CN106166119A - 3’-羟基染料木黄酮用于制备抑制黑色素生成的组合物的用途 - Google Patents
3’-羟基染料木黄酮用于制备抑制黑色素生成的组合物的用途 Download PDFInfo
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- CN106166119A CN106166119A CN201610339405.7A CN201610339405A CN106166119A CN 106166119 A CN106166119 A CN 106166119A CN 201610339405 A CN201610339405 A CN 201610339405A CN 106166119 A CN106166119 A CN 106166119A
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- melanin
- dye genitein
- hydroxy
- hydroxy dye
- suppression
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及一种3’‑羟基染料木黄酮用于制备抑制黑色素生成的组合物的用途,其是施予有效剂量的3’‑羟基染料木黄酮于皮肤,以抑制酪胺酸酶活性,达到抑制黑色素生成的用途,因此,3’‑羟基染料木黄酮可进一步作为美白的化妆材料组合物。
Description
技术领域
本发明是有关于一种3’-羟基染料木黄酮(3’-hydroxygenistein)用于制备抑制黑色素生成的组合物的用途,尤其是指3’-羟基染料木黄酮具有抑制酪胺酸酶与抑制黑色素生成的活性,因此可进一步当作化妆材料组合物,达到美白的功效。
背景技术
人类肤色主要取决于皮肤表皮层(epidermis)中黑色素(melanin)的含量,皮肤黑色素细胞(melanocyte)的黑色素小体(melanosome)透过黑色素生成作用(melanogenesis)产生黑色素以防御抵抗阳光中的紫外线。黑色素的生成过程包括多种酵素催化及化学反应,目前已知酪胺酸酶(tyrosinase)为调控黑色素生成的重要酵素之一,不仅参与黑色素生成过程中的许多反应,并且为催化反应中速率限制步骤(rate-limiting step)的关键酵素,因此酪胺酸酶的含量可作为黑色素生成反应的指标。尽管黑色素具有光保护作用,但当黑色素过多或异常分布时,会造成黑色素过量沉着(hyperpigmentation)及产生斑块而影响美观。因此,如何有效抑制酪胺酸酶活性及防止如黑斑(melisma)及老人斑等异常黑色素沉着情形发生,已成为相关业者的研发重点。
类黄酮(flavonoid)属于植物中一种重要的次级代谢产物,常见的类黄酮包括大豆黄酮(daidzein)、芹菜素(apigenin)、染料木黄酮(genistein)、甘草素(liquiritigenin)、柚皮素(naringenin)及儿茶素(catechin)。近年来发现类黄酮对于人体生理有许多功效,包含抗氧化性、预防骨质疏松、降低心血管疾病及减缓更年期症状等。举例而言,芹菜素(apigenin)及染料木黄酮(genistein)已被证实具有抗氧化(antioxidant)、抗发炎(anti-inflammatory)以及改善光损害的功效(Photochem Photobiol.2008 Mar-Apr;84(2):489-500)。
研究亦证实,位于类黄酮骨架上不同碳原子的官能基会影响类黄酮的生化活性,尤其羟基类黄酮(hydroxyl flavonoid)衍生物通常具有相异于前驱物类黄酮的生化活性。例如在本发明人过去的研究中,证实邻位-羟基大豆黄酮(ortho-hydroxydaidzein,OHDe)衍生物,包括6-hydroxydaidzein(6,7,4’-trihrdroxyisoflavone,6-OHDe,Biosci.Biotechnol.Biochem.2005,69(10),1999–2001)以及8-hydroxydaidzein(7,8,4’-trihrdroxyi-soflavone,8-OHDe,J.Agric.Food Chem.2007,55(5),2010–2015;Int.J.Mol.Sci.2009,10(10),4257–4266)具有酪胺酸酶抑制剂的活性,但该前驱物大豆黄酮(daidzein)则不具此活性。再者,根据本发明人的中国台湾发明专利第I312686号“皮肤黑色素抑制剂”,亦公开了6-OHDe、8-OHDe及8-hydroxygenistein(5,7,8,4’-tetrahydroxyisoflavone)对于抑制酪胺酸氧化酵素的抑制效果比前驱物大豆异黄酮甘胺黄酮(glycitein)强25倍、大豆黄酮(daidzein)强30倍、染料木黄酮(genistein)强90倍。显见羟基类黄酮衍生物的生化活性确实与其前驱物类黄酮差异极大。
