the solvent to couple 14.5 g of activated Fmoc-His(Trt)-OH to the peptide resin, and continue the reaction for 4 hours. Then wash these resins and repeat the deprotection process of the Fmoc group to couple the next amino acid. In the presence of 3.5 g of HOBt and 4.3 mL of DIC, use DMF as the solvent to continue coupling 7 g of Fmoc-Gly-OH. After the reaction is complete, wash the resin and remove the solvent by suction.

[0058] Deprotect the N-terminal Fmoc group of the peptide resin, deprotect Fmoc twice with 20% piperidine / DMF for 10 minutes each time. Samples were taken for K test, and the color developed was dark blue. The resin was washed 6 times with DMF, and the solvent was removed by suction. After shrinking and drying, 5 g of H-Gly-His(Trt)-Lys(Boc)-Lys(Boc)-2-CTC Resin was obtained.

[0059] 1.3 Deproteinization of resin

[0060] Measure 1 mL of TFA and 99 mL of DCM, mix and stir evenly to obtain a cleavage solution.

[0061] Weigh 5 g of H-Gly-His(Trt)-Lys(Boc)-Lys(Boc)-2-CTC Resin, add it to a round-bottom flask, add the above cleavage solution, and stir and react for 0.5 hours. Filter by suction, collect the filtrate, and evaporate to dryness to obtain 3.2 g of H-Gly-His(Trt)-Lys(Boc)-Lys(Boc)-OH.

[0062] 1.4 Cyclization

[0063] Weigh 3.2 g of H-Gly-His(Trt)-Lys(Boc)-Lys(Boc)-OH and dissolve it in 200 mL of DCM. Then add 1.6 g of HBTU and 0.6 g of DIPEA, and react for 12 h. Monitor by HPLC until the reaction is complete. Add pure water to the reaction solution for extraction three times, and rotary evaporate the aqueous phase to obtain 5 g of oily Cyclo-[Gly-His(Trt)-Lys(Boc)-Lys(Boc)].

[0064] 1.5 Cleavage (deprotection of protecting groups)

[0065] Measure 23 mL of TFA, 0.62 mL of TIS and 0.62 mL of water, mix them evenly, add the above-mentioned Cyclo-[Gly-His(Trt)-Lys(Boc)-Lys(Boc)], and stir well for 2 h. Then filter, precipitate solids, and wash with isopropyl ether four times to obtain 1 g of crude Cyclo-[Gly-His-Lys-Lys] cyclic peptide.

[0066] 1.6 Purification

[0067] Weigh 1 g of the crude Cyclo-[Gly-His-Lys-Lys] cyclic peptide and dissolve it in pure water. Filter it through a microporous filter membrane with a pore size of 0.45 μm to obtain a clear and transparent solution, and purify it by reverse-phase HPLC. The purification gradient is as follows:

[0068] Time (min) Flow rate (mL / min) A% (acetonitrile) B% (pure water) 0 40 0 100 8 40 0 100 18 40 5 95 20 40 20 80 25 40 20 80 27 40 0 100 35 40 0 100

[0069] Inject the filtered sample for purification, collect the fractions, concentrate and lyophilize to obtain Cyclo-[Gly-His-Lys-Lys] with a purity of 95.22%, denoted as cyclic peptide A.

[0070] Determine its molecular weight by ESI-MS. The test results of cyclic peptide A are shown in Figure 1 , and the results show that the mass-to-charge ratio (m / z) of the [M+H] + ion peak is 451.84, and the molecular weight measured by mass spectrometry is 450.84.

[0071] The linear peptide H-Gly-His-Lys-Lys-OH can be obtained by a similar preparation method.

[0072] Example 2 Determination of collagen I content

[0073] 2.1 Reagents and materials

[0074] Fetal bovine serum, DMEM medium, phosphate buffer (PBS), trypsin, RIPA lysis buffer, collagen I ELISA kit, BCA protein kit.

