WO2021017834A1 - Skin composition for external use having anti-inflammatory effect - Google Patents

Skin composition for external use having anti-inflammatory effect Download PDF

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Publication number
WO2021017834A1
WO2021017834A1 PCT/CN2020/102178 CN2020102178W WO2021017834A1 WO 2021017834 A1 WO2021017834 A1 WO 2021017834A1 CN 2020102178 W CN2020102178 W CN 2020102178W WO 2021017834 A1 WO2021017834 A1 WO 2021017834A1
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Prior art keywords
composition
birch sap
skin
concentration
external
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PCT/CN2020/102178
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French (fr)
Chinese (zh)
Inventor
王莎莎
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浙江养生堂天然药物研究所有限公司
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Publication of WO2021017834A1 publication Critical patent/WO2021017834A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates to an external skin composition with anti-inflammatory effects, which comprises concentrated birch tree sap with a concentration factor of about 1.05-8 times, preferably about 1.1-4 times.
  • the external skin composition includes a pharmaceutical composition and a cosmetic composition, especially a skin care cosmetic composition.
  • Birch sap is the sap that flows from the birch family plant. It is rich in polysaccharides, amino acids, vitamins, biotin, cytokinins, minerals, etc. that the human body needs. It has good anti-inflammatory and soothing effects and can inhibit various causes. (Including the external temperature is too cold and hot, ultraviolet radiation, detergent irritation, bacteria and viruses and other microorganisms whatsoever of the skin, etc.) skin erythema, edema, tingling, fever, itching, vasodilation problems.
  • the present invention relates to a concentrated birch sap with a concentration factor of about 1.05-8 times, preferably about 1.1-4 times.
  • the present invention relates to the use of concentrated birch tree juice in a skin external composition with anti-inflammatory effects, wherein the concentration factor of the concentrated birch tree juice is about 1.05-8 times, preferably about 1.1-4 times.
  • the present invention relates to a skin topical composition with anti-inflammatory effect, which comprises (A) concentrated birch sap with a concentration factor of about 1.05-8 times, preferably about 1.1-4 times.
  • the external skin composition includes a pharmaceutical composition and a cosmetic composition, especially a skin care cosmetic composition.
  • the birch sap involved in the present invention is obtained from the genus Betula, Betula alba, Betula pubescens, Betula Pendula and Asian white birch (Betula platyphylla). Varieties.
  • the birch sap is a colorless, transparent, no-sediment-free, and no-drug sap that is artificially collected by drilling holes at the base of the trunk of the birch from thawing to early spring.
  • the birch sap is commercially available and used as it is, for example, it can be purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd.
  • the concentrated birch sap in the present invention is obtained by concentrating the above-mentioned commercial products. Concentration methods are known in the art, such as heating concentration, low-temperature vacuum concentration, membrane concentration and the like. In the present invention, the concentration is preferably carried out by a low-temperature freeze concentration or membrane concentration process. For example, the commercially available birch juice stock solution is input into a low-temperature drying equipment, the temperature is lowered to -40°C to -70°C, and the vacuum is applied to 0.1-30Pa. Concentrated in vacuum at low temperature to obtain concentrated birch sap with different concentration times.
  • concentrated birch sap has significantly better anti-inflammatory effects, which can effectively protect mast cells, inhibit the release of inflammatory mediators, and relieve Skin erythema, edema, irritation, fever, itching, vasodilation caused by various reasons (including external temperature too cold and overheating, ultraviolet radiation, detergent stimulation, bacterial virus and other microorganisms persecuting the skin, etc.), repair fragile skin , Strengthen the skin barrier, soothe and treat sensitive skin.
  • controlling the concentration ratio of birch sap is critical.
  • controlling the concentration ratio of birch sap is about 1.05-8 times, preferably about 1.1-4 times.
  • the external skin composition of the present invention does not contain chelating agents such as EDTA salt, sodium polyphosphate, sodium metaphosphate, and gluconic acid.
  • chelating agents such as EDTA salt, sodium polyphosphate, sodium metaphosphate, and gluconic acid.
  • the skin external composition of the present invention does not contain any added water, but does not exclude moisture inherently contained in each component.
  • the content of the (A) concentrated birch sap may be about 18-98% by weight, preferably 20-95% by weight, more preferably 22-90% by weight, most preferably 30-90% by weight, based on the skin external composition The total weight.
  • the external skin composition may optionally contain (B) ingredients commonly used in skin external compositions, especially ingredients commonly used in skin care cosmetic compositions.
  • the common ingredients are known in the art, and include, for example, vehicles, active ingredients, and auxiliary materials.
  • Those skilled in the art can select the type and amount of component (B) according to needs. For example, the content of component (B) is about 2-82% by weight, based on the total weight of the skin external composition.
  • the vehicle is known in the art and includes, for example, a diluent, a dispersant, or a carrier. Examples thereof include, but are not limited to, ethanol, dipropylene glycol, butylene glycol and the like.
  • the content of the vehicle in the skin topical composition is known in the art, for example, it usually accounts for 0.5-20% of the total weight of component (B).
  • the active ingredients are known in the art and include, for example, emollients, moisturizers, anti-inflammatory active ingredients and the like.
  • emollient examples include, but are not limited to, olive oil, macadamia nut oil, sweet almond oil, grape seed oil, avocado oil, corn oil, sesame oil, soybean oil, peanut oil, white flower seed oil, safflower seed oil, Dogtooth rose hip oil, argan tree kernel oil, jojoba seed oil, sunflower seed oil, palm tree fruit oil, squalane, ethylhexyl palmitate, isopropyl myristate, hydrogenated polyisobutylene, isotene Hexane, isododecane, diethylhexyl carbonate, dioctyl carbonate, isopropyl lauroyl sarcosine, isononyl isononanoate, hydrogenated polydecene, glycerol tri(ethylhexanoate) , Cetyl alcohol ethyl hexanoate, bis-diethoxy diethylene glycol cyclohexane
  • solid emollients include, but are not limited to, cetyl alcohol, stearyl alcohol, cetearyl alcohol, behenyl alcohol, scylitol, lauric acid, myristic acid, palmitic acid, stearic acid, beeswax, candelilla Tree wax, carnauba wax, lanolin, ozokerite, jojoba seed wax, paraffin wax, microcrystalline wax, hydrogenated rice bran wax, hydrogenated coconut oil glycerides, glyceryl behenate/eicosanate, myristyl alcohol One or more of myristate, bis-diglyceride polyacyl adipate-2, shea butter, and muluxing palm seed butter.
  • the content of the emollient in the external skin composition is known in the art, for example, it usually accounts for 1-50% of the total weight of the component (B).
  • moisturizer examples include, but are not limited to, glycerin, diglycerin, butylene glycol, propylene glycol, 1,3-propanediol, dipropylene glycol, 1,2-pentanediol, polyethylene glycol-8, polyethylene glycol Alcohol-32, methylglucitol-10, methylglucitol-20, PEG/PPG-17/6 copolymer, glycerol-7, glycerol-26, glycerol glucoside, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PEG/PPG/polybutylene glycol-8/5/3 glycerin, sucrose, trehalose, rhamnose, mannose, raffinose, Betaine, erythritol, xylitol, urea, glyceryl polyether-5 lactate, sodium hyaluronate, hydrolyzed sodium hyaluronate, acetyl
  • anti-inflammatory active ingredients include, but are not limited to, dipotassium glycyrrhizinate, portulaca (PORTULACA OLERACEA) extract, oat (AVENA SATIVA) kernel extract (oatyl anthranilic acid), panthenol, allantoin , Biological sugar gum-1, ⁇ -glucan, fructan, SCUTELLARIA BAICALENSIS root extract, Aesculus HIPPOCASTANUM extract, bisabolol, 4-tert-butyl cyclohexanol, nerve Amide 3, hydrogenated lecithin, licorice root (GLYCYRRHIZA GLABRA) extract, hydrolyzed royal jelly protein, oryzanol, phytosphingosine, quercetin (quercetin), ginger root extract, rosemary leaf extract, white flower One or more of chamomile extract, calendula extract, centella asiatica extract, naringin, hesperidin, etc.
  • the anti-inflammatory active ingredient may also be one or more of glucocorticoids or calcineurin inhibitors, such as cortisone, erythromycin, mometasone furoate, fluticasone propionate, tacrolimus , Pimecrolimus and so on.
  • the content of the anti-inflammatory active ingredient in the skin external composition is known in the art, for example, it usually accounts for 0.01-10% of the total weight of the component (B).
  • auxiliary materials include, for example, emulsifiers, thickeners, preservatives, perfumes and the like.
  • emulsifier examples include, but are not limited to, cetearyl oleate, sorbitan oleate, polysorbate-60, polysorbate-80, methylglucose sesquistearic acid Ester, PEG-20 methyl glucose sesquistearate, PEG-40 hydrogenated castor oil, PPG-26-butanol-26, PEG-4 polyglycerol-2 stearate, PEG-60 hydrogenated Castor oil, steareth-2, steareth-21, PPG-13-decyltetradeceth-24, cetearyl glucoside, PEG-100 stearate, glycerin Stearate, Glyceryl Stearate SE, Coco Glucoside, Ceteareth-25, PEG-40 Stearate, Polyglyceryl-3 Methyl Glucose Distearate, Glyceryl stearate citrate, polyglyceryl-10 stearate, polyglyceryl-10 myristate, polyglyce
  • the thickener examples include, but are not limited to, carbomers, acrylic acid (ester) and its derivatives, xanthan gum, gum arabic, polyethylene glycol-14M, polyethylene glycol-90M, succinyl poly One or more of high molecular polymers such as sugar, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.
