CN109316422A - 一种植物性抗敏剂原液及其制备方法和应用 - Google Patents

一种植物性抗敏剂原液及其制备方法和应用 Download PDF

Info

Publication number
CN109316422A
CN109316422A CN201811467650.1A CN201811467650A CN109316422A CN 109316422 A CN109316422 A CN 109316422A CN 201811467650 A CN201811467650 A CN 201811467650A CN 109316422 A CN109316422 A CN 109316422A
Authority
CN
China
Prior art keywords
sensitizer
stoste
extract
paeoniflorin
matrine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
CN201811467650.1A
Other languages
English (en)
Inventor
高颖
赵富虎
董玉玲
朱志贤
李向阳
张凤凤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gansu Pan Pharmaceutical Co Ltd
Original Assignee
Gansu Pan Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gansu Pan Pharmaceutical Co Ltd filed Critical Gansu Pan Pharmaceutical Co Ltd
Priority to CN201811467650.1A priority Critical patent/CN109316422A/zh
Publication of CN109316422A publication Critical patent/CN109316422A/zh
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97Cosmetics 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
    • A61K8/9783Angiosperms [Magnoliophyta]
    • A61K8/9789Magnoliopsida [dicotyledons]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/12Ketones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/28Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35Ketones, e.g. benzophenone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60Sugars; Derivatives thereof
    • A61K8/602Glycosides, e.g. rutin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63Steroids; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/005Preparations for sensitive skin
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00Processes for the preparation of sugar derivatives
    • C07H1/06Separation; Purification
    • C07H1/08Separation; Purification from natural products
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04Heterocyclic radicals containing only oxygen as ring hetero atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30Extraction of the material
    • A61K2236/33Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30Extraction of the material
    • A61K2236/39Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50Methods involving additional extraction steps
    • A61K2236/51Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50Methods involving additional extraction steps
    • A61K2236/55Liquid-liquid separation; Phase separation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/59Mixtures
    • A61K2800/592Mixtures of compounds complementing their respective functions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74Biological properties of particular ingredients
    • A61K2800/78Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782Enzyme inhibitors; Enzyme antagonists

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Birds (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Mycology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Botany (AREA)
  • Rheumatology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Emergency Medicine (AREA)
  • Medical Informatics (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Cosmetics (AREA)

Abstract

本发明公开了一种植物性抗敏剂原液及其制备方法和应用,该抗敏剂原液由以下重量百分比的组分通过中医药基础理论复配而成:甘草酸二钾1.3~2.0%、苦参碱0.05~0.15%、光甘草定羟丙基‑β‑环糊精包合物0.003‑0.005%、芍药苷0.08~0.15%、四氢姜黄素0.07~0.10%、洋甘菊提取物0.03~0.05%、1,3‑丁二醇18.0~25.0%、苯氧乙醇0.6~1.0%、余量为水,并以重量百分比2‑10%加入美白、抗敏护肤品中。抗敏剂原液中各组分采用现代提取分离技术纯化精制得到,颜色浅、味道淡,改善了用户体验。其中,甘草酸二钾具有消炎、抗敏作用;配以苦参、芍药、氢化姜黄、洋甘菊提取物,使之更具收敛、修护、滋养皮肤的效果;且体外及人体评测试验均表明,该抗敏剂原液中各组分具有协同促进作用,抗敏、消炎作用良好。