[0075] 2.2 Instruments

[0076] Microplate reader, CO2 incubator, laminar flow hood.

[0077] 2.3 Cell lines

[0078] Human skin fibroblasts (HSF).

[0079] 2.4 Samples to be tested

[0080] Sample group: Cyclic peptide A, linear peptide (GHKK), both at a test concentration of 25 ppm;

[0081] Blank control group: PBS;

[0082] UV group: UV radiation, with PBS added.

[0083] 2.5 Experimental methods

[0084] Take HSF fibroblasts in the exponential growth phase with good condition, add 0.25% trypsin digestion solution, digest until the adherent cells detach, count (1 - 4)×10 5 cells / mL, and make a cell suspension.

[0085] Inoculate the diluted cell suspension on a 12 - well plate and culture for 24 h. When the cells grow to about 80%, establish a UV photo - aging model. The blank control group adds 200 μL PBS and supplements the medium to 800 μL without UV irradiation; for the UV group and the sample group, after adding an appropriate amount of PBS and washing repeatedly until colorless, add 200 μL PBS, place it under a UV lamp with an intensity of 80 mJ / cm 2 for irradiation, with a distance of 15 cm between the light source and the culture flask. After irradiation, discard the PBS. The UV group adds PBS solution and medium to 800 μL, and the sample group adds medium and the sample at the relevant concentration to 800 μL. The blank control group, the UV group, and the sample group continue to incubate in a 37°C, 5% CO2 incubator for 48 h.

[0086] After the culture is completed, collect the cells, centrifuge to discard the supernatant, add RIPA lysis buffer, homogenize with a vortex mixer 3 times (30 s each time, with an interval of 3 min), centrifuge at 12000 rpm for 10 min, aspirate the supernatant, and detect according to the collagen I ELISA operation manual.

[0087] 2.6 Experimental results

[0088] Type I collagen is the most abundant collagen in the human body. It has a thick and tightly arranged bundle structure, with strong tensile strength, providing a strong support structure and support force for the skin, endowing the skin with elasticity and toughness. Therefore, increasing the content of type I collagen is of great significance for preventing aging, increasing skin elasticity and firmness. In this experiment, test samples were used to treat cells irradiated with ultraviolet rays, and the content of type I collagen in the corresponding cells was detected to determine whether the cyclic peptides disclosed in this application can promote the production of type I collagen.

[0089] The results of the effect of the test samples on the content of collagen I are shown in Figure 2 . The results showed that compared with the blank control group, the content of collagen I in the UV group was significantly reduced, indicating that the model was successfully established (## indicates P < 0.01, with significant statistical differences); compared with the UV group, cyclic peptide A could significantly increase the content of collagen I and promote the production of type I collagen (** indicates P < 0.01, with significant statistical differences); while the linear peptide failed to increase the content of collagen I, indicating that the cyclic peptide A obtained by head-to-tail cyclization in this disclosure has a new effect compared with the linear peptide before cyclization, and can significantly promote the production of type I collagen, achieving unexpected technical effects.

[0090] It can be seen from this that the cyclic peptides disclosed in this application can increase the content of collagen in cells, promote the production of collagen, thereby increasing skin elasticity, improving skin firmness, and delaying skin aging.

[0091] Example 3 Measurement of Collagen III Content

[0092] 3.1 Reagents and Materials

[0093] Fetal bovine serum, DMEM medium, phosphate buffer solution (PBS), trypsin, RIPA lysis buffer, collagen III ELISA kit, BCA protein kit.

[0094] 3.2 Instruments

[0095] Microplate reader, CO2 incubator, laminar flow hood.

[0096] 3.3 Cell Lines

[0097] Human skin fibroblasts (HSF).

[0098] 3.4 Test Samples

[0099] Sample Group: Cyclic peptide A, linear peptide (GHKK), the test concentrations are both 25 ppm and 50 ppm;

[0100] Blank Control Group: PBS;

[0101] UV Group: UV radiation, plus PBS.