  • the content of the thickener in the external skin composition is known in the art, for example, it usually accounts for 0.1-10% of the total weight of the component (B).
  • preservatives examples include, but are not limited to, methylparaben, propylparaben, phenoxyethanol, benzyl alcohol, phenethyl alcohol, bis(hydroxymethyl)imidazolidinylurea, potassium sorbate, sodium benzoate, chlorobenzene Glycerol, sodium dehydroacetate, caprylic hydroxamic acid, 1,2-hexanediol, 1,2-pentanediol, p-hydroxyacetophenone, caprylyl glycol, glyceryl caprylate, undecylenic acid
  • the content of the preservative in the external skin composition is known in the art, for example, it usually accounts for 0.01-2% of the total weight of the component (B).
  • the skin external composition of the present invention can be prepared by any suitable method known in the art.
  • it can be prepared by dissolving tanks, emulsifying pots, dispersers, and delivery pumps commonly used in the cosmetics field.
  • dissolving tanks emulsifying pots, dispersers, and delivery pumps commonly used in the cosmetics field.
  • When preparing put the water-soluble substance into the water-phase dissolving kettle, and the oil-soluble substance into the oil-phase dissolving kettle, and heat the temperature of the two kettles to about 80°C.
  • the raw materials that are easy to agglomerate they can be mixed with a disperser first. Pre-dispersion. After the dissolution is completed, the oil phase and the water phase are transported to the emulsifying pot for homogenization and emulsification for about 5-15 minutes.
  • the temperature of the material body is reduced to normal temperature, optional flavors, preservatives, etc. are added, and the pH of the product is adjusted as necessary.
  • the products can be filled and shipped only after the relevant test indicators are qualified.
  • the above preparation methods can be deleted or adjusted according to dosage form requirements.
  • the external skin composition of the present invention may be a pharmaceutical composition or a cosmetic composition, especially a cosmetic composition.
  • the cosmetic composition can be in various dosage forms such as lotion, spray, lotion, cream, cream or gel.
  • Example 1 The effect of birch sap stock and concentrated birch sap on histamine release from RBL-2H3 cells
  • the fresh white birch sap stock purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd. is fed into low-temperature drying equipment, cooled to -65°C, vacuumed to 0.1Pa, and concentrated to 1.05 times, 1.1 times, 1.2 times, 1.5 times, and 2 Times, 4 times, 8 times.
  • Compound 48/80 (a G protein activator) is a tool drug that causes degranulation of mast cells. Its mechanism is to act on the mast cell membrane, causing an increase in intracellular calcium ions, thereby increasing the amount of second messengers cAMP and cGMP Changes occur, causing mast cells to degranulate and release histamine.
  • the cell line RBL-2H3 was provided by the Animal Center of Zhejiang Academy of Medical Sciences; the test samples included 6 sample compositions to be tested, and the reagents included fetal bovine serum, Tyrode's salt, compound 48/80, and histamine Elisa kit.
  • Compound 48/80 solution preparation Weigh 1.0mg of 48/80 powder, dilute with 1mL Tyrode's solution, take 50uL and dilute to 1000uL, that is, a 48/80 solution with a concentration of 50ug/mL, which needs to be prepared for immediate use .
  • Model group Take 700uL cell suspension centrifugation and resuspend it in background solution, and place it at 37°C for 30 minutes.
  • Sample group Take 700uL cell suspension centrifugation and resuspend the sample solution, and place it at 37°C for 30 minutes.
  • each tube is 200uL; model group and 6 sample groups: add 50uL of 48/80 solution to the cell suspension, the final concentration is 10ug/mL, and place it at 37°C for 20 minutes. 3 repetitions per group.
  • Histamine determination Put the samples of the above groups in an ice box to cool for 10 minutes to stop the reaction. Centrifuge the sample after termination of the reaction (4°C, 1500 rpm, 30 minutes) to allow the cells to settle on the bottom of the EP tube, and transfer the supernatant to a new centrifuge tube. Resuspend the precipitated cells with 250 ⁇ L of 1x Tyrode's solution, put them in a 90°C water bath for heating, take it out 5 minutes later, immediately put it in the ice box, wait for the sample to cool down completely, take it out, put it in a 90°C water bath to heat again, repeat Freeze and thaw several times to break the cells. The supernatant and cell fluid were diluted 10-fold, and the stock solution was stored in a refrigerator at -20°C. The diluted sample is determined and calculated with an imported histamine kit for histamine determination. The calculation formula of histamine release rate is:
  • Example 2 The effect of birch sap stock and concentrated birch sap on the degranulation of zebrafish mast cells
  • the fresh white birch sap stock purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd. is fed into low-temperature drying equipment, cooled to -65°C, vacuumed to 0.1Pa, and concentrated to 1.05 times, 1.1 times, 1.2 times, 1.5 times, and 2 Times, 4 times, 8 times.
  • Test animal zebrafish 5 days after fertilization (5dpf)
  • Sample group to be tested birch sap stock solution and birch sap with different concentration times + 15 ⁇ g/ml SP.
  • Example 3 The effect of birch sap stock and concentrated birch sap on the model of irritant contact dermatitis in mice
  • the fresh birch sap stock solution purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd. is fed into the reverse osmosis circulation device, the operating pressure is controlled at 0.5-5bar, and the operating temperature is controlled at 20-35°C, and circulated until the birch sap is respectively concentrated to 1.1 Times, 1.2 times, 1.5 times, 2 times, 4 times.
  • Test animal ICR mouse, male
  • Test reagents 10% sodium dodecyl sulfate solution (SDS), 1% hydrocortisone ointment, depilatory cream
  • mice were randomly grouped according to their body weight, each with 12 mice, divided into normal group, model group, positive group, and each sample group to be tested. All mice used depilatory cream to remove the skin and hair of about 2*2cm area on the mouse abdomen. No other treatments were done for the normal group.
  • the model group, the positive group, and each sample group to be tested were applied with 10% sodium lauryl sulfate solution for 5 consecutive days to complete the modeling. After modeling, the positive group was smeared with 1% hydrocortisone ointment 3 times a day for 2 consecutive days; the model group was not treated; each sample group to be tested was sprayed with the corresponding mixed birch sap, 3 times a day, 2 consecutive days day. On the 7th day of the experiment, the skin conditions of the experimental mice in each group were observed, and the serum of the mice was taken to determine the content of inflammatory factor IL-1a.
  • Example 4 The effect of birch sap stock and concentrated birch sap on mice models of allergic contact dermatitis
  • the fresh birch sap stock solution purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd. is fed into the reverse osmosis circulation device, the operating pressure is controlled at 0.5-5bar, and the operating temperature is controlled at 20-35°C, and circulated until the birch sap is respectively concentrated to 1.1 Times, 1.2 times, 1.5 times, 2 times, 4 times.
  • Test animal ICR mouse, male
  • Investigation indicators ear thickness index, ear weight, inflammation index interferon- ⁇ (IFN- ⁇ ), interleukin-4 (IL-4)
  • Test materials 1% 2,4-dinitrofluorobenzene (DNFB) acetone olive oil solution (4:1), 1% hydrocortisone ointment, depilatory cream
  • mice were randomly grouped according to their body weight, each with 12 mice, divided into normal group, model group, positive group, and each sample group to be tested.
  • Each group of experimental mice used depilatory cream to remove the skin and hair in the abdomen area of about 2*2cm.
  • the abdomen and ears of mice in the normal group were evenly coated with acetone olive oil solution for control.
  • Mice in the model group, positive group, and each sample group to be tested were smeared with 1% DNFB-containing acetone olive oil solution for sensitization and stimulation to establish a mouse model of allergic contact dermatitis.
  • model group After being challenged, the model group was sprayed with distilled water; the positive group was sprayed with 1% hydrocortisone ointment for 2 consecutive days, 3 times/day; each sample group to be tested was sprayed with the corresponding mixed birch sap, 3 times a day, continuous administration 2 days.
  • anti-inflammatory spray composition is prepared as follows:
  • VISIA-CR Using VISIA-CR to collect the facial images of volunteers under the condition of using front and rear polarized light, and use IPP software to analyze the erythema area of the same measurement area at different test time points on the left and right cheeks of volunteers.
  • the formula of the anti-inflammatory cream composition is shown in the following table:
  • the aforementioned anti-inflammatory cream composition is prepared as follows:
  • Oil phase Add raw materials 4, 6, 7, 8, 9, 11, 12, 13, and 15 to the oil phase pot, and heat to 80°C, dissolve, and mix well;
  • Emulsification add the water phase and the oil phase to the emulsification tank, keep it at 80°C, homogenize emulsification at 3000rpm for 5 minutes, add No. 19 raw material after emulsification is complete;
  • step 3 The mixture of step 3 is added when the temperature is lowered to 40°C by stirring, and the mixture is uniformly stirred and discharged to obtain the anti-inflammatory facial cream composition.
