CN1260712A - 气溶胶制剂 - Google Patents
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Abstract
一种喷雾时在施用部位凝结成果冻状的用于皮肤冷却的气溶胶制剂,它包含液化气体和含有C1—3低级醇及C10—22一元羧酸的储液,该气溶胶制剂中可含有对水不稳定的药物,而搀混这种对水不稳定的药物在以前的气溶胶制剂中一直是很困难的。本发明的气溶胶制剂使用时感觉极佳并且具有持久的冷却效果。因此,它可有效地缓解由于挫伤、扭伤、肌肉疲劳等引起的疼痛或由脚癣、虫子叮咬等引起的瘙痒。
Description
本发明涉及一种气溶胶制剂，该气溶胶制剂在喷雾时通过类似果冻状的凝结来增强冷却效果。
迄今为止，经常使用凝胶制剂或气溶胶制剂来缓解由于挫伤、扭伤、肌肉疲劳等引起的疼痛，或是由脚癣、虫子叮咬等引起的瘙痒。然而，这种凝胶制剂的直接效果比较差，而通常使用的气溶胶制剂的效果又不持久。
通常，将感染部位冷却可有效地缓解疼痛和瘙痒。为此，作为具有持久冷却效果的气溶胶制剂的例子，WO90/11068和日本特许公开4-103526的说明书公开了喷雾时形成果冻状泡沫凝胶的气溶胶制剂。但是，这些气溶胶制剂的生产过程比较复杂。而且，由于这些气溶胶制剂的储液必需含有水，因此，这些制剂中很难含有对水不稳定或高度亲脂性的药物。另外，这些气溶胶制剂在使用时缺乏令人满意的感觉。
本发明的目标是提供一种气溶胶制剂，它解决了现有技术的难点，并且在使用时具有强烈而且持久的皮肤冷却效果。
为了达到上述目的，经过广泛的研究，本发明的发明者发现含有低级醇、直链一元羧酸和液化气体的气溶胶制剂在喷雾时通过在施用部位凝结成果冻状而具有持久的冷却效果，并且使用时感觉极佳。由此，完成了本发明。
也就是，本发明涉及一种用于皮肤冷却的气溶胶制剂，它含有包括C1-3低级醇和C10-22直链一元羧酸的储液以及液化气体。喷雾时，这种气溶胶制剂在施用部位凝结成果冻状。
迄今为止，尚未发现任何用于皮肤冷却的气溶胶制剂，其冷却效果是由于该制剂中含有直链的一元羧酸产生的。现有的任何具有持久皮肤冷却效果的气溶胶制剂均是在喷雾时通过冷冻其中含有的水而凝结，从而维持其冷却效果。然而，本发明的气溶胶制剂通常并不必须含有水，其特征在于，喷雾时，本发明喷雾剂是在全新的条件下凝结的。
在本发明中，术语“果冻状”是指喷雾时，由于液化气体的蒸发致冷而使气溶胶制剂在施用部位部分凝结的一种状态，尤其是指在施用部位液体与细小结晶凝结物的一种搀混状态。在本发明中，喷雾时，呈液体的低级醇和呈细小结晶凝结物的直链一元羧酸搀混在一起，结果是获得了持久的冷却效果。
在本发明中，所述的C1-3低级醇是指直链或支链醇，其具体的例子是甲醇、乙醇、变性乙醇(denatured ethanol)、丙醇和异丙醇，优选乙醇和异丙醇。该低级醇的量优选为6-99％重量，更优选为10-95％重量，最优选30-90％重量(以该储液的重量计)。当所述低级醇含量以该储液的重量计低于6％重量时，该储液将可能不易与抛射剂混合。同时，当所述的低级醇的含量高于99％重量时，将会损害冷却效果的持久性。
在本发明中，所述的C10-22直链一元羧酸优选包括月桂酸、肉豆蔻酸、棕榈酸、硬脂酸或山嵛酸，最优选硬脂酸。
以储液的重量计，直链一元羧酸的含量范围优选为1-28％重量，更优选为1.5-20％重量，最优选为2-15％重量。当直链一元羧酸的含量基于储液的重量低于1％重量时，会使喷雾时气溶胶制剂不易凝结，从而损害其持久的冰冷感；同时，当其含量高于28％重量时，该直链一元羧酸将不易于溶解，从而使产品的生产工艺复杂化。
在本发明中，只有在所述的直链一元羧酸、低级醇和液化气体混合时形成完全均一体系，才能获得本发明的所述效果。因此，当所述的直链一元羧酸的溶解度不够时，可加入其它的溶剂、助溶剂、表面活性剂等。
