CN1094350C - 表皮用制剂和其制备方法 - Google Patents

表皮用制剂和其制备方法 Download PDF

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CN1094350C
CN1094350C CN94106504A CN94106504A CN1094350C CN 1094350 C CN1094350 C CN 1094350C CN 94106504 A CN94106504 A CN 94106504A CN 94106504 A CN94106504 A CN 94106504A CN 1094350 C CN1094350 C CN 1094350C
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本多伸介
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Sansho Pharmaceutical Co Ltd
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Abstract

本发明给出了一种表皮用制剂和其制备方法，该制剂包括曲酸和/或其衍生物，紫外线吸收剂，该制剂稳定性增强，并具有持久效能。稳定性的增强是通过向制剂中添加至少一种选自脂肪酸酯和脂肪酸甘油酯的物质而实现的。

Description

表皮用制剂和其制备方法
本发明涉及一种表皮用制剂，以及这种制剂的制备方法，该制剂含有曲酸和/或其衍生物，紫外线吸收剂，它还至少含有一种选自脂肪酸酯和脂肪酸甘油酯的物质，该物质用于增强曲酸和/或其衍生物的稳定性并使其效能持续长久。
表皮制剂的形式通常有两种：O/W乳剂(水包油)和W/O乳剂(油包水)，它们的水与油的比例不同且物理性能有异，但是，借助于表面活性剂，可以稳定地乳化和分散油相或水相，从而两种制剂均为均匀的制剂。
对曲酸和其衍生物本发明人进行过长期的研究，它们是公知的具有各种优异性能的有用试剂，如下文献均有报导：日本未审专利公开号55-157509，日本审查专利公开号S 56-18569，S 58-22151，S 58-22152，S 58-34446，S 60-7961，S 60-9722和S 60-10005，日本未审专利公开号S 60-137253，日本审查专利公开号S 61-10447和S 61-60801，日本未审专利公开号S62-5909，日本审查专利公开号S 62-3820和S 63-27322，日本未审专利公开号H 1-132502和日本审查专利公开号H 5-30422。
但是，曲酸和其衍生物(以下有时仅称之为曲酸)，也是公知的自身稳定性较差的试剂。特别是，当曲酸被掺入上述O/W乳剂或W/O乳剂中时，需要相当复杂的技术设计一种适宜的配方。因此，对于配制含曲酸的制剂来说，一个紧迫的任务是发展以下一种技术：该技术可使含曲酸的制剂具有足够的稳定性以耐受严重的分散机制，且当将其施加于皮肤上时不会有令人不快的感觉。
在各种表皮制剂中含有曲酸时，这些制剂被置于可能暴露于紫外线的条件至变性程度，紫外线可能是其变色或分解的外部原因。因此，可推断出应混合一种适量的紫外线吸收剂来抑制由紫外线辐射造成的损害。
例如，以下文献给出了相应的实例，日本未审专利公开号S62-108804和S 64-83008，日本审查专利公开号H 4-46924。
这些紫外线吸收剂多数存在溶解性问题，它们还会从制剂中离析出来，故难以完全显示其紫外线吸收能力，从而导致曲酸的稳定性降低。
为了克服上述缺陷，可适当地采用一些加溶剂。但是，大量使用油性加溶剂会带来如下问题：当将制剂施加于皮肤上时有一种令人不愉快的感觉如粘着感。
此外，对于形成含曲酸的外用制剂从抑制色变的角度来说，非离子表面活性剂为一种适宜的表面活性剂，且经使用该制剂后，有一种令人愉快的感觉而对皮肤无害，但是，非离子表面活性剂与离子型表面活性剂相比其乳化能力较弱，在高极性成分存在下乳化能力会降低，或者受pH值的影响。因而，在通常将pH值调至4-5的含曲酸制剂中，高极性紫外线吸收剂的掺入会造成随着时间变化乳化稳定性降低。
因而，本发明的目的是提供一种表皮用制剂，这种制剂克服了传统的含曲酸制剂存在的上述缺陷，即该制剂不会出现紫外线吸收剂的离析，增强了随时间变化曲酸色变和分解的稳定性，增强了该成分的效能的持久性，该制剂是通过至少加入一种选自脂肪酸酯和脂肪酸甘油酯的物质而制成的。
本发明的其它目的，特征及优点通过以下对本发明优选实施方式的详细描述将充分展现出来。
本发明所采用的曲酸(5-羟基-2-羟甲基-γ-吡酮)为第一种成分，它可为5-羟基-2-羟甲基-γ-吡酮的纯产物，包含曲酸作主要成分且通过培养已知的能产生曲酸的细菌菌株而得到的发酵液，发酵液的浓缩液，由发酵液中提取曲酸并使提取物结晶获得的产物，等等。
曲酸衍生物可单独使用，或者两种或多种组合使用，曲酸衍生物公开于例如以下的文献中：日本审查专利公开号S 60-10005，H1-45472和H 3-74229，曲酸和其衍生物的酯化产物公开于例如以下的文献中：日本审查专利公开号S 58-22151和S 58-22152，上述酯化产物中，糖被键合到曲酸的2-位的-CH2OH基团上。
曲酸和/或其衍生物在制剂中的掺入量为0.001-10％(wt)，优选0.1-5％(wt)，以外用制剂总量计。
