WO2023123479A1 - 一种六肽及其美容组合物或药用组合物和用途 - Google Patents

一种六肽及其美容组合物或药用组合物和用途 Download PDF

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WO2023123479A1
WO2023123479A1 PCT/CN2021/143978 CN2021143978W WO2023123479A1 WO 2023123479 A1 WO2023123479 A1 WO 2023123479A1 CN 2021143978 W CN2021143978 W CN 2021143978W WO 2023123479 A1 WO2023123479 A1 WO 2023123479A1
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phe
agents
agent
acid
optionally
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PCT/CN2021/143978
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English (en)
French (fr)
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丁文锋
彭晏
陈雪
赵文豪
孙新林
黄春青
观富宜
肖玉
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深圳市维琪科技股份有限公司
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Priority to PCT/CN2021/143978 priority Critical patent/WO2023123479A1/zh
Priority to CN202180095341.XA priority patent/CN116964071A/zh
Publication of WO2023123479A1 publication Critical patent/WO2023123479A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention relates to a hexapeptide, a cosmetic composition or a pharmaceutical composition containing these peptides and its application.
  • the skin can protect internal organs from ultraviolet radiation, physical and chemical damage and microbial invasion, prevent the loss of water, electrolytes and nutrients in the body, and participate in maintaining the normal physiological functions of the body.
  • UV radiation, physical and chemical damage, and microbial invasion can damage the barrier function of the skin to a certain extent, causing damage to skin tissue cells and triggering an inflammatory response, causing acute reactions such as redness, pain, and burning.
  • the skin barrier function is weak, the skin will be extremely sensitive to external stimuli, and any slight stimulation may cause facial telangiectasia and hyperplasia, leading to skin stress congestion and blood stasis, resulting in skin pores and capillaries Vascular necrosis, local reactions such as allergies and ulcers occur, and the fur and toxins are fused together or left on the human skin, causing chronic inflammation and allergic skin diseases.
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-6 IL-8
  • tumor necrosis factor TNF- ⁇ tumor necrosis factor- ⁇
  • IL-6 is synthesized and released by fibroblasts, endothelial cells, monocytes, keratinocytes and T lymphocytes.
  • fibroblasts fibroblasts
  • endothelial cells fibroblasts
  • monocytes monocytes
  • keratinocytes and T lymphocytes.
  • T lymphocytes tumor necrosis factor
  • IL-6 participates in the inflammatory response and is released early in the injury response, inducing macrophages, keratinocytes, endothelial cells, and stromal cells in the tissue to release pro-inflammatory cytokines. Since the increase of IL-6 is earlier than that of other cytokines, CRP and PCT, it can be used to assist in the early diagnosis of acute infection.
  • TNF- ⁇ As a cytokine involved in the systemic inflammatory response, TNF- ⁇ has the function of regulating the immune system and plays an important role in the process of inflammation, cell proliferation, differentiation and apoptosis.
  • TNF- ⁇ has a variety of biological effects, such as killing transformed cells, stimulating granulocytes and fibroblasts, and destroying endothelial cells; in vivo, TNF- ⁇ acts as an endogenous mediator of inflammation, immunity and host defense functions. plays a key role in many pathological conditions. At the same time, TNF- ⁇ can work independently and in conjunction with other factors that affect the whole different body functions.
  • Protease-activated receptor-2 is a cell surface receptor of trypsin, which is abundantly expressed in all types of skin cells, especially keratinocytes, and plays an important role in maintaining the dynamic balance of skin barrier function.
  • PAR-2 contains 7 transmembrane helices, of which the N-terminus is located outside the cell and has the protease cleavage site of the corresponding receptor; the C-terminus is located in the cell and is related to receptor desensitization and signal transduction. Trypsin cleaves the N-terminal amino acid residue of PAR-2 between Arg36 and Ser37, exposing the tethering ligands SLIGKV (human) or SLIGRL (mouse).
  • the tethered ligand binds to the second extracellular loop-2 of PAR-2, thereby activating the receptor and inducing the release of inflammatory mediators (IL-6 and IL-8) and the transient receptor potential vanilloid Subtype 1 (TRPV-1) is sensitized, thereby releasing the inflammatory polypeptides calcitonin gene-related peptide (CGRP) and substance P, which aggravates the inflammatory response.
  • IL-6 and IL-8 the transient receptor potential vanilloid Subtype 1
  • TRPV-1 transient receptor potential vanilloid Subtype 1
  • the present invention aims to provide a polypeptide with anti-inflammatory activity.
  • These peptides, cosmetic compositions or pharmaceutical compositions containing these peptides can exert anti-inflammatory activity by down-regulating the expression of IL-6 and TNF- ⁇ , and can be used in the field of cosmetics or medicine to improve skin inflammation, and can also be used to repair skin barrier.
  • the present invention provides a peptide represented by formula (I), or its stereoisomer, or a mixture of stereoisomers, or its cosmetically acceptable salt, or its pharmaceutically acceptable salt,
  • X1 is selected from: -Lys- or -His-;
  • X2 is selected from: -Val-, -Leu- or -Gly-;
  • R 1 is selected from: H or R 3 -CO-, wherein R 3 is selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
  • R 2 is selected from: -NR 4 R 5 or -OR 4 , wherein each R 4 and R 5 are independently selected from each other: H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl;
  • the alkyl refers to having 1-24 carbon atoms (optionally having 1-16 carbon atoms; optionally having 1-14 carbon atoms; optionally having 1-12 carbon atoms; optionally having 1, 2 , 3, 4, 5, or 6 carbon atoms) saturated aliphatic straight-chain or branched-chain alkyl; optionally selected from: methyl, ethyl, isopropyl, isobutyl, tert-butyl, Pentyl, hexyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, 2-ethylhexyl, 2-methylbutyl, or 5- methylhexyl;
  • the alkenyl refers to having 2-24 carbon atoms (optionally having 2-16 carbon atoms; optionally having 2-14 carbon atoms; optionally having 2-12 carbon atoms; optionally having 2, 3 , 4, 5, or 6 carbon atoms) straight-chain or branched alkenyl; said alkenyl has one or more carbon-carbon double bonds, optionally with 1, 2, or 3 conjugated or non-conjugated The carbon-carbon double bond of; said alkenyl is bound to the rest of the molecule through a single bond; optionally selected from: vinyl, oleyl, or linoleyl;
  • R is selected from: H, acetyl, tert-butyryl, hexanoyl, 2-methylhexanoyl, capryl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl Acyl or linoleoyl;
  • R is selected from H, acetyl, lauroyl, myristoyl or palmitoyl;
  • R 1 is H, acetyl or palmitoyl.
  • R 4 and R 5 are independently selected from: H, methyl, ethyl, hexyl, dodecyl or hexadecyl;
  • R is H and R is selected from: H, methyl, ethyl, hexyl, dodecyl or hexadecyl;
  • R 2 is -OH or -NH 2 .
  • the peptide represented by formula (I), or its stereoisomer, or a mixture of stereoisomers, or its cosmetically acceptable salt, or its pharmaceutically acceptable salt, is selected from the following peptides (1)- (18):
  • Palm-Phe-Phe-Trp-Phe-Lys-Val-NH 2 Palm-Phe-Phe-Trp-Phe-Lys-Val-NH 2 ;
  • the peptide represented by formula (I) of the present invention may exist as a stereoisomer or a mixture of stereoisomers; for example, these amino acids contained therein may have the configuration of L-, D-, or independently of each other racemic.
  • isomeric mixtures as well as racemic or diastereomeric mixtures, or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and which isomers are present.
  • Preferred structures of the peptides represented by formula (I) of the present invention are pure isomers, ie, enantiomers or diastereomers.
  • -Phe- is mentioned in the present invention, it should be understood that -Phe- is selected from -L-Phe-, -D-Phe-, or a mixture of both, and is racemic or non-racemic.
  • the preparation methods described in this document enable a person skilled in the art to obtain each stereoisomer of the peptides of the invention by selecting the amino acid with the correct configuration.
  • These peptides of the present invention may be compounds in which at least one hydrogen atom is replaced by deuterium or tritium.
  • compositions refers to a salt approved for use in animals, and more specifically in humans, including metal salts of peptides represented by formula (I),
  • the metals include, but are not limited to: lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum, etc.; including salts formed by peptides represented by formula (I) and inorganic acids or organic acids
  • the Organic acids include, but are 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 not limited to: hydrochloric acid, sulfuric acid, boric acid or carbonic acid.
  • Another aspect of the present invention provides a cosmetic or pharmaceutical composition, comprising an effective amount of the peptide represented by the above formula (I), or its stereoisomer, or a mixture of stereoisomers, or its cosmetic acceptable salt, or a pharmaceutically acceptable salt thereof, and at least one excipient and optionally a cosmetically or pharmaceutically acceptable adjuvant.
