CN101193907B - 三萜酸衍生物和包含其的皮肤外用剂 - Google Patents
三萜酸衍生物和包含其的皮肤外用剂 Download PDFInfo
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- CN101193907B CN101193907B CN2006800205185A CN200680020518A CN101193907B CN 101193907 B CN101193907 B CN 101193907B CN 2006800205185 A CN2006800205185 A CN 2006800205185A CN 200680020518 A CN200680020518 A CN 200680020518A CN 101193907 B CN101193907 B CN 101193907B
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- Prior art keywords
- acid
- skin
- quality
- salt
- ursonic
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Abstract
在具有羟基的三萜酸中，所述羟基的至少一个被磷酸化产生磷酸化三萜酸和/或其盐，由此提高三萜酸在皮肤外用剂中的溶解度并使三萜酸的生理活性充分发挥。磷酸化三萜酸优选为例如乌索酸磷酸酯和/或其盐。所述皮肤外用剂优选为化妆品，尤其优选为准药物。
Description
技术领域
本发明涉及新型三萜酸衍生物和包含其的皮肤外用剂。
背景技术
已知三萜酸如乌索酸具有各种生理学作用，如抗氧化作用、抗炎作用和黑色素产生抑制作用，而且将三萜酸混合到皮肤外用剂如化妆品中的技术是已知的(参见例如专利文献1、2、3、4和5)。但是，所述化合物在油性成分和水性成分中的溶解度都不够，并存在三萜酸在长期保存中沉淀的问题。三萜酸的生理学活性可能由于不足的溶解度而降低，导致不足的生理学作用。在这种情况下，通过例如酯化三萜酸产生三萜酸的衍生物来提高三萜酸在油性成分中的溶解度。但是，这种方法被认为不能令人满意地防止三萜酸的沉淀(参见例如专利文献6)。也就是说，需要提高在制剂中溶解度的手段，而不会损害已知具有各种生理学活性的三萜酸如乌索酸的生理学活性。
另一方面，磷酸化具有羟基的化合物得到磷酸酯的技术是已知的，在化妆品领域中，化学修饰为磷酸酯衍生物以稳定糖或糖类似物如抗坏血酸(参见例如专利文献7和8)。但是，没有为了提高溶解度而磷酸化的例子，且三萜酸的磷酸化化合物为文献中没有描述过的新型化合物。
专利文献1：JP 08-165231 A
专利文献2：JP 08-208424 A
专利文献3：JP 01/072265 A1
专利文献4：JP 11-012122 A
专利文献5：JP 2000-302659 A
专利文献6：JP 2004-331593 A
专利文献7：JP 11-158197 A
专利文献8：JP 2001-354513 A
发明内容
在上述情况下进行了本发明，本发明的一个目的是提供提高已知具有各种生理学活性的三萜酸如乌索酸的溶解度且不损害生理学活性的技术。
鉴于这些情况，本发明的发明人进行了广泛研究以便发现能提高已知具有各种生理学活性的具有羟基的三萜酸如乌索酸的溶解度且不损害生理学活性的技术，结果，本发明人发现，通过磷酸化三萜酸的至少一个羟基得到的磷酸化三萜酸具有这种性质，从而完成了本发明。也就是说，本发明如下：
(1)衍生自具有羟基的三萜酸并通过磷酸化所述羟基的至少一个得到的磷酸化三萜酸和/或其盐。
(2)根据第(1)项的磷酸化三萜酸和/或其盐，其为乌索酸磷酸酯和/或其盐。
乌索酸磷酸酯
(3)皮肤外用剂，其包含第(1)项或第(2)项的磷酸化三萜酸和/或其盐。
(4)根据第(3)项的皮肤外用剂，其为化妆品。
(5)根据第(4)项的皮肤外用剂，其中化妆品为准药物(quasi-drug)。
(6)根据第(5)项的皮肤外用剂，其用于抗炎。
(7)根据第(5)项的皮肤外用剂，其用于抑制黑色素产生。
具体实施方式
(1)本发明的化合物
