CN1086709A - 含视黄酸和生育酚的组合物 - Google Patents

含视黄酸和生育酚的组合物 Download PDF

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CN1086709A
CN1086709A CN93108425A CN93108425A CN1086709A CN 1086709 A CN1086709 A CN 1086709A CN 93108425 A CN93108425 A CN 93108425A CN 93108425 A CN93108425 A CN 93108425A CN 1086709 A CN1086709 A CN 1086709A
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tocopherol
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C·F·纳吉
T·W·奎克
S·S·夏皮罗
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Abstract

视黄酸和生育酚的组合物可以局部使用，而不产 生视黄酸所致的皮肤刺激。

Description

人们知道，视黄酸例如13-顺式-视黄酸和全反式-视黄酸具有益的皮肤学方面的作用，即对人的皮肤有益，而且可用于阻止光致老化对皮肤的作用，或用于消除痤疮，或一般用于改善皮肤的质量，然而，为这些皮肤学目的而将视黄酸反复局部用于人的皮肤开始可能会产生暂时的皮肤刺激作用（皮炎）。可以表现为红斑、脱落、瘙痒以及类似于晒伤的感觉。这样的结果也可以在用视黄酸反复局部给药后的动物身上观察到。
对动物皮肤产生刺激作用的视黄酸的炎性成分可以通过将炎性细胞注入皮肤而在组织学方面给予证实。例如在小鼠中，导致皮肤刺激作用的局部的视黄酸反复局部使用后会表现出炎性反应和表皮过度增生的特征。该作用可以从测定在皮肤的钻取活组织检查物中增强的髓过氧物酶（MPO）活性而在生物化学方面进行定量（Bradley等人，J.Invest.Dermatol.1982;78：206-209页）。
按照本发明，已经发现，为皮肤学作用而局部使用视黄酸会产生视黄酸诱发皮炎的问题可以通过将生育酚如α-生育酚加到该局部用组合物中而得以克服。
因此本发明的目的在于提供适于局部使用的液体组合物，它包括对于治疗皮肤疾病有效量的视黄酸或其药学上可接受的酯和足以减轻由所述视黄酸产生的皮肤刺激作用的一定量的α-生育酚。
在本发明组合物中，视黄酸的含量为治疗皮肤疾病的有效量;生育酚的含量为足以减轻视黄酸所致皮肤刺激作用的用量。视黄酸一词包括全反式-视黄酸、几何异构体如13-顺式-视黄酸和药学上可接受的酯;也包括如上述对皮肤具有益的治疗作用的天然或合成的视黄酸的类似物。
按照本发明，该液体组合物可以按常规局部用组合物用于人的皮肤。视黄酸的皮肤学作用已众所周知。这些作用使视黄酸可以在一定的范围内使用。例如视黄酸可以用来治疗皮肤疾病如痤疮、光损伤（photodamage）（即起皱）和可以通过治疗而减小的上皮癌。
这些局部用组合物为适于局部使用的液体组合物的形式（包括如乳膏剂、凝胶、油膏剂、微乳剂、洗发剂和溶液）。
视黄酸、具体讲是13-顺式-视黄酸的浓度可以在每体积液体组合物约0.05-0.2重量%的范围内，以及生育酚、具体讲是α-生育酚的浓度可以在每体积液体组合物约0.005-5.0重量%的范围内。具体来讲，α-生育酚的含量可以在每体积液体组合物约0.01-5.0重量%的范围内。
本发明也提供通过局部使用含视黄酸和α-生育酚的液体组合物而给皮肤局部使用视黄酸来治疗皮肤疾病而不产生所述的视黄酸诱发的皮肤刺激作用的方法，所述组合物按足以产生所述的视黄酸的皮肤学作用的量来使用，以及所述的α-生育酚的含量为足以减轻视黄酸所致皮肤刺激作用的用量。在这些方法中优选α-生育酚和13-顺式-视黄酸。具体使用的视黄酸的有效量已在本领域中众所周知（美国专利第5075333;4888342;4487782;4603146;和4877805），或可以通过如实施例1和实施例2中所述的分析或试验以实验为根据来定。可以用相似的方法来确定足以减轻皮肤刺激作用的α-生育酚的用量。用于上述液体组合物中的上述成分的用量具体为约0.01-5.0重量%生育酚和约0.05-0.2重量%视黄酸。
这些液体组合物可以用于身体的皮肤，具体讲是脸、腿、臂和手。它们可以按任何常规局部用制剂来使用，即与可用于局部给药的任何适宜的常规载体结合来使用。这样的局部用组合物包括乳膏剂、油膏剂、肥皂、溶液、洗剂、乳剂、洗发剂以及任何其它常规局部用制剂。在配制这些制剂时，任何常规无毒及皮肤学上可接受且在这些组合物中是稳定的基质或载体均可以接受。
优选的组合物可以含常规美容活性成分，常规美容活性物质的例子有：遮光剂、渗透增强剂、增湿剂（moisturizers）、表面活性剂、润滑药、着色剂、调节剂、杀菌剂、收敛剂、去污剂以及其它这样的物质。任何常规遮光剂均可以包括在所述的组合物中。
这些局部用组合物可以含有任何通常用在制备皮肤用组合物中的常规赋形剂和添加剂。常规添加剂或赋形剂包括防腐剂，增稠剂、香料等。此外，可以将常规抗氧剂如叔丁对甲氧酚（BHA）、抗坏血酸棕榈酸酯、没食子酸丙酯、柠檬酸、二叔丁对甲酚（BHT）、乙氧喹等掺入到这些组合物中。这些组合物可以含任何本领域熟知的增稠剂、助溶剂、润湿剂、乳化剂和粘度稳定剂。此外，这些组合物可以含常规用矫味剂，加香剂或着色剂。
该局部用组合物用于皮肤的使用频率应据病人个体而定。具体的使用方法应根据病人个体的年令、体重和皮肤状况来定。然而用视黄酸消除日光性损伤和减皱的典型方法是每周在皮肤上至少使用2或3次并至少使用5个月而且此后按照需要来保持皮肤的弹性。就痤疮治疗而言，典型方法是每天使用一次或一次以上，大约使用4-6周。
在以下实施例中将进一步举例说明本发明，这些实施例仅用于说明本发明而对本发明没有限制。
实施例1
实施例1验证：若将视黄酸与α-生育酚一同使用则可减轻由局部使用视黄酸所致的皮肤刺激作用，皮肤刺激作用由在使用区域内特别是耳部产生的炎症的量来定。炎症的数量与由使用视黄酸所致的耳组织中炎性细胞（中性白细胞）数量的增加相关。中性白细胞增加直接与MPO的活性（MPO是中性白细胞标记酶）成正比，MPO的活性通过加入底物并测定由MPO在底物上反应产生的光密度而比色法定量。由于炎症所致的耳重增加是另一项由使用视黄酸所致炎症的量的量度。