用于本发明中作为第二种成分的紫外线吸收剂没有特别限定。优选的实例包括：二苯酮衍生物如：羟苯酮(oxybenzone)，羟苯酮磺酸、羟基甲氧基二苯酮磺酸钠和二羟基二甲氧基二苯酮；水杨酸衍生物如：水杨酸乙二醇酯，水杨酸单酯和水杨酸苯酯；尿刊酸和尿刊酸乙酯；肉桂酸衍生物如：对甲氧基肉桂酸2-乙基己酯和甲氧基肉桂酸辛酯；对氨基苯甲酸衍生物如：对氨基苯甲酸甘油酯和对二甲基氨基苯甲酸2-乙基己酯；二苯甲酰甲烷衍生物如：4-叔丁基-4′-甲氧基二苯甲酰甲烷；和苯并三唑衍生物如：2-(2-羟基-5-甲苯基)苯并三唑。这些化合物可以单独使用或两种或多种组合使用。此外，其它具有紫外线吸收能力的动物或植物提取物也可适宜地单独或组合使用。
这些紫外线吸收剂的用量取决于其种类，但一般说来，其用量为0.001-10％(wt)，优选0.1-5％(wt)，以外用制剂总量计。
用于本发明作为第三种成分的脂肪酸酯可以为高级醇脂肪酸酯，如：己二醇异丙酯，鳄梨油脂肪酸乙酯，异硬脂酸异鲸蜡酯，异硬脂酸异丙酯，异壬酸异癸酯，异棕榈酸辛酯，异壬酸辛酯，芥酸辛基十二烷酯，羟基硬脂酸辛酯，油酸辛基十二烷酯，油酸油酯，油酸癸酯，琥珀酸二辛酯，二甲基辛酸己基癸酯，硬脂酸异鲸蜡酯，硬脂酸丁酯，乳酸辛基十二烷酯，乳酸油酯，乳酸鲸蜡酯，乳酸肉豆蒄酯，乳酸月桂酯，棕榈酸异硬脂酰酯，棕榈酸异丙酯，棕榈酸辛酯，棕榈酸鲸蜡酯，蓖麻油脂肪酸甲酯，苯二甲酸二乙酯，丙酸二十烷酯，庚酸硬脂酰酯，肉豆蒄酸异硬脂酰酯，肉豆蒄酸异鲸蜡酯，肉豆蒄酸异十三烷酯，肉豆蒄酸异丙酯，肉豆蒄酸辛基十二烷酯，肉豆蒄酸鲸蜡酯，肉豆蒄酸癸酯，肉豆蒄酸丁酯，肉豆蒄酸肉豆冠酯，月桂酸己酯，蓖麻酸辛基十二烷酯，蓖麻酸鲸蜡酯，亚油酸异丙酯，苹果酸二异硬脂酰酯；乙二醇脂肪酸酯，如：乙二醇脂肪酸酯，乙二醇二辛酸酯，乙二醇二油酸酯，乙二醇二硬脂酸酯，乙二醇单硬脂酸酯；聚乙二醇脂肪酸酯，如二乙二醇月桂酸酯，二乙二醇二月桂酸酯，硬脂酸-40-聚烃氧基酯，聚乙二醇棕榈酸酯，聚氧乙烯椰子油脂肪酸酯(6E.O.)，聚乙二醇肉豆蒄酸酯，聚乙二醇单油酸酯，聚乙二醇单月桂酸酯；丙二醇脂肪酸酯，如丙二醇脂肪酸酯，可自乳化丙二醇硬脂酸酯，丙二醇单硬脂酸酯，丙二醇二油酸酯，丙二醇二辛酸酯，丙二醇二辛酸酯；二醇脂肪酸酯，如新戊二醇二辛酸酯(dioctanoate)，新戊二醇二辛酸酯(dicaprylate)，丁二醇二褐煤酸酯；亚烷基(18，20)直链二醇单异硬脂酸酯；三羟甲基丙烷脂肪酸酯，如三羟甲基丙烷三异硬脂酸酯和三羟甲基丙烷三辛酸酯；季戊四醇脂肪酸酯，如季戊四醇脂肪酸(1)，季戊四醇四辛酸酯和季戊四醇四肉豆蒄酸酯；山梨醇脂肪酸酯，如山梨醇倍半异硬脂酸酯，山梨醇倍半油酸酯，山梨醇三油酸酯和山梨醇椰子油脂肪酸酯；聚氧乙烯山梨醇脂肪酸酯，如聚氧乙烯山梨醇(20E.O.)异硬脂酸酯，聚氧乙烯山梨醇(20E.O.)三油酸酯，聚氧乙烯山梨醇(20E.O.)三硬脂酸酯，聚氧乙烯山梨醇六硬脂酸酯，聚氧乙烯山梨醇蜂蜡，聚氧乙烯椰子油脂肪酸山梨醇(20E.O.)，聚氧乙烯山梨醇(6E.O.)单油酸酯；糖脂肪酸酯，如蔗糖苯甲酸酯，蔗糖乙酸酯，蔗糖异丁酸酯，蔗糖硬脂酸酯，椰子油脂肪酸的蔗糖酯。脂肪酸甘油酯可以为：甘油脂肪酸酯，如：甘油花生酸酯，甘油异硬脂酸酯，甘油油酸酯(1)，麦胚油脂肪酸甘油酯，混合脂肪酸三甘油酯，异棕榈酸二甘油酯，氢化大豆油脂肪酸二甘油酯；肉豆蒄酸二甘油酯，棉子脂肪酸二甘油酯，椰子油脂肪酸二甘油酯，氢化大豆油脂肪酸二甘油酯，硬脂酸苹果酸甘油酯，倍半油酸甘油酯，癸酸和辛酸三甘油酯，牛脂脂肪酸三甘油酯，肉豆蒄酸三甘油酯，椰子油脂肪酸三甘油酯，饱和脂肪酸三甘油酯，饱和脂肪酸甘油酯(2)，聚甘油脂肪酸酯如异硬脂酸二甘油酯，油酸二甘油酯，硬脂酸二甘油酯，二异硬脂酸二甘油酯，油酸四甘油酯，月桂酸四甘油酯，油酸六甘油酯，月桂酸六甘油酯，月桂酸十甘油酯，二异硬脂酸十甘油酯和十油酸十甘油酯；聚氧乙烯甘油脂肪酸酯，如：聚氧乙烯异硬脂酸甘油酯，聚氧乙烯三硬脂酸甘油酯，聚氧乙烯油酸甘油酯，聚氧乙烯单硬脂酸甘油酯。其中，最优选的是中链脂肪酸(含6-12个碳原子)的单甘油酯，二甘油酯和三甘油酯。这些化合物可以单独使用或两种或多种组合使用。
第三种成分的用量取决于其种类，但一般说来，其用量为0.001-20％(wt)，优选0.1-10％(wt)，以制剂总量计。
可以按已知的方法将上述三种成分制成外用制剂。该种制剂不会出现紫外线吸收剂的离析，因而该制剂为一种稳定的乳化制剂，其随着时间变化显示出良好的稳定性，其中曲酸表现出随时间变化对色变和分解的稳定性增强了，且表现出持久效能。
无需多言，本发明的制剂形式不限于乳剂如O/W乳剂和W/O乳剂，还可以为一种经适当选择成分而成的透明型制剂。此外，本发明也可适于作为一种基本技术用来制备多层乳剂制剂如W/O/W或O/W/O乳剂或微胶囊制剂。
本发明的表皮用制剂并不特别限制其使用方式，它可以以已知的药物、准药物和化妆品的使用方式使用，如泥敷剂、膏剂、糊剂、霜剂、软膏剂、气雾剂、乳剂、洗剂、香精(essence)、润肤膏、凝胶剂、粉剂、粉底(foundation)、防晒剂(suncare)、浴盐(bath salts)等。
在本发明的制剂制备过程中，各种已知的常用有效成分也可选择性地加入，但要求其量不会损坏本发明的目的。这些已知的有效成分的实例包括：毛细血管扩张剂，如氯化三甲胺丁酸甲酯、顶花防己碱、维生素E、烟酸维生素E、烟酸、烟酸酰胺、烟酸苯甲酯、姜酊和辣椒酊(ginger tincture，chili tincture)；冷却剂如樟脑、薄荷醇和薄荷油；抗微生物剂如：4-异丙基环庚二烯酚酮、苯扎氯铵、十一碳烯酸；抗炎剂如肾上腺皮质激素，氨基己酸、溶菌酶氯化物，甘草素、尿囊素；皮肤白嫩剂(fairness imparting agents)，如：抗坏血酸和熊果苷；各种动植物提取物，如，胎盘提取物、肝提取物，Lithospermun根提取物，乳酸菌培养液提取物。