  • Example 6 Anti-inflammatory emulsion composition
  • the anti-inflammatory emulsion composition described above is prepared as follows:
  • Oil phase add No. 4, 5, 6, 7, 12, 13 raw materials into the oil phase pot, and heat to 80°C, dissolve, and mix well;
  • Emulsification add the water phase and the oil phase to the emulsification tank, keep the temperature at 80°C, homogenize and emulsify for 5 minutes at 3000 rpm, and add No. 15 raw material after the emulsification is completed;
  • step 6 Add the mixture of step 3 when stirring and cooling down to 40°C, stir evenly and then discharge to obtain the anti-inflammatory emulsion composition.

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Abstract

A skin composition for external use having an anti-inflammatory effect, including concentrated birch sap, a degree of concentration being 1.05-8 times, preferably 1.1-4 times.

Description

具有抗炎功效的皮肤外用组合物External skin composition with anti-inflammatory effect 技术领域Technical field
本发明涉及一种具有抗炎功效的皮肤外用组合物，其包含浓缩桦树汁，其浓缩倍数为约1.05-8倍，优选约1.1-4倍。所述皮肤外用组合物包括药物组合物和化妆品组合物，尤其是护肤化妆品组合物。The present invention relates to an external skin composition with anti-inflammatory effects, which comprises concentrated birch tree sap with a concentration factor of about 1.05-8 times, preferably about 1.1-4 times. The external skin composition includes a pharmaceutical composition and a cosmetic composition, especially a skin care cosmetic composition.
背景技术Background technique
桦树汁是从桦木科植物中流出的汁液，富含人体需要的多糖、氨基酸、维生素、生物素、细胞***素、矿物质等，具有良好的抗炎舒敏功效，能够抑制由各种原因(包括外界温度过冷过热、紫外线辐射、洗涤剂刺激、细菌病毒等微生物对皮肤的迫害等)引起的皮肤红斑、水肿、刺痛、发热、瘙痒、血管扩张问题。Birch sap is the sap that flows from the birch family plant. It is rich in polysaccharides, amino acids, vitamins, biotin, cytokinins, minerals, etc. that the human body needs. It has good anti-inflammatory and soothing effects and can inhibit various causes. (Including the external temperature is too cold and hot, ultraviolet radiation, detergent irritation, bacteria and viruses and other microorganisms persecution of the skin, etc.) skin erythema, edema, tingling, fever, itching, vasodilation problems.
发明内容Summary of the invention
一方面，本发明涉及一种浓缩的桦树汁，其浓缩倍数为约1.05-8倍，优选约1.1-4倍。In one aspect, the present invention relates to a concentrated birch sap with a concentration factor of about 1.05-8 times, preferably about 1.1-4 times.
再一方面，本发明涉及浓缩的桦树汁在具有抗炎功效的皮肤外用组合物中的用途，其中浓缩的桦树汁的浓缩倍数为约1.05-8倍，优选约1.1-4倍。In another aspect, the present invention relates to the use of concentrated birch tree juice in a skin external composition with anti-inflammatory effects, wherein the concentration factor of the concentrated birch tree juice is about 1.05-8 times, preferably about 1.1-4 times.
另一方面，本发明涉及一种具有抗炎功效的皮肤外用组合物，其包含(A)浓缩桦树汁，其浓缩倍数为约1.05-8倍，优选约1.1-4倍。In another aspect, the present invention relates to a skin topical composition with anti-inflammatory effect, which comprises (A) concentrated birch sap with a concentration factor of about 1.05-8 times, preferably about 1.1-4 times.
所述皮肤外用组合物包括药物组合物和化妆品组合物，尤其是护肤化妆品组合物。The external skin composition includes a pharmaceutical composition and a cosmetic composition, especially a skin care cosmetic composition.
本发明中所涉及的桦树汁得自桦木科桦树属，其可来自白桦(Betula alba)、柔毛桦(Betula pubescens)、垂枝桦(Betula Pendula)和亚洲白桦(Betula platyphylla)这四个品种。所述桦树汁为在解冻至早春发叶之间，人工在桦树的树干基部钻孔收集而得的无色透明、无沉淀、无杂物，具有桦树清香营养丰富的汁液。所述桦树汁可商购获得并原样采用，例如可购自大兴安岭超越野生浆果开发有限责任公司。The birch sap involved in the present invention is obtained from the genus Betula, Betula alba, Betula pubescens, Betula Pendula and Asian white birch (Betula platyphylla). Varieties. The birch sap is a colorless, transparent, no-sediment-free, and no-drug sap that is artificially collected by drilling holes at the base of the trunk of the birch from thawing to early spring. The birch sap is commercially available and used as it is, for example, it can be purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd.
本发明中的浓缩桦树汁是将上述商购产品浓缩得到的。浓缩方法是本领域已知的，例如加热浓缩、低温真空浓缩、膜浓缩等。在本发明中，优选通过低温冷冻浓缩或膜浓缩工艺进行浓缩，例如，将商购的桦树汁原液输入低温干燥设备，降温至-40℃至-70℃，抽真空至0.1-30Pa而进行低温真空浓缩，从而得到不同浓缩倍数的浓缩桦树汁。The concentrated birch sap in the present invention is obtained by concentrating the above-mentioned commercial products. Concentration methods are known in the art, such as heating concentration, low-temperature vacuum concentration, membrane concentration and the like. In the present invention, the concentration is preferably carried out by a low-temperature freeze concentration or membrane concentration process. For example, the commercially available birch juice stock solution is input into a low-temperature drying equipment, the temperature is lowered to -40°C to -70°C, and the vacuum is applied to 0.1-30Pa. Concentrated in vacuum at low temperature to obtain concentrated birch sap with different concentration times.
意料不到地，本发明人发现，与未浓缩的桦树汁原液相比，浓缩桦树汁具有显著更好的抗炎功效，表现为能够有效保护肥大细胞，抑制炎症介质的释放，缓解由各种原因(包括外界温度过冷过热、紫外线辐射、洗涤剂刺激、细菌病毒等微生物对皮肤的迫害等)引起的皮肤红斑、水肿、刺痛、发热、瘙痒、血管扩张问题，修复脆弱肌肤，增强肌肤屏障，可舒缓和治疗敏感皮肤。Unexpectedly, the inventors discovered that, compared with unconcentrated birch sap, concentrated birch sap has significantly better anti-inflammatory effects, which can effectively protect mast cells, inhibit the release of inflammatory mediators, and relieve Skin erythema, edema, irritation, fever, itching, vasodilation caused by various reasons (including external temperature too cold and overheating, ultraviolet radiation, detergent stimulation, bacterial virus and other microorganisms persecuting the skin, etc.), repair fragile skin , Strengthen the skin barrier, soothe and treat sensitive skin.
进一步地，本发明人还发现，浓缩的桦树汁的抗炎功效与其浓缩程度并非简单的线性 关系，而是随着浓缩倍数增加而呈现先增加后下降的趋势。因此，控制桦树汁的浓缩倍数是关键的，在本发明中，控制桦树汁的浓缩倍数为约1.05-8倍，优选约1.1-4倍。Furthermore, the inventors also found that the anti-inflammatory effect of concentrated birch tree sap is not in a simple linear relationship with the degree of concentration, but a trend that first increases and then decreases as the concentration ratio increases. Therefore, controlling the concentration ratio of birch sap is critical. In the present invention, controlling the concentration ratio of birch sap is about 1.05-8 times, preferably about 1.1-4 times.
优选地，本发明的皮肤外用组合物不包含EDTA盐、多磷酸钠、偏磷酸钠、葡萄糖酸等螯合剂。Preferably, the external skin composition of the present invention does not contain chelating agents such as EDTA salt, sodium polyphosphate, sodium metaphosphate, and gluconic acid.
优选地，本发明的皮肤外用组合物不包含任何外加的水，但不排除各组分中固有地包含的水分。Preferably, the skin external composition of the present invention does not contain any added water, but does not exclude moisture inherently contained in each component.
所述(A)浓缩桦树汁的含量可以为约18-98％重量，优选20-95％重量，更优选22-90％重量，最优选30-90％重量，基于所述皮肤外用组合物的总重量。The content of the (A) concentrated birch sap may be about 18-98% by weight, preferably 20-95% by weight, more preferably 22-90% by weight, most preferably 30-90% by weight, based on the skin external composition The total weight.
除所述(A)浓缩桦树汁外，所述皮肤外用组合物还可以任选地包含(B)皮肤外用组合物中常用的成分，特别是护肤化妆品组合物中常用的成分。所述常用成分是本领域已知的，包括例如媒介物、活性成分和辅料等。本领域技术人员可根据需要选择组分(B)的类型和用量，例如，组分(B)的含量为约2-82％重量，基于所述皮肤外用组合物的总重量。In addition to the (A) concentrated birch sap, the external skin composition may optionally contain (B) ingredients commonly used in skin external compositions, especially ingredients commonly used in skin care cosmetic compositions. The common ingredients are known in the art, and include, for example, vehicles, active ingredients, and auxiliary materials. Those skilled in the art can select the type and amount of component (B) according to needs. For example, the content of component (B) is about 2-82% by weight, based on the total weight of the skin external composition.