Description

一种植物性抗敏剂原液及其制备方法和应用
技术领域
本发明属于化妆品领域,涉及一种植物性抗敏剂原液,本发明还涉及该抗敏剂原液的其制备方法和应用。
背景技术
目前,化妆品配方中抗敏性成分多以化学合成品为主。由于化学合成类的抗过敏原料不仅毒副作用大,还容易使皮肤形成依赖性。另外,现阶段国家对化妆品所添加的合成类的抗过敏原料要求越来越严格,使得市场上越来越需要天然的、功效特殊的抗过敏原料。
然而,目前化妆品中添加的植物性抗敏剂,由于其提取工艺简单、方法粗放,使得提取物本身具有颜色深、气味重的缺点,客户体验较差,因此使用受到限制;另外,目前化妆品中添加的植物性抗敏剂多为单一组分,抗敏效果欠佳。
发明内容
本发明的目的为了克服现有植物性抗敏剂存在的上述缺陷,提供一种客户体验效果佳、抗敏效果优良的植物性抗敏剂原液。
本发明的另一目的是提供一种上述植物性抗敏剂原液的制备方法。
本发明的再一目的是提供上述抗敏剂原液在化妆品中的应用。
一、植物性抗敏剂原液
本发明的植物性抗敏剂原液,以重量百分比为100%计,由以下组分混合而成:
甘草酸二钾1.3~2.0%、苦参碱0.05~0.15%、光甘草定羟丙基-β-环糊精包合物0.003-0.005%、芍药苷0.08~0.15%、四氢姜黄素0.07~0.10%、洋甘菊提取物0.03~0.05%、1,3-丁二醇(HPLC含量>72%)18.0~25.0%、苯氧乙醇0.6~1.0%、余量为水;
上述苦参碱的分离纯化工艺为:取苦参药材,粉碎后过20目筛,筛下物用70%乙醇以质量体积比1:5~8分别回流提取1.5h~2h;将两次提取液合并后过滤,滤液减压浓缩成浸膏,经中性氧化铝柱层析分离,分离条件为:浸膏与氧化铝重量比1:10~20,柱内径与氧化铝在柱中的高度比1:7~9,采用氯仿与甲醇体积比1.5~2.2:1的混合液洗脱,薄层检测,改良碘化铋钾试剂显色,合并苦参碱洗脱部分,浓缩,石油醚结晶,得到HPLC含量>98%的苦参碱;该分离纯化工艺经中性氧化铝柱层析分离、石油醚结晶除去颜色以及药材特有的气味,从而得到色浅、味淡的苦参碱。
芍药苷的分离纯化工艺为:取赤芍药材,粉碎后过20目筛,筛下物用70%乙醇以质量体积比1: 2.5~5分别回流提取1~2h,提取3次,将三次提取液合并后过滤,滤液减压浓缩至无醇味后加乙酸乙酯、正丁醇萃取,萃取液减压浓缩成浸膏;经硅胶柱层析分离,分离条件为:浸膏与氧化铝重量比1:12~20,柱内径与硅胶柱中的高度比1:5~8,采用二氯甲烷与甲醇体积比3.5~4.2:1的混合液洗脱,洗脱液薄层检查,合并芍药苷部分,回收溶剂,经硅胶柱层析分离,得到HPLC含量>98%的芍药苷;该分离工艺经硅胶柱层析分离、甲醇结晶除去颜色以及药材特有的气味,从而得到色浅、味淡的芍药苷。
洋甘菊提取物的分离纯化工艺为:取洋甘菊药材微粉碎(粒径1mm左右),采用50%乙醇分别以质量体积比1:4~7在75~85℃下加热搅拌提取两次,滤液合并后回收乙醇至干,得到滤渣;该滤渣研磨后干法上样,采用大孔吸附树脂吸附,然后用纯净水冲洗至基本无色后,用50%乙醇洗脱;洗脱液加入活性炭回流脱色20~40min,过滤;脱色液浓缩、喷雾干燥,得到洋甘菊提取物;该分离工艺经大孔吸附树脂吸附与活性炭回流脱色起到除色、除味效果,从而得到色浅、味淡的洋甘菊提取物。
作为本发明技术方案的优选,上述光甘草定羟丙基-β-环糊精包合物中光甘草定的重量百分比≥1.8%。
本发明植物性抗敏剂原液的制备方法中,各组分以组方量加入,具体包括以下步骤:
(1)先将1,3-丁二醇加入第一混合器中,然后依次加入光甘草定羟丙基-β-环糊精包合物和四氢姜黄素,搅拌状态下加热至50-60℃,保持10-20min,使各组分完全溶解,形成A溶液;
(2)先将水加入第二混合器中,然后依次加入甘草酸二钾、苦参碱、芍药苷和洋甘菊提取物,室温搅拌溶解,形成B溶液;
(3)将B溶液加入A溶液中,继续搅拌、降温至38-42℃时,加入苯氧乙醇,并用柠檬酸调pH至5.5-6.5,静置24h,得到抗敏剂原液,记为FZ AW-101。