[0102] 3.5 Experimental methods

[0103] Take HSF fibroblasts in good condition in the exponential growth phase, add 0.25% trypsin digestion solution, digest to make the adherent cells detached, and count (1 - 4)×10 5 cells / mL to prepare a cell suspension.

[0104] Inoculate the diluted cell suspension on a 12-well plate and culture for 24 h. When the cells grow to about 80%, establish a UV photoaging model. In the blank control group, add 200 μL PBS and supplement the medium to 800 μL without UV irradiation; in the UV group and the sample group, after adding an appropriate amount of PBS and washing repeatedly until colorless, add 200 μL PBS, and place it under a UV lamp with an intensity of 80 mJ / cm 2 for irradiation. The distance between the light source and the culture flask is 15 cm. After irradiation, discard the PBS. In the UV group, add PBS solution and medium to 800 μL, and in the sample group, add medium and samples at different concentrations to 800 μL. The blank control group, the UV group, and the sample group continue to be incubated in an incubator at 37 °C and 5% CO2 for 48 h.

[0105] After the culture is completed, collect the cells, centrifuge to discard the supernatant, add RIPA lysis buffer, homogenize with a vortex mixer 3 times (30 s each time, with an interval of 3 min), centrifuge at 12000 rpm for 10 min, aspirate the supernatant, and detect according to the operating instructions of the collagen III ELISA.

[0106] 3.6 Experimental results

[0107] Type III collagen belongs to the collagen that forms fibers and is mainly present at the junction of the dermis and the epidermis. It provides elasticity and stress resistance to the skin. At the same time, it can repair damaged type I collagen and stimulate the regeneration of type I collagen, having a good effect on promoting repair and healing. Therefore, increasing the content of type III collagen is of great significance for tightening the skin and repairing damaged skin. In this experiment, cells irradiated with ultraviolet rays were treated with the test sample, and the content of type III collagen in the corresponding cells was detected to determine whether the cyclic peptides of the present disclosure can promote the production of type III collagen.

[0108] The results of the influence of the test sample on the content of collagen III are shown in Figure 3 . The results show that compared with the blank control group, the content of collagen III in the UV group was significantly reduced, indicating that the model was successfully established (## indicates P < 0.01, with significant statistical differences); compared with the UV group, cyclic peptide A could significantly increase the content of collagen III and promote the production of type III collagen (* indicates P < 0.05, with statistical differences), while the linear peptide could not increase the content of collagen III, indicating that the cyclic peptide A of the present disclosure achieved unexpected technical effects compared with the linear peptide before cyclization.

[0109] It can be seen from this that the cyclic peptides of the present disclosure can increase the collagen content in cells, promote collagen production, thereby increasing skin elasticity and improving skin firmness. They can also repair the skin or mucous membranes, promote the regeneration or healing of the skin or mucous membranes, and have the effects of anti-aging and repair.

[0110] Example 4 Elastase Inhibition Experiment

[0111] 4.1 Reagents and Materials

[0112] PBS, elastase solution, AAAPAN (N-succinyl-alanine-alanine-alanine-p-nitroaniline) solution.

[0113] 4.2 Instruments

[0114] Microplate reader, electronic balance.

[0115] 4.3 Test Samples and Grouping

[0116] 4.3.1 Test Samples

[0117] Cyclic peptide A, linear peptide (GHKK), with test concentrations both being 10 ppm.

[0118] 4.3.2 Grouping

[0119] Sample group: test sample, PBS, elastase, AAAPAN;

[0120] Sample zero adjustment group: test sample, PBS, AAAPAN;

[0121] Blank control group: PBS, elastase, AAAPAN;

[0122] Blank zero adjustment group: PBS, AAAPAN.