  • the adjuvant is selected from: a collagen synthesis stimulator, an agent that regulates the synthesis of PGC-1 ⁇ , an agent that regulates the activity of PPAR ⁇ , an agent that increases or decreases the triglyceride content of adipocytes, stimulates or delays the adipocyte Differentiation agents, lipolytic agents or lipolysis stimulating agents, lipolytic agents, lipogenic agents, inhibitors of acetylcholine receptor aggregation, agents that inhibit muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloproteinases Inhibitors, melanin synthesis stimulators or inhibitors, whitening or depigmenting agents, hyperpigmentation agents, self-tanning agents, antiaging agents, NO-synthase inhibitors, 5 ⁇ -reductase inhibitors, lysyl hydroxylation Enzyme and/or prolyl hydroxylase inhibitors, antioxidants, free radical scavengers and/or anti-air pollution agents, active carbon
  • the formulation of said cosmetic or pharmaceutical composition is selected from the group consisting of creams, oils, milks, balms, foams, lotions, gels, liniments, serums, soaps, shampoos, conditioners, Serum, ointment, mousse, pomade, powder, stick, pen, spray, aerosol, capsule, tablet, granule, chewing gum, solution, suspension, emulsion, syrup, elixir, Polysaccharide film, jelly or gelatin;
  • the capsules include: soft capsules, hard capsules, optionally gelatin capsules;
  • the tablet includes: sugar-coated tablet.
  • the peptides of the invention have variable solubility in water depending on the nature of their sequence or any possible modification in the N-terminus and/or C-terminus.
  • the peptides of the present invention can thus be incorporated into compositions by aqueous solutions, and those that are insoluble in water can be dissolved in cosmetically or pharmaceutically acceptable conventional solvents such as and not limited to ethanol, propanol, isopropanol , propylene glycol, glycerin, butylene glycol, or polyethylene glycol, or any combination thereof.
  • the cosmetically or pharmaceutically effective amount of the peptides of the invention to be administered, as well as their dosage, will depend on many factors, including age, the state of the patient, the severity of the condition or disease, the route and frequency of administration, and the nature of the peptide to be used. specific nature.
  • Cosmetically or pharmaceutically effective amount means a non-toxic amount of one or more peptides of the invention which is sufficient to provide the desired effect.
  • the peptides of the invention are used in the cosmetic or pharmaceutical compositions of the invention in a cosmetically or pharmaceutically effective concentration to obtain the desired effect; in a preferred form, at 0.00000001% relative to the total weight of the composition (by weight) and 20% (by weight), preferably between 0.000001% (by weight) and 15% (by weight), more preferably between 0.0001% (by weight) and 10% ( by weight), and even more preferably between 0.0001% by weight and 5% by weight.
  • a cosmetically or pharmaceutically acceptable delivery system or sustained release system in order to achieve better penetration of the active ingredient and/or to improve its pharmacokinetic and pharmacodynamic properties, It contains an effective amount of the peptide represented by the above formula (I), or its stereoisomer, or a mixture of stereoisomers, or its cosmetically acceptable salt, or its pharmaceutically acceptable salt, or the above-mentioned cosmetic or medicinal composition.
  • delivery system refers to a diluent, adjuvant, excipient or carrier with which the peptides of the invention are administered, selected from the group consisting of: water, oil or surfactants, including petroleum sources, animal sources, plant sources, or Those of 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 Alcohol, Nonoxynol, Poloxamer, Polyoxyethylene, Macrogol, Dextrose, Glycerin, Digitonin and the like.
  • Those of ordinary skill in the art know the diluents that can be used in the different delivery systems in which the peptides of the invention can be administered.
  • sustained release is used in the conventional sense to refer to a delivery system that provides a gradual release of the compound over a period of time, and preferably, but not necessarily, a relatively constant level of compound release over the entire period of time.
  • Examples of delivery systems or sustained release systems are liposomes, oleosomes, nonionic surfactant liposomal vesicles, ethosomes, millimeter capsules, microcapsules, nanocapsules, nanostructured lipid carriers, sponges Cyclodextrins, lipid vesicles, micelles, millimeter spheres, microspheres, nanospheres, lipid spheres, microemulsions, nanoemulsions, millimeter particles, microparticles or nanoparticles.
  • Preferred delivery systems or sustained release systems are liposomes and microemulsions, more preferably water-in-oil microemulsions with an internal structure of reverse micelles.
  • Sustained release systems can be prepared by methods known in the art and can be administered, for example, by topical or transdermal administration, including adhesive patches, non-adherent patches, occlusive patches, and microelectronic patch; or by systemic administration such as and without limitation, oral or parenteral routes, including nasal, rectal, subcutaneous implantation or injection, or direct implantation or injection into specific body parts, and preferably should A relatively constant amount of these peptides of the invention is released.
  • the amount of peptide contained in the sustained release system will depend, for example, on the site where the composition is to be administered, the release kinetics and duration of the peptide of the invention, and the condition, disorder and/or condition to be treated and/or cared for. the nature of the disease.
  • Another aspect of the present invention provides a peptide represented by the above formula (I), or its stereoisomer, or a mixture of stereoisomers, or its cosmetically acceptable salt, or its pharmaceutically acceptable or the above-mentioned cosmetic or pharmaceutical composition, or the use of the above-mentioned cosmetic or pharmaceutically acceptable delivery system or slow-release system in the preparation of an anti-inflammatory cosmetic or pharmaceutical composition.
  • Another aspect of the present invention provides a peptide represented by the above formula (I), or its stereoisomer, or a mixture of stereoisomers, or its cosmetically acceptable salt, or its pharmaceutically acceptable or the above-mentioned cosmetic or pharmaceutical composition, or the above-mentioned cosmetically or pharmaceutically acceptable delivery system or slow-release system in the preparation of a cosmetic composition or a pharmaceutical composition for repairing the skin barrier.
  • the term “skin” is understood to mean the layers that make it up, from the uppermost layer or stratum corneum to the lowermost layer or subcutaneous tissue, both inclusive. These layers are composed of different types of cells, such as keratinocytes, fibroblasts, melanocytes, and/or adipocytes, among others. In the present invention, the term “skin” includes the scalp.
  • Lys denotes NH2 -CH( CH2CH2CH2CH2NH2 ) -COOH
  • Lys- denotes NH2 - CH( CH2CH2CH2CH2NH2 ) -CO-
  • -Lys represents -NH-CH(CH 2 CH 2 CH 2 CH 2 NH 2 )-COOH
  • -Lys- represents -NH-CH(CH 2 CH 2 CH 2 CH 2 NH 2 )-CO-.
  • the hyphen denoting a peptide bond eliminates the OH in the 1-carboxyl group of an amino acid (represented here in conventional non-ionized form) when located to the right of the symbol, and eliminates the OH when located to the left of the symbol.
  • Ac- is used in the present invention to denote the acetyl group (CH 3 -CO-), and the abbreviation “Palm-” is used to denote the palmitoyl group (CH 3 -(CH 2 ) 14 -CO-).
  • the peptide of the present invention is obtained by artificial design, easy to synthesize, can promote the proliferation of keratinocytes, down-regulate the expression of IL-6 and TNF- ⁇ , improve the skin barrier function, and can be used for anti-inflammation and skin repair in the field of cosmetics or medicine barrier.
  • Fig. 3 is a graph showing the effect of 100 ppm of the peptide of the present invention on the expression of IL-6.
  • Fig. 4 is a graph showing the results of improvement of TEWL value detected by using the peptide of the present invention for 3 days after SDS stimulation.
  • Fig. 5 is a picture of the skin imaging results tested on the first day and the third day respectively after being stimulated by SDS.
  • Fig. 6 is a graph showing the results of the erythema index tested on the first day and the third day respectively after being stimulated by SDS.
  • Fig. 7 is a graph showing the improvement results of the erythema index using the peptide of the present invention for 3 days after being stimulated by SDS. * indicates that there is a statistical difference between the polypeptide group and the SDS group, p ⁇ 0.05.
  • Amide Resin a starting resin for polypeptide synthesis (crosslinking degree 1%, substitution degree 1.42mmol/g); Fmoc-Linker: 4-[(2,4-dimethoxyphenyl) (Fmoc-amino ) methyl]phenoxyacetic acid; Ac 2 O: acetic anhydride; DMF: N,N-dimethylformamide; DIPEA: diisopropylethylamine; DIC: diisopropylcarbodiimide; piperidine: piperidine Pyridine; HOBt: 1-hydroxybenzotriazole; TFA: trifluoroacetic acid; TIS: triisopropylsilane; EDT: 1,2-ethanedithiol; Phe: phenylalanine; Trp: tryptophan ; His: histidine; Val: valine; Lys: lysine; Leu: leucine; Gly: glycine; Fmoc: 9-fluorenylmeth
  • the activated Fmoc-Linker was added to the swollen resin to react for 3.5 hours, the reaction solution was removed, the resin was washed, and the solvent was removed.
  • Fmoc-Linker-Amide Resin was de-Fmoc twice with 20% piperidine/DMF, 10min each time, sampled for K inspection, and the color was dark blue. The resin was washed 6 times with DMF and the solvent was aspirated.
  • the N-terminal Fmoc group was deprotected and 8.7 g of activated Fmoc-Lys(Boc)-OH was coupled to the peptidyl resin in the presence of 3.011 g HOBt and 3.8 mL DIC using DMF as solvent On, continue to react for 2h. The resins were then washed and the deprotection treatment of the Fmoc group repeated for coupling of the next amino acid.
  • the N-terminal Fmoc group of the peptidyl resin obtained in Example 1 was deprotected, and 20% piperidine/DMF was used to de-Fmoc twice, each time for 10 minutes, and a sample was taken for inspection, and the color was dark blue.
  • the resin was washed 6 times with DMF and the solvent was aspirated.
  • the isopropyl ether was stored in a -18°C refrigerator for later use.
