CN100374109C - 用于治疗皮脂溢和痤疮的、基于亚油酸乙酯和柠檬酸三乙酯的组合物 - Google Patents

用于治疗皮脂溢和痤疮的、基于亚油酸乙酯和柠檬酸三乙酯的组合物 Download PDF

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CN100374109C
CN100374109C CNB028255534A CN02825553A CN100374109C CN 100374109 C CN100374109 C CN 100374109C CN B028255534 A CNB028255534 A CN B028255534A CN 02825553 A CN02825553 A CN 02825553A CN 100374109 C CN100374109 C CN 100374109C
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G·德保利安布罗西
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Abstract

本发明涉及用于治疗和改善皮肤美学状况的局部用组合物，其包含亚油酸乙酯和柠檬酸三乙酯的混合物作为活性成分。该组合物可有效治疗皮脂溢和痤疮。

Description

用于治疗皮脂溢和痤疮的、基于亚油酸乙酯和柠檬酸三乙酯的组合物
发明领域
本发明涉及在治疗痤疮、酒渣鼻和皮脂溢中具有药物和/或美容剂用途的新产品。
现有技术
大量的人患有痤疮，其病理学皮肤状况的特征是毛囊皮脂腺器官的形态学和功能的改变，伴有出现粟粒疹(封闭性粉刺)、黑头粉刺(开放性粉刺)、丘疹以及更严重的形式：脓疱、结节、囊肿和瘢痕。
痤疮感染约80％的12至30岁人群，尤其是在女性中，可以甚至持续至更大年龄。
痤疮的发病机理与下述情况密切相关：
●皮脂产生增加(皮脂溢)
●毛囊皮脂腺导管异常角化
●细菌建群。
皮脂溢是皮脂腺对雄激素的作用、更确切地说，是对睾酮被5-α还原酶还原所产生雄诺龙的作用发生激惹反应的结果。
毛囊皮脂腺导管的异常角化是形成角质栓的直接原因，也是形成细微粉刺以及随后形成痤疮损害的原因。由于皮脂产生增加，在形成细微粉刺之前，存在皮肤腐生菌如痤疮丙酸杆菌(Propionilbacterium Acnes)的异常生长。由于释放分解酶(蛋白酶和脂酶)，后者能破坏皮脂腺的蛋白结构并水解正常包含在皮脂(由于雄诺龙的作用其额外地被大量产生)中的甘油三酯，释放脂肪酸和甘油。以此方式释放的脂肪酸以其产生粉刺作用为特征并因此被氧化，形成引发炎症的化合物。
在痤疮的药物治疗或皮脂溢的美容剂治疗中迄今所用的治疗主要基于角质层分离剂和/或抗生素物质或其它活性成分，例如视黄醛衍生物的作用。
在这些物质中可提及的有例如水杨酸、酒石酸、乙醇酸、间苯二酚、苯酚等，它们均能通过角质层分离类机制实现其旨在在临床上改善痤疮状况的作用。
在迄今用于控制痤疮丙酸杆菌增长的抗生素物质中值得提及的有克林霉素、米诺环素、红霉素、甲硝唑等。
用于治疗痤疮的其它活性成分有反式-视黄酸，发现其很有效，但是其特征是具有高毒性、光致毒性和致畸性。
发明目的和发明概述
本发明的目的是提供具有以下特征的新产品：高度有效且皮肤耐受性优，特别是在治疗皮脂溢、痤疮和酒渣鼻中。
本发明用组合物实现了本发明的目的，该组合物的特征在于如下事实：其含有包含亚油酸的乙酯(亚油酸乙酯)和柠檬酸的三乙酯(柠檬酸三乙酯)的混合物作为活性成分。
其中，该组合物能抑制特定酶如5-α还原酶、脂酶和酯酶的活性，使得能控制皮脂溢，且通常能控制痤疮和酒渣鼻状况的发展。
发明详述
根据本发明，在一个方面，提供用于治疗和改善皮肤美学状况的局部用组合物，其包含亚油酸乙酯和柠檬酸三乙酯混合物作为活性成分。
根据本发明，亚油酸乙酯和柠檬酸三乙酯可分别以重量比0.1至99.9％的量，优选分别以1.00至40％的相等量包含在组合物中，该重量百分比基于组合物的最终重量。
根据本发明的一个实施方案，本发明的局部用组合物包含0.1至99％重量/重量的亚油酸乙酯和99％至0.1％重量/重量的柠檬酸三乙酯。
根据本发明的另一个实施方案，本发明的局部用组合物包含的单一或联合使用的活性成分的量为0.001至90％重量/重量。
根据本发明的再一个实施方案，本发明的组合物中包含的至少一种添加剂的含量为组合物的0.001至90％重量/重量。
此外，基于亚油酸乙酯和柠檬酸三乙酯的组合物还可含有多种活性成分，为了描述简单将其定义为增效剂。