[0123] 4.4 Experimental Method

[0124] Take a 96-well plate. Add 85 μL of PBS, 15 μL of the test sample, and 25 μL of the elastase solution (2 mg / mL) to the sample group; add 110 μL of PBS and 15 μL of the test sample to the sample zero adjustment group; add 100 μL of PBS and 25 μL of the elastase solution (2 mg / mL) to the blank control group; add 125 μL of PBS to the blank zero adjustment group. Incubate at 25 °C for 15 min, then add 25 μL of the AAAPAN solution (1.015 mmol / L) to each well, and incubate at 25 °C for 15 min. Measure the OD 410 value.

[0125]

[0126] In the formula: A1 is the OD of the sample zero - adjustment group 410 value, A2 is the OD of the sample group 410 value, A3 is the OD of the blank zero - adjustment group 410 value, A4 is the OD of the blank control group 410 value.

[0127] 4.5 Experimental results

[0128] Elastase has the ability to degrade various proteins such as collagen and elastin. Elastin in the skin is closely related to skin aging. Therefore, inhibiting the activity of elastase and reducing its degradation of elastin are of great significance for restoring skin elasticity and delaying skin aging. AAAPAN is a substrate of elastase and will be decomposed under the catalytic action of elastase. The decomposition product will absorb visible light with a wavelength of 410 nm. In this experiment, the test sample was used to treat elastase, and by detecting the reaction amount of AAAPAN, it was determined whether the cyclic peptide of the present disclosure could inhibit the activity of elastase. The inhibition rate results of the test sample on the activity of elastase are shown in Table 1.

[0129] Table 1 Inhibition rate of the test sample on the activity of elastase (n = 3)

[0130] Concentration Cyclic peptide A Linear peptide 10 ppm 30.4％ 16.1％

[0131] The results show that at a low concentration of 10 ppm, the inhibition rate of the cyclic peptide A of the present disclosure on the activity of elastase is 30.4%, while the inhibition rate of the linear peptide on the activity of elastase is only 16.1%. At the same concentration, the elastase inhibition rate of the cyclic peptide A of the present disclosure is significantly higher than that of the linear peptide, indicating that the cyclic peptide A obtained by head - to - tail cyclization in the present disclosure has better technical effects than the linear peptide before cyclization, and its ability to inhibit the activity of elastase has been significantly improved.

[0132] It can be seen that the cyclic peptide of the present disclosure has excellent ability to inhibit the activity of elastase. By inhibiting the activity of elastase, the decomposition of elastin is reduced, the skin elasticity is increased and / or the skin firmness is improved, and skin problems such as skin relaxation and wrinkles are improved, achieving the effects of anti - aging, firming and wrinkle removal.

[0133] Example 5 Hyaluronidase inhibition experiment

[0134] 5.1 Reagents and materials

[0135] Sodium acetate buffer solution (pH = 5.6), hyaluronidase, calcium chloride, sodium hyaluronate, acetylacetone, absolute ethanol, sodium carbonate, P - DAB (prepared by uniformly mixing 0.8 g of p - dimethylaminobenzaldehyde, 15 mL of concentrated hydrochloric acid and an equal amount of glacial acetic acid).

[0136] 5.2 Instruments

[0137] Microplate reader, electronic balance.

[0138] 5.3 Samples to be measured and grouping

[0139] 5.3.1 Samples to be measured

[0140] Cyclic peptide A, linear peptide (GHKK), with a test concentration of 500 ppm for both.

[0141] 5.3.2 Grouping

[0142] Sample group: Samples to be measured, hyaluronidase, sodium hyaluronate;

[0143] Sample zero adjustment group: Samples to be measured, sodium acetate buffer;

[0144] Blank control group: Distilled water, hyaluronidase, sodium hyaluronate;

[0145] Blank zero adjustment group: Distilled water, sodium acetate buffer.

[0146] 5.4 Experimental method

[0147] Both hyaluronidase and sodium hyaluronate are dissolved in sodium acetate buffer.