  • PBS Phosphate buffered saline
  • MTT thiazolium blue
  • DMSO dimethylsulfoxide
  • DMEM high glucose medium
  • fetal bovine serum Gibco
  • Microplate reader (MD, USA), CO 2 incubator (Shanghai Yiheng), ultra-clean bench (Suzhou Purification).
  • HaCaT Human keratinocytes
  • test concentrations are 1ppm, 10ppm, 50ppm, 100ppm;
  • test concentrations were 1ppm, 10ppm, 50ppm, 100ppm;
  • test concentrations were 1ppm, 10ppm, 50ppm, 100ppm;
  • Peptide (17) the tested concentrations were 1 ppm, 10 ppm, 50 ppm, and 100 ppm, respectively.
  • the cryopreserved HaCaT cells were cultured, subcultured to about 5 passages according to the ratio of 1:2, and the cells with better growth were selected as the experimental objects.
  • Inoculate 2000 cells/well in a 96-well plate After the cells adhere to the wall, add the samples of the administration group and the control group respectively according to the doubling dilution method, supplement the medium to 200 ⁇ L, and place at 37°C, 5% CO 2 Incubate in the incubator for 72h.
  • MTT method is a method for detecting cell survival and growth.
  • control group as the reference ratio
  • 4 dosage concentrations are set for each sample from high to low, and the cell activity detection experiment is carried out on HaCaT cells.
  • Fig. 1 is a graph showing the effect of the peptide of the present invention on the activity of HaCaT cells. The results showed that, compared with the control group, peptide (5), peptide (11), peptide (17) and the reference peptide had no toxicity to HaCaT cells within 100 ppm. The reference peptide and peptide (5) had significant proliferative effects on cells at concentrations of 50ppm and 100ppm, respectively.
  • Microplate reader constant temperature CO2 incubator, constant temperature box.
  • the cryopreserved RAW264.7 cells were cultured and subcultured at a ratio of 1:2 to about 5 passages, and the cells with better growth were selected as the experimental objects.
  • Inflammatory factors such as TNF- ⁇ , IL-6, etc. can cause excessive immune response of the body, leading to skin ulceration, redness and swelling, etc. Therefore, inhibiting the secretion of TNF- ⁇ , IL-6 and other inflammatory factors by monocytes in the skin can achieve Anti-inflammatory repair effect.
  • the inflammation model was established by stimulating RAW264.7 cells with 200ng/mL LPS, and the anti-inflammatory repairing effect of the peptide of the present invention was explored.
  • TNF- ⁇ , IL-6 cytokines were significantly up-regulated.
  • 100ppm of peptide (5), peptide (11), peptide (17), and reference peptide can significantly down-regulate the expression of TNF- ⁇ , and its effect is equivalent to that of the positive drug dexamethasone, and even has a stronger effect than dexamethasone.
  • Excellent effect wherein peptide (5) has a stronger effect on inhibiting the expression of TNF- ⁇ .
  • 100ppm of peptide (5), peptide (11), peptide (17) and reference peptide can also significantly down-regulate the expression of IL-6.
  • SDS Sodium dodecyl sulfate
  • Finn chamber spot tester side length 8mm, area 64mm 2
  • transdermal moisture diffusion tester C-Cube skin imaging system.
  • SDS group 10% SDS solution.
  • Solvent group 0.3% carbomer 980, 0.3% arginine, the balance is water.
  • Preparation method Disperse carbomer in water, heat to 80°C, stir to dissolve completely; cool down to about 45°C, add arginine, stir to mix and dissolve.
  • reference peptide group On the basis of the solvent group, add reference peptide, mix and dissolve to make the final concentration 50ppm.
  • 50ppm peptide (5) group On the basis of the solvent group, add peptide (5), mix and dissolve so that the final concentration is 50ppm.
  • a post-administration test was performed. Before each measurement, the test site was cleaned with water and blotted dry with lint-free absorbent paper towels. Sit quietly in a standard test environment for at least 20 minutes, without drinking water and beverages, with the forearm exposed, keep relaxed, and avoid touching the patch area.
  • the TEWL value at the center of each patch area was measured, each area was measured twice, and the measurement results were expressed as the average value of TEWL values in 10 patch areas on a single arm.
  • the interval between the set measurement time points shall not be less than 1d, and the set instrument test time: D1 and D3 after modeling.
  • the test indicators are TEWL (Transepidermal Water Loss) and C-Cube 2D image analysis.
  • the TEWL value is based on Fick's diffusion law. Under the specified temperature and humidity conditions, the value is obtained by measuring the water vapor partial pressure gradient at different points near the epidermis (within 1 cm) per unit time and unit cross-sectional area. The higher the TEWL value, the more transepidermal water loss per unit time and unit cross-sectional area, and the more severely damaged the skin barrier; the lower the TEWL value, the less transepidermal water loss per unit time and unit cross-sectional area , the skin barrier is less damaged.
  • the TEWL values measured on the first day and the third day of administration were compared with the initial value (D0), and the improvement results of TEWL values are shown in Figure 4.
  • the TEWL of the peptide (5) was significantly reduced, while the TEWL improvement of the vehicle group was not obvious at 3 days compared with the 0 day, indicating that the peptide (5) can reduce the TWEL value after SDS stimulation , repair the skin barrier after SDS stimulation, and peptide (5) has a better skin barrier repair effect than the reference peptide.
  • Fig. 5 is a picture of the skin imaging results tested on the first day and the third day respectively after being stimulated by SDS. The results showed that after SDS stimulation, the area of skin erythema increased significantly. On day 3, peptide (5) significantly improved the area of erythema compared with the SDS group.
  • Figure 6 and Figure 7 are the analysis results of erythema index. The results showed that compared with the SDS group, the peptide (5) could significantly reduce the erythema index, and the improvement of the erythema index by the peptide (5) was better than that of the reference peptide.
  • Dissolve allantoin and glycerin in water heat to 85°C, and keep warm for 30 minutes; dissolve PEG-7 glycerin cocoate and peptide (5) in water; mix the above solutions after cooling, and stir evenly to obtain a mixed solution; , preservatives, and flavors are added to the above mixed solution in sequence, and water is added to stir evenly to obtain the product.
  • Embodiment 10 contains the emulsion composition of peptide (17)
  • phase A dissolve glycerin, allantoin, polyacrylamide (and) C13-14 isoparaffin (and) laureth-7 in water, and heat to 85°C to obtain phase B; Quickly add phase B, homogenize at constant temperature for 3-5 minutes, cool; cool to below 60°C, add preservative, stir evenly, cool to below 45°C, add polypeptide solution and essence, and the product is ready.