所述的液化气体包括可用于常见气溶胶制剂的抛射剂，其优选的例子是二甲醚、正丁烷、异丁烷、丙烷和液化石油气，这些既可以单独使用，也可以混合使用，尤其优选二甲醚、正丁烷和异丁烷。
基于1重量份的所述储液，所述液化气体的量优选是0.5-20重量份，更优选1-9重量份。当所述液化气体的用量基于一重量份所述储液低于0.5重量份时，将会损害所述气溶胶制剂使用时的冰冷感，从而损害其缓解疼痛和瘙痒的效果；同时，当所述液化气体的用量高于20重量份时，该气溶胶制剂在喷雾时将可能不会形成果冻状固体，从而不易获得所述的持久冷却效果。
本发明的气溶胶制剂可通过如下方法制备：溶解所述的低级醇和直链一元羧酸，从而得到一种均一体系，并且，如果需要的话，还可向该储液中混入不破坏该均一体系的其它组分，然后将所得储液与所述的液化气体一起装入气溶胶容器中。考虑到所述的冷却效果的持久性，优选含有适量的水作为不破坏该均一体系的这种其它组份。在所述储液含有水的情况下，加入的水基于该储液组合物的总量不能超过90％重量；为使所述制剂易于配制，优选向所述的储液中混入20-60％重量的水。
为了增强对感染部位疼痛与瘙痒的缓解效果，可向本发明的气溶胶制剂中搀混药物有效组分，如消炎和止痛药、止痒药、抗真菌药、血管舒张药、抗组胺药、局部麻醉药、抗生素、消炎药、角质层分离剂、清凉剂等。尤其是，可向本发明的气溶胶制剂中搀混对水不稳定或亲脂性较高的药物。这种药物有效组分的量可根据该组分的种类而变化，但其范围通常为0.001-10％重量(基于所述制剂的总量)。
如果需要的话，本发明的气溶胶制剂可以含有可用于常规的气溶胶制剂的任何添加剂，例如，抗氧化剂、经皮吸收促进剂、致湿剂、乳化助剂、胶凝剂、增稠剂、香精、染料等。
本发明将通过以下实施例和测试例进行更为详细的说明。实施例1
混合3.11重量份的硬脂酸和21.41重量份的乙醇，得到储液。将该储液装入耐压容器中，其上连接一阀门，然后加入0.08重量份的丙烷、2.11重量份的正丁烷、1.07重量份的异丁烷和72.22重量份的二甲醚，从而得到气溶胶制剂。实施例2
混合0.31重量份的吲哚美辛，4.11重量份的聚乙二醇400、1.23重量份的硬酯酸、1.23重量份的聚氧乙烯十六烷基醚、16.47重量份的变性乙醇和13.39重量份的纯净水，搅拌并均一溶解，从而得到储液。将该储液装入耐压容器中，其上连有阀门。装入63.26重量份的二甲醚，从而得到气溶胶制剂。实施例3
混合0.18重量份的吡罗昔康、1.76重量份的聚乙二醇400、0.7重量份的甘油、0.53重量份的硬脂酸、0.53重量份的棕榈酸、0.7重量份的聚氧乙烯硬脂(酰)基醚、0.35重量份的聚氧乙烯氢化蓖麻油、16.85重量份的变性乙醇和8.74重量份的纯净水，搅拌并均一溶解从而得到储液。将所述储液装入耐压容器中，其上连有阀门，装入69.49重量份的二甲醚，从而获得气溶胶制剂。实施例4
混合0.35重量份的硝酸咪康唑、1.76重量份的己二酸二异丙酯、1.06重量份的肉豆蔻酸异丙酯、0.7重量份的甘油、0.35重量份的聚乙二醇二硬脂酸酯、0.35重量份的十甘油基二硬脂酸酯(decaglyceryldistearate)、0.35重量份的聚氧乙烯丙三醇单硬脂酸酯、0.7重量份的肉豆蔻酸、0.35重量份的硬脂酸、0.7重量份的山嵛酸和16.83重量份的乙醇，搅拌并均一溶解，从而得到一储液。将该储液装入耐压容器中，其上连有阀门，并装入0.86重量份的丙烷、4.22重量份的正丁烷、2.14重量份的异丁烷和69.32重量份的二甲醚，从而得到气溶胶制剂。对比实施例1
按照实施例1中的同样方法，采用实施例1的配方，只是其中用乙醇代替硬脂酸，获得气溶胶制剂。对比实施例2