除了已知的有效成分，各种添加剂均可使用，如润湿剂、防腐剂、抗氧化剂、螯合剂、pH调节剂、香料、着色剂，以及基底成分如脂肪和油，只要它的加入不会损坏本发明上述药物、准药物和化妆品的应用方式。
通过下述实验和配方对本发明进行更为详细的描述，它们不是对本发明的限制。
实施例1
制剂稳定性试验实验方法：
按照表1所示配方制备各种乳油(pH约4.5)。将它们置于4盎司的蜡瓶中，在50℃下放置2个月并同时用紫外线照射。2个月后，测量其色差(ΔE)(使用Nihon Denshoku Kogyo制造的Z-1001DP型色差仪)，同时对其外观变化进行观察(紫外线吸收剂的离析和乳剂的稳定性)并评估其应用效果。实验结果：
如表1所示，本发明包含有成分1-8的制剂没有出现紫外线吸收剂的离析，同时表明了极佳的乳剂稳定性。制剂中所包含的曲酸的色变未观测到，且应用感觉良好。
                                    表1-1
                              测试样品及实验结果
  组份名称                               实施例
    1     2     3     4     5     6     7     8
1.肉豆蔻酸三甘油酯2.乳酸肉豆蔻酯3.丙二醇二油酸酯4.二异硬脂酸二甘油酯5.四肉豆蔻酸季戊四醇酯6.倍半异硬脂酸山梨醇酯7.聚氧乙烯山梨醇(20E.O.)三硬脂酸酯8.氢化大豆油脂肪酸甘油酯   5.00-------   5.002.00------   2.00-5.00-----     ---0.50----     --0.50-1.50---     -----0.50--     -2.00----1.50-     -------3.00
9.曲酸  1.00   1.00   1.00  1.00   1.00  1.00   1.00   1.00
10.Oxybenzone11.4-叔丁基-4′-甲氧基-二苯甲酰甲烷12.对氨基苯甲酸甘油酯13.水杨酸乙二醇酯14.甲氧基肉桂酸辛酯  1.50----     -1.00---   0.800.50---     --0.20--     ---1.00-     ----0.50     -0.200.10--    --1.50-0.10
15.蜂蜡16.凡士林17.西蒙得木油  4.502.807.00  4.502.807.00  4.502.807.00  4.502.807.00   4.502.807.00   4.502.807.00   4.502.807.00   4.502.807.00
(续)
18.维生素E19聚氧乙烯鲸蜡醚(25E.O.)20.聚氧乙烯硬脂酰基醚(20E.O.)21.羧乙烯聚合物22.dl-吡咯烷酮羧酸钠23.乙二胺四乙酸二钠24.柠檬酸25.柠檬酸钠26.纯化水   0.041.500.700.086.000.02*1*1*2   0.041.500.700.086.000.02*1*1*2   0.041.500.700.086.000.02*1*1*2  0.041.500.700.086.000.02*1*1*2   0.041.500.700.086.000.02*1*1*2   0.041.500.700.086.000.02*1*1*2   0.041.500.700.086.000.02*1*1*2   0.041.500.700.086.000.02*1*1*2
测试结果     表观     *3 无     无     无    无     无     无     无     无
    *4 ◎     ◎     ◎    ◎     ◎     ◎     ◎     ◎
(ΔE)  色差 3.4   3.0    2.9   2.5    2.8    3.1    2.0    2.7
应用感觉评价(*5) *6 ◎     ◎     ◎    ◎     ◎     ◎     ◎     ◎
*7 ◎     ◎     ◎    ◎     ◎     ◎     ◎     ◎
*8 ◎     ◎     ◎    ◎     ◎     ◎     ◎     ◎
*1：微量
*2：足以使总量达100％(重量)的量
*3：分离紫外线吸收剂
*4：乳液状态(分离)
    ◎：良好；△：部分分离；×：分离；
*5：评价标准
    ◎：良好；○：几乎没问题；△：有轻微问题；
    ×：差
*6：粗糙感
*7：粘着感
*8：皮肤舒适
                                  表1-2
                             测试样品及实验结果
    组份名称     对比实施例
    1   2   3   4   5   6   7   8   9
1三豆蔻酸甘油酯2乳酸肉豆蔻酯3.二油酸丙二醇酯4二异硬脂酸二甘油酯5四豆蔻酸季戊四醇酯6倍半异硬脂酸山梨醇酯7.聚氧乙烯山梨醇(20E.O.)三硬脂酸酯8.氢化大豆油脂肪酸甘油酯    --------    --------    --------    --------    --------     --------     --------     --------    --------