增效剂可选自乙酸、乳酸、水杨酸、酒石酸、乙醇酸、克林霉素、红霉素、甲硝唑、阿莫西林、二氯苯氧氯酚、辛酰基甘氨酸、壬二酸、氢氧化锌、氯化锌、反式-视黄酸、间苯二酚、透明质酸、庆大霉素、氯甲烯土霉素、苯酚、抗坏血酸、生育酚、硫辛酸、磷脂酰胆碱、磷脂酰丝氨酸、氯己定、卤卡班、阿达帕林、磷脂，通常它们均可为右旋形式、左旋形式、外消旋混合物、顺式形式、反式形式以及相应的盐、酯和酰胺，其可与特定的添加剂和赋形剂一起配制以供外用。
根据本发明的再一个方面，其中供外用的制剂包括油包水乳剂、水包油乳剂、单相溶液、双相假溶液、单相凝胶、双相凝胶或逊胶束凝胶、无水软膏剂、粉末喷洒剂、醇化物、醇溶液、水-醇溶液。
这些增效剂可以单独地或者两种或多种联合地与亚油酸乙酯和柠檬酸三乙酯一起存在于组合物中。
当亚油酸乙酯和柠檬酸三乙酯的比例分别为重量比0.5至90.5％时，这些增效剂可以以基于终配方的0.001至70％、优选0.5至15％的可变重量包含在组合物中。
临床功效和使用安全性是以以下事实为特征的独特作用机制的结果：本身为惰性物质的亚油酸乙酯和柠檬酸三乙酯一旦与皮肤接触均被转变成活性成分。这种从惰性物质向活性成分的转变是水解作用的结果，所述水解通过能释放乙醇并分别释放亚油酸、柠檬酸二乙酯然后是柠檬酸单乙酯最后是柠檬酸的特定皮肤酶或细菌(脂酶和酯酶)发生。
本发明组合物的作用机制可以更详细地描述如下。
亚油酸乙酯和柠檬酸三乙酯能协同地减轻皮脂溢和毛囊皮脂腺导管的角化过度；该作用通过脂酶菌作用将酯水解从而释放各自的酸形式来实现。
在本发明中，已证实由脂酶菌进行的亚油酸乙酯和柠檬酸三乙酯的水解优先于由相同的脂酶菌进行的甘油三酯(皮脂中的脂类成分)的水解，从而避免了由于释放甘油三酯水解产生的脂肪酸引起的刺激情况。
对于毛囊皮脂腺导管的角化过度，亚油酸乙酯和柠檬酸三乙酯的联合作用是创新性的，因为前者防止角化过度，而后者作为角质层分离剂可将其治愈。与分别使用两种成分的效果相比，该联合作用产生了更高的功效。
对于皮脂溢，亚油酸乙酯和柠檬酸三乙酯的联合作用是创新性的，因为其通过抑制5-α还原酶实现了皮脂水平的下降，如上所述该酶是使睾酮还原为能增加皮脂产生的雄诺龙的原因。一旦亚油酸乙酯被水解成亚油酸，它就能通过直接机制抑制5-α还原酶的活性，而柠檬酸三乙酯一旦被水解成柠檬酸将以间接方式发挥作用，创造出阻碍上述酶活性的环境。
换言之，脂酶菌将亚油酸乙酯和柠檬酸三乙酯的混合物识别为优先底物，而不是皮脂中的甘油三酯，因此不干扰这些甘油三酯的结构，从而减轻皮脂溢和痤疮的炎性病理学。
在用样品进行的试验中本发明的效果
根据本发明，使用皮脂厚度测量仪(sebumetric measuring device)通过临床试验进行了试验以便用实验方法评价两种产品，即洗剂和乳膏剂在治疗痤疮中的作用。
目的
所述试验能评价在针对痤疮的治疗中供试产品是否提供有效的治疗以及它们是否能减轻由于存在痤疮灶引起的变红。
试验样本
具有油脂性皮肤并患有痤疮的五名15至28岁的女性志愿者。
样品制剂
各样品必须根据其使用特点以原样应用。
样品的应用方法
根据分发给志愿者的说明卡片所给出的指示，样品必须均匀地应用于面部的特定部位。
洗剂用于面部右侧；乳膏剂用于面部左侧。
进行试验
找到进行试验的志愿者之后，进行以下仪器评价：
用符合EEC法规的经批准的皮脂厚度计(sebumetric device，SKINLAB)测定基础皮脂
Figure C0282555300081
用符合EEC法规的经批准的仪器(SKIN LAB)测定基础水合
Figure C0282555300082
用符合EEC法规的经批准的仪器(Tewameter)测定基础TEWL-仅在面部左侧
Figure C0282555300083
用具有偏振光的摄像机-VIDEOCAP-获得显微照片，放大20倍，可能时，放大200倍。要深入观察痤疮造成的微小斑点并突出所检验的治疗中的任何改善，显微图像是必需的。
Figure C0282555300084
用Mini DV获得宏观照片。该照片可用于确定总体的起始情况，并记录使用产品过程中任何肉眼可见的改善。
此外，提供给志愿者一张卡片，在上面记录每天对产品的美容有益性质及其性能的观察结果。
给每名志愿者一张卡片，描述她必须如何应用各种供试产品。为了便于完成任务，首次应用在场所内进行。
在用洗剂和乳膏剂治疗7天(t7)、十四天(t14)、二十一天(t21)和二十八天(t28)后采取以下措施。
在上述实验后，应用产品前后所测定的皮脂厚度值、角蛋白值和TEWL值之差，用偏振光摄像机和Mini DV对疖和痤疮脓疱的变化进行评价。