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Abstract

本发明涉及一种六肽及其美容组合物或药用组合物和用途，所述肽具有以下通式：R1-Phe-Phe-Trp-Phe-X1-X 2-R2。本发明所述的肽、其立体异构体、立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或它们的美容组合物或药用组合物、以及它们在制备用于抗炎、修复皮肤屏障的美容组合物或药物组合物中的用途。

Description

一种六肽及其美容组合物或药用组合物和用途 技术领域
本发明涉及一种六肽、以及含有这些肽的美容组合物或药用组合物及其用途。
背景技术
皮肤作为人体最大的器官，可以保护内部器官免受紫外线辐射、物理化学性伤害和微生物入侵，阻止机体内部水分、电解质及营养物质丢失，参与维持机体正常的生理功能。但是，UV辐射、物理化学性伤害和微生物入侵会在一定程度上损伤皮肤的屏障功能，导致皮肤组织细胞损伤并引发炎症反应，出现红肿、疼痛和灼热等急性反应。另一方面，如果人体皮肤屏障功能脆弱，皮肤对外界的刺激会异常敏感，任何微小的刺激都有可能引发面部毛细血管扩张和增生，导致皮肤应激充血和血液淤积，造成皮肤的毛孔和毛细血管坏死，出现过敏、溃烂等局部反应，皮毛及毒素相融一体或留于人体皮肤上，引发慢性炎症过敏性皮肤病。
在炎症反应过程中，存在着一些进行细胞间信息传递的炎症因子如白介素IL-1α、IL-6、IL-8和肿瘤坏死因子TNF-α。IL-6作为一种促炎细胞因子，由成纤维细胞、内皮细胞、单核细胞，角化细胞和T淋巴细胞等合成并释放。同时它的合成受到Toll样受体和IL-1的强烈刺激，在炎症反应过程中具有较高的浓度。IL-6参与炎症反应并在损伤反应早期释放，诱导组织内巨噬细胞、角质形成细胞、内皮细胞和基质细胞释放促炎细胞因子。由于IL-6的升高早于其他细胞因子及CRP和PCT，因此可以用于辅助急性感染的早期诊断。TNF-α作为一种参与全身炎症反应的细胞因子，对免疫***具有调节功能，同时在炎症、细胞增殖、分化及凋亡过程中发挥着重要作用。在体外TNF-α具有多种生物学作用，可以杀死转化细胞、刺激粒细胞和成纤维细胞和破坏内皮细胞等；在体内TNF-α作为炎症、免疫和宿主防御功能的内源性介质起着关键作用，涉及许多病理状况。同时TNF-α能够独立发挥作用，并与影响整个不同身体机能的其他因素共同起作用。
蛋白酶激活受体-2(PAR-2)是胰蛋白酶的细胞表面受体，在皮肤的所有类型细胞尤其是角质形成细胞中可以丰富地表达，对维持皮肤屏障功能的动态平衡具有重要作用。PAR-2含有7个跨膜螺旋，其中N端位于细胞外，有相应受体的蛋白酶裂解位点；C端位于细胞内，与受体脱敏和信号转导有关。胰蛋白酶自Arg36和Ser37之间切下PAR-2的N-末端氨 基酸残基，暴露出系锁配体SLIGKV(人)或SLIGRL(鼠)。系锁配体与PAR-2的第二个细胞外回型结构(extracellular loop-2)结合，从而激活受体并诱导炎症介质(IL-6和IL-8)释放和瞬时受体电位香草酸亚型1(TRPV-1)致敏，由此释放炎性多肽降钙素基因相关肽(CGRP)和P物质，加重炎症反应。
本发明人对PAR-2及其系锁配体进行研究，意外地发现一些多肽可以抑制炎症因子的生成，尤其是炎症因子IL-6和TNF-α的生成，同时可以促进细胞增殖，修复皮肤屏障。
发明内容
本发明旨在提供一种具有抗炎活性的多肽。这些肽、含有这些肽的美容组合物或药用组合物，通过下调IL-6和TNF-α的表达，发挥抗炎活性，可以在化妆品或医药领域用于改善皮肤炎症，亦可用于修复皮肤屏障。
鉴于此，本发明提供一种式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，
R 1-Phe-Phe-Trp-Phe-X 1-X 2-R 2  (I)
式(I)中，
X 1选自：-Lys-或-His-；
X 2选自：-Val-、-Leu-或-Gly-；
R 1选自：H或R 3-CO-，其中R 3选自：取代的或未取代的烷基、取代的或未取代的烯基；
R 2选自：-NR 4R 5或-OR 4，其中各个R 4和R 5彼此独立地选自：H、取代的或未取代的烷基、取代的或未取代的烯基；
所述烷基是指具有1-24个碳原子(可选具有1-16个碳原子；可选具有1-14个碳原子；可选具有1-12个碳原子；可选具有1、2、3、4、5、或6个的碳原子)的饱和脂肪族直链或支链的烷基；可选选自：甲基、乙基、异丙基、异丁基、叔丁基、戊基、己基、庚基、辛基、癸基、十二烷基、十四烷基、十六烷基、十八烷基、2-乙基己基、2-甲基丁基、或5-甲基己基；
所述烯基是指具有2-24个碳原子(可选具有2-16个碳原子；可选具有2-14个碳原子；可选具有2-12个碳原子；可选具有2、3、4、5、或6个碳原子)的直链或支链烯基；所述 烯基具有一个或多个碳-碳双键，可选具有1、2或3个共轭或非共轭的碳-碳双键；所述烯基是通过一个单键而结合至分子的其余部分；可选选自：乙烯基、油烯基、或亚油烯基；
可选地，所述“取代的烷基”、“取代的烯基”中的取代基选自C 1-C 4烷基；羟基；C 1-C 4烷氧基；氨基；C 1-C 4氨基烷基；C 1-C 4羰氧基；C 1-C 4氧基羰基；卤素(如氟、氯、溴、以及碘)；氰基；硝基；叠氮化物；C 1-C 4烷基磺酰基；硫醇；C 1-C 4烷硫基；C 6-C 30芳氧基如苯氧基；-NR b(C＝NR b)NR bR c，其中R b和R c是独立地选自：H、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 3-C 10环烷基、C 6-C 18芳基、C 7-C 17芳烷基、具有三至十元的杂环基、或氨基的保护基。
可选地，R 1选自：H、乙酰基、叔-丁酰基、己酰基、2-甲基己酰基、辛酰基、癸酰基、月桂酰基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油酰基或亚油酰基；
可选地，R 1选自H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基；
可选地，R 1是H、乙酰基或棕榈酰基。
可选地，R 4、R 5彼此独立地选自：H、甲基、乙基、己基、十二烷基或十六烷基；
可选地，R 4是H并且R 5选自：H、甲基、乙基、己基、十二烷基或十六烷基；
可选地，R 2是-OH或-NH 2。
式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，选自下列肽(1)-(18)：
(1)H-Phe-Phe-Trp-Phe-Lys-Val-OH；
(2)Ac-Phe-Phe-Trp-Phe-Lys-Val-OH；
(3)Palm-Phe-Phe-Trp-Phe-Lys-Val-OH；
(4)H-Phe-Phe-Trp-Phe-Lys-Val-NH 2；
(5)Ac-Phe-Phe-Trp-Phe-Lys-Val-NH 2；
(6)Palm-Phe-Phe-Trp-Phe-Lys-Val-NH 2；
(7)H-Phe-Phe-Trp-Phe-His-Leu-OH；
(8)Ac-Phe-Phe-Trp-Phe-His-Leu-OH；
(9)Palm-Phe-Phe-Trp-Phe-His-Leu-OH；
(10)H-Phe-Phe-Trp-Phe-His-Leu-NH 2；
(11)Ac-Phe-Phe-Trp-Phe-His-Leu-NH 2；
(12)Palm-Phe-Phe-Trp-Phe-His-Leu-NH 2；
(13)H-Phe-Phe-Trp-Phe-His-Gly-OH；
(14)Ac-Phe-Phe-Trp-Phe-His-Gly-OH；
(15)Palm-Phe-Phe-Trp-Phe-His-Gly-OH；
(16)H-Phe-Phe-Trp-Phe-His-Gly-NH 2；
(17)Ac-Phe-Phe-Trp-Phe-His-Gly-NH 2；
(18)Palm-Phe-Phe-Trp-Phe-His-Gly-NH 2。
本发明的式(I)所示的肽可以作为立体异构体或立体异构体的混合物存在；例如，其所包含的这些氨基酸可以具有L-、D-的构型、或彼此独立地是外消旋的。因此，有可能获得同分异构混合物以及外消旋混合物或非对映混合物、或纯的非对映异构体或对映异构体，这取决于不对称碳的数量和存在什么同分异构体或同分异构混合物。本发明的式(I)所示的肽的优选的结构是纯的同分异构体，即，对映异构体或非对映异构体。
例如，当本发明所述-Phe-时，应理解-Phe-选自-L-Phe-、-D-Phe-、或两者的混合物，是外消旋的或非外消旋的。在本文件中描述的制备方法使本领域的普通技术人员能够通过选择具有正确构型的氨基酸来获得本发明的肽的每种立体异构体。
本发明的这些肽可以是其中至少一个氢原子被氘或氚代替的化合物。
