CN1142773C - 一种含有d2激动剂的经由皮肤治疗帕金森氏症的体系及其制备方法 - Google Patents

一种含有d2激动剂的经由皮肤治疗帕金森氏症的体系及其制备方法 Download PDF

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CN1142773C
CN1142773C CNB998047511A CN99804751A CN1142773C CN 1142773 C CN1142773 C CN 1142773C CN B998047511 A CNB998047511 A CN B998047511A CN 99804751 A CN99804751 A CN 99804751A CN 1142773 C CN1142773 C CN 1142773C
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瓦尔特·米勒
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詹姆斯·V·佩克
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Abstract

本发明涉及一种含有D2激动剂的经由皮肤治疗帕金森氏症的体系，其包含有一个不会和基质成分起化学作用的支持层，一个含有有效量的(-)-5，6，7，8-四氢-6-[丙基[2-(2-噻吩基)乙基]氨基]-1-萘酚的自粘性基质层及一个使用前须撕除的保护箔片或膜片，其特征在于基质是一个以丙烯酸酯或硅氧烷为基础的非水溶性聚合物粘着体系，使(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的溶解度≥5重量%；其中上述以硅氧烷为基础的聚合物粘着体系是抗胺的硅氧烷粘着剂。

Description

一种含有D2激动剂的经由皮肤治疗帕金森氏症的体系及其制备方法
技术领域
本发明涉及一种经由皮肤治疗帕金森氏症的体系，其包含有一个不会和基质成分起化学作用的支持层，一个含有有效量的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的自粘性基质层，其分子式如下图所示，
Figure C9980475100051
以及一个使用前须撕除的保护层。
背景技术
世界上大约有2.5至3％的人患有所谓的帕金森氏症，而此疾病主要发生于58至62岁之间。此疾病的病征会出现运动神经失调，如颤抖、肌肉僵硬，植物性失调，如唾液和泪液的增加、体温控制失调、低血压以及膀胱和肠功能失调，同时也会有精神失调的症状，如会有优柔寡断以及沮丧的心情。
帕金森氏症是由位于黑质内的多巴胺能神经元退化而引起。其会导致大脑特定区域，特别是脑干神经节内的多巴胺用尽。此结果扰乱了神经传导物质乙酰胆碱和多巴胺之间的平衡，最后会引起此疾病的病征。过多的乙酰胆碱会导致所谓的正向病征(plus symptoms)，而过少的多巴胺会导致所谓的负向病征(minus symptoms)。
因此帕金森氏症可以用所谓的抗胆碱能药或左旋多巴来治疗。抗胆碱激素会阻断胆碱能药的神经传导，而多巴胺的先质，左旋多巴会穿过血脑障壁并在大脑内转换成多巴胺。
另一种治疗帕金森氏症的方法是通过多巴胺受体激动剂来治疗。虽然多巴胺激动剂的结构和多巴胺不同，但是其可和相同的受体结合而与多巴胺有类似的功能。由于多巴胺受体激动剂的分子结构使得其可以克服血脑障壁。如果这些物质能有选择性的和多巴胺受体的子群，即和D2受体结合，则对于减少副作用是有利的。由于此缘故，物质(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚具有上述的分子式，且已被证实是一种特别有效的D2激动剂。
由于此化合物的半衰期以及高首次通过效应，因此，口服此种物质是有很大的问题的。短的半衰期导致必须频繁的用药，而高的首次通过效应导致必须使用高的剂量。然而用药频率可以用适当的口服分配解决，而高首次通过效应的问题原则上可以用非口服的施用此活性物质来解决。
在WO 94-07468中已经描述过一种经由皮肤治疗的体系，其是为使用上述分子式的D2激动剂而设计的。此体系包含有活性物质，如盐酸盐，存在于一个两相的基质中，而此基质是主要由疏水性的聚合物所形成，其为一个连续相有且水合硅酸盐散布其中以通用亲水的药盐，而此体系另外还含有或可能含有疏水性的溶剂，如促进渗透剂及分散剂。