按照实施例2中的同样方法，采用实施例2的配方，只是分别用变性乙醇和纯净水代替其中的聚氧乙烯十六烷基醚和硬脂酸，得到用于对比的气溶胶制剂。对比实施例3
混合0.36重量份的吲哚美辛、1.79重量份的己二酸二异丙酯、1.07重量份的肉豆蔻酸异丙酯、0.71重量份的甘油、17.06重量份的变性乙醇和8.27重量份的纯净水，搅拌并均一溶解，从而得到储液。将该储液装入耐压容器中，其上连有阀门并装入70.74重量份的二甲醚，从而获得用于对比的气溶胶制剂。对比实施例4
基于日本专利公开4-103526的实施例1中所述的制备果冻状气溶胶制剂的方法，获得气溶胶制剂。
也就是，在加热条件下溶解0.31重量份的吲哚美辛、4.07重量份的己二酸二异丙酯、1.22重量份的聚氧乙烯脱水山梨糖醇单硬脂酸酯、0.81重量份的聚氧乙烯脱水山梨糖醇三硬脂酸酯和1.22重量份的脱水山梨糖醇单硬脂酸酯，向其中加入15.94重量份的热的纯净水并充分混合，进一步搅拌冷却后，向其中加入14.23重量份的变性乙醇并均匀分散，从而得到储液。将该储液装入耐压容器中，其上连有阀门，并装入62.20重量份的二甲醚，从而获得气溶胶制剂。测试例1
用胶带将热偶传感器固定在薄片(sheet)上，并将该薄片展铺在恒温于33℃的水浴上。用实施例1-4和对比实施例1-4中所获得的气溶胶制剂分别对热偶传感器喷雾3秒钟。观察喷雾后，气溶胶制剂的性质，并且随着时间推移，记录热偶传感器的示数值，结果如表1所示：
表1
○表示喷雾时气溶胶制剂凝结成果冻状×表示喷雾时气溶胶制剂没有凝结成果冻状
| 喷雾后的气溶胶制剂 | 热偶传感器的温度变化(℃) | ||||||||
| 喷雾前 | 15秒 | 30秒 | 45秒 | 60秒 | 90秒 | 120秒 | 180秒 | ||
| 实施例1实施例2实施例3实施例4对比实施例1对比实施例2对比实施例3对比实施例4 | ○○○○×××○ | 33.133.033.033.133.133.033.033.0 | 14.913.914.314.422.824.024.915.6 | 15.714.114.914.931.930.831.715.5 | 17.117.916.715.132.432.532.119.2 | 20.221.421.020.832.632.532.523.4 | 22.624.123.221.732.832.632.831.2 | 30.030.931.229.932.932.832.931.3 | 31.432.032.632.033.033.032.933.0 |
表1显示：实施例1-4和对比实施例4的气溶胶制剂在喷雾时都凝结成果冻状。但对比实施例1-3并不形成任何果冻状凝结物。表1还表明，对于热偶传感器的温度变化来说，对比实施例1-3的气溶胶制剂在喷雾后30秒时，传感器温度达到30℃或更高并在45秒时回复到初始温度，与此相反的是，实施例1-4和对比实施例4的气溶胶制剂则具有持久的冷却效果。测试例2
30名试验者对实施例4和对比实施例4的气溶胶制剂进行“使用感觉”试验，二者均具有类似的冷却效果，受试者有下列三种选择，也就是，哪种气溶胶制剂使用时感觉较好：①实施例4，②对比实施例4，或③互相差不多，结果是：选择①的受试者有27人，选择②的有0个人，选择③的有1人。
由测试例2的结果，可以证实：在使用时本发明的气溶胶制剂的感觉要好于现有技术的果冻状气溶胶制剂。
本发明使得生产这样的一种气溶胶制剂成为可能，即该气溶胶制剂在使用时具有较好的感觉并具有长时间的持久冷却效果。另外，本发明使得还可以生产含有对水不稳定的药物的用于皮肤冷却的气溶胶制剂，而搀混这种对水不稳定的药物在过去一直是很困难的。
Claims (7)