本发明植物性抗敏剂原液的应用方法为,将上述的抗敏剂原液以重量百分比为2-10%加入美白、抗敏护肤品中;该美白、抗敏护肤品为溶液、悬浊液、乳状液、霜剂、膏状、凝胶、奶液或护肤液中的任意一种。
二、抗敏效果评价试验
常用的抗敏类化妆品及其原料抗敏效果的评价方法主要包括体外试验、动物试验、人体评测试验三大类。本发明通过体外试验和人体评测试验对抗敏剂原液的抗敏效果进行了测试。
(一)体外试验
透明质酸酶体外抑制试验常作为测定物质抗过敏活性的生化评价方法。判定各种物质是否具有抗过敏活性,前期可以利用透明质酸酶活性抑制率来判断,透明质酸酶抑制率越高则表明该物质的抗敏效果越强,反之则越弱。
采用透明质酸酶体外抑制法测定本发明抗敏剂原液、苦参碱、芍药苷以及洋甘菊提取物的抗敏功效,对比数据如图1所示。
从图1中可以看出,浓度分别为5.0mg/mL-1、20.0mg/mL-1时,抗敏剂原液透明质酸活性抑制率分别为76.5%、96.5%,远高于同浓度下的苦参等其他提取物,这表明本发明抗敏剂原液中的各组分具有协同促进作用。
(二)人体评测试验
1、皮肤红斑指数试验
受试者共计8人,具体性别构成随机确定。
选择受试者左、右手臂内侧作为受试部位,用清水清洗受试区域(同一区域),受试者静坐10min,涂抹0.05mL纯水后进行空白值的测量,随后进入涂抹试验阶段;用50%的辣椒素水溶液(约0.01mL)对受试区域进行刺激;持续刺激15min及30min后,分别进行数值采集;在受试区域涂抹测试样品(样品浓度为10mg/mL-1)0.05mL,分别于15min、30min、45min后进行数据采集;统计受试者试验部位每次测得的数值,分析红值的变化,对比数据如图2所示。
从图2中可以看出,抗敏剂原液对辣椒素水溶液刺激后的皮肤有一定程度的修复功效。涂抹45min后,红值变化率由23%下降至2%,皮肤基本恢复正常,空白对照红值变化率由24%下降至13%,这表明抗敏剂原液对皮肤刺激后的修复效果显著,能快速修复受损肌肤。
2、人体斑贴试验
选取符合化妆品卫生规范中要求标准的受试者22人,受试部位为志愿者上背部脊椎两侧皮肤,并将皮肤分为两部分区域,采用斑试器一部分区域涂抹化妆品常见致敏原作为空白对照,另一部分区域涂抹含量为1%抗敏剂原液的乳液后再涂抹化妆品常见致敏原。斑贴试验时间48h,贴敷48h后去除斑试器,30min后观察受试部位,记录试验结果如图3所示。
从图3中可以看出,涂抹含有抗敏剂原液的乳液后,再进行化妆品过敏原的斑贴试验,刺激源对涂抹区域皮肤所造成的损伤大大减缓,其中檀香油、山梨酸、羊毛脂、薄荷油、丙二醇对皮肤的致敏率接近零,几乎对皮肤没有表现出刺激性,远小于空白对照的致敏率;对十二烷基硫酸钠、咪唑烷基脲、尼泊金酯和硫柳汞的致敏率有减小趋势,致命率分别减小75.73%、68.0%、82.47%和46.77%。这表明涂抹含有抗敏剂原液的乳液后,能在一定程度上保护细胞膜结构的完整性及屏障功能,提高皮肤的耐受性,并有修复受损肌肤减轻过敏症状的功效。
相比于现有植物性抗敏剂,本发明具有以下有益效果:
1、本发明抗敏剂原液中各组分均采用现代提取分离技术纯化精制得到,颜色浅、味道淡,改善了用户体验,扩大了其使用范围。
2、本发明抗敏剂原液根据中药方剂中的君臣佐使理论复配得到,甘草酸二钾具有抑菌、消炎、抗敏作用;配以苦参、芍药、氢化姜黄、洋甘菊植物提取物,使之在抗敏、消炎的作用外,并起到收敛、修护、滋养皮肤的效果:
其中,甘草酸二钾为君药,其通过抑制透明质酸酶的活性和组胺的释放,达到消除皮肤过敏症状的效果,有较强的抗过敏作用,是替代激素的最佳选择;
苦参碱为臣药,既能辅助甘草酸二钾加强抗过敏、抗菌消炎的作用,又能平衡油脂分泌,疏通毛孔,清除皮肤内毒素,促进受损血管细胞的生长和修复,恢复皮下毛细血管细胞活力,使肌肤重现紧致细滑的状态;
芍药苷与苦参碱共为臣药,具有增强抗炎、抗氧化的作用;