所述媒介物是本领域已知的，包括例如稀释剂、分散剂或载体等。其实例包括但不限于乙醇、双丙甘醇、丁二醇等。所述媒介物在所述皮肤外用组合物中的含量是本领域已知的，例如，其通常占组分(B)总重量的0.5-20％。The vehicle is known in the art and includes, for example, a diluent, a dispersant, or a carrier. Examples thereof include, but are not limited to, ethanol, dipropylene glycol, butylene glycol and the like. The content of the vehicle in the skin topical composition is known in the art, for example, it usually accounts for 0.5-20% of the total weight of component (B).
所述活性成分是本领域已知的，包括例如润肤剂、保湿剂、抗炎活性成分等。The active ingredients are known in the art and include, for example, emollients, moisturizers, anti-inflammatory active ingredients and the like.
所述润肤剂的实例包括但不限于橄榄油、澳洲坚果油、甜杏仁油、葡萄籽油、鳄梨油、玉米油、芝麻油、大豆油、花生油、白池花籽油、红花籽油、狗牙蔷薇果油、刺阿干树仁油、霍霍巴籽油、向日葵籽油、毛瑞榈果油、角鲨烷、棕榈酸乙基己酯、肉豆蔻酸异丙酯、氢化聚异丁烯、异十六烷、异十二烷、碳酸二乙基己酯、碳酸二辛酯、月桂酰肌氨酸异丙酯、异壬酸异壬酯、氢化聚癸烯、甘油三(乙基己酸)酯、鲸蜡醇乙基己酸酯、双-二乙氧基二甘醇环己烷1,4-二羧酸酯、辛酸/癸酸甘油三酯、油醇芥酸酯、辛基十二醇肉豆蔻酸酯、辛基十二醇、聚二甲基硅氧烷、辛基聚甲基硅氧烷、鲸蜡基聚二甲基硅氧烷、环五聚二甲基硅氧烷等的一种或多种。固体润肤剂的实例包括但不限于鲸蜡醇、硬脂醇、鲸蜡硬脂醇、山嵛醇、鲨肝醇、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、蜂蜡、小烛树蜡、巴西棕榈蜡、羊毛脂、地蜡、霍霍巴籽蜡、石蜡、微晶蜡、氢化米糠蜡、氢化椰油甘油酯类、甘油山嵛酸酯/二十酸酯、肉豆蔻醇肉豆蔻酸酯、双-二甘油多酰基己二酸酯-2、牛油果树果脂、木鲁星果棕籽脂等中的一种或多种。所述润肤剂在所述皮肤外用组合物中的含量是本领域已知的，例如其通常占组分(B)总重量的1-50％。Examples of the emollient include, but are not limited to, olive oil, macadamia nut oil, sweet almond oil, grape seed oil, avocado oil, corn oil, sesame oil, soybean oil, peanut oil, white flower seed oil, safflower seed oil, Dogtooth rose hip oil, argan tree kernel oil, jojoba seed oil, sunflower seed oil, palm tree fruit oil, squalane, ethylhexyl palmitate, isopropyl myristate, hydrogenated polyisobutylene, isotene Hexane, isododecane, diethylhexyl carbonate, dioctyl carbonate, isopropyl lauroyl sarcosine, isononyl isononanoate, hydrogenated polydecene, glycerol tri(ethylhexanoate) , Cetyl alcohol ethyl hexanoate, bis-diethoxy diethylene glycol cyclohexane 1,4-dicarboxylate, caprylic/capric triglyceride, oleyl erucate, octyldodecanol Myristate, Octyldodecanol, Dimethicone, Octyl Dimethicone, Cetyl Dimethicone, Cyclopenta Dimethicone, etc. One or more. Examples of solid emollients include, but are not limited to, cetyl alcohol, stearyl alcohol, cetearyl alcohol, behenyl alcohol, scylitol, lauric acid, myristic acid, palmitic acid, stearic acid, beeswax, candelilla Tree wax, carnauba wax, lanolin, ozokerite, jojoba seed wax, paraffin wax, microcrystalline wax, hydrogenated rice bran wax, hydrogenated coconut oil glycerides, glyceryl behenate/eicosanate, myristyl alcohol One or more of myristate, bis-diglyceride polyacyl adipate-2, shea butter, and muluxing palm seed butter. The content of the emollient in the external skin composition is known in the art, for example, it usually accounts for 1-50% of the total weight of the component (B).
所述保湿剂的实例包括但不限于甘油、双甘油、丁二醇、丙二醇、1,3-丙二醇、双丙甘醇、1,2-戊二醇、聚乙二醇-8、聚乙二醇-32、甲基葡糖醇聚醚-10、甲基葡糖醇聚醚-20、PEG/PPG-17/6共聚物、甘油聚醚-7、甘油聚醚-26、甘油葡糖苷、PPG-10甲基葡糖醚、PPG-20甲基葡糖醚、PEG/PPG/聚丁二醇-8/5/3甘油、蔗糖、海藻糖、鼠李糖、甘露糖、棉子糖、甜菜碱、赤藓醇、木糖醇、尿素、甘油聚醚-5乳酸酯、透明质酸钠、水解透明质酸钠、乙酰化透明质酸钠、聚谷氨酸钠、水解小核菌胶、出芽短梗酶多糖、银耳多糖、酸豆籽多糖等中的一种或多种。所述保湿剂在所述皮肤外用组合物中的含量是本领域已知的， 例如，其通常占组分(B)总重量的1-30％。Examples of the moisturizer include, but are not limited to, glycerin, diglycerin, butylene glycol, propylene glycol, 1,3-propanediol, dipropylene glycol, 1,2-pentanediol, polyethylene glycol-8, polyethylene glycol Alcohol-32, methylglucitol-10, methylglucitol-20, PEG/PPG-17/6 copolymer, glycerol-7, glycerol-26, glycerol glucoside, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PEG/PPG/polybutylene glycol-8/5/3 glycerin, sucrose, trehalose, rhamnose, mannose, raffinose, Betaine, erythritol, xylitol, urea, glyceryl polyether-5 lactate, sodium hyaluronate, hydrolyzed sodium hyaluronate, acetylated sodium hyaluronate, sodium polyglutamate, Sclerotium hydrolysate One or more of gum, short-stemming enzyme polysaccharide, tremella polysaccharide, caper seed polysaccharide, etc. The content of the moisturizer in the skin external composition is known in the art, for example, it usually accounts for 1-30% of the total weight of the component (B).
所述抗炎活性成分的实例包括但不限于甘草酸二钾、马齿苋(PORTULACA OLERACEA)提取物、燕麦(AVENA SATIVA)仁提取物(燕麦酰基邻氨基苯甲酸)、泛醇、尿囊素、生物糖胶-1、β-葡聚糖、果聚糖、黄芩(SCUTELLARIA BAICALENSIS)根提取物、欧洲七叶树(AESCULUS HIPPOCASTANUM)提取物、红没药醇、4-叔丁基环己醇、神经酰胺3、氢化卵磷脂、光果甘草(GLYCYRRHIZA GLABRA)提取物、水解蜂王浆蛋白、谷维素、植物鞘氨醇、五羟黄酮(槲皮素)、姜根提取物、迷迭香叶提取物、白花黄春菊提取物、金盏花提取物、积雪草提取物、柚皮苷、橙皮苷等中的一种或多种。所述抗炎活性成分也可以是糖皮质激素或钙调神经磷酸酶抑制剂中的一种或多种，例如可的松、红霉素、糠酸莫米松、丙酸氟替卡松、他克莫司、吡美莫司等。所述抗炎活性成分在所述皮肤外用组合物中的含量是本领域已知的，例如，其通常占组分(B)总重量的0.01-10％。Examples of the anti-inflammatory active ingredients include, but are not limited to, dipotassium glycyrrhizinate, portulaca (PORTULACA OLERACEA) extract, oat (AVENA SATIVA) kernel extract (oatyl anthranilic acid), panthenol, allantoin , Biological sugar gum-1, β-glucan, fructan, SCUTELLARIA BAICALENSIS root extract, Aesculus HIPPOCASTANUM extract, bisabolol, 4-tert-butyl cyclohexanol, nerve Amide 3, hydrogenated lecithin, licorice root (GLYCYRRHIZA GLABRA) extract, hydrolyzed royal jelly protein, oryzanol, phytosphingosine, quercetin (quercetin), ginger root extract, rosemary leaf extract, white flower One or more of chamomile extract, calendula extract, centella asiatica extract, naringin, hesperidin, etc. The anti-inflammatory active ingredient may also be one or more of glucocorticoids or calcineurin inhibitors, such as cortisone, erythromycin, mometasone furoate, fluticasone propionate, tacrolimus , Pimecrolimus and so on. The content of the anti-inflammatory active ingredient in the skin external composition is known in the art, for example, it usually accounts for 0.01-10% of the total weight of the component (B).
所述辅料是本领域已知的，包括例如乳化剂、增稠剂、防腐剂、香料等。The auxiliary materials are known in the art and include, for example, emulsifiers, thickeners, preservatives, perfumes and the like.