[0148] Take a 96-well plate. Add 25 μL of the sample to be measured and 25 μL of hyaluronidase (1000 U / mL) to the sample group; add 25 μL of the sample to be measured and 25 μL of sodium acetate buffer to the sample zero adjustment group; add 25 μL of distilled water and 25 μL of hyaluronidase (1000 U / mL) to the blank control group; add 25 μL of distilled water and 25 μL of sodium acetate buffer to the blank zero adjustment group. After placing it in a 37°C constant temperature air bath and shaking for 20 min, add 5 μL of calcium chloride solution (2.5 mol / L) to each well, and then place it in a 37°C constant temperature air bath and shake for 20 min. Add 25 μL of sodium hyaluronate (1 mg / mL) to the sample group and the blank control group, add 25 μL of sodium acetate buffer to the sample zero adjustment group and the blank zero adjustment group, place it in a 37°C constant temperature air bath and shake for 40 min, and then let it stand at room temperature for 10 min. Add 25 μL of distilled water, 5 μL of sodium hydroxide solution (5 mol / L), and 25 μL of acetylacetone solution to each well, place it in a 90°C oven for 15 min, then ice bath for 10 min, and finally let it stand at room temperature for 10 min. Add 50 μL of P-DAB to each well, then add 100 μL of absolute ethanol, let it stand at room temperature for 30 min, and measure the OD 570 value.

[0149]

[0150] Where: A1 is the OD of the sample zero adjustment group 570Value, A2 is the OD of the sample group 570 Value, A3 is the OD of the blank zeroing group 570 Value, A4 is the OD of the blank control group 570 Value.

[0151] 5.5 Experimental results

[0152] Hyaluronidase can decompose hyaluronic acid in the body, turning it into a low-molecular-weight acidic stimulant, thereby causing histamine release and inducing sensitive symptoms in the body. In addition, the reduction of hyaluronic acid will damage the skin barrier function, resulting in water loss inside the skin. Therefore, inhibiting the activity of hyaluronidase can achieve the effects of soothing, moisturizing, and repairing the skin barrier. In this experiment, the test sample was used to treat hyaluronidase, and by detecting the reaction amount of sodium hyaluronate, it was determined whether the cyclic peptide of the present disclosure could inhibit the activity of hyaluronidase. The results of the inhibition rate of the test sample on the activity of hyaluronidase are shown in Table 2.

[0153] Table 2 Inhibition rate of the test sample on the activity of hyaluronidase (n = 3)

[0154] Concentration Cyclic peptide A Linear peptide 500 ppm 74.4％ 42.5％

[0155] The results show that at a concentration of 500 ppm, the inhibition rate of the cyclic peptide A of the present disclosure on the activity of hyaluronidase is as high as 74.4%, while the inhibition rate of the linear peptide on the activity of hyaluronidase is 42.5%. At the same concentration, the hyaluronidase inhibition rate of the cyclic peptide A of the present disclosure is significantly higher than that of the linear peptide, indicating that the cyclic peptide A obtained by head-to-tail cyclization in the present disclosure has better technical effects compared to the linear peptide before cyclization, and its ability to inhibit the activity of hyaluronidase has been significantly improved.

[0156] It can be seen from this that the cyclic peptide of the present disclosure can inhibit the activity of hyaluronidase and play the role of soothing, moisturizing, and repairing the skin barrier.

[0157] Example 6 Mushroom tyrosinase inhibition experiment

[0158] 6.1 Reagents and materials

[0159] PBS, mushroom tyrosinase, L-DOPA (L-DOPA).

[0160] 6.2 Instruments

[0161] Constant temperature water bath, microplate reader.

[0162] 6.3 Test samples and grouping

[0163] 6.3.1 Test samples

[0164] Cyclic peptide A, linear peptide (GHKK), the test concentrations are both 200 ppm and 500 ppm.

[0165] 6.3.2 Grouping

[0166] Sample group: sample to be tested, tyrosinase, PBS, L-DOPA;

[0167] Sample zero-adjustment group: sample to be tested, PBS, L-DOPA;

[0168] Blank control group: PBS, tyrosinase, L-DOPA;

[0169] Blank zero-adjustment group: PBS, L-DOPA.