9.曲酸 1.00 1.00 1.00 1.00 1.00  1.00  1.00  1.00 1.00
10.Oxybenzone11.4-叔丁基-4′-甲氧基-二苯甲酰甲烷12.对氨基苯甲酸甘油酯13.水杨酸乙二醇酯14.甲氧基肉桂酸辛酯15.蜂蜡16.凡士林17.西蒙得木油18.天然维生素E ----4.502.807.000.04 1.50----4.502.807.000.04   -1.00---4.502.807.000.04 0.800.50--4.502.807.000.04   --0.20--4.502.807.000.04    ---1.00-4.502.807.000.04    ----0.504.502.807.000.04    -0.200.10--4.502.807.000.04   --1.50-0.104.502.807.000.04
(续)
19.聚氧乙烯鲸蜡醚(25E.O.)20聚氧乙烯硬脂酰基醚(20E.O.)21羧乙烯聚合物22 dl-吡咯烷酮羧酸钠溶液23乙二胺四乙酸二钠24.柠檬酸25.柠檬酸钠26.纯化水   1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*2*2  1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*1*2 1.500.700.086.000.02*1*1*2   1.500.700.086.000.02*1*1*2   1.500.700.086.000.02*1*1*2   1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*2*3
    测试结果     表观   *3    -   无   有   有   有：   有   有   有   有
  *4    △   ×   ×   ×   ×   ×   ×   ×   ×
  色差(ΔE)    9.1   8.5   7.7   7.9   10.3   7.2   8.6  8.1  6.5
应用感觉评价(*5)   *6    ○   ○   ○   ×   ×   ×   ×   ×   ×
  *7    △   ×   ×   △   △   △   △   ×   ×
  *8 △ △ × △ × △ × × △
*1：微量
*2：足以使总量达100％(重量)的量
*3：分离紫外线吸收剂
*4：乳液状态(未分离)
    ◎：良好；△：部分分离；×：分离
*5：评价标准：
    ◎：良好；○：几乎没问题；△：有轻微问题
    ×：不好
*6：粗糙感
*7：粘着感
*8：皮肤舒适实施例2
对由UV光诱导的豚鼠的色素沉积抑制效果
用黄棕色豚鼠来测定抑制色素沉积的效果。
表2列出了该实验的结果。
从表2的结果可以看出，本发明的制剂表出了极好的持久的色素沉积抑制作用。实验方法：
剪掉黄色豚鼠背部乱毛使其背部皮肤裸露，用电动剃须刀剃净裸露的背部皮肤。每个剃过的背部用一带有四个方孔(2.0×2.0cm)的铝箔露盖，并每三天一次，共四次，每次以UV-B(有3SE灯；140mJ/cm2)照射90秒。从照射开始起，将实验1得到的每种制剂施用于照射过的测试部位，每天三次，连续20天。在开始照射UV光的第13至第20天之间，测定肌肉组织中的组份浓度并对色素沉积进行评分。
依下列标准用裸眼对测试皮肤的变黑程度进行评分。评分标准：
3：未观察到色素沉积。
2：观察到轻微的色素沉积。
1：观察到中度色素沉积。
0：观察到的色素沉积程度与对照部位(未治疗)相同。
-1：观察到的色素沉积程度较对照部位(未治疗)更强。实验结果：
据证实，本发明的制剂立即显示出了极好的色素沉积抑制作用。
                                   表2-1
                                  实验结果
    组份名称                                     实施例
    1     2     3     4     5     6     7     8
1.肉豆蔻酸三甘油酯2.乳酸肉豆蔻酯3.二油酸丙二醇酯4.二异硬脂酸二甘油酯-5.四肉豆蔻酸季戊四醇酯6.倍半异硬脂酸山梨醇酯7.聚氧乙烯山梨醇(20E.O.)三硬脂酸酯8.氢化大豆油脂肪酸甘油酯 5.00------- 5.002.00------ 2.00-5.00-----   ---0.50----   --0.50-1.50---    -----0.50--   -2.00----1.50-   --------3.00
9.曲酸 1.00 1.00 1.00 1.00  1.00  1.00 1.00 1.00
10.Oxybenzone11.4-叔丁基-4′-甲氧基-二苯甲酰甲烷12.对氨基苯甲酸甘油酯13.水杨酸乙二醇酯14.甲氧基肉桂酸辛酯15.蜂蜡16.凡士林17.西蒙得木油18.天然维生素E 1.50----4.502.807.000.04   -1.00---4.502.807.000.04 0.800.50---4.502.807.000.04   --0.20--4.502.807.000.04    ---1.00-4.502.807.000.04   ----0.504.502.807.000.04   -0.200.10--4.502.807.000.04   --1.50-0.104.502.807.000.04
(续)