本发明的化合物为通过磷酸化具有羟基的三萜酸(下文中有时简单地称为三萜酸)中的至少一个羟基得到的磷酸化三萜酸。对具有羟基的三萜酸没有特殊限制，只要它用在皮肤外用剂如化妆品领域中即可，其优选例子包括乌索酸、齐墩果酸、桦木酸和积雪草酸((2α，3β，4α)-2，3，23-三羟基-12-烯-乌索酸((2α，3β，4α)-2，3，23-三羟基乌索-12-烯-28-酸))。在这些中，乌索酸是尤其优选的，因为它作为试剂出售并容易得到，且作为皮肤外用剂具有特别显著的生理学活性。
从三萜酸衍生三萜酸磷酸酯可按照通常已知的磷酸化方法进行。例如，在四唑存在下用1-3倍当量的二乙基-N，N-二乙基氨基磷酸酯(diethyl-N，N-diethylphosphoramidate)处理三萜酸，并与叔丁基氢过氧化物反应产生三萜酸的甲基磷酸酯，然后使溴三甲基硅烷与其反应，由此产生三萜酸磷酸酯。
通过按这种方式处理乌索酸得到的乌索酸磷酸酯具有上面显示的结构。通过使该酸与药物或化妆品中常用的碱反应可将这样得到的磷酸化三萜酸转化成盐。这类盐的优选例子包括：碱金属盐如钠盐和钾盐；碱土金属盐如钙盐和镁盐；有机胺盐如铵盐、三乙醇胺盐和三乙胺盐；和碱性氨基酸盐如赖氨酸盐和精氨酸盐。这样得到的磷酸化三萜酸或其盐在水性载体中具有显著的溶解度，并且与三萜酸相比具有显著提高的药物活性。在包含本发明的磷酸化三萜酸的皮肤外用剂情况下，相对于皮肤外用剂的总量，磷酸化三萜酸含量优选为0.001-0.1质量％。这是因为，如果含量太小，则可能不表达药物活性，而如果含量太大，则药物活性可能达到平台。
(2)本发明的皮肤外用剂
本发明的皮肤外用剂的特征在于：包含本发明的上述磷酸化三萜酸和/或其盐。本发明的皮肤外用剂的例子包括化妆品和皮肤外用药，在这些中，化妆品是优选的。在化妆品中，准药物是优选的。准药物为被认为具有日本国药事法规定的特定作用和效力并且与药物相比具有温和作用的产品。在本发明中，准药物指不仅为了美丽而且为了预防或改善特定症状而使用的化妆品。本发明的皮肤外用剂还包括类似于日本的准药物并用于相同目的的化妆品。这类化妆品的例子包括韩国的药用化妆品和中国的含药化妆品。
在本发明的皮肤外用剂中，用作必须成分的磷酸化三萜酸和/或其盐具有抗炎作用和黑色素产生抑制作用，因此制剂优选用作抗炎用皮肤外用剂或用于抑制黑色素产生或皮肤增白的皮肤外用剂。在这些中，优选的为抗炎用准药物和黑色素产生抑制用准药物，并优选在这类准药物的包装或附加文件中指明抗炎作用或黑色素产生抑制作用。因此，可清楚指明皮肤外用剂使用方式，并要求使用者合适地使用它。
本发明的皮肤外用剂不仅可包括上述磷酸化三萜酸和其盐，而且可包括药物或化妆品中常用的各种成分，即下列中的一种或多种：水性成分、油性成分、粉末成分、表面活性剂、保湿剂、增稠剂、着色剂、香味剂、抗氧化剂、pH调节剂、螯合剂、防腐剂，和药物如防紫外线剂、抗炎药、伤口愈合药、新陈代谢促进剂和皮肤增白剂。
水性成分的例子包括水和低级醇(乙醇、丙醇和异丙醇)。
油性成分的例子包括高级脂肪酸(如硬脂酸、棕榈酸、肉豆蔻酸、月桂酸和它们的酯)、高级醇(如鲸蜡醇、羊毛脂醇、硬脂醇和十六十八醇(cetostearyl alcohol))、蜡(如固体石蜡、微晶蜡、地蜡、聚乙烯蜡、蜂蜡、植物蜡、巴西棕榈蜡和小烛树蜡)、天然或合成油状物质(如角鲨烷、液体石蜡、羊毛脂或其衍生物、橄榄油、山茶油、棉籽油、油醇、蓖麻油、矿脂、己二酸二乙氧基乙酯、硅油和氟烃)。
粉末成分的例子包括氧化铝、二氧化钛、氧化锌、铁丹、铁黄、群青、铁蓝、丙烯酸类树脂粉、二氧化硅、滑石、绢云母、云母和云母钛。
表面活性剂的例子包括：阴离子表面活性剂如脂肪酸皂(如月桂酸钠和棕榈酸钠)、月桂基硫酸钾和三乙醇胺烷基醚硫酸酯；阳离子表面活性剂如硬脂酰基三甲基氯化铵、苯扎氯铵和氧化月桂胺；两性表面活性剂如咪唑啉系两性表面活性剂(如2-椰油基-2-咪唑啉鎓氢氧化物-1-羧基乙氧基-2-钠)、甜菜碱系两性表面活性剂(如烷基甜菜碱、酰胺甜菜碱和磺基甜菜碱)和酰基甲基牛磺酸；非离子表面活性剂如失水山梨糖醇脂肪酸酯(如失水山梨糖醇单硬脂酸酯和失水山梨糖醇倍半油酸酯)、甘油脂肪酸酯(如甘油单硬脂酸酯)、丙二醇脂肪酸酯(如丙二醇单硬脂酸酯)、氢化蓖麻油衍生物、甘油烷基醚、聚氧乙烯(POE)失水山梨糖醇脂肪酸酯(如POE失水山梨糖醇单油酸酯和聚氧乙烯失水山梨糖醇单硬脂酸酯)、POE山梨糖醇脂肪酸酯(如POE-山梨糖醇单月桂酸酯)、POE甘油脂肪酸酯(如POE-甘油单异硬脂酸酯)、POE