[0170] 6.4 Experimental Method

[0171] Take a 96-well plate. Add 50 μL of the sample to be tested and 50 μL of tyrosinase (final concentration 25 U / mL) to the sample group; add 50 μL of the sample to be tested and 50 μL of PBS to the sample zero-adjustment group; add 50 μL of PBS and 50 μL of tyrosinase (final concentration 25 U / mL) to the blank control group; add 100 μL of PBS to the blank zero-adjustment group. Incubate at 37 °C for 5 min. Then add 50 μL of PBS and 50 μL of L-DOPA (final concentration 0.5 mmol / L) to each well, and incubate at 37 °C for 10 min. Measure the OD 475 value at 475 nm, and calculate the tyrosinase inhibition rate.

[0172]

[0173] In the formula: A1 is the OD 475 value of the sample zero-adjustment group, A2 is the OD 475 value of the sample group, A3 is the OD 475 value of the blank zero-adjustment group, A4 is the OD 475 value of the blank control group.

[0174] 6.5 Experimental Results

[0175] The results of the inhibition rate of the test sample on tyrosinase activity are shown in Table 3.

[0176] Table 3 Inhibition rate of the test sample on tyrosinase activity (n = 3)

[0177]

[0178] The results showed that the linear peptide basically had no effect on the activity of tyrosinase, while cyclic peptide A could significantly inhibit the activity of tyrosinase at the same concentration. The inhibition rate of cyclic peptide A on tyrosinase activity was 11.7% at a concentration of 200 ppm, and further increased to 16.0% at a concentration of 500 ppm. This shows that compared with the linear peptide before cyclization, the cyclic peptide A of the present disclosure has a new effect, can inhibit the activity of tyrosinase, and achieves unexpected technical effects.

[0179] It can be seen therefrom that the cyclic peptide of the present disclosure can inhibit the activity of tyrosinase, reduce the production of melanin, can be used to brighten skin color, fade freckles or eliminate uneven skin tone, achieve the effect of whitening and freckle removal, can be used in products for whitening and freckle removal, and can also be used to prepare sunscreen agents.

[0180] Example 7 An essence containing cyclic peptide A

[0181]

[0182] Preparation method: According to the formula dosage, add the materials in phase A to the stirring pot, stir and heat to 80 - 85 °C; mix the materials in phase B evenly until there are no powder particles, add them to the stirring pot, and continue to stir for 10 - 15 min; start to cool down, cool down to 60 - 65 °C, and add the materials in phase C; cool down to 35 - 40 °C, add the materials in phase D and phase E, and stir for 10 - 15 min to obtain the product.

[0183] Example 8 A cream containing cyclic peptide A

[0184]

[0185]

[0186] Preparation method: According to the formula dosage, heat the materials in phase D in a suitable container to 55 - 60 °C and dissolve them completely for standby; add the materials in phase A to the stirring pot and stir and heat to 80 - 85 °C; add the materials in phase B to the oil phase pot, stir and heat to 75 - 80 °C until completely dissolved and transparent; put phase B into phase A, turn on the vacuum, homogenize for 5 min, maintain stirring, and keep warm for 20 min; start to cool down, cool down to 60 - 65 °C, add the materials in phase C and the pre-dissolved materials in phase D, and homogenize for 2 min; cool down to 35 - 40 °C, add the materials in phase E, and stir for 10 - 15 min to obtain the product.

[0187] In this disclosure, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprising", "including" or any other variant thereof are intended to cover non-exclusive inclusion, such that a process, method, article or terminal device comprising a series of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article or terminal device. Without further limitation, an element defined by the phrase "comprising an..." does not exclude the presence of additional identical elements in the process, method, article or terminal device comprising the element.

