CN1345213A - 具有烟碱并添加单萜酮的经皮治疗系统 - Google Patents
具有烟碱并添加单萜酮的经皮治疗系统 Download PDFInfo
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Abstract
一种经皮治疗系统,它具有一个背层、至少一个含有尼古丁层或矿物区域,它也能呈现粘附性质,以及一个可重复移除和再施加的保护层,其特征在于含有至少一种得自薄荷的精油或在这种精油中找到的单萜酮。
Description
本发明是关于添加气味改进物质至含有烟碱的经皮治疗系统(TTSs)中。更具体地，它是关于包含此类添加物的含有烟碱的TTSs，以及用以掩盖这种TTSs的令人不愉快气味的方法，并且关于气味改进物质的用途，用以掩盖因烟碱含量所引起的这种TTSs的令人不愉快的气味。
在全世界，含有烟碱的TTSs是广泛地被用于戒烟的治疗上。然而，在市场上可获得的系统显示明显的烟碱气味，当从包装中取出该系统并在其使用时，特别会被察觉到。
在一般2至3年储藏期的过程中，由于部分分解，会发生这种气味明显加强，并且变成在主观上非常令人不愉快之类的气味。
WO95/08324 A1叙述至少两层的TTSs的制造方法，它是使用高挥发性的成分作为专有的溶剂。这些TTSs可含有不同的活性剂，包括烟碱、以及特别是薄荷醇、或其他的挥发性萜衍生物作为皮肤渗透增进剂。已叙述到在含烟碱的TTSs中的这些添加物，对气味方面没有特别的作用。关于“挥发性的萜衍生物”，在单萜醇类以及单萜酮类之间并没有区别。
EP 0 356 382 A2揭示基于某些嵌段共聚物的TTSs，其中也可使用烟碱作为活性剂。为了改进皮肤渗透性，提出了桉叶油素或桉树油类，特别强调以桉树脑为主要的组份；没有考虑薄荷油类的原料。在包含烟碱的贴片的令人不愉快气味方面，同样地未被考虑。
美国专利US 5 599 554 A是关于经粘液或经皮使用的烟碱，其中所使用的组合物也可包含芳香的物质或香料。所提及的有烟碱的特征气味是真的，但是其未被叙述为一种缺点。芳香族化合物，例如：薄荷醇或桉叶油素，被提及作为可选择的原料，但不是必要的薄荷油类或萜酮类。没有指出那些添加物的功能。可能其作为在口服施用中改进味道。
美国专利US 5 593 684 A叙述一种基于同时经粘液及经皮施用的烟碱的治疗的方法。在此，含有萜的植物分泌物在口服片剂中被用作“醚性油类”，以掩盖烟碱的令人不悦的气味。
美国专利US 4 933 184是关于已改进的经皮传送活性物质的TTSs，特别是用于烟碱的，而薄荷醇被用做增强剂；没有提及存在于薄荷类的醚性油类的其他物质，例如：单萜酮。薄荷油被用作增强剂，作为薄荷醇的替代物，但是令人惊奇的是没有产生该效果。对于其它的，这出版物只是关于活性物质渗透的改进，而不是涉及改进TTSs气味的方法。
因此，在含烟碱的TTSs的本发明目的，是根据权利要求1的介绍部分，通过添加适当的芳香物质，以中和这一特征性气味、或以更令人愉快的气味来掩盖之。
现在已发现的解决方法，是添加不同薄荷物种或其组份的精油类，特别是单萜酮类。根据本发明，这些添加物可用来掩盖或改进包含烟碱的TTSs的令人不悦气味。根据本发明的TTSs具有萃自薄荷物种的至少一种精油、或存在于这些精油类中的单萜酮的含量。
不同薄荷物种的精油类的组分，是以萜的代谢的产物为主，更精确的是以单萜类为主。
通常薄荷油的特征是其令人愉快的新鲜气味。所用的油类的实例为洋薄荷(peppermint)油、留兰香油或欧洲胡薄荷(poleimin)油，每一种都是萃自不同的植物。包含于这些油类的独特单萜类，可被分为单萜醇类及单萜酮类。
一般，单萜醇类为：薄荷醇、异薄荷醇、新薄荷醇、新异薄荷醇、及异长叶薄荷醇。一般的单萜酮类为薄荷酮、异薄荷酮、香芹酮、胡椒酮、长叶薄荷酮及异长叶薄荷酮。实际上，所有的这些代表物都是以对映异构体存在，都有光学上左旋及右旋的两种形式。
作为这组的代表物检测的有洋薄荷(Oleum Menthae peperitae)、留兰香(Oleum Menthae crispae)及(日本)薄荷(Oleum Menthae arvensis)的精油类。