在雄性CD-1小鼠（出生5周）右耳背侧局部给药共8天，每天25μl，所给药物为含0.08%（20μg/25μl）13-顺式-视黄酸和剂量范围在0.01-5.0%（2.5μg-1.2mg）内的α-生育酚（维生素E）的丙酮溶液。每组用8只动物。对照组或者只用0.08%13-顺式-视黄酸溶液处理，或者用溶剂（丙酮）处理。在第9天将动物通过吸入CO2处死并从处理过的耳朵上钻取活组织检查物（直径为6mm）。将该钻取活组织检查物称重、匀化并按上述引文中Bradley等人的方法用96孔微量滴定盘测定该组织匀浆的MPO活性。MPO活性通过在96孔盘读出器（SLT实验室仪器）于450nm处测量该反应混合物在2分钟时间内的光密度变化来定。按照下式将这些数据表示为α-生育酚（维生素E）处理组相对于对照组的抑制百分数：
抑制%＝ (△O.D.RA-△O.D.（RA+E）)/(△O.D.RA-△O.D.对照) ×100
式中：△O.D.RA是视黄酸处理组在450nm处每分钟的光密度变化;△O.D.（RA+E）是视黄酸和α-生育酚处理组在450nm处每分钟的光密度变化;△O.D.对照是溶媒处理组在450nm处每分钟的光密度变化。
在小鼠耳部局部使用8天13-顺式-视黄酸则导致剂量相关的多形核中性白细胞浸水痘-带状疱疹病毒增加，如MPO活性增加所示。耳湿重也按剂量相关的方式增加并且该增加部分是由于耳朵对视黄酸的反应而产生的耳朵炎症和表皮过度增生所致。图1是8天后13-顺式-视黄酸对鼠的局部刺激作用的剂量效应。从图中结果表明MPO活性和小鼠耳中钻取物湿重随13-顺式-视黄酸剂量增大而增加，MPO活性如上所述是炎症反应的量度。浓度在0.01-5.0%的α-生育酚以剂量相关的方式抑制视黄酸诱导的MPO活性（中性白细胞浸水痘-带状疱疹病毒）的增加。图2是局部使用α-生育酚对13-顺式-视黄酸所致的鼠皮肤刺激的抑制作用。从图中结果表明在鼠耳中视黄酸诱导的MPO活性随α-生育酚的剂量增加而降低。当α-生育酚的浓度5.0%时可获得13-顺式-视黄酸诱导的中阝性白细胞浸润的最大抑制作用（70%）。这些数据清楚地证实了局部使用α-生育酚（最适量）可以改善由反复局部使用13-顺式-视黄酸而诱发的炎症部位。
实施例2
本文所述的液体组合物可按乳膏剂、洗剂、洗发剂和任何其它的局部用制剂而用于局部。在这些实施例中给出的百分数为基于该液体组合物总体积的重量百分数。具体配制描述如下。然而任何常规制剂均可用于所述的组合物中。
a.脂质体制剂
成分        重量%
异维生素A酸（Isotretinoin）        0.050-1.000
维生素E        0.005-5.000
L-α-双十四烷基磷脂酰胆碱        0.062
胆固醇        0.062
叔丁醇        31.089
乳糖        6.000
适量净化水至        100.000
b.油包水乳膏剂
成分        重量%
异维生素A酸        0.050-1.000
维生素E        0.005-5.000
丙二醇二辛酸酯/二癸酸酯
和Stearalkonium    Bentonite
（和）丙烯碳酸酯        20.000
辛/癸三酸甘油酯        20.000
异硬脂酰二甘油琥珀酸酯        5.000
适量净化水至        100.000
c.调理发胶
成分        重量%
异维生素A酸        0.050-1.000
维生素E        0.005-5.000
PEG-7-甘油Cocoate        10.000
无水乙醇        24.000
甲基pyrol        5.000
肉豆蔻酰磷脂酰胆碱        0.030
抗坏血酸钠        0.030
柠檬酸        0.100
聚羧乙烯制剂940        0.500
β-氨基丙酸        0.500
适量净化水至        100.000
d.水包油乳膏剂
成分        重量%
异维生素A酸        0.05-1.00
维生素E        0.005-5.00
丙二醇二辛酸酯/二癸酸酯        8.95
十八烷醇        0.75
甘油硬脂酸酯        4.00
Ceteareth-12        0.50
Ceteareth-20        0.50
对羟基苯甲酸丙酯        0.10
对羟基苯甲酸甲酯        0.15
乙二胺四乙酸二钠        0.03
甘油        5.00
适量净化水至        100.000
e.乳膏剂（无水）
成分        重量%
异维生素A酸        0.05-1.00
维生素E        0.005-5.00
甘油辛/癸/硬脂三酸酯        29.00
甘油Cocoate（和）
Ceteareth-25        43.00
丙二醇二辛酸酯/二癸酸酯        8.95
适量矿物油至        100.000
f.水包油微乳剂
成分        重量%
异维生素A酸        0.05-1.00
维生素E        0.005-5.00
DEA-Oleth-3磷酸酯        8.95
Oleth-20        1.00
Oleth-10        15.00
矿物油        4.00
丙二醇二辛酸酯/二癸酸酯        8.00
BHT        0.03
双辛氢啶        0.10
柠檬酸        0.05
抗坏血酸钠        0.10
山梨酸        0.10
甘油        5.00
适量净化水至        100.000
g.局部用溶液
成分        重量%
异维生素A酸        0.050-1.000
维生素E        0.005-5.000
PEG-7-甘油Cocoate        10.000
无水乙醇        25.000
适量净化水至        100.000