光甘草定羟丙基-β-环糊精包合物和氢化姜黄提取物都作为佐助药存在于复配原液中,光甘草定在细胞色素P450/NADPH氧化系统中显示出很强的抗自由基、抗氧化及抗过敏作用,能明显抑制体内新陈代谢过程中所产生的自由基,有效抑制多巴向黑色素的转化过程,从而减少晒斑的形成和黑色素在皮肤表面的停留,是公认的美白成分,光甘草定羟丙基-β-环糊精包合物与光甘草定性质相同,但相比于光甘草定具有更好的水溶性;四氢姜黄素具有抑制酪氨酸酶的强效活性,能有效抑制氧自由基,并能清除已经形成的自由基,具有明显的抗氧化作用,如抗人体皮肤衰老、修复、淡化色素、祛斑等作用;
金黄洋甘菊自古就被视为“神花”,其提取物具有修护敏感肌肤、减少红血丝和面部发红、消炎杀菌等作用,是不可缺少的“药引子”,即为使药。
3、体外试验和人体评测实验表明,本发明抗敏剂原液中各组分具有协同促进作用,抗敏、消炎作用良好。
附图说明
图1为本发明透明质酸酶体外抑制法试验的结果图;
图2为本发明皮肤红斑指数试验的结果图;
图3为本发明人体斑贴试验的结果图。
具体实施方式
下面通过具体实施例对本发明抗敏剂原液及其制备方法和应用作进一步详细说明。
本发明甘草酸二钾具有低残氨、低残醇及低色调的优点,其HPLC含量>72%,制备工艺参见专利申请201710651185.6。
实施例1
本实施例的植物性抗敏剂原液FZ AW-101由以下组分混合而成:
甘草酸二钾1.3%、苦参碱0.05%、光甘草定羟丙基-β-环糊精包合物0.005%、芍药苷0.1%、四氢姜黄素0.07%、洋甘菊提取物0.03%、1,3-丁二醇18%、苯氧乙醇0.6%、水79.8%;
上述苦参碱的分离纯化工艺为:取苦参药材100g,粉碎后过20目筛,筛下物用600mL、70%乙醇分别回流提取2h、1.5h;将两次提取液合并后过滤,滤液减压浓缩成浸膏,经中性氧化铝柱层析分离,分离条件为:浸膏与氧化铝重量比1:15,柱内径与氧化铝在柱中的高度比1:8,采用氯仿与甲醇体积比2:1的混合液洗脱,薄层检测,改良碘化铋钾试剂显色,合并苦参碱洗脱部分,浓缩,石油醚结晶,得到色浅、纯度为99%的苦参碱;
芍药苷的分离纯化工艺为:取赤芍药材100g,粉碎后过20目筛,筛下物用400mL、300mL、300mL 的70%乙醇分别回流提取1.5h、1h、1h;将三次提取液合并后过滤,滤液减压浓缩至无醇味后加乙酸乙酯、正丁醇萃取,萃取液减压浓缩成浸膏;经硅胶柱层析分离,分离条件为:浸膏与氧化铝重量比1:15,柱内径与硅胶柱中的高度比1:6,采用二氯甲烷与甲醇体积比4:1的混合液洗脱,洗脱液薄层检查,合并芍药苷部分,回收溶剂,经甲醇结晶,得到颜色浅、纯度为98.5%的芍药苷;
洋甘菊提取物的分离纯化工艺为:取洋甘菊药材100g微粉碎,分别采用600mL、400mL的50%乙醇在80℃下加热搅拌提取两次,滤液合并后回收乙醇至干,得到滤渣;该滤渣研磨后干法上样,采用大孔吸附树脂吸附,然后用纯净水冲洗至基本无色后,用50%乙醇洗脱;洗脱液加入活性炭回流脱色30min,过滤;脱色液浓缩、喷雾干燥,得到纯净的洋甘菊提取物。
光甘草定羟丙基-β-环糊精包合物中光甘草定的重量百分比为1.8%。
其制备方法具体包括以下步骤:
(1)先将36mL 的1,3-丁二醇加入250mL的三口瓶中,然后依次加入0.010g光甘草定羟丙基-β-环糊精包合物和0.14g四氢姜黄素,搅拌状态下加热至55℃,保持20min,使各组分完全溶解,形成A溶液;
(2)先将50mL的水加入100mL烧杯中,然后依次加入2.62g甘草酸二钾、0.103g苦参碱、0.21g芍药苷和0.06g洋甘菊提取物,室温搅拌溶解,形成B溶液;
(3)将B溶液加入A溶液中,继续搅拌、降温至42℃时,加入1.2mL苯氧乙醇,并用10%柠檬酸调pH至6.23,加水至100mL后静置24h,得到抗敏剂原液。该抗敏剂原液以重量百分比2%加入到美白、抗敏护肤品中。
实施例2
本实施例的植物性抗敏剂原液FZ AW-101由以下组分混合而成:
甘草酸二钾1.8%、苦参碱0.13%、光甘草定羟丙基-β-环糊精包合物0.005%、芍药苷0.08%、四氢姜黄素0.10%、洋甘菊提取物0.05%、1,3-丁二醇25%、苯氧乙醇1.0%、水71.8%;
上述苦参碱的分离纯化工艺中,筛下物用500mL、70%乙醇分别回流提取1.5h、2h;分离条件为:浸膏与氧化铝重量比1:10,柱内径与氧化铝在柱中的高度比1:7,采用氯仿与甲醇体积比1.5:1的混合液洗脱,其他操作同实施例1,得到色浅、纯度为98.5%的苦参碱;
芍药苷的分离纯化工艺中,筛下物用500mL、250mL、250mL 的70%乙醇分别回流提取2h、1.5h、1h;分离条件为:浸膏与氧化铝重量比1:12,柱内径与硅胶柱中的高度比1:5,采用二氯甲烷与甲醇体积比3.5:1的混合液洗脱,其他操作同实施例1,得到颜色浅、纯度为98.2%的芍药苷;
洋甘菊提取物的分离纯化工艺中,取洋甘菊药材100g微粉碎,分别采用700mL、400mL的50%乙醇在75℃下加热搅拌提取两次;洗脱液加入活性炭回流脱色20min,其他操作同实施例1,得到纯净的洋甘菊提取物;
光甘草定羟丙基-β-环糊精包合物中光甘草定的重量百分比为2.0%。
其制备方法具体包括以下步骤:
(1)先将250mL的1,3-丁二醇加入2000mL的三口瓶中,然后依次加入0.010g光甘草定羟丙基-β-环糊精包合物和0.14g四氢姜黄素,搅拌状态下加热至50℃,保持15min,使各组分完全溶解,形成A溶液;
(2)先将500mL的水加入1000mL烧杯中,然后依次加入18.02g甘草酸二钾、1.33g苦参碱、0.81g芍药苷和0.51g洋甘菊提取物,室温搅拌溶解,形成B溶液;
(3)将B溶液加入A溶液中,继续搅拌、降温至40℃时,加入10mL苯氧乙醇,并用10%柠檬酸调pH至6.5,加水至1000mL后静置24h,得到抗敏剂原液。该抗敏剂原液以重量百分比5%加入到美白、抗敏护肤品中。
实施例3
本实施例的植物性抗敏剂原液FZ AW-101由以下组分混合而成:
甘草酸二钾2.0%、苦参碱0.15%、光甘草定羟丙基-β-环糊精包合物0.003%、芍药苷0.15%、四氢姜黄素0.08%、洋甘菊提取物0.05%、1,3-丁二醇22%、苯氧乙醇1.0%、水74.5%;
上述苦参碱的分离纯化工艺中,筛下物用800mL、70%乙醇分别回流提取1.5h、1.5h;分离条件为:浸膏与氧化铝重量比1:20,柱内径与氧化铝在柱中的高度比1:9,采用氯仿与甲醇体积比2.2:1的混合液洗脱,其他操作同实施例1,得到色浅、纯度为98.7%的苦参碱;
芍药苷的分离纯化工艺中,筛下物用500mL、300mL、250mL 的70%乙醇分别回流提取2h、1h、1h;分离条件为:浸膏与氧化铝重量比1:20,柱内径与硅胶柱中的高度比1:8,采用二氯甲烷与甲醇体积比4.2:1的混合液洗脱,其他操作同实施例1,得到颜色浅、纯度为98.7%的芍药苷;
洋甘菊提取物的分离纯化工艺中,取洋甘菊药材100g微粉碎,分别采用700mL、500mL的50%乙醇在85℃下加热搅拌提取两次;洗脱液加入活性炭回流脱色40min,其他操作同实施例1,得到纯净的洋甘菊提取物;
光甘草定羟丙基-β-环糊精包合物中光甘草定的重量百分比为2.2%。
其制备方法具体包括以下步骤:
(1)先将2200mL的1,3-丁二醇加入3000mL的三口瓶中,然后依次加入0.010g光甘草定羟丙基-β-环糊精包合物和0.14g四氢姜黄素,搅拌状态下加热至60℃,保持10min,使各组分完全溶解,形成A溶液;
(2)先将5000mL的水加入10L不锈钢桶中,然后依次加入200.051g甘草酸二钾、15.032g苦参碱、15.002g芍药苷和5.01g洋甘菊提取物,室温搅拌溶解,形成B溶液;
(3)将B溶液加入A溶液中,继续搅拌、降温至38℃时,加入100mL苯氧乙醇,并用10%柠檬酸调pH至5.5,加水至10L后静置24h,得到抗敏剂原液。该抗敏剂原液以重量百分比10%加入到美白、抗敏护肤品中。