洋薄荷油且特别是薄荷油，是以单萜醇类为主，特别是薄荷醇。相对地，留兰香油，包含上述所有的单萜酮类，特别是香芹酮(参照：在1997年版的欧洲药典中的论文“Pfefferminzol”[洋薄荷油])；在1997年版的德国药典中的论文“Minzol”[薄荷油]；以及G.施耐德(Schneider)在1998处所著的第2版Pharmazeutische Biologie[医药生物学]，BI学术出版社[BIWissenschaftsverlag]343-345页)。
做为单一物质，(-)-薄荷醇以及(-)-薄荷酮分别被做为一般的单萜醇及一般的单萜酮来测试。
实施例：
为了检验这种添加物的效果，设计出简化气味测试的模式。
烟碱以7％重量浓度与miglyol 812混合。Miglyol 812是一种饱和的三酸甘油酯，用作一种无气味的载体。7％重量浓度的烟碱相对应于在TTSs中所使用活性物质浓度约5-10％重量。对miglyol中的烟碱而言，造成与TTSs可比较的蒸气压以及因此类似强度的气味。在这测试混合物中添加5个测试物质或测试混合物：
(-)-薄荷醇、(-)-薄荷酮、洋薄荷油(根据欧洲药典的品质)、留兰香油(根据Deutscher Arzneimittel Codex DAC[德国医药法典]的品质)以及薄荷油(根据德国药典的品质)。
在每一个情况下所添加的量是0.5、1.0以及2.0％重量的份量。
产生了15个测试样品。另外，有一个样品的制备是没有气味改进添加物的。
这16个样品以6个人员来评估气味，各别添加物的种类以及量对该人员不是已知的。
评估的标准及等级数包含：
1.烟碱气味：感觉不到(4)；微弱(3)；中等(2)；明显(1)
2.整体的印象：令人不悦(1)；中等(2)；令人愉快(3)；有香味(4)
在将每一个样品及人员的两个数值相加之前，整体印象的评估是乘以因数2，用来更强调针对烟碱的气味。较高的数值代表较良好的评估。所用的等级数字用来形成平均值。理论的最小值是3.0，且理论最大值是12.0。
结果显示于表1中：
| 测试的产品/份量 | 0.5％重量 | 1.0％重量 | 2.0％重量 |
| (-)-薄荷醇 | 4.0 | 4.1 | 4.9 |
| (-)-薄荷酮 | 6.6 | 6.4 | 8.6 |
| 洋薄荷油 | 6.9 | 8.7 | 9.3 |
| 留兰香油 | 7.3 | 7.7 | 9.6 |
| 薄荷油 | 6.0 | 7.0 | 9.0 |
没有添加物的产品产生的值为4.0。
结果的图示列于图1中。
这表示薄荷酮超过薄荷醇的非常令人惊讶的清楚优点。与一般包含高至32％的薄荷酮(1997年的欧洲药典)的洋薄荷油比较，以薄荷醇为主(G.施耐德[Schneider]在1998年所著的第2版的医药生物学[PharmazeutischeBiologie]，BI学术出版社[BI Wissenschaftsverlag]，第345页)的薄荷油的较差的结果，是这些发现的支持证据。
最后，以香芹酮为主、并且实际上没有薄荷醇的留兰香油，产生最佳的结果。
总之，这说明单萜酮类、或单萜醇类与单萜酮类的混合物，超过纯单萜醇类的一个清楚优点。
因为该物质的高挥发性，根据本发明对含有烟碱的TTSs添加该物质的实际实施，具有某些困难；然而，这些困难可以参照PCT/WO 95 08324的介绍而排除。
根据本发明，在气味改进的TTSs的包含烟碱基质中，所含的单萜酮(类)或其精油的量是0.1至5.0％重量，优选为0.5至2％重量的量。
因此根据本发明，将物质添加到含有烟碱的TTSs中，造成一种有用的方式，用来改进这种TTSs的令人不悦的气味。
如权利要求1中介绍部分中所叙述的，该TTSs具有的特性是如上面所提及的，含有至少一种萃自薄荷物种中的精油、或存在于这些精油类的单萜酮。
优选地，单萜酮可以得自香芹酮、二氢基香芹酮、薄荷酮、异长叶薄荷酮、异薄荷酮、新薄荷酮、新异薄荷酮、或洋薄荷酮中之一。单萜酮类可以以纯的对映异构体或其混合物使用。
作为精油，特佳的是使用留兰香油(Oleum Menthae crispae)。
在含有尼古丁的基质中，单萜酮(类)或其精油类的含量优选是0.1至5％重量，特别是0.5至2％重量。
本发明还关于经皮治疗系统中掩盖由烟碱含量所引起的令人不悦气味的方法，这方法的特征在于添加至少一种气味改进物质到含有烟碱的经皮治疗系统，该物质是一种萃自薄荷物种的精油、或包含于萃自薄荷物种的精油中的单萜酮。
在此，优选地，上面所提及的单萜酮或洋薄荷油可被分别以单萜酮类或精油使用，其可以以纯的对映异构体或其混合物来使用。