所述乳化剂的实例包括但不限于鲸蜡硬脂醇橄榄油酸酯、山梨坦橄榄油酸酯、聚山梨醇酯-60、聚山梨醇酯-80、甲基葡糖倍半硬脂酸酯、PEG-20甲基葡糖倍半硬脂酸酯、PEG-40氢化蓖麻油、PPG-26-丁醇聚醚-26、PEG-4聚甘油-2硬脂酸酯、PEG-60氢化蓖麻油、硬脂醇聚醚-2、硬脂醇聚醚-21、PPG-13-癸基十四醇聚醚-24、鲸蜡硬脂基葡糖苷、PEG-100硬脂酸酯、甘油硬脂酸酯、甘油硬脂酸酯SE、椰油基葡糖苷、鲸蜡硬脂醇聚醚-25、PEG-40硬脂酸酯、聚甘油-3甲基葡糖二硬脂酸酯、甘油硬脂酸酯柠檬酸酯、聚甘油-10硬脂酸酯、聚甘油-10肉豆蔻酸酯、聚甘油-10二油酸酯、聚甘油-10月桂酸酯、聚甘油-10异硬脂酸酯、聚甘油-10油酸酯、聚甘油-10二异硬脂酸酯、聚甘油-6月桂酸酯、聚甘油-6肉豆蔻酸酯、蔗糖硬脂酸酯、蔗糖多硬脂酸酯等中的一种或多种。所述乳化剂在所述皮肤外用组合物中的含量是本领域已知的，例如，其通常占组分(B)总重量的0.5-10％。Examples of the emulsifier include, but are not limited to, cetearyl oleate, sorbitan oleate, polysorbate-60, polysorbate-80, methylglucose sesquistearic acid Ester, PEG-20 methyl glucose sesquistearate, PEG-40 hydrogenated castor oil, PPG-26-butanol-26, PEG-4 polyglycerol-2 stearate, PEG-60 hydrogenated Castor oil, steareth-2, steareth-21, PPG-13-decyltetradeceth-24, cetearyl glucoside, PEG-100 stearate, glycerin Stearate, Glyceryl Stearate SE, Coco Glucoside, Ceteareth-25, PEG-40 Stearate, Polyglyceryl-3 Methyl Glucose Distearate, Glyceryl stearate citrate, polyglyceryl-10 stearate, polyglyceryl-10 myristate, polyglyceryl-10 dioleate, polyglyceryl-10 laurate, polyglyceryl-10 isostearate Fatty acid ester, polyglyceryl-10 oleate, polyglyceryl-10 diisostearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate, sucrose stearate, sucrose polystearate One or more of acid esters. The content of the emulsifier in the skin external composition is known in the art, for example, it usually accounts for 0.5-10% of the total weight of the component (B).
所述增稠剂的实例包括但不限于卡波姆类、丙烯酸(酯)类及其衍生物、黄原胶、***胶、聚乙二醇-14M、聚乙二醇-90M、琥珀酰聚糖、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素等高分子聚合物中的一种或多种。所述增稠剂在所述皮肤外用组合物中的含量是本领域已知的，例如，其通常占组分(B)总重量的0.1-10％。Examples of the thickener include, but are not limited to, carbomers, acrylic acid (ester) and its derivatives, xanthan gum, gum arabic, polyethylene glycol-14M, polyethylene glycol-90M, succinyl poly One or more of high molecular polymers such as sugar, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. The content of the thickener in the external skin composition is known in the art, for example, it usually accounts for 0.1-10% of the total weight of the component (B).
所述防腐剂的实例包括但不限于羟苯甲酯、羟苯丙酯、苯氧乙醇、苯甲醇、苯乙醇、双(羟甲基)咪唑烷基脲、山梨酸钾、苯甲酸钠、氯苯甘醚、脱氢乙酸钠、辛酰羟肟酸、1,2-己二醇、1,2-戊二醇、对羟基苯乙酮、辛甘醇、甘油辛酸酯、十一碳烯酸甘油酯、山梨坦辛酸酯、乙基己基甘油、牡丹根提取物等中的一种或多种。所述防腐剂在所述皮肤外用组合物中的含量是本领域已知的，例如，其通常占组分(B)总重量的0.01-2％。Examples of the preservatives include, but are not limited to, methylparaben, propylparaben, phenoxyethanol, benzyl alcohol, phenethyl alcohol, bis(hydroxymethyl)imidazolidinylurea, potassium sorbate, sodium benzoate, chlorobenzene Glycerol, sodium dehydroacetate, caprylic hydroxamic acid, 1,2-hexanediol, 1,2-pentanediol, p-hydroxyacetophenone, caprylyl glycol, glyceryl caprylate, undecylenic acid One or more of glycerides, sorbitan caprylate, ethylhexylglycerol, tree peony root extract, etc. The content of the preservative in the external skin composition is known in the art, for example, it usually accounts for 0.01-2% of the total weight of the component (B).
本发明的皮肤外用组合物可以通过本领域已知的任何合适的方法制备。例如，使用化妆品领域中常用的溶解槽、乳化锅、分散器、输送泵等设备制备。制备时先将水溶性物质投入水相溶解釜，将油溶性物质投入油相溶解釜，将两个釜的温度加热至约80℃，其中对于易结块的原料，可先用分散器将其预分散。待溶解完成后将油相和水相输送至乳化锅中， 均质乳化约5-15分钟。乳化完成后将料体温度降至常温，加入任选的香精、防腐剂等，并视需要调节产物的pH。相关检测指标都合格后方可灌装出货。以上制备方法可根据剂型要求进行删减或调整。The skin external composition of the present invention can be prepared by any suitable method known in the art. For example, it can be prepared by dissolving tanks, emulsifying pots, dispersers, and delivery pumps commonly used in the cosmetics field. When preparing, put the water-soluble substance into the water-phase dissolving kettle, and the oil-soluble substance into the oil-phase dissolving kettle, and heat the temperature of the two kettles to about 80°C. For the raw materials that are easy to agglomerate, they can be mixed with a disperser first. Pre-dispersion. After the dissolution is completed, the oil phase and the water phase are transported to the emulsifying pot for homogenization and emulsification for about 5-15 minutes. After the emulsification is completed, the temperature of the material body is reduced to normal temperature, optional flavors, preservatives, etc. are added, and the pH of the product is adjusted as necessary. The products can be filled and shipped only after the relevant test indicators are qualified. The above preparation methods can be deleted or adjusted according to dosage form requirements.
本发明的皮肤外用组合物可以是药物组合物或者化妆品组合物，尤其是化妆品组合物。所述化妆品组合物可以是化妆水、喷雾、乳液、膏、霜或凝胶等各种剂型。The external skin composition of the present invention may be a pharmaceutical composition or a cosmetic composition, especially a cosmetic composition. The cosmetic composition can be in various dosage forms such as lotion, spray, lotion, cream, cream or gel.
实施例Example
以下结合实施例，对本发明进行进一步详细说明。但是，应当理解为，这些实施例、对比例仅仅是用于更详细地说明本发明，而不应理解为用于以任何形式限制本发明所附权利要求书的范围。Hereinafter, the present invention will be further described in detail with reference to the embodiments. However, it should be understood that these examples and comparative examples are only used to describe the present invention in more detail, and should not be understood as limiting the scope of the appended claims of the present invention in any form.
实施例1：桦树汁原液和浓缩桦树汁对RBL-2H3细胞释放组胺的影响Example 1: The effect of birch sap stock and concentrated birch sap on histamine release from RBL-2H3 cells
在本实施例中，测试和对比桦树汁原液和不同浓缩倍数的浓缩桦树汁对RBL-2H3细胞释放组胺的影响。In this example, the effects of the original birch sap and the concentrated birch sap with different concentration ratios on the release of histamine from RBL-2H3 cells were tested and compared.
1.桦树汁的浓缩1. Concentration of birch sap
将购自大兴安岭超越野生浆果开发有限责任公司的新鲜白桦树汁原液输入低温干燥设备，降温至-65℃，抽真空至0.1Pa，分别浓缩至1.05倍、1.1倍、1.2倍、1.5倍、2倍、4倍、8倍。The fresh white birch sap stock purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd. is fed into low-temperature drying equipment, cooled to -65℃, vacuumed to 0.1Pa, and concentrated to 1.05 times, 1.1 times, 1.2 times, 1.5 times, and 2 Times, 4 times, 8 times.
2.测试方法2. Test method
实验原理：化合物48/80(一种G蛋白激活剂)是引起肥大细胞脱颗粒反应的工具药，其机制是作用于肥大细胞膜，引起细胞内钙离子的增加从而使第二信使cAMP和cGMP量发生改变，导致肥大细胞脱颗粒并释放组胺。Experimental principle: Compound 48/80 (a G protein activator) is a tool drug that causes degranulation of mast cells. Its mechanism is to act on the mast cell membrane, causing an increase in intracellular calcium ions, thereby increasing the amount of second messengers cAMP and cGMP Changes occur, causing mast cells to degranulate and release histamine.
实验材料：细胞RBL-2H3细胞株由浙江省医学科学院动物中心提供；测试样品包括6种待测样品组合物，试剂包括胎牛血清、台氏盐、化合物48/80、组胺Elisa试剂盒。Experimental materials: The cell line RBL-2H3 was provided by the Animal Center of Zhejiang Academy of Medical Sciences; the test samples included 6 sample compositions to be tested, and the reagents included fetal bovine serum, Tyrode's salt, compound 48/80, and histamine Elisa kit.