目前尚无相关研究指出3’-羟基染料木黄酮是否具有抑制酪胺酸酶的活性,因此发明人为研发出更多具有抑制黑色素生成的类黄酮衍生物种类,以期发展出低剂量、高效能的皮肤保养品,于是本着孜孜不倦的精神,并通过其丰富专业知识及多年的实务经验,研创出本发明。
发明内容
本发明主要目的为提供一种3’-羟基染料木黄酮用于制备抑制黑色素生成的组合物的用途,其是将3’-羟基染料木黄酮作为化妆材料组合物,以抑制酪胺酸酶活性与抑制黑色素生成,达到美白淡斑的功效。
为了达到上述目的,本发明提供了一种3’-羟基染料木黄酮用于制备抑制黑色素生成的组合物的用途,其是施予有效剂量的3’-羟基染料木黄酮于皮肤,以抑制酪胺酸酶活性,达到抑制黑色素生成的用途,其中有效剂量可为10-40μM,较佳为10-20μM。
因此,3’-羟基染料木黄酮可进一步作为美白的化妆材料组合物,例如水剂、乳剂、膏剂、粉剂的化妆品,亦可添加于具有其他功能性(如保湿、抗皱)的化妆品中合并使用。
附图说明
图1为本发明的一实施例中利用生物转换作用合成3’-羟基染料木黄酮的示意图。
图2为3’-羟基染料木黄酮对酪胺酸酶活性的影响结果。
图3为3’-羟基染料木黄酮的细胞毒性的实验结果。
图4为3’-羟基染料木黄酮对黑色素生成的影响结果。
具体实施方式
本发明的组合物及其功能,将依据以下所示的结构,配合具体实施例予以说明。
本发明提供一种3’-羟基染料木黄酮用于制备抑制黑色素生成的组合物的用途,其是施予有效剂量的3’-羟基染料木黄酮于皮肤,以抑制酪胺酸酶活性,达到抑制黑色素生成的用途,其中有效剂量可为10-40μM,较佳为10-20μM。
值得注意的是,3’-羟基染料木黄酮的制备方式有很多种,本发明在此并不加以限定其制备方式,凡是涉及利用3’-羟基染料木黄酮用于制备抑制黑色素生成的组合物,应视为本发明所保护的范围内。
此外,通过下述具体实施例,可进一步证明本发明可实际应用的范围,但不以任何形式限制本发明的范围。
实验一:制备3’-羟基染料木黄酮
首先,本发明的3’-羟基染料木黄酮可如以下述生物转换作用(biotransformation)制备而得,在此并不限定3’-羟基染料木黄酮的制备方式。
(1)建构含融合基因的重组毕赤酵母以进行类黄酮生物转换作用
将含有CYP57B3基因与细胞色素还原酶(cytochrome reductase,CPR)基因的环状重组质体置于微生物表达系统毕赤酵母(Pichia pastoris)中表达,其中CYP57B3基因是来自米曲菌(Aspergillus oryzae),CPR基因是来自酿酒酵母(Saccharomyces cerevisiae)。有关建构含有CYP57B3与CPR融合基因的重组毕赤酵母(recombinant P.pastoris)的技术已为公知常识,已公开于发明人的中国台湾专利申请号第102145727号“利用生物转换制备6-羟基芹菜素的方法”(公告号TWI507527(B))中,于此不再赘述。
(2)发酵及制备3’-羟基染料木黄酮
将毕赤酵母重组体培养于100mL YNB培养基(含2%葡萄糖(dextrose)及100μg/ml的抗生素Zeocin)内,条件为28℃、200rpm培养48小时以作为种菌培养物(seedculture)。再将种菌培养物接种(inoculate)到5L的发酵槽中,此发酵槽是含有2.5L的YNB培养基,并添加有2%葡萄糖(dextrose)、250μM的δ-氨基-γ-酮戊酸(δ-aminolevulinic acid)以及100μM染料木黄酮(genistein),然后伴随通气(0.5,v/v/m)和搅拌(280rpm),于28℃进行发酵反应72小时。
(3)利用超高效液相色谱方法(UPLC)分析该滤液
收集发酵后的培养物,并利用超高效液相色谱(UPLC)分析染料木黄酮(genistein)与3’-羟基染料木黄酮(3’-hydroxygenistein)的含量。通过分析型C18逆向管柱(C18reversed-phase column)(Acquity UPLC BEH C18,1.7μm,2.1i.d.×100mm,Waters,USA)进行分析的操作条件是包括:利用含有1%(v/v)醋酸(acetic acid)的水溶液A与甲醇溶液B梯度冲提(gradient elution),以及线性梯度(linear gradient)15%至35%的溶液B冲提5分钟,流速为0.3毫升/分钟,并以吸光值260nm侦测。通过分析标准品得到的标准曲线,计算生成的3’-羟基染料木黄酮含量。