Claims (5)

1.一种植物性抗敏剂原液,其特征是,以重量百分比为100%计,该原液由以下组分混合而成:
甘草酸二钾1.3~2.0%、苦参碱0.05~0.15%、光甘草定羟丙基-β-环糊精包合物0.003-0.005%、芍药苷0.08~0.15%、四氢姜黄素0.07~0.10%、洋甘菊提取物0.03~0.05%、1,3-丁二醇18.0~25.0%、苯氧乙醇0.6~1.0%、余量为水;
上述苦参碱的分离纯化工艺为:取苦参药材,粉碎后过20目筛,筛下物用70%乙醇以质量体积比1:5~8分别回流提取1.5h~2h;将两次提取液合并后过滤,滤液减压浓缩成浸膏,经中性氧化铝柱层析分离,分离条件为:浸膏与氧化铝重量比1:10~20,柱内径与氧化铝在柱中的高度比1:7~9,采用氯仿与甲醇体积比1.5~2.2:1的混合液洗脱,薄层检测,改良碘化铋钾试剂显色,合并苦参碱洗脱部分,浓缩,石油醚结晶,得到HPLC含量>98%的苦参碱;
芍药苷的分离纯化工艺为:取赤芍药材,粉碎后过20目筛,筛下物用70%乙醇以质量体积比1: 2.5~5分别回流提取1~2h,提取3次,将三次提取液合并后过滤,滤液减压浓缩至无醇味后加乙酸乙酯、正丁醇萃取,萃取液减压浓缩成浸膏;经硅胶柱层析分离,分离条件为:浸膏与氧化铝重量比1:12~20,柱内径与硅胶柱中的高度比1:5~8,采用二氯甲烷与甲醇体积比3.5~4.2:1的混合液洗脱,洗脱液薄层检查,合并芍药苷部分,回收溶剂,经甲醇结晶,得到HPLC含量>98%的芍药苷;
洋甘菊提取物的分离纯化工艺为:取洋甘菊药材微粉碎,采用50%乙醇分别以质量体积比1:4~7在75~85℃下加热搅拌提取两次,滤液合并后回收乙醇至干,得到滤渣;该滤渣研磨后干法上样,采用大孔吸附树脂吸附,然后用纯净水冲洗至基本无色后,用50%乙醇洗脱;洗脱液加入活性炭回流脱色20~40min,过滤;脱色液浓缩、喷雾干燥,得到洋甘菊提取物。
2.如权利要求1所述的一种植物性抗敏剂原液,其特征是,所述光甘草定羟丙基-β-环糊精包合物中光甘草定的重量百分比≥1.8%。
3.一种如权利要求1或2所述的植物性抗敏剂原液的制备方法,其特征是,各组分以组方量加入,该制备方法包括以下步骤:
(1)先将1,3-丁二醇加入第一混合器中,然后依次加入光甘草定羟丙基-β-环糊精包合物和四氢姜黄素,搅拌状态下加热至50-60℃,保持10-20min,使各组分完全溶解,形成A溶液;
(2)先将水加入第二混合器中,然后依次加入甘草酸二钾、苦参碱、芍药苷和洋甘菊提取物,室温搅拌溶解,形成B溶液;
(3)将B溶液加入A溶液中,继续搅拌、降温至38-42℃时,加入苯氧乙醇,并用柠檬酸调pH至5.5-6.5,静置24h,得到抗敏剂原液。
4.一种植物性抗敏剂原液的应用,其特征是,将权利要求1或2所述的抗敏剂原液以重量百分比为2-10%加入美白、抗敏护肤品中。
5.根据权利要求4所述一种植物性抗敏剂原液的应用,其特征是,所述美白、抗敏护肤品为溶液、悬浊液、乳状液、霜剂、膏状、凝胶或奶液中的任意一种。
CN201811467650.1A 2018-12-03 2018-12-03 一种植物性抗敏剂原液及其制备方法和应用 Withdrawn CN109316422A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811467650.1A CN109316422A (zh) 2018-12-03 2018-12-03 一种植物性抗敏剂原液及其制备方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811467650.1A CN109316422A (zh) 2018-12-03 2018-12-03 一种植物性抗敏剂原液及其制备方法和应用