实验步骤：Experimental steps:
(1)化合物48/80溶液配制：称取1.0mg的48/80粉末，用1mL台氏液稀释，取50uL稀释到1000uL，即浓度为50ug/mL的48/80溶液，需现配现用。(1) Compound 48/80 solution preparation: Weigh 1.0mg of 48/80 powder, dilute with 1mL Tyrode's solution, take 50uL and dilute to 1000uL, that is, a 48/80 solution with a concentration of 50ug/mL, which needs to be prepared for immediate use .
(2)台氏液配制：台氏盐一份，用80mL灭菌去离子水稀释，定容到100mL配制成10倍浓度台氏液，并高压灭菌。(2) Preparation of Tyrode's solution: One portion of Tyrode's salt, diluted with 80mL of sterilized deionized water, dilute to 100mL to prepare 10 times the concentration of Tyrode's solution, and autoclave.
(3)细胞处理：对数生长期RBL-2H3细胞铺满培养瓶底后用含0.25％胰蛋白酶，0.03％EDTA的消化液消化细胞，1200rpm，5分钟离心；1倍台氏液重悬计数，稀释到1*104/mL；再次1200rpm，5分钟离心去上清。(3) Cell processing: After the logarithmic growth phase of RBL-2H3 cells is covered with the bottom of the culture flask, the cells are digested with a digestion solution containing 0.25% trypsin and 0.03% EDTA, centrifuged at 1200 rpm for 5 minutes; 1 times Tyrode's solution is resuspended and counted , Diluted to 1*104/mL; centrifuge again at 1200rpm for 5 minutes to remove the supernatant.
(4)样品分组及测试：(4) Sample grouping and testing:
模型组：取700uL细胞悬液离心后台氏液重悬，37℃放置30分钟。Model group: Take 700uL cell suspension centrifugation and resuspend it in background solution, and place it at 37℃ for 30 minutes.
样品组：取700uL细胞悬液离心后样品液重悬，37℃放置30分钟。Sample group: Take 700uL cell suspension centrifugation and resuspend the sample solution, and place it at 37°C for 30 minutes.
将以上样品混匀后分装到3管，每管200uL；模型组和6个样品组：加50uL的48/80溶液到细胞悬液，终浓度为10ug/mL，37℃放置20分钟。每组3个重复。After mixing the above samples, divide them into 3 tubes, each tube is 200uL; model group and 6 sample groups: add 50uL of 48/80 solution to the cell suspension, the final concentration is 10ug/mL, and place it at 37°C for 20 minutes. 3 repetitions per group.
(5)组胺测定：将上述各组样本置入冰盒冷却10分钟以终止反应。将反应终止后的样本离心(4℃，1500rpm，30分钟)，使细胞沉淀在EP管底部，转移上清到新的离心管。以250μL的1倍台氏液重悬沉淀的细胞，置入90℃水浴锅加热，5分钟后取出，立即置入冰盒，待样本彻底冷却后取出，再次置入90℃水浴锅加热，反复冻融数次，破碎细胞。将上清和细胞液稀释10倍，原液于-20℃冰箱保存。稀释后的样品采用进口组胺试剂盒进行组胺测定并计算。组胺释放率计算公式为：(5) Histamine determination: Put the samples of the above groups in an ice box to cool for 10 minutes to stop the reaction. Centrifuge the sample after termination of the reaction (4°C, 1500 rpm, 30 minutes) to allow the cells to settle on the bottom of the EP tube, and transfer the supernatant to a new centrifuge tube. Resuspend the precipitated cells with 250μL of 1x Tyrode's solution, put them in a 90℃ water bath for heating, take it out 5 minutes later, immediately put it in the ice box, wait for the sample to cool down completely, take it out, put it in a 90℃ water bath to heat again, repeat Freeze and thaw several times to break the cells. The supernatant and cell fluid were diluted 10-fold, and the stock solution was stored in a refrigerator at -20℃. The diluted sample is determined and calculated with an imported histamine kit for histamine determination. The calculation formula of histamine release rate is:
组胺释放率(％)＝胞外组胺释放量/(胞外组胺释放量+胞内组胺量)*100％Histamine release rate (%)=extracellular histamine release/(extracellular histamine release+intracellular histamine release)*100%
测试结果如表1所示。The test results are shown in Table 1.
表1Table 1
Figure PCTCN2020102178-appb-000001
Figure PCTCN2020102178-appb-000001
以上结果表明，与模型组相比，桦树汁原液及浓缩倍数为1.05-8倍的桦树汁均能够显著降低RBL-2H3细胞的组胺释放率。尤其是浓缩倍数为1.1-4倍的桦树汁的RBL-2H3细胞组胺释放率显著低于桦树汁原汁。The above results show that compared with the model group, birch sap and birch sap with a concentration of 1.05-8 times can significantly reduce the histamine release rate of RBL-2H3 cells. In particular, the histamine release rate of birch sap with a concentration of 1.1-4 times was significantly lower than that of birch sap raw sap in RBL-2H3 cells.
实施例2：桦树汁原液和浓缩桦树汁对斑马鱼肥大细胞脱颗粒的影响Example 2: The effect of birch sap stock and concentrated birch sap on the degranulation of zebrafish mast cells
在本实施例中，测试和对比桦树汁原液和不同浓缩倍数的桦树汁对斑马鱼肥大细胞脱颗粒的影响。In this example, the effects of birch sap stock solution and birch sap with different concentration multiples on the degranulation of zebrafish mast cells were tested and compared.
1.桦树汁的浓缩1. Concentration of birch sap
将购自大兴安岭超越野生浆果开发有限责任公司的新鲜白桦树汁原液输入低温干燥设备，降温至-65℃，抽真空至0.1Pa，分别浓缩至1.05倍、1.1倍、1.2倍、1.5倍、2倍、4倍、8倍。The fresh white birch sap stock purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd. is fed into low-temperature drying equipment, cooled to -65℃, vacuumed to 0.1Pa, and concentrated to 1.05 times, 1.1 times, 1.2 times, 1.5 times, and 2 Times, 4 times, 8 times.
2.测试2. Test
试验动物：受精后5天(5dpf)的斑马鱼Test animal: zebrafish 5 days after fertilization (5dpf)
考察指标：类胰蛋白酶释放量Investigation index: tryptase release
实验方法：experimental method:
收集AB野生型斑马鱼胚胎，在28.5℃培养箱中用E3buffer培养至5dpf，每天换液。随机将5dpf的斑马鱼幼鱼以每孔10尾的数量转入48孔细胞培养板中分组，每组4个复 孔。Collect AB wild-type zebrafish embryos, culture them with E3buffer to 5dpf in a 28.5℃ incubator, and change the medium every day. Randomly transfer 5 dpf zebrafish juveniles to a 48-well cell culture plate with 10 tails per well and group them into 4 replicate wells per group.
模型组：RO水(纯水)+15μg/ml P物质(SP)；Model group: RO water (pure water) + 15μg/ml P substance (SP);
阳性药组：60μg/ml酮替芬+15μg/ml SP；Positive drug group: 60μg/ml ketotifen + 15μg/ml SP;
待测样品组：桦树汁原液和不同浓缩倍数的桦树汁+15μg/ml SP。Sample group to be tested: birch sap stock solution and birch sap with different concentration times + 15μg/ml SP.
以及对应于上述加入SP诱导脱颗粒各组，另设阴性对照组(不含SP)和背景对照组(不含斑马鱼幼鱼)。And corresponding to the aforementioned groups of SP induced degranulation, a negative control group (without SP) and a background control group (without zebrafish juveniles) were set up.
吸干各组孔内残余的E3buffer并加入250μl对应各个组别的溶液，在28.5℃培养箱中避光反应60分钟。60分钟后，取各组上清液200ul于96孔细胞培养板中，再分别加入酶反应底物Na-苯甲酰-DL-精氨酸-对硝基酰胺盐酸盐(BAPNA)使其浓度达到400μg/ml。将96孔板避光加盖放入28.5℃培养箱中反应2h，2h后测量一次全板405nm下的光吸收值，数值大小反映了斑马鱼肥大细胞的类胰蛋白酶释放情况。Absorb the remaining E3buffer in each group of wells and add 250μl of the solution corresponding to each group, and react for 60 minutes in the incubator at 28.5°C in the dark. After 60 minutes, take 200ul of supernatant from each group in a 96-well cell culture plate, and then add the enzyme reaction substrate Na-benzoyl-DL-arginine-p-nitroamide hydrochloride (BAPNA) to make it The concentration reaches 400μg/ml. The 96-well plate was placed in a 28.5°C incubator with a cover and placed in a 28.5°C incubator to react for 2h. After 2h, the light absorption value of the whole plate at 405nm was measured. The value reflects the release of tryptase from zebrafish mast cells.
测试结果如表2所示。The test results are shown in Table 2.
表2Table 2
Figure PCTCN2020102178-appb-000002
Figure PCTCN2020102178-appb-000002
以上结果表明，与模型组相比，桦树汁原液及浓缩倍数为1.05-8倍的桦树汁均能够非常显著地抑制斑马鱼类过敏模型的脱颗粒程度，显著降低类胰蛋白酶的释放。尤其是浓缩倍数为1.1-4倍的桦树汁的斑马鱼肥大细胞的保护率显著高于桦树汁原汁。The above results show that, compared with the model group, birch sap and birch sap with a concentration of 1.05-8 times can significantly inhibit the degranulation of the zebra fish allergy model and significantly reduce the release of tryptase. In particular, the protection rate of zebrafish mast cells of birch sap with a concentration of 1.1-4 times was significantly higher than that of birch sap.