将皮脂厚度值、角蛋白值和TEWL值与下表中的结果一起进行记录、整理并以图形表示。
结果的表格和图形表示
长期使用后的皮脂厚度值
Figure C0282555300091
长期使用后的水合指数
Figure C0282555300101
长期使用后的皮脂厚度值
长期使用后的水合指数
Figure C0282555300121
长期使用后的TEWL值
Figure C0282555300131
制剂实施例
以下是本发明的一些制剂实施例。
制剂01-溶于脂肪油形成的组合物(oleolita)
编号  描述                   ％w/w
01    亚油酸乙酯             20.00
02    柠檬酸三乙酯           80.00
制备方法：将01混合在02中
制剂02-醇溶液
编号  描述                   ％w/w
01    亚油酸乙酯             20.00
02    柠檬酸三乙酯           20.00
03    水杨酸                 2.00
04    乙醇                   58.00
制备方法：将03溶解在04中，向该溶液中混合入01+02
制剂03-乳剂
编号   描述                   ％w/w
A相
01    亚油酸乙酯             5.00
02    柠檬酸三乙酯           5.00
03    抗坏血酸棕榈酸酯       1.50
04    Ppg-15硬脂醚           10.00
05    辛酰基甘氨酸           4.00
06    Steareth-2             3.00
07    Steareth-21            2.00
B相
08    防腐剂                适量
09    甘油                     3.00
10    水                       适量
制备方法：A相，将01+02+03+04+05+06+07混合并加热至75℃；B相，将08+09+10混合并将该预混合物加热至+75℃，然后在搅拌下将B相加入A相中。在持续搅拌下冷却至室温。
制剂04-醇溶液
编号   描述                ％w/w
01    亚油酸乙酯           20.00
02    柠檬酸三乙酯         20.00
03    红霉素               10.00
04    乙醇                 50.00
制备方法：将03溶解在04中，在溶液中混合入01+02
制剂05-醇溶液
编号  描述                 ％w/w
01    反式-视黄酸          0.025
02    亚油酸乙酯           5.00
03    柠檬酸三乙酯         20.00
04    乙醇                 适量
制备方法：将01+02+03溶解在04中
制剂06-醇溶液
编号  描述                ％w/w
01    克林霉素             1.00
02    亚油酸乙酯           5.00
03    柠檬酸三乙酯         20.00
04    乙醇                 适量
制备方法：将02+03+04混合，然后将01溶解在其中。
因此已证实：考虑到具体的生物学、药理学、生理学和生物化学作用机制，已发现亚油酸乙酯和柠檬酸三乙酯的作用比在治疗痤疮、油脂性皮肤和皮脂溢中所述的作用更宽，可用于治疗多种其它的皮肤病理学如特应性皮炎、脂溢性皮炎、剥脱性皮炎、郁积性皮炎、神经性皮炎、痤疮、酒渣鼻、斑形脱发、瘢痕性脱发(scaring alopecia)、女性脱发、生长期脱发、希波克拉底脱发(Hippocratic alopecia)、银屑病、苔藓、鱼鳞病、干皮病、毛发角化病、褥疮性溃疡、营养不良性溃疡、torpid sores、angioma nevus或血管束、血管瘤、毛细管扩张性肉芽肿、脂溢性角化病等。
由于其在皮肤上的独特作用机制，亚油酸乙酯和柠檬酸三乙酯及其与适宜增效剂的联合应用是创新性的，甚至是在其美容剂用途方面，如：旨在改善皮肤美学状况并预防皮肤衰老迹象的抗衰老组合物；抗皱；增湿剂；治疗皮肤色素沉着过度；美容治疗具有发展为痤疮趋势的皮脂溢。