Publications (1)

Publication Number Publication Date
CN109316422A true CN109316422A (zh) 2019-02-12

Family

ID=65256740

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811467650.1A Withdrawn CN109316422A (zh) 2018-12-03 2018-12-03 一种植物性抗敏剂原液及其制备方法和应用

Country Status (1)

Country Link
CN (1) CN109316422A (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110101642A (zh) * 2019-06-21 2019-08-09 广州市澳源科技集团有限公司 一种抗敏褪红组合物、其制备方法和护肤制品
CN110613629A (zh) * 2019-09-11 2019-12-27 青岛优度生物工程有限公司 一种美白组合物以及微乳型化妆品制备方法
CN114788799A (zh) * 2022-04-14 2022-07-26 郑州迈健医药科技有限公司 一种美肤化妆品

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1787806A (zh) * 2003-05-16 2006-06-14 强生消费者公司 皮肤病的局部治疗
CN101869539A (zh) * 2010-06-08 2010-10-27 董萍 一种用于敏感性皮肤修复的脱敏复合纳米乳及其制备方法
CN103705426A (zh) * 2014-01-07 2014-04-09 梁云生 一种修复皮肤屏障功能抗过敏保湿组合物及其外用制剂
CN105596282A (zh) * 2016-01-22 2016-05-25 柳州博泽科技有限公司 一种具有祛斑美白功效的洗面乳
CN105616236A (zh) * 2014-10-31 2016-06-01 郁丁丁 一种具有镇定抗敏功能的乳液
CN106668331A (zh) * 2016-12-30 2017-05-17 杭州惠博士生物科技有限公司 一种具有消炎抑菌及促进创面愈合的组合物及制配方法
CN106726896A (zh) * 2016-12-06 2017-05-31 杭州惠博士生物科技有限公司 一种具有消炎抑菌功效的美容保健组合物及其制作方法
CN107998020A (zh) * 2017-12-18 2018-05-08 福建省海乐威生物工程有限公司 一种具有抗过敏功效的护肤霜
CN108066269A (zh) * 2017-12-27 2018-05-25 国东启 一种镇静抗敏美白抗皱组合物、其护肤品及制备方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1787806A (zh) * 2003-05-16 2006-06-14 强生消费者公司 皮肤病的局部治疗
CN101869539A (zh) * 2010-06-08 2010-10-27 董萍 一种用于敏感性皮肤修复的脱敏复合纳米乳及其制备方法
CN103705426A (zh) * 2014-01-07 2014-04-09 梁云生 一种修复皮肤屏障功能抗过敏保湿组合物及其外用制剂
CN105616236A (zh) * 2014-10-31 2016-06-01 郁丁丁 一种具有镇定抗敏功能的乳液
CN105596282A (zh) * 2016-01-22 2016-05-25 柳州博泽科技有限公司 一种具有祛斑美白功效的洗面乳
CN106726896A (zh) * 2016-12-06 2017-05-31 杭州惠博士生物科技有限公司 一种具有消炎抑菌功效的美容保健组合物及其制作方法
CN106668331A (zh) * 2016-12-30 2017-05-17 杭州惠博士生物科技有限公司 一种具有消炎抑菌及促进创面愈合的组合物及制配方法
CN107998020A (zh) * 2017-12-18 2018-05-08 福建省海乐威生物工程有限公司 一种具有抗过敏功效的护肤霜
CN108066269A (zh) * 2017-12-27 2018-05-25 国东启 一种镇静抗敏美白抗皱组合物、其护肤品及制备方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
叶柳青等: ""光甘草定羟丙基-β-环糊精包合物的制备及其对透皮吸收的影响研究"", 《天津中医药》 *
徐东翔: "《植物资源化学》", 30 September 2004, 湖南科学技术出版社 *
杨智荣等: "《美容保健技术》", 31 July 2006, 中国中医药出版社 *
杨秀伟: "《中药成分代谢分析》", 30 September 2003, 中国医药科技出版社 *
黄荣: "《化妆品制备基础》", 31 May 2015, 四川大学出版社 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110101642A (zh) * 2019-06-21 2019-08-09 广州市澳源科技集团有限公司 一种抗敏褪红组合物、其制备方法和护肤制品
CN110613629A (zh) * 2019-09-11 2019-12-27 青岛优度生物工程有限公司 一种美白组合物以及微乳型化妆品制备方法
CN114788799A (zh) * 2022-04-14 2022-07-26 郑州迈健医药科技有限公司 一种美肤化妆品