脂肪酸酯(如聚乙二醇单油酸酯和POE二硬脂酸酯)、POE烷基醚(如POE2-辛基十二烷基醚)、POE烷基苯基醚(如POE壬基苯基醚)、Pluronics(商标)、POE·POP烷基醚(如POE·POP2-癸基十四烷基醚)、Tetronics(商标)、POE蓖麻油·氢化蓖麻油衍生物(如POE蓖麻油和POE氢化蓖麻油)、蔗糖脂肪酸酯和烷基糖苷。
保湿剂的例子包括：多元醇如甘油、丙二醇、1，3-丁二醇、双丙甘醇、乙二醇、1，4-丁二醇、双甘油、三甘油、和聚乙二醇；葡萄糖、麦芽糖、麦芽糖醇、蔗糖、果糖、苏糖醇、赤藓醇、山梨糖醇或其衍生物、淀粉分解糖、透明质酸、硫酸软骨素、水解胶原、水解弹性蛋白、羧甲基甲壳质、酪蛋白苏打(casein soda)、粘蛋白、糖鞘脂。相对于所有成分，这些可占0.1-30wt％。
增稠剂的例子包括羧基乙烯基聚合物、CP凝胶、羧甲基纤维素、角叉菜胶、藻酸钠、膨润土、硅酸镁铝(veegum)和合成锂蒙脱石。
抗氧化剂的例子包括二丁基化羟基甲苯(BHT)、丁基化羟基茴香醚(BHA)、生育酚焦亚硫酸钠、硫酸钠和生育酚乙酸。
pH调节剂的例子包括柠檬酸、乳酸、酒石酸和磷酸盐。
螯合剂的例子包括乙二胺四乙酸(EDTA)。
防腐剂的例子包括对羟基苯甲酸的甲基、乙基、丙基或丁基酯、苯氧基乙醇、邻-苯基苯酚、脱氢乙酸或其盐、对甲酚、间甲酚和邻-氯-间-二甲苯酚。
防紫外线剂的例子包括尿刊酸或其衍生物、异阿魏酸或其盐、羟甲氧苯酮(oxybenzone)或其衍生物、对氨基苯甲酸或其衍生物、二苯甲酰基甲烷或其衍生物和对甲氧基肉桂酸或其衍生物。相对于所有成分，这些可占0.01-30wt％。
抗炎药的例子包括甘草次酸或其衍生物如甘草次酸硬脂酯、甘草酸或其盐、马栗提取物和芦荟提取物。相对于所有成分，这些可占0.01-5wt％。
伤口愈合药的例子包括蜂王浆提取物、当归根(angelica root)提取物、迷迭香提取物和迷迭香酸。相对于所有成分，这些可占0.01-5wt％。
新陈代谢促进剂的例子包括胎盘提取物、γ-谷维素、氨基酸或其衍生物和维生素E或其衍生物。相对于所有成分，这些可占0.01-5wt％。
皮肤增白剂的例子包括泛酰巯基乙胺-S-磺酸、抗坏血酸、或其磷酸
镁盐、熊果苷、曲酸、亚油酸、凝血酸和七叶苷。
在上述任意成分中，特别地，抗炎用活性成分优选用在抗炎用准药物中。这类活性成分的优选例子包括甘草次酸硬脂酯和甘草酸二钾。这类活性成分的浓度优选为0.01-5质量％。
另外，用于抑制黑色素产生或用于皮肤增白的活性成分尤其优选用在用于抑制黑色素产生的准药物中。这类活性成分的例子包括抗坏血酸和其盐、抗坏血酸磷酸酯和其盐、抗坏血酸葡糖苷和其盐、熊果苷和其盐、鞣花酸和其盐、凝血酸和其盐，以及4-甲氧基水杨酸和其盐。这类活性成分的浓度优选为0.01-5质量％。
可通过按照常规方法处理上述必须成分和任意成分制造本发明的皮肤外用剂。
下文中，将通过实施例更详细地描述本发明，但本发明不仅限于这些实施例。
实施例
<实施例1>
将乌索酸(48.1g，0.105mol)、二甲基-N，N-二乙基氨基磷酸酯(34.82g，0.211mol)、干燥四氢呋喃(1250ml)的混合物加热到35℃制备透明溶液，并在27℃的内部温度下一次性加入1H-四唑(44.25g，0.632mol)，然后在室温(22℃)下搅拌1小时。在通过TLC证实产生亚磷酸二甲酯后，用丙酮-干冰冷却反应溶液，在-20℃下向其中滴加70％叔丁基氢过氧化物的水溶液(84mL，0.607mol)。移去冰浴，逐渐升温到室温，进行TLC以证实亚磷酸二甲酯的消失和磷酸二甲酯的产生，然后在0℃下用10％亚硫酸氢钠的水溶液(300ml)终止反应。向反应溶液中加入乙酸乙酯(1250mL)，并分离有机层。依次用10％亚硫酸氢钠的水溶液(100ml×3)、5％碳酸氢钠水溶液(200ml×3)和饱和食盐水溶液洗涤有机层，并用无水硫酸镁干燥。随后，向有机层加入硅胶(400mL)，然后在减压下浓缩干燥。用吸附有机层的硅胶填充柱，然后充满己烷。然后，进一步用己烷填充柱洗脱未吸附的物质，并进行用己烷/乙酸乙酯(2∶1)的展开。在洗脱流分中，浓缩具有单一成分的流分，从而产生35g标题化合物，为凝胶粉末。这种产物通过使用NMR发现乙酸乙酯和洗涤中使用的二氯甲烷的吸收。另外，得到包含痕量杂