19.聚氧乙烯鲸蜡醚(25E.O.)20.聚氧乙烯硬脂酰基醚(20E.O.)21.羧乙烯聚合物22.dl-吡咯烷酮羧酸钠溶液23.乙二胺四乙酸二钠24.柠檬酸25.柠檬酸钠26.纯化水  1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*1*2  1.500.700.086.000.02*1*1*2
效果评分 肌肉组织中曲酸浓度(μg/g) 0.5 0.4 0.4 0.7 0.4 0.6 0.5 0.4
形成色素程度     3     3    3     3     3     3     3     3
获得色素形成疗效所需天数(天)    14    15   13    14    15    13    14    15
*1：微量
*2：足以使总量达100％(重量)的量
                                                    表2-2
                                                  实验结果
    组份名称                            对比实施例
    1     2     3     4     5     6     7     8     9
1.三肉豆蔻酸甘油酯2.乳酸肉豆蔻酯3.二油酸丙二醇酯4.二异硬脂酸二甘油酯5.四肉豆蔻酸季戊四醇酯6.倍半异硬脂酸山梨醇酯7.聚氧乙烯山梨醇(20E.O.)三硬脂酸酯8.氢化大豆油脂肪酸甘油酯    --------   --------   --------   --------   --------    --------    --------    --------    --------
9.曲酸  1.00 1.00 1.00 1.00 1.00  1.00  1.00  1.00  1.00
10.Oxybenzone11.4-叔丁基-4′-甲氧基-二苯甲酰甲烷12.对氨基苯甲酸甘油酯13.水杨酸乙二醇酯14.甲氧基肉桂酸辛酯15.蜂蜡16.凡士林17.西蒙得木油18.天然维生素E ----4.502.807.000.04 1.50----4.502.807.000.04   -1.00---4.502.807.000.04 0.800.50--4.502.807.000.04   --0.20--4.502.807.000.04    ---1.00-4.502.807.000.04    ----0.504.502.807.000.04    -0.200.10--4.502.807.000.04   --1.50-0.104.502.807.000.04
(续)
19聚氧乙烯鲸蜡醚(25E.O.)20.聚氧乙烯硬脂酰基醚(20E.O.)21.羧乙烯聚合物22.dl-吡咯烷酮羧酸钠溶液23.乙二胺四乙酸二钠24.柠檬酸25.柠檬酸钠26.纯化水  1.500.700.086.000.02*1*1*2 1.500.700.086.000.02*1*1*2 1.500.700.086.000.02*1*2*3 1.500.700.086.000.02*1*1*2 1.500.700.086.000.02*1*1*2 1.500.700.086.000.02*1*1*2 1.500.700.086.000.02*1*1*2 1.500.700.086.000.02*1*1*2 1.500.700.086.000.02*1*2*3
效果评分 肌肉组织中曲酸浓度(μg/g) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
色素形成程度     1   1   1   1   1   1   1   1   1
获得色素形成疗效所需天数(天)    18   19  18  18   19  19  18  19  19
*1：微量
*2：足以使总量达100％(重量)的量
下面表示了本发明的配制实施例。配制实施例1〔霜剂(1)〕
                                        (重量％)1.曲酸                                        1.002.羟苯酮磺酸(Oxybenzonesulfonic acid)         0.503.己二酸二异丙酯                              2.004.肉豆蒄酸异丙酯                              3.005.聚氧乙烯鲸蜡醚(25E.O.)                      5.006.硬脂酸                                      5.007.鳄梨油                                      1.008.杏仁油                                      10.009.dl-吡咯烷酮羧酸钠溶液                       5.0010.对羟基苯甲酸酯                             0.2011.乙二胺四乙酸二钠                           0.0112.纯化水加至                                 100.00配制实施例2〔霜剂(2)〕                        (重量％)1.