(4)分离并利用高效液相色谱方法(HPLC)鉴定生物转换作用的产物
此实验是准备四批2.5升发酵液用以纯化生物转换作用的产物。发酵之后,利用2L乙酸乙酯萃取总培养液两次,将此含有3’-羟基染料木黄酮的乙酸乙酯萃取液于真空下合并浓缩以形成残留物(residue),再将残留物回溶于400ml的50%甲醇中,并于利用2.2μm尼龙膜于真空下过滤纯化以得到滤液。通过制备型C18逆向管柱(C18reversed-phase column)(Inertsil,10μm,20.0i.d.×250mm,ODS3,GLSciences,Japan)进行HPLC分析的操作条件是包括:利用水溶液A与甲醇溶液B梯度冲提(gradientelution),以及线性梯度(linear gradient)25%至50%的溶液B冲提25分钟,流速为15毫升/分钟,并以吸光值260nm侦测,注射体积为10ml。进一步地,收集对应于UPLC分析中相同峰(peak)的冲提液(elution),于真空下浓缩并冷冻干燥结晶以得到11.5mg结晶物,利用NMR和质谱分析确认结晶物的化学结构。
请参阅图1,毕赤酵母重组体在含有染料木黄酮(genistein)发酵72小时进行生物转换作用之后得到的产物,在UPLC色谱图中滞留时间(retention time)3.6分钟处出现。进一步地,将产物利用HPLC方法分离,并利用NMR和质谱分析鉴定。获得的数据如下,ESI/MS m/z:295[M-H]+,1H-NMR(DMSO-d6,500MHz)δ:6.20(1H,d,J=1.8Hz,H-6),6.36(1H,d,J=1.8Hz,H-8),6.76(1H,d,J=8.0Hz,H-5′),6.78(1H,dd,J=8.0,1.8Hz,H-6′),6.96(1H,d,J=1.8Hz,H-2′),8.22(1H,s,H-2),13C-NMR(DMSO-d6,125MHz)δ:180.6(C-4,C=O),164.7(C-7),162.3(C-5),157.9(C-9),154.3(C-2),145.8(C-3′),145.2(C-4′),122.8(C-1′),122.0(C-3),120.4(C-6′),116.8(C-5′),115.8(C-2′),104.8(C-10),99.4(C-6),94.1(C-8)。比对文献,得知上述产物为3’-羟基染料木黄酮(JBiotechnol 2014;176:11–17)。后续将取生物转换作用得到的3’-羟基染料木黄酮进行试验。
实验二:检测3’-羟基染料木黄酮对于酪胺酸酶活性的影响
由于酪胺酸酶在黑色素生成中扮演重要角色,因此利用3’-羟基染料木黄酮测试其对于酪胺酸酶活性的影响。取1μL 3’-羟基染料木黄酮(溶于DMSO)与5μL酪胺酸酶混合于94μL的50mMPBS(pH6.8),再加入0.9mL的2.5mML-DOPA(溶于50mM、pH6.8的PBS),在25℃反应10分钟。多巴色素(dopachrome)的形成是利用分光亮度计(U-5100,Hitachi,日本)测量475nm处的吸亮度,酪胺酸酶活性是以相对于DMSO对照组的百分比(%)表示。在此实验中,曲酸(kojic acid)与染料木黄酮是作为正对照组。
请参阅图2,Y轴代表酪胺酸酶活性(tyrosinase activity),X轴代表不同处理条件,结果显示10~40μM的3’-羟基染料木黄酮皆具有抑制酪胺酸酶活性,且具有浓度相关性(dose dependent),随着剂量越高抑制效果越佳。此外,3’-羟基染料木黄酮对于酪胺酸酶活性的半抑制浓度(IC50)为15.9μM,与目前已知具有很强抑制酪胺酸酶活性、常当作标准品的曲酸(半抑制浓度(IC50为183.6μM)相较下,3’-羟基染料木黄酮对于酪胺酸酶的抑制效果约为曲酸的11倍。同时由图2结果可知,同样浓度的染料木黄酮完全不具有抑制酪胺酸酶的效果。
实验三:检测3’-羟基染料木黄酮的细胞毒性及对于黑色素生成的影响
(1)细胞存活率的测定