质的流分，由此产生6g化合物。将这样合成的乌索酸3-甲基磷酸酯(35g，62mmol)溶解在干燥二氯甲烷(350ml)中，并在氩气流中加入溴代三甲基硅烷(25mL，186mmol)，然后在室温下反应1小时。在TLC证实后，在减压下浓缩反应溶液，将残余物溶解在干燥甲苯中并浓缩(200ml×2)，完全除去过量溴代三甲基硅烷。将浓缩物溶解在95％甲醇(300mL)中，在室温下搅拌溶液1小时，由此析出晶体。在减压下浓缩溶液并在减压下用磷酸酐在50℃下干燥过夜，由此产生23.5g乌索酸磷酸酯。
1H-NMR(ppm)：5.23(m，1H)，3.87(m，1H)，2.20(d，1H)，2.05-1.25(m，25H)，1.12(s，3H)，1.02(s，3H)，0.99(s，3H)，0.97(d，3H)，0.87(d，3H)，0.85(s，3H)，Mass：535(M+)IR(cm-1)：2948，1694，1456，1378，1028，661，566
<试验例1>
比较这样得到的乌索酸磷酸酯和乌索酸(对照)的溶解度。将20mg乌索酸磷酸酯或乌索酸放在2-mL玻璃容器中，向其中加入表1所示的溶剂。搅拌混合物16小时，并通过0.45μm过滤器。然后，通过HPLC进行浓度测定。结果显示在表1中。结果表明，与乌索酸的溶解度相比，本发明的乌索酸磷酸酯的溶解度得到提高。
表1：溶解度比较
| 饱和浓度(μg/mL) | ||
| 溶剂 | pUA | UA |
| EtOH | ＞100000 | ＜1 |
| 8％EtOH/DW | 134.9 | ＜1 |
| DW | 20.1 | ＜1 |
| 8％EtOH/0.1M磷酸盐缓冲液(pH9) | 7.5 | ＜1 |
| 0.1M磷酸盐缓冲液(pH9) | 119.7 | ＜1 |
| 8％EtOH/0.1M磷酸盐缓冲液(pH7.0) | 31.1 | ＜1 |
pUA(乌索酸磷酸酯)
UA(乌索酸)
<试验例2>
使用10只Hartley白豚鼠进行豚鼠最大值试验以检查乌索酸磷酸酯对豚鼠是否存在皮肤过敏。对5只豚鼠分别皮内注射包含等体积蒸馏水和弗氏完全佐剂(FCA)的乳化物、试验物质(溶解在橄榄油中，5％)和包括等体积试验物质和FCA的混合物，在两个部位注射，各0.1mL。第二天，剪去皮内注射部位的毛发，向其上涂布10％十二烷基硫酸钠/矿脂的混合物。第三天，将0.1ml 5％乌索酸磷酸酯(溶解在橄榄油中)用贴片施加48小时到剪发部位以完成敏化作用的诱导。在诱导敏化作用结束后，设置10天休息期。在休息期结束后，剪去背部未处理部位的毛发。然后，用贴片施加各0.1ml 5％、0.5％和0％乌索酸磷酸酯(溶解在橄榄油中)24小时到三个部位上以诱导敏化作用。除去贴片30分钟和24小时后，观察皮肤反应。按照Draize标准进行皮肤反应的观察(-：无反应；±：具有可疑红斑的反应，+：具有明显红斑的反应，++：具有浮肿、丘疹或脱屑的反应)。结果，对于皮肤反应，在样品施与组和对照组之间没有差异，在这个试验中，没有观察到乌索酸磷酸酯对皮肤的过敏作用。
<实施例2>
按照下面的处方制备抗炎洗剂，其为本发明的皮肤外用剂。即，将处方成分加热到80℃并充分混合，然后搅拌冷却，由此得到洗剂1。在比较例1中，用乌索酸代替乌索酸磷酸酯，进行与上述相同的过程，由此制备比较例1的洗剂。洗剂1即使在5℃、20℃和40℃下保存3个月后也是透明的，是稳定的，而比较例1的洗剂在制造后立即变混浊。
1，3-丁二醇 8质量％
1，2-戊二醇 2质量％
苯氧基乙醇 0.5质量％
1％甘草酸二钾溶液 5质量％
甘油 3质量％
1％乌索酸磷酸酯溶液 1质量％
POE(60)氢化蓖麻油 0.1质量％
水 80.4质量％
<试验例3>
将患有皮肤障碍(skin disorders)的二十个调查对象分成各由10个
调查对象组成的两个组。一个组的调查对象连续使用洗剂1两周，而另一个组的调查对象连续使用比较例1的洗剂两周，然后观察皮肤障碍症状变化。
三个专家由通过视频显微镜(video microscope)放大的颊的图象判断皮肤障碍状态，并根据以下基准评分。在这个试验中，感到皮肤不适的调查对象立即停止试验，并被判断为退出病例。结果显示在表2中。结果表明，本发明的准药物具有等于或超过包含乌索酸的准药物的抗炎作用。在洗剂1的情况下，没有退出病例，而在比较例1的情况下，有一个退出病例。