术语“美容上可接受的盐或药学上可接受的盐”指被认可的在动物，并且更确切地说在人类中使用的一种盐，包括式(I)所示的肽的金属盐，所述金属包括，但不局限于：锂、钠、钾、钙、镁、锰、铜、锌或铝等；包括式(I)所示的肽与无机酸或有机酸形成的盐，所述有机酸包括，但不局限于：乙酸、柠檬酸、乳酸、丙二酸、马来酸、酒石酸、延胡索酸、苯甲酸、天冬氨酸、谷氨酸、琥珀酸、油酸、三氟乙酸、草酸、扑酸(pamoate)或葡萄糖酸等；所述无机酸包括，但不局限于：盐酸、硫酸、硼酸或碳酸。
本发明的另一方面，提供一种美容或药用组合物，包括有效量的上述式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，以及至少一种赋形剂和任选的美容上或药学上可接受的佐剂。
可选地，所述佐剂选自：胶原合成刺激剂、调节PGC-1α合成的剂、调节PPARγ的活性的剂、增加或减少脂肪细胞的甘油三酸酯含量的剂、刺激或延迟脂肪细胞分化的剂、脂解剂或刺激脂肪分解的剂、溶脂剂、生脂剂、乙酰胆碱受体聚集的抑制剂、抑制肌肉收缩的剂、 抗胆碱能试剂、弹性蛋白酶抑制剂、基质金属蛋白酶抑制剂、黑色素合成刺激或抑制剂、增白剂或脱色剂、促色素沉着剂、自晒黑剂、抗老化剂、NO-合酶抑制剂、5α-还原酶抑制剂、赖氨酰羟化酶和/或脯氨酰羟化酶的抑制剂、抗氧化剂、自由基清除剂和/或抗大气污染的剂、活性羰基类物质清除剂、抗糖化剂、抗组胺剂、抗病毒剂、抗寄生虫剂、乳化剂、润肤剂、有机溶剂、液体推进剂、皮肤调理剂、保湿剂、保留水分的物质、α羟基酸、β羟基酸、增湿剂、表皮水解酶、维生素、氨基酸、蛋白质、色素或着色剂、染料、生物聚合物、胶凝聚合物、增稠剂、表面活性剂、软化剂、粘合剂、防腐剂、抗皱剂、能够减少或治疗下眼袋的剂、去角质剂、角质剥离剂、角质层分离剂、抗微生物剂、抗真菌剂、抑真菌剂、灭菌剂、抑菌剂、刺激真皮或表皮大分子的合成和/或能够抑制或预防它们的降解的剂、刺激弹性蛋白合成的剂、刺激核心蛋白聚糖合成的剂、刺激层粘连蛋白合成的剂、刺激防御素合成的剂、刺激伴侣蛋白合成的剂、刺激cAMP合成的剂、热休克蛋白、刺激HSP70合成的剂、刺激热休克蛋白合成的剂、刺激透明质酸合成的剂、刺激纤连蛋白合成的剂、刺激去乙酰化酶合成的剂、刺激脂质和角质层组分的合成的剂、神经酰胺、脂肪酸、抑制胶原降解的剂、抑制弹性蛋白降解的剂、抑制丝氨酸蛋白酶的剂、刺激成纤维细胞增殖的剂、刺激角质形成细胞增殖的剂、刺激脂肪细胞增殖的剂、刺激黑色素细胞增殖的剂、刺激角质形成细胞分化的剂、抑制乙酰胆碱酯酶的剂、皮肤松弛剂、刺激糖胺聚糖合成的剂、抗角化过度剂、粉刺溶解剂、抗银屑病剂、抗皮炎剂、抗湿疹剂、DNA修复剂、DNA防护剂、稳定剂、止痒剂、用于治疗和/或护理敏感性皮肤的剂、固化剂、紧致剂、重构剂、抗拉伸纹剂、粘合剂、调节皮脂产生的剂、止汗剂、刺激愈合的剂、协助愈合的剂、刺激再上皮化的剂、协助再上皮化的剂、细胞因子生长因子、镇静剂、抗炎剂、麻醉剂、作用于毛细血管循环和/或微循环的剂、刺激血管生成的剂、抑制血管渗透性的剂、静脉紧张剂、作用于细胞代谢的剂、用于改善真皮-表皮接合的剂、诱导毛发生长的剂、毛发生长抑制或延缓剂、香料、螯合剂、植物提取物、精油、海洋提取物、得自生物发酵过程的剂、无机盐、细胞提取物、防晒剂、以及有效抗A和/或B紫外线的有机或无机光防护剂或其混合物。
可选地，所述美容或药用组合物的制剂选自：霜剂、油、奶、香膏、泡沫、洗剂、凝胶、擦剂、浆液、皂、洗发精、润发乳、血清、软膏、摩丝、润发油、粉末、杆剂、笔剂、喷雾剂、气溶胶、胶囊剂、片剂、颗粒剂、口香糖、溶液、混悬液、乳剂、糖浆剂、酏剂、多糖薄膜、胶冻或明胶；
可选地，所述胶囊剂包括：软胶囊剂、硬胶囊剂，可选为明胶胶囊剂；
可选地，所述片剂包括：糖衣片剂。
本发明的肽根据它们的序列的性质或N-末端和/或C-末端中的任何可能的修饰，在水中具有可变的溶解度。因此本发明的肽可以通过水溶液掺入组合物中，且不溶于水的那些可溶解于美容上或药学上可接受的常规溶剂中，所述溶剂例如并且不限于乙醇、丙醇、异丙醇、丙二醇、甘油、丁二醇或聚乙二醇或其任何组合。
待施用的美容上或药学上有效量的本发明的肽以及它们的剂量将依赖于许多因素，包括年龄、患者的状态、病症或疾病的严重性、施用的途径和频率以及待使用的肽的具体性质。
“美容上或药学上有效量”意指无毒性的但足以提供希望的效果的本发明的一种或多种肽的量。在本发明的美容组合物或药用组合物中以获得希望的效果的美容上或药学上有效的浓度使用本发明的肽；在一个优选形式中，相对于组合物的总重量，在0.00000001％(按重量计)和20％(按重量计)之间，优选在0.000001％(按重量计)和15％(按重量计)之间、更优选在0.0001％(按重量计)和10％(按重量计)之间，并且甚至更优选在0.0001％(按重量计)和5％(按重量计)之间。
本发明的另一方面，提供一种美容上或药学上可接受的递送***或缓释***，以便实现有效成分的更好渗透和/或改进它的药物代谢动力学和药效动力学特性，其包含有效量的上述式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，或上述的美容或药用组合物。
术语“递送***”是指与本发明的肽一起施用的稀释剂、佐剂、赋形剂或载体，它们选自：水、油或表面活性剂、包括石油来源、动物来源、植物来源、或合成来源的那些，例如并且不限于花生油、大豆油、矿物油、芝麻油、蓖麻油、聚山梨醇酯、脱水山梨糖醇酯、醚硫酸酯、硫酸酯、甜菜碱、葡萄糖苷、麦芽糖苷、脂肪醇、壬苯醇醚、泊洛沙姆、聚氧乙烯、聚乙二醇、右旋糖、甘油、毛地黄皂苷和类似物。本领域的普通技术人员已知在可以给予本发明的肽的不同递送***中可以使用的稀释剂。
术语“缓释”以常规含义使用，指提供化合物在一段时间内逐渐释放的化合物的递送***，且优选地但不是必须地，在整个时间段内具有相对恒定的化合物释放水平。
递送***或缓释***的实例是脂质体、油质体、非离子型表面活性剂脂质体囊泡、醇质体、毫米胶囊、微米胶囊、纳米胶囊、纳米结构的脂质载体、海绵状物、环糊精、类脂囊泡、 胶束、毫米球、微米球、纳米球、脂质球、微米乳液、纳米乳液、毫米粒子、微米粒子或纳米粒子。优选的递送***或缓释***是脂质体和微米乳液，更优选具有反胶束的内部结构的油包水型微米乳液。
缓释***可以通过现有技术中已知的方法来制备，并且可以例如通过以下方式来给予：通过局部或经皮给药，包括粘附贴剂、非粘附贴剂、封闭贴剂、以及微电子贴剂；或通过全身给药例如并且不局限于，口服或胃肠外途径，包括鼻、直肠、皮下植入或注射、或直接植入或注射至特定身体部位中，并且优选地应该释放相对恒定量的本发明的这些肽。在该缓释***中包含的肽的量将取决于例如该组合物将被给予的部位、本发明的肽的释放动力学和持续时间、以及有待治疗和/或护理的病状、病症和/或疾病的性质。
本发明的另一方面，提供一种上述式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，或上述美容或药用组合物，或上述的美容上或药学上可接受的递送***或缓释***在制备用于抗炎的美容组合物或药物组合物中的用途。
本发明的另一方面，提供一种上述式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，或上述美容或药用组合物，或上述的美容上或药学上可接受的递送***或缓释***在制备用于修复皮肤屏障的美容组合物或药物组合物中的用途。
为了便于理解本发明，对在本发明所使用的一些术语和表述的含义说明如下：
在本发明中，术语“皮肤”应理解为是构成它的多个层，从最上层或角质层至最下层或皮下组织，两个端点都包括在内。这些层由不同类型的细胞组成，如角质形成细胞、成纤维细胞、黑色素细胞、和/或脂肪细胞等。在本发明中，术语“皮肤”包括头皮。
在本说明书中，用于氨基酸的缩写遵循IUPAC-IUB生化命名委员会(IUPAC-IUB Commission of Biochemical Nomenclature)在欧洲生物化学杂志(Eur.J.Biochem.1984,138:9-37)中所指定的规则。
因此，例如，Lys表示NH 2-CH(CH 2CH 2CH 2CH 2NH 2)-COOH，Lys-表示NH 2-CH(CH 2CH 2CH 2CH 2NH 2)-CO-，-Lys表示-NH-CH(CH 2CH 2CH 2CH 2NH 2)-COOH，并且-Lys-表示-NH-CH(CH 2CH 2CH 2CH 2NH 2)-CO-。因此，表示肽键的连字符消除了当位于该符号的右侧时的氨基酸(在此用常规非离子化形式来表示)1-羧基中的OH，并且消除了当位于 该符号的左侧时的氨基酸2-氨基中的H；两种修饰可以应用于同一个符号(见表1)。
表1氨基酸残基的结构以及它们的单字母和三字母缩写符号
Figure PCTCN2021143978-appb-000001
缩写“Ac-”在本发明中用来表示乙酰基(CH 3-CO-)，并且缩写“Palm-”用来表示棕榈酰基(CH 3-(CH 2) 14-CO-)。
本发明相对于现有技术所取得的有益效果包括：
本发明所述的肽通过人工设计得到，合成方便，能够促进角质形成细胞增殖，下调IL-6和TNF-α的表达，改善皮肤屏障功能，可以在化妆品或医药领域用于抗炎和修复皮肤屏障。
附图说明
图1是本发明的肽对HaCaT细胞活性影响结果图。*表示给药组与control组相比具有统计学差异，p<0.05(n＝4)。