1.一种使用时在施用部位凝结为果冻状的用于皮肤冷却的气溶胶制剂，它包含液化气体和含有C1-3低级醇及C10-22直链一元羧酸的储液。
2.根据权利要求1的用于皮肤冷却的气溶胶制剂，其中，基于该储液的重量计，所述低级醇的量为6-99％重量，所述一元羧酸的量为1-28％重量；并且基于1重量份的该储液，所述液化气体的量为0.5-20重量份。
3.根据权利要求1或2的用于皮肤冷却的气溶胶制剂，其中所述的直链一元羧酸是选自月桂酸、肉豆蔻酸、棕榈酸、硬脂酸和山嵛酸的一种或多种直链一元羧酸。
4.根据权利要求1或2的用于皮肤冷却的气溶胶制剂，其中所述的直链一元羧酸是硬脂酸。
5.根据权利要求1-4任一项的用于皮肤冷却的气溶胶制剂，其中所述的低级醇是至少一种选自乙醇和异丙醇的低级醇。
6.根据权利要求1-5任一项的用于皮肤冷却的气溶胶制剂，其中，基于所述储液的重量，该储液含有20-60％重量的水。
7.根据权利要求1-6任一项的用于皮肤冷却的气溶胶制剂，其中所述的液化气体是选自丙烷、正丁烷、异丁烷和二甲醚中的一种或多种液化气体。
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| US9211259B2 (en) | 2002-11-29 | 2015-12-15 | Foamix Pharmaceuticals Ltd. | Antibiotic kit and composition and uses thereof |
| US8119109B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Foamable compositions, kits and methods for hyperhidrosis |
| US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
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| FR2873293B1 (fr) * | 2004-07-21 | 2006-11-17 | Cerep Sa | Utilisation d'un acide gras pour la preparation d'une composition topique destinee a l'apaisement des reactions inflammatoires dues aux piqures d'hymenopteres a venin |
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| WO2009069006A2 (en) | 2007-11-30 | 2009-06-04 | Foamix Ltd. | Foam containing benzoyl peroxide |
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| AU7673998A (en) | 1998-12-30 |
| KR20010013701A (ko) | 2001-02-26 |
| EP0993827A1 (en) | 2000-04-19 |
| AU729680B2 (en) | 2001-02-08 |
| CA2293622A1 (en) | 1998-12-17 |
| WO1998056350A1 (fr) | 1998-12-17 |
| HK1027968A1 (en) | 2001-02-02 |
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