为了确认3’-羟基染料木黄酮对于细胞的非毒性浓度范围,进一步利用MTT法与结晶紫(crystal violet)染色法检测3’-羟基染料木黄酮的细胞存活率。小鼠B16黑色素瘤细胞(4A5)是由生物资源保存及研究中心(BCR,新竹财团法人食品工业发展研究所)购得。将细胞培养于含有10%(v/v)胎牛血清(FBS)的DMEM培养基内,在37℃、5%CO2的湿润培养箱中培养。培养1天之后,利用3’-羟基染料木黄酮处理小鼠B16黑色素瘤细胞48小时,将培养液移除,加入溶于PBS的1mg/mL MTT溶液培养2小时,再将MTT溶液移除,并加入DMSO。利用分光亮度计(U-5100,Hitachi,日本)测量溶解的甲臜晶体(formazan crystals)于570nm处的吸亮度,细胞存活率是以相对对照组的百分比(%of control)表示。
结果如图3所示,Y轴代表细胞存活率(cell survival),X轴代表不同处理条件,与对照组(0μM)相较下,浓度10~20μM的3’-羟基染料木黄酮不具细胞毒杀性,浓度40μM的3’-羟基染料木黄酮则具有细胞毒杀性。因此,后续仅利用最高浓度为20μM的3’-羟基染料木黄酮探讨对于黑色素含量的抑制效果。
(2)黑色素含量的测定
在此实验中,利用IBMX作为黑色素生成刺激剂(melanogenic-stimulating agen),并分别利用染料木黄酮以及已被证实具有抑制黑色素生成活性的danazol作为正对照组。将小鼠B16黑色素瘤细胞(4A5培养于含有10%(v/v)胎牛血清(FBS)的DMEM培养基内,在37℃、5%CO2的湿润培养箱中培养。以适当细胞密度将细胞种于24-well培养皿中,经过一天培养后,将细胞于存有400μM黑色素生成刺激剂(IBMX)的条件下,分别利用5、10或20μM的3’-羟基染料木黄酮处理细胞,并培养2天。之后收集细胞并以PBS缓冲液洗涤细胞2次,再将沉淀细胞溶解于含20mM磷酸钠(pH6.8)和1%TritonX-100的裂解缓冲液(lysis buffer)。以15,000×g离心15分钟后,在95℃下将黑色素沉淀物(melanin pellets)溶解于含有20%DMSO的1N NaOH中1小时。黑色素含量的测定是利用分光亮度计(U-5100,Hitachi,日本)测量490nm处的吸亮度,黑色素含量是以相对对照组(IBMX刺激组别)的百分比(% of control)表示。
结果请参阅图4,Y轴代表黑色素含量(melanin content),X轴代表不同处理条件,与对照组相较下,10μM及20μM的3’-羟基染料木黄酮皆各别呈现抑制B16细胞黑色素含量的能力,尤其20μM的3’-羟基染料木黄酮组别的黑色素含量仅剩50.5%,此外实验结果亦发现,相较于强效黑色素生成抑制剂danazol(Arch Pharm Res 2010;33:1959–1965),本发明的3’-羟基染料木黄酮对于黑色素的抑制效果较danazol佳。同时由图4结果可知,同样浓度的染料木黄酮完全不具有抑制黑色素生成的效果。
综上所述,本发明的3’-羟基染料木黄酮确实具有抑制酪胺酸酶与抑制黑色素生成的活性,因此,可利用3’-羟基染料木黄酮作为美白的化妆材料组合物,例如水剂、乳剂、膏剂、粉剂等化妆品,且化妆材料组合物可进一步包含有一般广泛使用的化妆品上可接受的佐剂(cosmetically acceptable adjuvant),例如包含一或多种选自于溶剂、胶凝剂、活性剂、防腐剂、抗氧化剂、遮蔽剂(screening agent)、螯合剂、界面活性剂、增稠剂(thickening agent)、香料以及气味吸收剂的佐剂,且佐剂的选用是本领域技术人员的公知常识。
另外,本发明的化妆材料组合物亦可与一或多种选自于下列的已知活性的外用剂(external use agents)一起合并使用:美白剂(whitening agents)、保湿剂、抗发炎剂(anti-inflammatory agents)、紫外线吸收剂(ultraviolet absorbers)、植物萃取物(plantextracts)、抗痘剂(anti-acne agent)、抗汗剂(antipsoriatic agents)、抗老化剂(antiager)、抗皱剂(antiwrinkle agents)以及伤口治疗剂(wound-healing agents),以达到较佳功效并减少黑色素异常沉着。
由上述的实施说明可知,本发明与现有技术相较之下,本发明具有以下优点:
1.本发明首次证实3’-羟基染料木黄酮(3’-hydroxygenistein)具有抑制酪胺酸酶与抑制黑色素生成的活性,因此本发明提供可作为美白的化妆材料组合物的新颖类黄酮衍生物。
2.本发明证实低剂量(10μM~20μM)的3’-羟基染料木黄酮具有更佳的抑制酪胺酸酶与抑制黑色素生成活性,其抑制能力明显优于常规的酪胺酸酶抑制剂曲酸,与黑色素生成抑制剂danazol,并且相同浓度(10μM~20μM)的染料木黄酮并不具有任何抑制酪胺酸酶与抑制黑色素生成的活性。事实上,已有文献报告指出染料木黄酮在30μM~60μM浓度下会促进黑色素细胞加速生成黑色素(J Nutr Biochem 2002;13:421-426)。因此3’-羟基染料木黄酮具有低剂量、高效能的皮肤美白效果。