图2是100ppm本发明的肽对TNF-α表达的影响结果图。###表示单独LPS刺激组与control组相比差异极为显著，p<0.001(n＝4)。***表示给药组与单独LPS刺激组相比差异极为显著，p<0.001(n＝4)。
图3是100ppm本发明的肽对IL-6表达的影响结果图。###表示单独LPS刺激组与control组相比差异极为显著，p<0.001(n＝4)。*表示给药组与单独LPS刺激组相比具有统计学差异，p<0.05(n＝4)。***表示给药组与单独LPS刺激组相比差异极为显著，p<0.001(n＝4)。
图4是经SDS刺激后，使用本发明的肽3天时检测得到的TEWL值改善结果图。
图5是经SDS刺激后，在第1天和第3天分别测试得到的皮肤成像结果图。
图6是经SDS刺激后，在第1天和第3天分别测试得到的红斑指数结果图。
图7是经SDS刺激后，使用本发明的肽3天红斑指数改善结果图。*表示多肽组与SDS组相比具有统计学差异，p<0.05。
具体实施方式
为了更好地理解本发明，下面结合实施例及附图对发明作详细的说明，然而，应当理解的是，这些实施例及附图仅用作说明目的，并且不旨在限制本发明的范围。
缩写
用于氨基酸的缩写遵循IUPAC-IUB的生物化学命名委员会在Eur J.Biochem.(1984)138：9-37和J.Chem(1989)264：633-673中指定的规则。
Amide Resin：一种多肽合成用的起始树脂(交联度1％，替代度1.42mmol/g)；Fmoc-Linker：4-[(2,4-二甲氧基苯基)(Fmoc-氨基)甲基]苯氧乙酸；Ac 2O：醋酸酐；DMF：N,N-二甲基甲酰胺；DIPEA：二异丙基乙胺；DIC：二异丙基碳二亚胺；piperidine：哌啶；HOBt：1-羟基苯并三氮唑；TFA：三氟乙酸；TIS：三异丙基硅烷；EDT：1,2-乙二硫醇；Phe：苯丙氨酸；Trp：色氨酸；His：组氨酸；Val：缬氨酸；Lys：赖氨酸；Leu：亮氨酸；Gly：甘氨酸；Fmoc：9-芴基甲氧羰基；Boc：叔丁氧基羰基；Trt：三苯甲基。
实施例1 Fmoc-Phe-Phe-Trp(Boc)-Phe-Lys(Boc)-Val-Linker-Amide Resin的制备
1.1 Fmoc-Linker-Amide Resin的制备
称取Amide Resin树脂5g于固相合成反应柱中，用DMF溶胀，洗涤树脂，抽走溶剂。
称取Fmoc-Linker 8.3g、HOBt 2.517g于干燥三角瓶中。用DMF溶剂溶解后置于冰水浴中冷却2min，加DIC 3.187mL活化3min，避免水汽。
将活化后的Fmoc-Linker加入溶胀后的树脂中反应3.5h，抽走反应液，洗涤树脂，抽走溶剂。
继续加入Ac 2O 3.8g、DIPEA 0.956g、DMF 20mL，封端1.5h。洗涤树脂，抽走溶剂。
1.2脱Fmoc
Fmoc-Linker-Amide Resin用20％piperidine/DMF脱Fmoc二次，每次10min，取样K检，显色深蓝。用DMF洗涤树脂6次，抽走溶剂。
1.3投料反应
称取6.3g的Fmoc-Val-OH，3.011g的HOBt加入干燥三角瓶中。加入DMF使其溶解，密封置于-18℃冰箱30min。加3.8mL DIC活化3min，避免水汽。将活化后的氨基酸加入脱保护后树脂中反应2h，抽走反应液。K检树脂无色透明说明反应完全。
对N-末端Fmoc基团进行脱保护，并且在存在3.011g HOBt和3.8mL DIC的情况下，使用DMF作为溶剂，将活化后的8.7g Fmoc-Lys(Boc)-OH偶联至肽基树脂上，持续反应2h。然后洗涤这些树脂并且重复Fmoc基团的脱保护处理以便偶联下一个氨基酸。在每次偶联中，在存在3.011g HOBt和3.8mL DIC的情况下，使用DMF作为溶剂，顺序地偶联7.2g的Fmoc-Phe-OH；9.8g的Fmoc-Trp(Boc)-OH；7.2g的Fmoc-Phe-OH以及随后7.2g的Fmoc-Phe-OH。反应完全之后，洗涤树脂，抽走溶剂。
实施例2 Ac-Phe-Phe-Trp(Boc)-Phe-Lys(Boc)-Val-Linker-Amide Resin的制备
将在实施例1中所获得的肽基树脂的N-末端Fmoc基团脱保护，用20％piperidine/DMF脱Fmoc二次，每次10min，取样K检，显色深蓝。用DMF洗涤树脂6次，抽走溶剂。
加入Ac 2O 3.8g、DIPEA 1.2mL、DMF 20mL，反应1.5h。洗涤树脂，抽走溶剂。
实施例3 Ac-Phe-Phe-Trp-Phe-Lys-Val-NH 2的制备
3.1裂解液配制
量取38.5mL的TFA、1.05mL的TIS、1.05mL的水、1.05mL的EDT加入三角锥瓶中， 磁力搅拌混合均匀后得到裂解液，封口放置-18℃冰箱备用。
异丙醚放置于-18℃冰箱冷冻备用。
3.2裂解及沉降
称取10g Ac-Phe-Phe-Trp(Boc)-Phe-Lys(Boc)-Val-Linker-Amide Resin，加入圆底烧瓶中，加入上述冷冻好的裂解液，搅拌反应2.5h。抽滤，收集滤液浓缩到体积的1/4备用。
向5L集气瓶中加入320mL预冻好的异丙醚，在搅拌条件下，将上述浓缩备用的浓缩液缓慢加入集气瓶中，有大量固体析出，上层变清，固液分层明显。
将上层清液倒出，剩余液体装入250mL的离心瓶中，4000rpm，离心2min。弃去上清液。加入异丙醚搅拌洗涤离心6次，直至pH值为3-4。
将上述离心得到的固体，真空干燥。得到5.5g粗肽(纯度76％)。
3.3纯化
取5.5g粗肽加入200mL溶剂(甲醇：乙酸：水＝8：1：1)溶解，0.22μm微孔滤膜过滤得到澄清透明溶液，通过反相HPLC纯化处理，纯化梯度如下：
时间(min) 流速(mL/min) A％(乙腈) B％(0.1％醋酸水溶液)
0 40 15 85
12 40 18 82
40 40 45 55
54 40 60 40
57 40 75 25
68 40 75 25
将过滤后的样品进样纯化，收集馏分，浓缩冻干，得到纯度99.027％的肽(5)Ac-Phe-Phe-Trp-Phe-Lys-Val-NH 2。
实施例4
本发明式(I)中的其他化合物可以通过上述类似的方法制备。
所获得的这些肽通过ESI-MS测定其分子量，部分化合物的测试结果见下表2。
表2质谱法测定分子量
编号 序列 分子量质谱分析结果
(5) Ac-Phe-Phe-Trp-Phe-Lys-Val-NH 2 913.53
(11) Ac-Phe-Phe-Trp-Phe-His-Leu-NH 2 936.54
(17) Ac-Phe-Phe-Trp-Phe-His-Gly-NH 2 880.38
实施例5细胞活性实验
5.1试剂与材料
磷酸盐缓冲液(PBS)(Gibco)、噻唑蓝(MTT)(Sigma)、二甲基亚砜(DMSO)(Sigma)、高糖培养基(DMEM)(Gibco)、胎牛血清(Gibco)。
5.2仪器
酶标仪(美国MD)、CO 2培养箱(上海一恒)、超净工作台(苏州净化)。
5.3细胞株
人角质形成细胞(HaCaT)购买自中国科学院典型培养物保藏委员会昆明细胞库。
5.4待测样品
给药组：
肽Ac-Phe-Phe-Trp-Phe-His-Val-NH 2(下称为参比肽)，测试浓度分别为1ppm、10ppm、50ppm、100ppm；
肽(5)，测试浓度分别为1ppm、10ppm、50ppm、100ppm；
肽(11)，测试浓度分别为1ppm、10ppm、50ppm、100ppm；
肽(17)，测试浓度分别为1ppm、10ppm、50ppm、100ppm。
control组：
PBS空白对照。
5.5实验方法
取冻存的HaCaT细胞培养，按照1：2传代至5代左右，选择长势较好的细胞作为实验对象。
将细胞2000个/孔接种在96孔板中，待细胞贴壁后，按照倍比稀释法，分别加入给药 组和对照组样品，补充培养基至200μL，置于37℃、5％CO 2培养箱中孵育72h。
之后每孔加入22μL 5mg/ml MTT，继续于37℃、5％CO 2培养箱中孵育4h。弃去原溶液，加入150μL/孔的DMSO。5min后使用酶标仪读取490nm和630nm波长下的参比OD值。
5.6结果
MTT法是一种检测细胞存活和生长的方法，以对照组为参照比值，各样品由高到低设定4个给药浓度，在HaCaT细胞上开展细胞活性检测实验，测得的OD值与细胞活性成正比。
图1为本发明的肽对HaCaT细胞活性影响结果图。结果显示，与control组相比，肽(5)、肽(11)、肽(17)及参比肽在100ppm以内对HaCaT细胞没有毒性。参比肽、肽(5)分别在50ppm、100ppm浓度对细胞产生显著的增殖作用。
实施例6抗炎细胞实验
6.1试剂与材料
胎牛血清、DMEM培养基、青霉素、链霉素、IL-6ELISA试剂盒、TNF-αELISA试剂盒。
6.2仪器
酶标仪、恒温CO 2培养箱、恒温箱。
6.3细胞株
小鼠单核巨噬细胞(RAW264.7细胞)。
6.4待测样品
给药组：
100ppm参比肽、100ppm肽(5)、100ppm肽(11)、100ppm肽(17)，用PBS溶液溶解。