含有烟碱基质中的单萜酮(类)或精油(类)，优选使用的浓度是0.1至5.0％重量，特别优选的浓度是0.5至2％重量。
另外，本发明包含萃自薄荷物种的精油、和/或包含于萃自薄荷物种的精油中的单萜酮，用以掩盖经皮治疗系统中的令人不悦的气味，该气味是由该经皮治疗系统中的烟碱的含量所引起的。
优选地，所使用的单萜酮是得自香芹酮、二氢基香芹酮、薄荷酮、异长叶薄荷酮、异薄荷酮、新薄荷酮、新异薄荷酮、或洋薄荷酮中之一，其可以以纯的对映异构体或其混合物。
做为精油，特别优选的是使用洋薄荷油(Oleum Menthae crispae)。
根据本发明，在使用用来掩盖含有烟碱的经皮治疗系统的令人不悦气味时，将单萜酮(类)或精油添加到含有烟碱的基质中，加入量优选的浓度为0.1至5.0％重量比，特别优选的浓度为0.5至2％重量。
Claims (13)
1.一种经皮治疗系统，具有一个背层、至少一个含有尼古丁层或矿物区域，其可具有压敏的粘着性质，以及一个可移除的保护层，其特征在于，含有至少一种萃自薄荷物种中的精油，或至少一种包含于这些精油类中的单萜酮。
2.根据权利要求1的经皮治疗系统，其特征在于，该单萜酮是选自香芹酮、二氢基香芹酮、薄荷酮、异长叶薄荷酮、异薄荷酮、新薄荷酮、新异薄荷酮、或洋薄荷酮中之一。
3.根据权利要求2的经皮治疗系统，其特征在于，该单萜酮是以纯的对映异构体或其混合物而使用。
4.根据权利要求1的经皮治疗系统，其特征在于，该精油是留兰香油(Oleum Menthae crispae)。
5.根据权利要求之一或以上的经皮治疗系统，其特征在于，在含烟碱的基质中的单萜酮(类)的含量为0.1至5.0％重量，优选为0.5至2％重量。
6.用来掩盖由烟碱含量所引起的经皮治疗系统的令人不悦气味的方法，其特征在于，添加至少一种气味改进物质至含有烟碱的经皮治疗系统中，该物质是一种萃自薄荷物种中的精油、或包含于萃自薄荷物种中的精油中的一种单萜酮。
7.根据权利要求6的方法，其特征在于，该精油是洋薄荷油(OleumMenthae crispae)。
8.根据权利要求6的方法，其特征在于，该单萜酮是得自香芹酮、二氢基香芹酮、薄荷酮、异长叶薄荷酮、异薄荷酮、新薄荷酮、新异薄荷酮、或洋薄荷酮中之一。
9.根据权利要求8的方法，其特征在于将该单萜酮(类)添加到含有烟碱的基质中，优选的浓度为0.1至5.0％重量，特别优选的浓度为0.5至2％重量。
10.一种萃自薄荷物种中的精油及或包含于萃自薄荷物种中的精油中的一种单萜酮的用途，其是用以掩盖经皮治疗系统的令人不悦的气味，该气味由该经皮治疗系统中的烟碱含量所引起。
11.根据权利要求10的用途，其特征在于，该单萜酮是得自香芹酮、二氢基香芹酮、薄荷酮、异长叶薄荷酮、异薄荷酮、新薄荷酮、新异薄荷酮、或洋薄荷酮中之一。
12.根据权利要求11的用途，其特征在于，将该单萜酮(类)添加到含有烟碱的基质中，优选的浓度为0.1至5.0％重量，特别优选的浓度为0.5至2％重量。
13.根据权利要求10的用途，其特征在于，该精油是洋薄荷油(OleumMenthae crispae)。
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| DE19913732.3 | 1999-03-26 | ||
| DE19913732A DE19913732A1 (de) | 1999-03-26 | 1999-03-26 | Nikotin-TTS mit einem Zusatz von Monoterpenketonen |
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| US20070225379A1 (en) * | 2001-08-03 | 2007-09-27 | Carrara Dario Norberto R | Transdermal delivery of systemically active central nervous system drugs |
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| US7198801B2 (en) * | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