Claims (11)

1.用于治疗和改善皮肤美学状况的局部用组合物，其包含亚油酸乙酯和柠檬酸三乙酯混合物作为活性成分。
2.根据权利要求1的局部用组合物，其特征在于：包含0.1至99％重量/重量的亚油酸乙酯和99％至0.1％重量/重量的柠檬酸三乙酯。
3.根据权利要求1或2的局部用组合物，其还含有单一或联合使用的活性成分，包括乙酸、乳酸、水杨酸、酒石酸、乙醇酸、克林霉素、米诺环素、红霉素、甲硝唑、阿莫西林、二氯苯氧氯酚、辛酰基甘氨酸、壬二酸、氢氧化锌、氯化锌、反式-视黄酸、间苯二酚、透明质酸、庆大霉素、氯甲烯土霉素、苯酚、抗坏血酸、生育酚、硫辛酸、磷脂酰胆碱、磷脂酰丝氨酸、氯己定、卤卡班、阿达帕林、磷脂，通常它们均为右旋形式、左旋形式、外消旋混合物、顺式形式、反式形式以及相应的盐，其配制于特定的添加剂和赋形剂基质中以供外用。
4.根据权利要求3的局部用组合物，其中包含的单一或联合使用的活性成分的量为0.001至90％重量/重量。
5.根据权利要求4的局部用组合物，其中包含的单一或联合使用的活性成分的量为0.5至15％重量/重量。
6.根据权利要求1或2的局部用组合物，其被制备成供外用的制剂。
7.根据权利要求6的局部用组合物，其中供外用的制剂包括油包水乳剂、水包油乳剂、单相溶液、双相假溶液、单相凝胶、双相凝胶或逊胶束凝胶、无水软膏剂、粉末喷洒剂、醇化物、醇溶液、水-醇溶液。
8.用于治疗和改善皮肤美学状况的局部用组合物，其基本上由作为活性成分的亚油酸乙酯和柠檬酸三乙酯混合物组成；且
其中该组合物进一步含有至少一种选自下组的添加剂：乙酸、乳酸、水杨酸、酒石酸、乙醇酸、克林霉素、米诺环素、红霉素、甲硝唑、阿莫西林、二氯苯氧氯酚、辛酰基甘氨酸、壬二酸、氢氧化锌、氯化锌、反式-视黄酸、间苯二酚、透明质酸、庆大霉素、氯甲烯土霉素、苯酚、抗坏血酸、生育酚、硫辛酸、磷脂酰胆碱、磷脂酰丝氨酸、氯己定、卤卡班、阿达帕林，及其右旋形式、左旋形式、外消旋混合物、顺式形式、反式形式、盐；且
其中该组合物被配制成选自以下的形式用于外用：油包水乳剂、水包油乳剂、单相溶液、双相假溶液、单相凝胶、双相凝胶、逊胶束凝胶、无水软膏剂、粉末喷洒剂、醇化物、醇溶液、水-醇溶液。
9.权利要求8的组合物，其中亚油酸乙酯的含量为组合物的1至40％重量/重量，柠檬酸三乙酯的含量为组合物的1至40％重量/重量，至少一种添加剂的含量为组合物的0.001至90％重量/重量。
10.根据权利要求1或2的局部用组合物在制备用于治疗和改善皮肤美学状况的药物或美容剂中的用途。
11.根据权利要求10的用途，其中的皮肤美学状况为皮脂溢、痤疮和酒渣鼻。
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