[0188] Although specific embodiments of the present disclosure have been described for purposes of illustrative explanation, those skilled in the art can make various modifications or improvements without departing from the spirit and scope of the present disclosure. These modifications or improvements shall fall within the scope of the appended claims of the present disclosure.

Claims

1. A cyclic peptide or a salt thereof, characterized in that, The cyclic peptide has the structure shown in formula (I): Cyclo-[Gly-His-Lys-Lys] (I).

2. The cyclic peptide shown in formula (I) according to claim 1 or a salt thereof, characterized in that the salt includes a metal salt of the cyclic peptide shown in formula (I), and the metal includes: lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum; alternatively, the salt includes a salt formed by the cyclic peptide shown in formula (I) and an organic base, and the organic base includes: ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine; alternatively, the salt includes a salt formed by the cyclic peptide shown in formula (I) and an inorganic acid or an organic acid, and the organic acid includes: acetic acid, citric acid, lactic acid, malonic acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, aspartic acid, glutamic acid, succinic acid, oleic acid, trifluoroacetic acid, oxalic acid, pamoic acid or gluconic acid; the inorganic acid includes: hydrochloric acid, sulfuric acid, boric acid or carbonic acid.

3. A composition, characterized in that, Comprising an effective amount of the cyclic peptide shown in formula (I) according to claim 1 or 2 or a salt thereof, and at least one excipient and optionally an adjuvant.

4. The composition according to claim 3, wherein The adjuvant is selected from: analgesics, agents that inhibit PAR-2 activity, collagen synthesis stimulants, agents that regulate PGC-1α synthesis, agents that regulate the activity of PPARγ, agents that increase or decrease the triglyceride content of adipocytes, agents that stimulate or delay adipocyte differentiation, lipolytic agents or agents that stimulate lipolysis, lipolytic solvents, lipogenic agents, inhibitors of acetylcholine receptor aggregation, agents that inhibit muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloproteinase inhibitors, melanin synthesis stimulants or inhibitors, whitening agents or decolorizing agents, pigmentation promoters, self-tanning agents, anti-aging agents, NO-synthase inhibitors, 5α-reductase inhibitors, inhibitors of lysyl hydroxylase and / or prolyl hydroxylase, antioxidants, free radical scavengers and / or agents against air pollution, reactive carbonyl species scavengers, anti-glycation agents, antihistamines, antiviral agents, anti-parasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, moisture-retaining substances, α-hydroxy acids, β-hydroxy acids, humectants, epidermal hydrolases, vitamins, amino acids, proteins, pigments, dyes, biopolymers, gum polymers, thickeners, surfactants, softeners, adhesives, preservatives, anti-wrinkle agents, agents capable of reducing or treating lower eyelid bags, keratolytic agents, anti-microbial agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and / or are capable of inhibiting or preventing their degradation, agents that stimulate elastin synthesis, agents that stimulate the synthesis of decorin, agents that stimulate the synthesis of laminin, agents that stimulate the synthesis of defensins, agents that stimulate the synthesis of chaperone proteins, agents that stimulate cAMP synthesis, agents that stimulate hyaluronic acid synthesis, agents that stimulate fibronectin synthesis, agents that stimulate deacetylase synthesis, agents that stimulate the synthesis of lipids and stratum corneum components, ceramides, fatty acids, agents that inhibit collagen degradation, agents that inhibit elastin degradation, agents that inhibit serine proteases, agents that stimulate fibroblast proliferation, agents that stimulate keratinocyte proliferation, agents that stimulate adipocyte proliferation, agents that stimulate melanocyte proliferation, agents that stimulate keratinocyte differentiation, agents that inhibit acetylcholinesterase, skin relaxants, agents that stimulate glycosaminoglycan synthesis, anti-hyperkeratotic agents, comedolytic agents, anti-psoriatic agents, anti-eczema agents, DNA repair agents, DNA protectants, stabilizers, antipruritic agents, agents for treating and / or caring for sensitive skin, curing agents, firming agents, restructuring agents, anti-stretch mark agents, agents that regulate sebum production, antiperspirants, agents that stimulate healing, agents that assist in healing, agents that stimulate re-epithelialization, agents that assist in re-epithelialization, cytokines, sedatives, anti-inflammatory agents, agents that act on capillary circulation and / or microcirculation, agents that stimulate angiogenesis, agents that inhibit vascular permeability, venotonic agents, agents that act on cell metabolism, agents for improving the dermal-epidermal junction, agents that induce hair growth, hair growth inhibitors or retardants, fragrances, chelating agents, plant extracts, essential oils, marine extracts, agents obtained from biological fermentation processes, inorganic salts, cell extracts, sunscreens, and organic or inorganic light protectants that are effectively resistant to ultraviolet A and / or B or mixtures thereof.