control组：
PBS空白对照。
6.5实验方法
取冻存的RAW264.7细胞培养，按照1：2传代至5代左右，选择长势较好的细胞作为实验对象。
适当稀释取100000个/孔细胞悬液接种于6孔板上，待细胞长满至80％左右时，建立LPS刺激炎症模型。设置空白对照组(control)、LPS组、***组(DXM)、多肽组。空白对照组补充培养基至1000μL；LPS组加入200ng/mL LPS，补加培养基至1000μL；***组加入200ng/mL LPS及50ng/mL***，补加培养基至1000μL；多肽组加入200ng/mL LPS及多肽，补加培养基至1000μL(多肽最终测试浓度为100ppm)。继续于37℃、5％CO 2培养箱中孵育48h。3000rmp离心15min收集细胞上清获得样本液，按照IL-6、TNF-αELISA操作说明书进行操作。
6.6结果
炎症因子如TNF-α、IL-6等能够引起机体的免疫过度应答，导致肌肤的溃烂、红肿等问题，因此抑制皮肤中的单核细胞分泌的TNF-α、IL-6等炎症因子可以达到抗炎修复的功效。通过200ng/mL LPS刺激RAW264.7细胞建立炎症模型，探究本发明的肽的抗炎修复作用。
实验结果如图2、图3所示，经过LPS刺激，TNF-α、IL-6细胞因子明显上调。给药后，100ppm的肽(5)、肽(11)、肽(17)、参比肽能明显下调TNF-α的表达，其效果与阳性药物***相当，甚至具有比***更优的效果，其中肽(5)抑制TNF-α表达的作用更强。100ppm的肽(5)、肽(11)、肽(17)、参比肽亦能明显下调IL-6的表达。
由此说明，本发明的肽具有明显的抗炎修复作用。
实施例7皮肤受损屏障修复实验
7.1志愿者
7.1.1纳入标准：
18岁～60岁符合试验要求的志愿者。
7.1.2剔除及脱落标准：
未按规定用测试品，无法判定疗效者；
自行退出或未完成规定观察期而影响疗效判定者；
纳入病例因发生不良反应事件而不能继续接受试验者。
7.2试剂与仪器
十二烷基硫酸钠(SDS)、Finn chamber斑试器(边长8mm，面积64mm 2)、经皮水分扩散测试仪、C-Cube皮肤成像***。
7.3样品配制及分组
空白对照：不置任何物质。
SDS组：10％SDS溶液。
溶剂组：0.3％卡波姆980，0.3％精氨酸，余量为水。制备方法：将卡波姆分散在水中，加热至80℃，搅拌溶解完全；降温至45℃左右，加入精氨酸，搅拌混合溶解即得。
50ppm参比肽组：在溶剂组的基础上，加入参比肽，混合溶解使之最终浓度为50ppm即得。
50ppm肽(5)组：在溶剂组的基础上，加入肽(5)，混合溶解使之最终浓度为50ppm即得。
7.4测定步骤
7.4.1皮肤屏障受损状态的建立
将25μL 10％SDS溶液注入斑试器小室内，浸润滤纸片，用低致敏胶带贴敷于受试者左臂曲侧，相邻斑试器小室边缘间距不小于3cm，用手掌轻压使之均匀地贴敷于皮肤上，持续6-8h。去除斑试器后，受试者在符合标准的测试环境中静坐30min(待压痕消失后)，测量各斑贴区域中心位置的TEWL值，每区域测量两次，测量结果以单臂10个斑贴区域TEWL值的平均值表示，作为初始值(D0)。静坐期间，受试者不能喝水和饮料。前臂暴露，呈测试状态放置，保持放松，避免触碰斑贴区域。
7.4.2 TEWL测定
TEWL初始值测量结束后，进行给药后测试。每次测量前，用清水清洁受试部位，并用无屑吸水干纸巾吸干。在符合标准的测试环境中静坐至少20min，不能喝水和饮料，前臂暴露，保持放松，避免触碰斑贴区域。在设定的测量时间点，测量各斑贴区域中心位置的TEWL值，各区域测量两次，测量结果以单臂10个斑贴区域内TEWL值的平均值表示。设定的测量时间点间隔不少于1d，设定仪器测试时间：造模后D1、D3。
7.4.3 C-Cube拍照
使用C-Cube对受损区域拍照，记录红斑指数。
7.5试验评估
测试指标为经表皮水分流失TEWL(Transepidermal Water Loss)以及C-Cube 2D图像分析。其中，TEWL值是基于菲克扩散定律，在规定的温湿度条件下，通过测量单位时间、单位横截面积，近表皮(近1cm以内)上不同点的水蒸气分压梯度，得到该值。TEWL值越高，代表单位时间、单位横截面积的经表皮水分流失量越多，皮肤屏障受损越严重；TEWL值越低，代表单位时间、单位横截面积的经表皮水分流失量越少，皮肤屏障受损越轻微。
将给药第1天、第3天测得的TEWL值分别与初始值(D0)进行比较，TEWL值改善结果见图4。结果显示，经SDS刺激后，与空白组相比，其余各组在第1天的时间点测试时，TEWL值明显增加。在3d时间点时，与SDS组相比，肽(5)的TEWL明显降低，而溶剂组3天与0天相比，TEWL改善值不明显，说明肽(5)能够降低SDS刺激后TWEL值，修复SDS刺激后的皮肤屏障，且肽(5)具有比参比肽更优的皮肤屏障修复作用。
红斑指数能直观反映皮肤受损状态，其值越大，皮肤受损越严重。图5是经SDS刺激后，在第1天和第3天分别测试得到的皮肤成像结果图。结果显示，经SDS刺激后，皮肤红斑面积明显增大。在第3天时，与SDS组相比，肽(5)能明显改善红斑面积。图6、图7是红斑指数分析结果。结果显示，与SDS组相比，肽(5)能明显降低红斑指数，且肽(5)对红斑指数改善值优于参比肽。
由此表明，肽(5)能够修复受损皮肤，具有优异的皮肤屏障修复作用。
实施例8含肽(5)的爽肤水的制备
Figure PCTCN2021143978-appb-000002
将尿囊素、甘油用水溶解，加热至85℃，保温30分钟；将PEG-7甘油椰油酸酯、肽(5)用水溶解；上述溶液冷却后混合，搅拌均匀，得混合溶液；将丙二醇、防腐剂、香精依次加入上述混合溶液，加水搅拌均匀，即得。
实施例9含肽(11)的洁面啫喱的制备
Figure PCTCN2021143978-appb-000003
将肽(11)加水溶解，搅拌均匀，得多肽溶液；将卡波姆、EDTA加水溶解，加热至85℃，保温30分钟，冷却后加入三乙醇胺，搅拌均匀，得混合溶液；将上述混合溶液、多肽溶液、防腐剂、香精依次加入水中搅拌，搅拌至完全溶胀，即得。
实施例10含肽(17)的乳液组合物
Figure PCTCN2021143978-appb-000004
Figure PCTCN2021143978-appb-000005
将0.01g肽(17)配制为0.02mg/mL的水溶液；将鲸蜡硬脂醇(和)鲸蜡硬脂基葡糖苷、霍霍巴油、矿物油、棕榈酸异丙酯加热至85℃，搅拌均匀；得A相；将甘油、尿囊素、聚丙烯酰胺(和)C13-14异链烷烃(和)月桂醇聚醚-7用水溶解，加热至85℃，得B相；将A相快速加入B相，恒温均质3-5min，冷却；冷却至60℃以下加入防腐剂，搅拌均匀，冷却至45℃以下加入多肽溶液、香精，即得。
以上内容是结合具体的优选实施方式对本发明所做的进一步详细的说明，但是不表示本发明的具体实施是局限于这些说明。对于本发明所属领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或是替换，都应视为属于本发明的保护范围。

Claims (10)

  1. 式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，
    R 1-Phe-Phe-Trp-Phe-X 1-X 2-R 2(I)
    式(I)中，
    X 1选自：-Lys-或-His-；
    X 2选自：-Val-、-Leu-或-Gly-；
    R 1选自：H或R 3-CO-，其中R 3选自：取代的或未取代的烷基、取代的或未取代的烯基；
    R 2选自：-NR 4R 5或-OR 4，其中各个R 4和R 5彼此独立地选自：H、取代的或未取代的烷基、取代的或未取代的烯基；
    所述烷基是指具有1-24个碳原子(可选具有1-16个碳原子；可选具有1-14个碳原子；可选具有1-12个碳原子；可选具有1、2、3、4、5、或6个的碳原子)的饱和脂肪族直链或支链的烷基；可选选自：甲基、乙基、异丙基、异丁基、叔丁基、戊基、己基、庚基、辛基、癸基、十二烷基、十四烷基、十六烷基、十八烷基、2-乙基己基、2-甲基丁基、或5-甲基己基；
    所述烯基是指具有2-24个碳原子(可选具有2-16个碳原子；可选具有2-14个碳原子；可选具有2-12个碳原子；可选具有2、3、4、5、或6个碳原子)的直链或支链烯基；所述烯基具有一个或多个碳-碳双键，可选具有1、2或3个共轭或非共轭的碳-碳双键；所述烯基是通过一个单键而结合至分子的其余部分；可选选自：乙烯基、油烯基、或亚油烯基；
    可选地，所述“取代的烷基”、“取代的烯基”中的取代基选自C 1-C 4烷基；羟基；C 1-C 4烷氧基；氨基；C 1-C 4氨基烷基；C 1-C 4羰氧基；C 1-C 4氧基羰基；卤素(如氟、氯、溴、以及碘)；氰基；硝基；叠氮化物；C 1-C 4烷基磺酰基；硫醇；C 1-C 4烷硫基；C 6-C 30芳氧基如苯氧基；-NR b(C＝NR b)NR bR c，其中R b和R c是独立地选自：H、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 3-C 10环烷基、C 6-C 18芳基、C 7-C 17芳烷基、具有三至十元的杂环基、或氨基的保护基。