实施例3：桦树汁原液和浓缩桦树汁对小鼠刺激性接触性皮炎模型的影响Example 3: The effect of birch sap stock and concentrated birch sap on the model of irritant contact dermatitis in mice
在本实施例中，测试和对比桦树汁原液和不同浓缩倍数的桦树汁对小鼠刺激性接触性皮炎模型的影响。In this example, the effects of birch sap stock and different concentration of birch sap on the irritant contact dermatitis model in mice were tested and compared.
1.桦树汁的浓缩1. Concentration of birch sap
将购自大兴安岭超越野生浆果开发有限责任公司的新鲜白桦树汁原液输入反渗透循环装置，运行压力控制在0.5-5bar，运行温度控制在20-35℃，循环，直至桦树汁分别浓缩至1.1倍、1.2倍、1.5倍、2倍、4倍。The fresh birch sap stock solution purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd. is fed into the reverse osmosis circulation device, the operating pressure is controlled at 0.5-5bar, and the operating temperature is controlled at 20-35℃, and circulated until the birch sap is respectively concentrated to 1.1 Times, 1.2 times, 1.5 times, 2 times, 4 times.
2.测试方法2. Test method
试验动物：ICR小鼠，雄性Test animal: ICR mouse, male
考察指标：血清中炎症因子白介素-1a(IL-1a)Investigation index: serum inflammatory factor interleukin-1a (IL-1a)
试验试剂：10％十二烷基硫酸钠溶液(SDS)、1％氢化可的松软膏、脱毛膏Test reagents: 10% sodium dodecyl sulfate solution (SDS), 1% hydrocortisone ointment, depilatory cream
实验方法：将ICR小鼠按体重随机分组，每组12只，分为正常组、模型组、阳性组、各待测样品组。所有小鼠用脱毛膏去除小鼠腹部约2*2cm区域面积皮肤毛发。正常组不做其他处理，模型组、阳性组、各待测样品组连续5天涂抹10％十二烷基硫酸钠溶液完成造模。造模后，阳性组用1％氢化可的松药膏涂抹皮肤，每天3次，连续2天；模型组不做处理；各待测样品组喷涂相应的混合桦树汁，每天3次，连续2天。实验第7天，观察各组实验小鼠皮肤状况，并取小鼠血清测定炎症因子IL-1a含量。Experimental method: ICR mice were randomly grouped according to their body weight, each with 12 mice, divided into normal group, model group, positive group, and each sample group to be tested. All mice used depilatory cream to remove the skin and hair of about 2*2cm area on the mouse abdomen. No other treatments were done for the normal group. The model group, the positive group, and each sample group to be tested were applied with 10% sodium lauryl sulfate solution for 5 consecutive days to complete the modeling. After modeling, the positive group was smeared with 1% hydrocortisone ointment 3 times a day for 2 consecutive days; the model group was not treated; each sample group to be tested was sprayed with the corresponding mixed birch sap, 3 times a day, 2 consecutive days day. On the 7th day of the experiment, the skin conditions of the experimental mice in each group were observed, and the serum of the mice was taken to determine the content of inflammatory factor IL-1a.
测试结果如表3所示。The test results are shown in Table 3.
表3table 3
Figure PCTCN2020102178-appb-000003
Figure PCTCN2020102178-appb-000003
注：*表示与原汁相比为显著，P值小于0.05；**表示与原汁相比为极显著，P值小于0.01。Note: * indicates that it is significant compared with the original juice, and the P value is less than 0.05; ** indicates that it is extremely significant compared to the original juice, and the P value is less than 0.01.
以上结果表明，与模型组相比，桦树汁原液及浓缩倍数为1.05-8倍的桦树汁均能够显著地抑制刺激性接触性皮炎小鼠血清中IL-1a的表达。特别地，与桦树汁原液相比，浓缩倍数为1.1-4倍的桦树汁的IL-1a的表达量显著低于桦树汁原液。The above results show that, compared with the model group, birch sap stock solution and birch sap with a concentration of 1.05-8 times can significantly inhibit the expression of IL-1a in the serum of mice with irritant contact dermatitis. In particular, compared with the birch sap stock solution, the expression level of IL-1a in the birch sap with a concentration factor of 1.1-4 times was significantly lower than that of the birch sap stock.
实施例4：桦树汁原液和浓缩桦树汁对小鼠变应性接触性皮炎模型的影响Example 4: The effect of birch sap stock and concentrated birch sap on mice models of allergic contact dermatitis
在本实施例中，测试和对比桦树汁原液和不同浓缩倍数的桦树汁对小鼠变应性接触性皮炎模型的影响。In this example, the effects of birch sap stock and different concentration of birch sap on mice models of allergic contact dermatitis were tested and compared.
1.桦树汁的浓缩1. Concentration of birch sap
将购自大兴安岭超越野生浆果开发有限责任公司的新鲜白桦树汁原液输入反渗透循环装置，运行压力控制在0.5-5bar，运行温度控制在20-35℃，循环，直至桦树汁分别浓缩至1.1倍、1.2倍、1.5倍、2倍、4倍。The fresh birch sap stock solution purchased from Daxinganling Chaoyue Wild Berry Development Co., Ltd. is fed into the reverse osmosis circulation device, the operating pressure is controlled at 0.5-5bar, and the operating temperature is controlled at 20-35℃, and circulated until the birch sap is respectively concentrated to 1.1 Times, 1.2 times, 1.5 times, 2 times, 4 times.
2.测试方法2. Test method
试验动物：ICR小鼠，雄性Test animal: ICR mouse, male
考察指标：耳厚度指数、耳重量、炎症指标γ干扰素(IFN-γ)、白介素-4(IL-4)Investigation indicators: ear thickness index, ear weight, inflammation index interferon-γ (IFN-γ), interleukin-4 (IL-4)
试验材料：1％2,4-二硝基氟苯(DNFB)丙酮橄榄油溶液(4:1)、1％氢化可的松软膏、脱毛膏Test materials: 1% 2,4-dinitrofluorobenzene (DNFB) acetone olive oil solution (4:1), 1% hydrocortisone ointment, depilatory cream
实验方法：将ICR小鼠按体重随机分组，每组12只，分为正常组、模型组、阳性组、各待测样品组。各组实验小鼠用脱毛膏去除腹部约2*2cm区域面积皮肤毛发。正常组小鼠腹部及耳部均匀涂以丙酮橄榄油溶液对照。模型组、阳性组、各待测样品组小鼠涂抹含1％DNFB的丙酮橄榄油溶液，进行致敏和激发建立小鼠变应性接触性皮炎模型。激发后，模型组喷以蒸馏水；阳性组涂以1％氢化可的松软膏，连续2天，3次/天；各待测样品组喷涂相应的混合桦树汁，每天3次，连续给药2天。Experimental method: ICR mice were randomly grouped according to their body weight, each with 12 mice, divided into normal group, model group, positive group, and each sample group to be tested. Each group of experimental mice used depilatory cream to remove the skin and hair in the abdomen area of about 2*2cm. The abdomen and ears of mice in the normal group were evenly coated with acetone olive oil solution for control. Mice in the model group, positive group, and each sample group to be tested were smeared with 1% DNFB-containing acetone olive oil solution for sensitization and stimulation to establish a mouse model of allergic contact dermatitis. After being challenged, the model group was sprayed with distilled water; the positive group was sprayed with 1% hydrocortisone ointment for 2 consecutive days, 3 times/day; each sample group to be tested was sprayed with the corresponding mixed birch sap, 3 times a day, continuous administration 2 days.
测试结果如表4所示。The test results are shown in Table 4.
表4Table 4
Figure PCTCN2020102178-appb-000004
Figure PCTCN2020102178-appb-000004
注：*表示与原汁相比为显著，P值小于0.05；**表示与原汁相比为极显著，P值小于0.01。Note: * indicates that it is significant compared with the original juice, and the P value is less than 0.05; ** indicates that it is extremely significant compared to the original juice, and the P value is less than 0.01.
结果表明，与模型组相比，桦树汁原汁及浓缩倍数为1.05-8倍的桦树汁均能够显著抑制变应性接触性皮炎小鼠的耳厚度和耳重量，并显著提高血清中IL-4/IFN-γ的比值。这表明浓缩倍数1.05-8倍的浓缩桦树汁具有显著的抗炎效果，尤其是浓缩倍数为1.1-4倍时，耳厚度和耳重量显著低于桦树汁原液，血清中IL-4/IFN-γ的比值显著高于桦树汁原液。The results showed that compared with the model group, birch sap raw juice and birch sap with a concentration of 1.05-8 times can significantly inhibit the ear thickness and ear weight of mice with allergic contact dermatitis, and significantly increase the serum content. IL-4/IFN-γ ratio. This shows that the concentrated birch sap with a concentration of 1.05-8 times has a significant anti-inflammatory effect, especially when the concentration is 1.1-4 times, the ear thickness and ear weight are significantly lower than that of the birch sap stock, and the serum IL-4/ The ratio of IFN-γ was significantly higher than that of birch sap.