Claims (5)
1.一种3’-羟基染料木黄酮用于制备抑制黑色素生成的组合物的用途,其是施予有效剂量的3’-羟基染料木黄酮于皮肤,以抑制酪胺酸酶活性,达到抑制黑色素生成的用途。
2.如权利要求1所述的用途,其中,所述有效剂量是10-40μM。
3.如权利要求2所述的用途,其中,所述有效剂量是10-20μM。
4.如权利要求1所述的用途,其中,所述3’-羟基染料木黄酮是作为美白的化妆材料组合物。
5.如权利要求4所述的用途,其中,所述化妆材料组合物为水剂、乳剂、膏剂、粉剂的化妆品。
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CN109825518A (zh) * | 2019-02-25 | 2019-05-31 | 佐登妮丝(广州)美容化妆品有限公司 | 3′-羟基染料木黄酮的制备方法及其用途 |
TWI663972B (zh) * | 2017-03-06 | 2019-07-01 | 嘉藥學校財團法人嘉南藥理大學 | 3’-甲氧基染料木黃酮於抑制或治療黑色素瘤之用途 |
CN112107530A (zh) * | 2020-09-30 | 2020-12-22 | 佐登妮丝(广州)美容化妆品有限公司 | 一种抗衰老组合物 |
CN114836489A (zh) * | 2021-02-01 | 2022-08-02 | 佐登妮丝国际股份有限公司 | 3’-羟基染料木黄酮的制备方法 |
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TWI691599B (zh) * | 2018-10-11 | 2020-04-21 | 佐登妮絲國際股份有限公司 | 3’-羥基染料木黃酮之製備方法 |
CN111265469A (zh) * | 2020-03-20 | 2020-06-12 | 佐登妮丝(广州)美容化妆品有限公司 | 一种抗氧化美白组合物及其制备方法和应用 |
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CN1635907A (zh) * | 2001-11-06 | 2005-07-06 | 奎格利公司 | 用于治疗电离辐射的副作用的局部组合物和方法 |
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- 2016-05-11 US US15/151,738 patent/US20160338992A1/en not_active Abandoned
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JPH06321752A (ja) * | 1993-05-07 | 1994-11-22 | Kao Corp | 美白剤 |
CN1376050A (zh) * | 1999-07-30 | 2002-10-23 | 荷兰联合利华有限公司 | 皮肤护理组合物 |
CN1635907A (zh) * | 2001-11-06 | 2005-07-06 | 奎格利公司 | 用于治疗电离辐射的副作用的局部组合物和方法 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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TWI663972B (zh) * | 2017-03-06 | 2019-07-01 | 嘉藥學校財團法人嘉南藥理大學 | 3’-甲氧基染料木黃酮於抑制或治療黑色素瘤之用途 |
CN109825518A (zh) * | 2019-02-25 | 2019-05-31 | 佐登妮丝(广州)美容化妆品有限公司 | 3′-羟基染料木黄酮的制备方法及其用途 |
CN112107530A (zh) * | 2020-09-30 | 2020-12-22 | 佐登妮丝(广州)美容化妆品有限公司 | 一种抗衰老组合物 |
CN114836489A (zh) * | 2021-02-01 | 2022-08-02 | 佐登妮丝国际股份有限公司 | 3’-羟基染料木黄酮的制备方法 |
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