| AR030312A1 (es) * | 2000-08-03 | 2003-08-20 | Antares Pharma Ipl Ag | Composicion novedosa para la administracion transdermica y/o transmucosica de compuestos activos, que asegura adecuados niveles terapeuticos |
| ES2377932T3 (es) * | 2003-10-10 | 2012-04-03 | Ferring Bv | Formulación farmacéutica transdérmica para minimizar los residuos sobre la piel |
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| WO2007124250A2 (en) | 2006-04-21 | 2007-11-01 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
| US8067399B2 (en) * | 2005-05-27 | 2011-11-29 | Antares Pharma Ipl Ag | Method and apparatus for transdermal or transmucosal application of testosterone |
| KR100699582B1 (ko) | 2005-07-11 | 2007-03-23 | 삼성전기주식회사 | 출력 버퍼회로 |
| DE102005033543A1 (de) * | 2005-07-14 | 2007-01-18 | Grünenthal GmbH | Ein einen Duftstoff aufweisendes transdermales therapeutisches System |
| IL177071A0 (en) * | 2005-08-01 | 2006-12-10 | Nitto Denko Corp | Method of preparing a nicotine transdermal preparation |
| ES2499067T3 (es) * | 2005-10-13 | 2014-09-26 | Nitto Denko Corporation | Preparación transdérmica de nicotina y método de producción de la misma |
| WO2008067991A2 (en) * | 2006-12-08 | 2008-06-12 | Antares Pharma Ipl Ag | Skin-friendly drug complexes for transdermal administration |
| EP2552245B1 (en) * | 2010-03-26 | 2018-11-14 | Philip Morris Products S.A. | Inhibition of sensory irritation during consumption of non-smokeable tobacco products |
| JP5730355B2 (ja) * | 2013-07-24 | 2015-06-10 | 学校法人近畿大学 | Ｃｙｐ２ａ１３阻害剤 |
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| JP4750282B2 (ja) | 2011-08-17 |
| EP1164996B1 (de) | 2003-10-22 |
| KR20010112366A (ko) | 2001-12-20 |
| ATE252356T1 (de) | 2003-11-15 |
| RU2228740C2 (ru) | 2004-05-20 |
| ZA200107864B (en) | 2002-11-27 |
| CA2367615C (en) | 2009-10-13 |
| EP1164996A1 (de) | 2002-01-02 |
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