Claims (4)

1、适用于局部使用的液体组合物，所述组合物含治疗皮肤疾病有效量的视黄酸或其药学上可接受的酯和足以减轻所述视黄酸所致的皮肤刺激作用的一定量的α-生育酚。
2、适用于局部使用的液体组合物，每体积所述组合物含约0.05-0.2重量%视黄酸和约0.005-5.0重量%α-生育酚。
3、权利要求1的组合物，其中视黄酸是13-顺式-视黄酸。
4、权利要求1的液体组合物，每体积所述组合物含约0.01-5.0重量%α-生育酚。
CN93108425A 1992-07-10 1993-07-09 含视黄酸和生育酚的组合物 Expired - Fee Related CN1051704C (zh)

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CN104755128A (zh) * 2012-11-02 2015-07-01 考司美德制药株式会社 视黄酸微针

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ES2137209T3 (es) 1999-12-16
EP0578077A2 (en) 1994-01-12
NZ248069A (en) 1994-12-22
EP0578077A3 (en) 1994-06-29
AU4156493A (en) 1994-01-13
DE69326292D1 (de) 1999-10-14
CN1051704C (zh) 2000-04-26
EP0578077B1 (en) 1999-09-08
JPH0751490B2 (ja) 1995-06-05
AU666949B2 (en) 1996-02-29
CA2098550A1 (en) 1994-01-11
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DE69326292T2 (de) 2000-05-11
JPH0687741A (ja) 1994-03-29

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