曲酸                                         5.002.4-叔丁基-4′-甲氧基-二苯甲酰甲烷             0.503.乳酸辛基癸酯                                 1.004.乳酸肉豆蒄酯                                 0.205.聚氧乙烯羊毛脂                                              3.006.二甲基硅氧烷甲基(聚氧乙烯-聚氧丙烯共聚物)                   3.007.西蒙得木油                                                  7.008.十甲基环戊硅氧烷                                            3.009.八甲基环丁硅氧烷                                            3.0010.二甲基聚硅氧烷                                             5.0011.天然维生素E                                                0.0412.1％透明质酸钠溶液                                          2.0013.角叉菜胶                                                   1.0014.乙二胺四乙酸二钠                                           0.0115.纯化水加至                                                 100.00配制实施例3〔乳剂(1)〕                                       (重量％)1.曲酸                                                        4.002.2-乙基己基-对甲氧基肉桂酸酯                                 2.003.异硬脂酸甘油酯                                              4.004.硬脂酸聚氧乙烯单甘油酯                                      2.005.聚氧乙烯鲸蜡醚(25E.O.)                                      0.506.聚氧乙烯油醚(20E.O.)                                        1.007.硬脂酸                                                      0.508.牛油树脂                                                    0.509.鳄梨油                                                      4.0010.对羟基苯甲酸酯                                   0.2011.栌子提取物                                       5.0012.黄原胶                                           0.1413.乙二胺四乙酸二钠                                 0.0114.纯化水加至                                       100.00配制实施例4〔乳剂(2)〕                             (重量％)1.曲酸                                              0.502.水杨酸乙二醇酯                                    0.103.甲氧基肉桂酸辛酯                                  2.004.可可油脂肪酸蔗糖酯                                0.505.肉豆蒄酸肉豆冠酯                                  4.006.可可油脂肪酸单乙醇酰胺                            2.007.硬脂酸                                            0.508.肉豆蒄酸                                          0.509.鳄梨油                                            4.0010.天然维生素E                                      0.0411.对羟基苯甲酸酯                                   0.2012.透明质酸钠                                       5.0013.黄原胶                                           0.1414.