(标准)
分数1：显著皮肤障碍
分数2：明显皮肤障碍
分数3：轻微皮肤障碍
分数4：健康皮肤
表2：评价结果
| 分数1 | 分数2 | 分数3 | 分数4 | ||
| 洗剂1 | 试验前试验后 | 2 | 8 6 | 2 | 2 |
| 比较例1 | 试验前试验后 | 2 | 8 7 | 1 | 1 |
<实施例3>
按照下面的处方制备抗炎洗剂，其为本发明的皮肤外用剂。即，将处方成分加热到80℃并充分混合，并向组分(i)中加入组分(ii)，然后中和。然后，向其中加入组分(iii)，强烈搅拌乳化混合物，搅拌冷却混合物，由此得到乳液1。在比较例2中，用乌索酸代替乌索酸磷酸酯，进行与上述相同的过程，由此制备比较例2的乳液。在5℃、20℃和40℃下存放乳液1个月。结果，乳液1没有变化，而在所有温度条件下，在比较例2的乳液中都析出不溶的“颗粒”。
(i)
丙烯酸烷基酯(10-30个碳原子)·丙烯酸共聚物(GoodrichCorporation制造的PEMLEN TR-2) 0.4质量％
聚乙二醇1500 0.5质量％
1，3-丁二醇 5质量％
甘油 8质量％
麦芽糖醇 0.4质量％
1％羟基脯氨酸溶液 0.2质量％
1％丝氨酸溶液 0.2质量％
1％甘氨酸溶液 0.2质量％
异构糖(Pentapharm Corporation生产的PENTAVITIN)0.1质量％
聚氧乙烯(60)氢化蓖麻油 0.3质量％
甲基葡萄糖苷20(Methyl gluceth-20) 0.5质量％
POP(23)POE(34)硬脂酰 0.2质量％
乌索酸磷酸酯 0.3质量％
水 77.1质量％
(ii)
10％氢氧化钾溶液 3质量％
水 7质量％
(iii)
液体石蜡 5质量％
二十二醇 1质量％
鲨油醇 0.5质量％
甘草次酸硬脂酯 0.1质量％
<实施例4>
按照下面的处方制备抑制黑色素产生用洗剂，其为本发明的皮肤外用剂。即，将处方成分加热到80℃并充分混合，然后搅拌冷却，由此得到洗剂2。在比较例3中，用乌索酸代替乌索酸磷酸酯，进行与上述相同的过程，由此制备比较例3的洗剂。洗剂2即使在5℃、20℃和40℃下保存3个月后也是透明的，是稳定的，而比较例3的洗剂在制备后立即变混浊。
1，3-丁二醇 8质量％
1，2-戊二醇 2质量％
苯氧基乙醇 0.5质量％
抗坏血酸葡糖苷 5质量％
甘油 3质量％
1％乌索酸磷酸酯溶液 1质量％
POE(60)氢化蓖麻油 0.1质量％
水 80.4质量％
<实施例5>
按照下面的处方制备抑制黑色素产生用洗剂，其为本发明的皮肤外用剂。即，将处方成分加热到80℃并充分混合，然后搅拌冷却，由此得到洗剂3。在比较例4中，用乌索酸代替乌索酸磷酸酯，进行与上述相同的过程，由此制备比较例4的洗剂。洗剂3即使在5℃、20℃和40℃下保存3个月后也是透明的，是稳定的，而比较例4的洗剂在制备后立即变混浊。
1，3-丁二醇 8质量％
1，2-戊二醇 2质量％
苯氧基乙醇 0.5质量％
抗坏血酸-2-磷酸镁钾 5质量％
甘油 3质量％
1％乌索酸磷酸酯溶液 1质量％
POE(60)氢化蓖麻油 0.1质量％
水 80.4质量％
<实施例6>
按照下面的处方制备抑制黑色素产生用洗剂，其为本发明的皮肤外用剂。即，将处方成分加热到80℃并充分混合，然后搅拌冷却，由此得到洗剂4。在比较例5中，用乌索酸代替乌索酸磷酸酯，进行与上述相同的过程，由此制备比较例5的洗剂。洗剂4即使在5℃、20℃和40℃下保存3个月后也是透明的，是稳定的，而比较例5的洗剂在制备后立即变混浊。
1，3-丁二醇 8质量％
1，2-戊二醇 2质量％
苯氧基乙醇 0.5质量％
熊果苷 2质量％
甘油 3质量％
1％乌索酸磷酸酯溶液 1质量％
POE(60)氢化蓖麻油 0.1质量％
水 83.4质量％
产业实用性
本发明可提供提高已知具有各种生理活性的具有羟基的三萜酸如乌索酸的溶解度而不会损害生理活性的技术。本发明的皮肤外用剂可合适地用于抗炎或黑色素产生抑制用化妆品(准药物)。
Claims (5)
1.皮肤外用剂，其包含乌索酸磷酸酯和/或其盐。
2.根据权利要求1的皮肤外用剂，其为化妆品。
3.根据权利要求2的皮肤外用剂，其中化妆品为准药物。
4.根据权利要求3的皮肤外用剂，其用于抗炎。