5. A delivery system or sustained release system, characterized in that, Comprising an effective amount of the cyclic peptide of formula (I) as claimed in claim 1 or 2 or a salt thereof, or the composition as claimed in claim 3 or 4; The delivery system or sustained release system includes: liposomes, oleosomes, ethosomes, millimeter capsules, micron capsules, nano capsules, nanostructured lipid carriers, sponges, inclusion compounds, niosomes, micelles, lipid spheres, microemulsions, nanoemulsions, millimeter particles, micron particles or nanoparticles.

6. A cosmetic, characterized in that, Comprising an effective amount of the cyclic peptide of formula (I) as claimed in claim 1 or 2 or a salt thereof, or the composition as claimed in claim 3 or 4, or the delivery system or sustained release system as claimed in claim 5.

7. The cosmetic according to claim 6, characterized in that, The dosage forms of the cosmetics include ointments, creams, emulsions, aqueous solutions, oils, gels, powders, tablets, muds, patches, films, aerosols, sprays, freeze-dried preparations or nano preparations.

8. Use of the cyclic peptide of formula (I) as claimed in claim 1 or 2 or a salt thereof, or the composition as claimed in claim 3 or 4, or the delivery system or sustained release system as claimed in claim 5 in the preparation of a composition for nursing or treating skin or mucous membranes.

9. Use of the cyclic peptide of formula (I) as claimed in claim 1 or 2 or a salt thereof, or the composition as claimed in claim 3 or 4, or the delivery system or sustained release system as claimed in claim 5 in the preparation of a composition for anti-aging, repair, moisturizing or soothing.

10. The use according to claim 9, characterized in that, The anti-aging includes inhibiting elastase activity.

11. The use according to claim 9, characterized in that, The soothing includes inhibiting hyaluronidase activity.

12. Use of the cyclic peptide of formula (I) as claimed in claim 1 or 2 or a salt thereof, or the composition as claimed in claim 3 or 4, or the delivery system or sustained release system as claimed in claim 5 in the preparation of a composition for whitening, brightening skin color, removing age spots and / or eliminating uneven skin tone.

13. The use according to claim 12, wherein The whitening includes inhibiting tyrosinase activity.

14. Use of the cyclic peptide of formula (I) as claimed in claim 1 or 2 or a salt thereof, or the composition as claimed in claim 3 or 4, or the delivery system or sustained release system as claimed in claim 5 in the preparation of a composition for promoting collagen production, or in the preparation of a composition for increasing skin elasticity and / or improving skin firmness, or in the preparation of a composition for promoting the regeneration or healing of skin or mucous membranes, or in the preparation of a composition for repairing the skin barrier, or in the preparation of a composition for inhibiting melanogenesis.

15. Use of the cyclic peptide of formula (I) as claimed in claim 1 or 2 or a salt thereof, or the composition as claimed in claim 3 or 4, or the delivery system or sustained release system as claimed in claim 5 in the preparation of a sunscreen.

16. Use of the cyclic peptide of formula (I) as claimed in claim 1 or 2 or a salt thereof, or the composition as claimed in claim 3 or 4, or the delivery system or sustained release system as claimed in claim 5 in the preparation of cosmetics.

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