乙二胺四乙酸二钠                                 0.0115.纯化水加至                                       100.00配制实施例5〔洗剂〕                                        (重量％)1.曲酸葡糖苷                                                7.002.4-叔丁基-4′-甲氧基-二苯甲酰甲烷                          2.003.2-乙基己基-对甲氧基肉桂酸酯                               0.054.单硬脂酸乙二醇酯                                          3.005.聚氧乙烯鲸蜡醚(60E.O.)                                    5.006.人参提取物                                                2.007.日本Chirate提取物                                         0.508.对羟基苯甲酸酯                                            0.109.抗坏血酸                                                  0.1010.柠檬酸钠                                                 0.3011.5％弹性蛋白水解液                                        4.0012.乙二胺四乙酸二钠                                         0.0113.纯化水加至                                               100.00配制实施例6〔霜剂润肤膏〕                                  (重量％)1.曲酸乙酯                                                  2.002.4-叔丁基-4′-甲氧基-二苯甲酰甲烷                          0.503.三羟甲基丙烷三辛酸酯                                      2.004.油酸甘油酯                                                5.005.硬脂酸二乙醇酰胺                                          5.006.硬脂酸                                                    5.007.肉豆蒄酸                                                 0.508.可可油                                                   15.009.天然维生素E                                              0.0410.对羟基苯甲酸酯                                          0.2011.dl-吡咯烷酮羧酸钠溶液                                   5.0012.乙二胺四乙酸二钠                                        0.0113.纯化水加至                                              100.00配制实施例7〔软膏剂〕                                     (重量％)1.曲酸                                                     1.002.羟苯酮磺酸(Oxybenzonesulfonic acid)                      0.103.水杨酸苯酯                                               0.404.羟基甲氧基二苯酮磺酸钠                                   1.005.倍半异硬脂酸山梨醇酯                                     2.006.可可油脂肪酸单乙醇酰胺                                   5.007.凡士林                                                   10.008.硬脂酸                                                   5.009.油酸                                                     1.0010.橄榄油                                                  10.0011.对羟基苯甲酸酯                                          0.2012.