  2. 根据权利要求1所述的式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，其特征在于，R 1选自：H、乙酰基、叔-丁酰基、己酰基、2-甲基己酰基、辛酰基、癸酰基、月桂酰基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油酰基或亚油酰基；
    可选地，R 1选自H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基；
    可选地，R 1是H、乙酰基或棕榈酰基。
  3. 根据权利要求1所述的式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，其特征在于，R 4、R 5彼此独立地选自：H、甲基、乙基、己基、十二烷基或十六烷基；
    可选地，R 4是H并且R 5选自：H、甲基、乙基、己基、十二烷基或十六烷基；
    可选地，R 2是-OH或-NH 2。
  4. 根据权利要求1-3任一项所述的式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，其特征在于，选自下列肽(1)-(18)：
    (1)H-Phe-Phe-Trp-Phe-Lys-Val-OH；
    (2)Ac-Phe-Phe-Trp-Phe-Lys-Val-OH；
    (3)Palm-Phe-Phe-Trp-Phe-Lys-Val-OH；
    (4)H-Phe-Phe-Trp-Phe-Lys-Val-NH 2；
    (5)Ac-Phe-Phe-Trp-Phe-Lys-Val-NH 2；
    (6)Palm-Phe-Phe-Trp-Phe-Lys-Val-NH 2；
    (7)H-Phe-Phe-Trp-Phe-His-Leu-OH；
    (8)Ac-Phe-Phe-Trp-Phe-His-Leu-OH；
    (9)Palm-Phe-Phe-Trp-Phe-His-Leu-OH；
    (10)H-Phe-Phe-Trp-Phe-His-Leu-NH 2；
    (11)Ac-Phe-Phe-Trp-Phe-His-Leu-NH 2；
    (12)Palm-Phe-Phe-Trp-Phe-His-Leu-NH 2；
    (13)H-Phe-Phe-Trp-Phe-His-Gly-OH；
    (14)Ac-Phe-Phe-Trp-Phe-His-Gly-OH；
    (15)Palm-Phe-Phe-Trp-Phe-His-Gly-OH；
    (16)H-Phe-Phe-Trp-Phe-His-Gly-NH 2；
    (17)Ac-Phe-Phe-Trp-Phe-His-Gly-NH 2；
    (18)Palm-Phe-Phe-Trp-Phe-His-Gly-NH 2。
  5. 根据权利要求1所述的式(I)所示的肽，或其立体异构体、或立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐，其特征在于，
    所述美容上可接受的盐或药学上可接受的盐包括式(I)所示的肽的金属盐，所述金属包括：锂、钠、钾、钙、镁、锰、铜、锌或铝；
    可选地，所述美容上可接受的盐或药学上可接受的盐包括式(I)所示的肽与无机酸或有机酸形成的盐，所述有机酸包括：乙酸、柠檬酸、乳酸、丙二酸、马来酸、酒石酸、延胡索酸、苯甲酸、天冬氨酸、谷氨酸、琥珀酸、油酸、三氟乙酸、草酸、扑酸或葡萄糖酸；
    可选地，所述无机酸包括：盐酸、硫酸、硼酸或碳酸。
  6. 一种美容或药用组合物，其特征在于，包括有效量的权利要求1-5任一项所述的式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，以及至少一种赋形剂和任选的美容上或药学上可接受的佐剂；
    可选地，所述佐剂选自：胶原合成刺激剂、调节PGC-1α合成的剂、调节PPARγ的活性的剂、增加或减少脂肪细胞的甘油三酸酯含量的剂、刺激或延迟脂肪细胞分化的剂、脂解剂或刺激脂肪分解的剂、溶脂剂、生脂剂、乙酰胆碱受体聚集的抑制剂、抑制肌肉收缩的剂、抗胆碱能试剂、弹性蛋白酶抑制剂、基质金属蛋白酶抑制剂、黑色素合成刺激或抑制剂、增白剂或脱色剂、促色素沉着剂、自晒黑剂、抗老化剂、NO-合酶抑制剂、5α-还原酶抑制剂、赖氨酰羟化酶和/或脯氨酰羟化酶的抑制剂、抗氧化剂、自由基清除剂和/或抗大气污染的剂、活性羰基类物质清除剂、抗糖化剂、抗组胺剂、抗病毒剂、抗寄生虫剂、乳化剂、润肤剂、有机溶剂、液体推进剂、皮肤调理剂、保湿剂、保留水分的物质、α羟基酸、β羟基酸、增湿剂、表皮水解酶、维生素、氨基酸、蛋白质、色素或着色剂、染料、生物聚合物、胶凝聚合物、增稠剂、表面活性剂、软化剂、粘合剂、防腐剂、抗皱剂、能够减少或治疗下眼袋的剂、去角质剂、角质剥离剂、角质层分离剂、抗微生物剂、抗真菌剂、抑真菌剂、灭菌剂、抑菌剂、刺激真皮或表皮大分子的合成和/或能够抑制或预防它们的降解的剂、刺激弹性蛋白合成的剂、刺激核心蛋白聚糖合成的剂、刺激层粘连蛋白合成的剂、刺激防御素合成的剂、刺激伴侣蛋白合成的剂、刺激cAMP合成的剂、热休克蛋白、刺激HSP70合成的剂、刺激热休克蛋白合成的剂、刺激透明质酸合成的剂、刺激纤连蛋白合成的剂、刺激去乙酰化酶合成的剂、刺激脂质和角质层组分的合成的剂、神经酰胺、脂肪酸、抑制胶原降解的剂、抑制 弹性蛋白降解的剂、抑制丝氨酸蛋白酶的剂、刺激成纤维细胞增殖的剂、刺激角质形成细胞增殖的剂、刺激脂肪细胞增殖的剂、刺激黑色素细胞增殖的剂、刺激角质形成细胞分化的剂、抑制乙酰胆碱酯酶的剂、皮肤松弛剂、刺激糖胺聚糖合成的剂、抗角化过度剂、粉刺溶解剂、抗银屑病剂、抗皮炎剂、抗湿疹剂、DNA修复剂、DNA防护剂、稳定剂、止痒剂、用于治疗和/或护理敏感性皮肤的剂、固化剂、紧致剂、重构剂、抗拉伸纹剂、粘合剂、调节皮脂产生的剂、止汗剂、刺激愈合的剂、协助愈合的剂、刺激再上皮化的剂、协助再上皮化的剂、细胞因子生长因子、镇静剂、抗炎剂、麻醉剂、作用于毛细血管循环和/或微循环的剂、刺激血管生成的剂、抑制血管渗透性的剂、静脉紧张剂、作用于细胞代谢的剂、用于改善真皮-表皮接合的剂、诱导毛发生长的剂、毛发生长抑制或延缓剂、香料、螯合剂、植物提取物、精油、海洋提取物、得自生物发酵过程的剂、无机盐、细胞提取物、防晒剂、以及有效抗A和/或B紫外线的有机或无机光防护剂或其混合物。
  7. 根据权利要求6所述的美容或药用组合物，其特征在于，所述美容或药用组合物的制剂选自：霜剂、油、奶、香膏、泡沫、洗剂、凝胶、擦剂、浆液、皂、洗发精、润发乳、血清、软膏、摩丝、润发油、粉末、杆剂、笔剂、喷雾剂、气溶胶、胶囊剂、片剂、颗粒剂、口香糖、溶液、混悬液、乳剂、糖浆剂、酏剂、多糖薄膜、胶冻或明胶；
    可选地，所述胶囊剂包括：软胶囊剂、硬胶囊剂，可选为明胶胶囊剂；
    可选地，所述片剂包括：糖衣片剂。
  8. 一种美容上或药学上可接受的递送***或缓释***，其特征在于，包含有效量的权利要求1-5任一项所述的式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，或权利要求6或7所述的美容或药用组合物；
    所述美容上或药学上可接受的递送***或缓释***选自：脂质体、油质体、非离子型表面活性剂脂质体囊泡、醇质体、毫米胶囊、微米胶囊、纳米胶囊、纳米结构的脂质载体、海绵状物、环糊精、类脂囊泡、胶束、毫米球、微米球、纳米球、脂质球、微米乳液、纳米乳液、毫米粒子、微米粒子或纳米粒子；可选为脂质体或微米乳液，可选具有反胶束的内部结构的油包水型微米乳液。
  9. 权利要求1-5任一项所述的式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，或权利要求6或7所述美容或药用组合物，或权利要求8所述的美容上或药学上可接受的递送***或缓释***在制备用于抗炎 的美容组合物或药物组合物中的用途。
  10. 权利要求1-5任一项所述的式(I)所示的肽，或其立体异构体、或立体异构体的混合物，或其美容上可接受的盐、或其药学上可接受的盐，或权利要求6或7所述美容或药用组合物，或权利要求8所述的美容上或药学上可接受的递送***或缓释***在制备用于修复皮肤屏障的美容组合物或药物组合物中的用途。
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CN117106021A (zh) * 2023-10-25 2023-11-24 深圳市维琪科技股份有限公司 六肽及其组合物和用途
CN117106021B (zh) * 2023-10-25 2023-12-26 深圳市维琪科技股份有限公司 六肽及其组合物和用途

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