5.根据权利要求3的皮肤外用剂，其用于抑制黑色素产生。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP170220/2005 | 2005-06-10 | ||
| JP2005170220 | 2005-06-10 | ||
| PCT/JP2006/307818 WO2006132033A1 (ja) | 2005-06-10 | 2006-04-13 | 新規トリテルペン酸誘導体及びそれを含有してなる皮膚外用剤 |
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| Publication Number | Publication Date |
|---|---|
| CN101193907A CN101193907A (zh) | 2008-06-04 |
| CN101193907B true CN101193907B (zh) | 2012-07-11 |
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| CN (1) | CN101193907B (zh) |
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| ES (1) | ES2469566T3 (zh) |
| HK (1) | HK1121766A1 (zh) |
| RU (1) | RU2407748C2 (zh) |
| TW (1) | TWI376368B (zh) |
| WO (1) | WO2006132033A1 (zh) |
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| JP4528745B2 (ja) * | 2006-06-14 | 2010-08-18 | 日光ケミカルズ株式会社 | チロシナーゼ産生抑制剤 |
| JP5695289B2 (ja) * | 2007-08-02 | 2015-04-01 | ポーラ化成工業株式会社 | 乳化剤形の皮膚外用剤 |
| CA2800109C (en) * | 2010-05-20 | 2020-06-30 | University Of Iowa Research Foundation | Methods for inhibiting muscle atrophy |
| US11090313B2 (en) | 2010-05-20 | 2021-08-17 | University Of Iowa Research Foundation | Methods for inhibiting muscle atrophy |
| US9168207B2 (en) | 2010-08-19 | 2015-10-27 | Johnson & Johnson Consumer Inc. | Compositions comprising Paulownia tomentosa wood extracts and uses thereof |
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| US9173913B2 (en) | 2010-08-19 | 2015-11-03 | Johnson & Johnson Consumer Inc. | Compositions comprising Paulownia tomentosa wood extracts and uses thereof |
| WO2012024394A2 (en) * | 2010-08-19 | 2012-02-23 | Johnson & Johnson Consumer Companies, Inc. | Compositions comprising paulownin and/or paulownia extracts and uses thereof |
| US9161958B2 (en) | 2010-08-19 | 2015-10-20 | Johnson & Johnson Consumer Inc. | Methods of treating cellulite |