角叉菜胶                                                5.0013.乙二胺四乙酸二钠                                        0.0113.纯化水加至                                           100.00配制实施例8〔泥敷剂〕                                  (重量％)1.曲酸果糖苷                                             0.502.对氨基苯甲酸甘油酯                                     4.003.己基癸基二甲基辛酸酯                                   1.004.硬脂酸二乙醇酰胺                                       3.005.聚丙烯酸                                               27.006.甘草提取物(乙醇提取物)                                 0.107.黄芩根提取物(水提取物)                                 0.058.乙二胺四乙酸二钠                                       0.059.聚丙烯酸钠                                             7.0010.氯化铝                                                0.3011.浓甘油                                                20.0012.氧化钛                                                4.0013.纯化水加至                                            100.00配制实施例9〔香精〕                                     (重量％)1.曲酸                                                    1.002.尿刊酸                                                  0.503.2-乙基己基-对甲氧基肉桂酸酯                             1.004.硬脂酸-40-聚烃氧基酯                                    0.505.辛基十二烷基肉豆蒄酸酯                                  1.506.可可油脂肪酸单乙醇酰胺                                  2.007.硬脂酸                                                  0.508.亚麻酸                                                  0.509.鳄梨油                                                  2.0010.龟油                                                   3.0011.天然维生素E                                            0.0412.对羟基苯甲酸酯                                         0.2013.1％羧乙烯聚合物水溶液                                  5.0014.黄原胶                                                 0.1415.乙二胺四乙酸二钠                                       0.0116.纯化水加至                                             100.00
已证实上述配制实施例1-9提供了具有同样令人满意效果(如表1和2中所示)的制剂。
在不背离本发明精神和基本特征的前提下，本发明可以其它特定形式实现。因此本发明的具体方案在各方面均被认为是用于说明而非限制，本发明的范围通过附录的权利要求而不是前面的描述来指明，并且其中包括了在权利要求相当的方法和范围内发生的全部变化。

Claims (2)

1.一种制剂稳定性和药效速效性优良的表皮用制剂，它含有0.001-10％重量的曲酸和/或其衍生物，和0.001-10％重量的紫外线吸收剂，其中添加了0.001-20％重量的至少一种选自如下的脂肪酸酯：C3-18醇的C3-22脂肪酸的酯、乙二醇或聚乙二醇的C8-18脂肪酸酯、丙二醇的C8-18脂肪酸酯、三羟甲基丙烷的C8-18脂肪酸酯、季戊四醇的C8-14脂肪酸酯、蔗糖C18脂肪酸酯、甘油以及聚甘油的C6-20脂肪酸和聚氧乙烯甘油C18脂肪酸酯。
2.权利要求1的表皮用制剂，它的形式选自泥敷剂、膏剂、糊剂、霜剂、软膏剂、气雾剂、乳剂、洗剂、香精、润肤膏、凝胶剂、粉剂、粉底、防晒剂和沐浴盐。
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