实施例5：抗炎喷雾组合物的制备Example 5: Preparation of anti-inflammatory spray composition
所述抗炎喷雾组合物的配方如下表所述：The formula of the anti-inflammatory spray composition is described in the following table:
Figure PCTCN2020102178-appb-000005
Figure PCTCN2020102178-appb-000005
Figure PCTCN2020102178-appb-000006
Figure PCTCN2020102178-appb-000006
上述抗炎喷雾组合物如下制备：The above-mentioned anti-inflammatory spray composition is prepared as follows:
1.将原料1、2、3、4、5、6、7、8、9、10投入乳化锅，边搅拌边升温至80℃，保温10分钟；1. Put the raw materials 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 into the emulsification pot, stir and heat up to 80°C, keep it for 10 minutes;
2.边搅拌边降温至45℃；2. Cool down to 45℃ while stirring;
3.加入原料11，搅拌10分钟；3. Add raw material 11 and stir for 10 minutes;
4.检验合格后出料。4. Discharge after passing the inspection.
对18名自评为敏感性皮肤的志愿者进行半脸对照测试，测试周期4周:A half-face control test was conducted on 18 volunteers who rated themselves as sensitive skin, and the test period was 4 weeks:
1)用Periscan PIM 3测试志愿者左右两侧面颊部位的血流灌注值；1) Use Periscan PIM 3 to test the blood perfusion value of the volunteers' left and right cheeks;
2)用Neurometer CPT对志愿者左右两侧面颊部位的电流感觉阈值进行测定；2) Use Neurometer CPT to measure the current sensory threshold of the volunteers on the left and right cheeks;
3)通过VISIA-CR采集志愿者在使用前后偏正光条件下的面部图形，利用IPP软件分析志愿者左右两侧面颊部位不同测试时间点同一测量区域的红斑面积。3) Using VISIA-CR to collect the facial images of volunteers under the condition of using front and rear polarized light, and use IPP software to analyze the erythema area of the same measurement area at different test time points on the left and right cheeks of volunteers.
结果显示，与使用A2配方的一侧相比，使用A1抗炎护肤喷雾的面颊部位的血流灌注值显著下降，红斑面积显著减少，电流感觉阈值显著提高。The results showed that compared with the side using the A2 formula, the blood perfusion value of the cheek area using the A1 anti-inflammatory skin care spray was significantly reduced, the erythema area was significantly reduced, and the current perception threshold was significantly increased.
实施例6：抗炎面霜组合物的制备Example 6: Preparation of anti-inflammatory cream composition
所述抗炎面霜组合物的配方如下表所示：The formula of the anti-inflammatory cream composition is shown in the following table:
Figure PCTCN2020102178-appb-000007
Figure PCTCN2020102178-appb-000007
上述抗炎面霜组合物如下制备：The aforementioned anti-inflammatory cream composition is prepared as follows:
1.油相：将4、6、7、8、9、11、12、13、15号原料加入油相锅，并加热至80℃，溶解，混合均匀；1. Oil phase: Add raw materials 4, 6, 7, 8, 9, 11, 12, 13, and 15 to the oil phase pot, and heat to 80°C, dissolve, and mix well;
2.将2、16、18号原料在常温下混合均匀；2. Mix No. 2, 16 and 18 raw materials evenly at room temperature;
3.将10、14、17号原料在常温下混合均匀；3. Mix No. 10, 14, and 17 materials uniformly at room temperature;
4.水相：将1、3、5号原料加热到80℃，加入步骤2的混合物，溶解，混合均匀；4. Water phase: Heat 1, 3, and 5 raw materials to 80°C, add the mixture of step 2, dissolve, and mix well;
5.乳化：将水相和油相加入乳化罐中，保温在80℃，在3000rpm速度下均质乳化5分钟，乳化完成后加入19号原料；5. Emulsification: add the water phase and the oil phase to the emulsification tank, keep it at 80°C, homogenize emulsification at 3000rpm for 5 minutes, add No. 19 raw material after emulsification is complete;
6.搅拌降温至40℃时加入步骤3的混合物，搅拌均匀后出料，得到所述抗炎面霜组合物。6. The mixture of step 3 is added when the temperature is lowered to 40°C by stirring, and the mixture is uniformly stirred and discharged to obtain the anti-inflammatory facial cream composition.
20名受试者使用上述配方的抗炎面霜4周后，对使用情况进行主观评估。结果有18人反映皮肤含水量显著增加，面部刺痛、发热和红血丝情况得到明显改善，皮肤变得更加光滑细嫩。After 20 subjects used the anti-inflammatory cream of the above formula for 4 weeks, subjective evaluation of the use was made. As a result, 18 people reported a significant increase in skin water content, facial irritation, fever, and redness were significantly improved, and their skin became smoother and more tender.
实施例6：抗炎乳液组合物Example 6: Anti-inflammatory emulsion composition
所述抗炎乳液组合物的配方如下表所示：The formula of the anti-inflammatory emulsion composition is shown in the following table:
Figure PCTCN2020102178-appb-000008
Figure PCTCN2020102178-appb-000008
上述抗炎乳液组合物如下制备：The anti-inflammatory emulsion composition described above is prepared as follows:
1.油相：将4、5、6、7、12、13号原料加入油相锅，并加热至80℃，溶解，混合均匀；1. Oil phase: add No. 4, 5, 6, 7, 12, 13 raw materials into the oil phase pot, and heat to 80°C, dissolve, and mix well;
2.将2、8、11号原料在常温下混合均匀；2. Mix No. 2, 8, and 11 materials evenly at room temperature;
3.将9、10、16号原料等原料在常温下混合均匀；3. Mix the raw materials such as No. 9, 10, 16 at room temperature evenly;
4.水相：将1、3、14号原料加热到80℃，加入步骤2的混合物，溶解，混合均匀；4. Water phase: Heat 1, 3, and 14 raw materials to 80°C, add the mixture of step 2, dissolve, and mix well;
5.乳化：将水相和油相加入乳化罐中，保温在80℃，在3000rpm速度下均质乳化5分钟，乳化完成后加入15号原料；5. Emulsification: add the water phase and the oil phase to the emulsification tank, keep the temperature at 80°C, homogenize and emulsify for 5 minutes at 3000 rpm, and add No. 15 raw material after the emulsification is completed;
6.搅拌降温至40℃时加入步骤3的混合物，搅拌均匀后出料，得到所述抗炎乳液组合物。6. Add the mixture of step 3 when stirring and cooling down to 40°C, stir evenly and then discharge to obtain the anti-inflammatory emulsion composition.
以上所述实施例的技术方案是本发明优选实施方式，在不脱离本发明原理的前提下还可以进行若干改进和变换，这些改进和变化也应视为在本发明的保护范围内。The technical solutions of the above-mentioned embodiments are preferred implementations of the present invention. Several improvements and changes can be made without departing from the principle of the present invention, and these improvements and changes should also be regarded as falling within the protection scope of the present invention.

Claims (10)

  1. 一种浓缩的桦树汁，其浓缩倍数为1.05-8倍，优选1.1-4倍。A concentrated birch sap with a concentration ratio of 1.05-8 times, preferably 1.1-4 times.
  2. 浓缩的桦树汁在具有抗炎功效的皮肤外用组合物中的用途，其中所述浓缩桦树汁的浓缩倍数为1.05-8倍，优选1.1-4倍。The use of concentrated birch sap in a skin external composition with anti-inflammatory effects, wherein the concentration of the concentrated birch sap is 1.05-8 times, preferably 1.1-4 times.
  3. 权利要求2所述的用途，其中所述皮肤外用组合物是药物组合物或者化妆品组合物。The use according to claim 2, wherein the external skin composition is a pharmaceutical composition or a cosmetic composition.
  4. 权利要求2或3所述的用途，其中所述皮肤外用组合物是护肤化妆品组合物。The use according to claim 2 or 3, wherein the external skin composition is a skin care cosmetic composition.
  5. 权利要求2-4任一项所述的用途，其中所述皮肤外用组合物不包含任何外加的水。The use according to any one of claims 2-4, wherein the external skin composition does not contain any added water.
  6. 一种具有抗炎功效的皮肤外用组合物，其包含(A)浓缩桦树汁，所述浓缩桦树汁的浓缩倍数为1.05-8倍，优选1.1-4倍。An external skin composition with anti-inflammatory effect, comprising (A) concentrated birch sap, the concentration of the concentrated birch sap is 1.05-8 times, preferably 1.1-4 times.
  7. 权利要求6所述的皮肤外用组合物，其是药物组合物或者化妆品组合物。The external skin composition of claim 6, which is a pharmaceutical composition or a cosmetic composition.
  8. 权利要求6或7所述的皮肤外用组合物，其中所述皮肤外用组合物是护肤化妆品组合物。The external skin composition according to claim 6 or 7, wherein the external skin composition is a skin care cosmetic composition.
  9. 权利要求6-8任一项所述的皮肤外用组合物，其不包含任何外加的水。The external skin composition of any one of claims 6-8, which does not contain any added water.
  10. 权利要求6-9任一项所述的皮肤外用组合物，其中所述(A)浓缩桦树汁的含量为18-98％重量，优选20-95％重量，更优选22-90％重量，最优选30-90％重量，基于所述皮肤外用组合物的总重量。The skin external composition according to any one of claims 6-9, wherein the content of the (A) concentrated birch sap is 18-98% by weight, preferably 20-95% by weight, more preferably 22-90% by weight, Most preferably 30-90% by weight, based on the total weight of the skin external composition.
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