| US9387349B2 (en) | 2010-08-19 | 2016-07-12 | Johnson & Johnson Consumer Inc. | Compositions comprising Paulownia tomentosa wood extracts and uses thereof |
| US9168219B2 (en) | 2010-08-19 | 2015-10-27 | Johnson & Johnson Consumer Inc. | Compositions comprising Paulownia tomentosa wood extracts and uses thereof |
| US9962326B2 (en) | 2010-08-19 | 2018-05-08 | Johnson & Johnson Consumer Inc. | Compositions comprising paulownia tomentosa wood extracts and uses thereof |
| EP3520793B1 (en) | 2011-06-06 | 2023-03-29 | University of Iowa Research Foundation | Substances and compostions for use in methods of inhibiting muscle atrophy |
| JP6026785B2 (ja) * | 2011-10-31 | 2016-11-16 | 富士フイルム株式会社 | 水性組成物 |
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| JP5964176B2 (ja) * | 2012-08-21 | 2016-08-03 | ポーラ化成工業株式会社 | 皮膚外用組成物 |
| JP5964177B2 (ja) * | 2012-08-21 | 2016-08-03 | ポーラ化成工業株式会社 | 皮膚外用組成物 |
| JP6086707B2 (ja) * | 2012-11-14 | 2017-03-01 | ポーラ化成工業株式会社 | 高い紫外線吸収効果を有する皮膚外用組成物 |
| JP5768114B2 (ja) * | 2013-11-29 | 2015-08-26 | ポーラ化成工業株式会社 | エージング対応用の皮膚外用剤の製造方法 |
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| KR101684432B1 (ko) * | 2015-06-12 | 2016-12-08 | 서울대학교 산학협력단 | 카테치노세아노틱산 화합물 및 이를 포함하는 약학적 조성물 |
| JP6389308B1 (ja) * | 2017-08-23 | 2018-09-12 | 一丸ファルコス株式会社 | 皮膚外用剤 |
| KR20200083969A (ko) | 2017-09-14 | 2020-07-09 | 피닉스 바이오테크놀러지 인코포레이티드. | 신경학적 상태를 치료하기 위한 방법 및 개선된 신경보호 조성물 |
| MX2020002883A (es) | 2017-09-14 | 2020-10-05 | Phoenix Biotechnology Inc | Método y composiciones para tratar la infección viral. |
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| EP4009981B1 (en) | 2020-03-31 | 2023-08-16 | Phoenix Biotechnology, Inc. | Method and compositions for treating coronavirus infection |
| JP7153083B2 (ja) | 2020-03-31 | 2022-10-13 | フェニックス・バイオテクノロジー・インコーポレイテッド | コロナウイルス感染を治療するための方法および組成物 |