Similar Documents

Publication Publication Date Title
CN109316422A (zh) 一种植物性抗敏剂原液及其制备方法和应用
CN105411951B (zh) 黑柄炭角菌提取物在美白保湿化妆品中的应用
CN112438925B (zh) 一种抗敏修复组合物及其应用
CN104666178B (zh) 一种美白保湿组合物及面膜
CN105147991A (zh) 一种抑制黑色素形成的中药组合物及其制备方法和应用
JP6757807B2 (ja) Tie2活性化剤、血管の成熟化剤、及び血管の安定化剤、並びに経口用組成物
KR20080073466A (ko) 생약 혼합물을 이용하여 이루어진 조성물 및 그 제조 방법
JP2020514279A (ja) ヒトの身体を療法により治療する方法に使用するためのヘディキウム・コロナリウム(Hedychium coronarium)種植物の抽出物を含む組成物
CN105998195A (zh) 一种具有抗敏感保湿作用的汉麻提取物及其应用
EP2320922B1 (de) Kombination von extrakten aus verschiedenen pflanzen zur verbesserung der symptome von demenzerkrankungen
KR100701222B1 (ko) 화장료 조성물
CN105154252B (zh) 一种银杏叶提取物及其提取方法与应用
CN110037958A (zh) 一种含金莲花成分的祛痘美白保湿面膜及其制备方法
CN109846762A (zh) 一种具有美白功效的组合物及其制备方法、应用
KR101813606B1 (ko) 인도천연물을 함유하는 미백용 화장료 조성물
CN107773508A (zh) 一种面膜及其制作方法
CN106176455A (zh) 一种美白抗衰老护肤品及其制备方法
CN115844939A (zh) 具有trpv1蛋白抑制作用的青蒿提取物
JP2007045733A (ja) ヒアルロニダーゼ阻害剤
KR101731264B1 (ko) 아임계추출조건으로 추출한 사간추출물을 포함하는 피부미백용 화장료 조성물
CN111568831B (zh) 用于皮肤化妆品的中草药提取物的组合物及其制备方法
CN107773506A (zh) 一种眼贴及其制作方法
JP2006241033A (ja) くすみ改善用皮膚外用剤
JP4076477B2 (ja) 皮膚外用剤
KR102142931B1 (ko) 붉나무 열매 추출물을 포함하는 피지분비 억제용 조성물

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WW01 Invention patent application withdrawn after publication
WW01 Invention patent application withdrawn after publication

Application publication date: 20190212