| CN111481657B (zh) * | 2020-06-18 | 2021-06-15 | 武汉永尚生物医药有限公司 | Jzy-17以及化合物在制备用于治疗银屑病的药剂中的用途 |
| CN111643509B (zh) * | 2020-06-18 | 2021-07-09 | 山东君瑞医药科技有限公司 | Jzy-13以及化合物在制备用于治疗银屑病的药剂中的用途 |
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- 2006-04-13 RU RU2008100042/04A patent/RU2407748C2/ru not_active IP Right Cessation
- 2006-04-13 KR KR1020087000637A patent/KR101254938B1/ko active IP Right Grant
- 2006-04-13 JP JP2007520036A patent/JP5080249B2/ja active Active
- 2006-04-13 EP EP06731754.5A patent/EP1889850B1/en active Active
- 2006-04-13 WO PCT/JP2006/307818 patent/WO2006132033A1/ja active Application Filing
- 2006-04-13 ES ES06731754.5T patent/ES2469566T3/es active Active
- 2006-04-13 CN CN2006800205185A patent/CN101193907B/zh not_active Expired - Fee Related
- 2006-04-13 US US11/912,477 patent/US7718635B2/en not_active Expired - Fee Related
- 2006-06-08 TW TW095120361A patent/TWI376368B/zh not_active IP Right Cessation
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Also Published As
| Publication number | Publication date |
|---|---|
| EP1889850B1 (en) | 2014-03-05 |
| EP1889850A1 (en) | 2008-02-20 |
| ES2469566T3 (es) | 2014-06-18 |
| RU2008100042A (ru) | 2009-07-20 |
| AU2006256351A2 (en) | 2006-12-14 |
| US20090075946A1 (en) | 2009-03-19 |
| CA2611435C (en) | 2013-01-08 |
| AU2006256351B2 (en) | 2011-08-04 |
| TW200716661A (en) | 2007-05-01 |
| US7718635B2 (en) | 2010-05-18 |
| HK1121766A1 (en) | 2009-04-30 |
| RU2407748C2 (ru) | 2010-12-27 |
| CA2611435A1 (en) | 2006-12-14 |
| WO2006132033A1 (ja) | 2006-12-14 |
| EP1889850A4 (en) | 2011-08-03 |
| CN101193907A (zh) | 2008-06-04 |
| KR20080016948A (ko) | 2008-02-22 |
| AU2006256351A1 (en) | 2006-12-14 |
| JPWO2006132033A1 (ja) | 2009-01-08 |
| KR101254938B1 (ko) | 2013-04-16 |
| TWI376368B (en) | 2012-11-11 |
| JP5080249B2 (ja) | 2012-11-21 |
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