这个体系的缺点是：此活性物盐必须在水溶液中与硅酸盐相混合，而且必须外加乳化剂以便此水溶液可与通常溶在己烷、庚烷或乙酸乙酯等有机溶剂中的亲脂聚合物乳化。由于涂布的问题，此乳剂非常不容易被制成经由皮肤治疗的体系。此外，这样的体系只能使用盐类，因为只有盐类有足够的亲水性被溶在水中。
发明内容
因此，本发明的目的在于开发用于(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的体系，并且防止在WO 94-07468中所描述的此体系的缺点。
因此，本发明特别注重在使此活性物质能最有效地被包含在此体系中，以及皮肤的传送。
根据本发明的经由皮肤治疗的体系，即一开始所提及的类型及开发的一种含有D2激动剂的经由皮肤治疗帕金森氏症的体系，其包含有一个不会和基质成分起化学作用的支持层，一个含有有效量的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的自粘性基质层及一个使用前须撕除的保护箔片或膜片，其特征在于基质是一个以丙烯酸酯或硅氧烷为基础的非水溶性聚合物粘着体系，使(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的溶解度≥5重量％；其中上述以硅氧烷为基础的聚合物粘着体系是抗胺的硅氧烷粘着剂。而溶解度决定于环境温度。
所述透皮体系选择性地含有低于0.5％(重量)、更优选低于0.05％(重量)的无机硅酸盐微粒，或者该透皮体系的基质基本上不含无机硅酸盐颗粒。
在最简单的实施例中，这些基质体系是单相的基质。其包含有一支持层，一个含有活性物质的自粘性基质，以及一个使用前须撕除的保护膜。较复杂的实施例是包含有多层的基质，而这些基质可能也包含有非粘着层与控制膜。选择性地，基质也可含有惰性的填料以改进成分间的凝聚力。
聚丙烯酸酯是由丙烯酸衍生物或甲基丙烯酸衍生物经由自由基聚合作用所产生，其也有可能用其他合适的化合物，例如乙酸乙烯酯作为额外的单体。经由选择适合的单体，可给予每个生成物特定的性质。
以多价的金属离子来交联聚丙烯酸酯以加强粘性的物理性质，或使其适应于某种特定的要求是很常见的。上述的金属离子大部分是以金属合物的形式被使用，其可溶于有机溶剂中。特别合适的化合物有乙酰乙酸铝或乙酰乙酸钛。
硅氧烷粘着剂在大多数情况下是聚二甲基硅氧烷。然而其他的有机残基，例如乙基或苯基，原则上可被用来取代甲基。这样只有一种成分的硅氧烷粘着剂却有两种变体，即所谓的抗胺以及非抗胺粘着剂。基于(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的基本性质，对于此含有活性物质的硅氧烷粘着剂，使用的是抗胺粘着剂。
这样的抗胺硅氧烷粘着剂绝对不能有游离的硅烷功能。在特殊的过程中硅-氢氧基被提供作为烷基残基。这样的粘着剂及其的制造在EP 0 180377中有详细的描述。
粘着剂溶解活性物质的能力对于基质体系的开发是一重要的参数，就像活性物质在基质中的活动性，及其经由表面的接触传送的皮肤，而此活性物质的传送实际上是由分布系数及皮肤的吸收力来决定。如此导致相当复杂的影响，而且应该被考虑进去。
在体系里，活性物质仅部分地被溶解，活性物质溶解的浓度等于饱合的浓度，且在此情况下其拥有最大的热力学活性。通常，尤其是在粘着剂中游离的官能基团的种类及含量对于聚丙烯酸酯的溶解力很重要。然而，发现(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的溶解度在很大程度上与那些无关，其溶解度范围为15至35％(重量)。因此这样的体系含有溶解度至少为10％(重量)的活性物质以接近最大的热力学活性。对于(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚盐酸盐而言，于聚丙烯酸酯的溶解。度为5至10％(重量)是很低的，所以在这样的体系里，活性物质优选是部分地溶解。
因此，由于盐酸盐的亲水性，使其通过角质层障壁的情形很差，因此，必须于药贴片的基质中加入单价酸，例如油酸等亲脂物质，以便氯化氢部分转变成较具亲脂性的油酸酯，此外，油酸等亲脂物也扮演促进渗透入皮肤的功能。
有利的是，以丙烯酸酯为基础的聚合物粘着剂包含下列单体之中的至少两种：丙烯酸、丙烯酰胺、丙烯酸己酯、丙烯酸2-乙基己酯、丙烯酸羟乙酯、丙烯酸辛酯、丙烯酸丁酯、丙烯酸甲酯、丙烯酸缩水甘油酯、甲基丙烯酸、甲基丙烯酰胺、甲基丙烯酸己酯、甲基丙烯酸2-乙基己酯、甲基丙烯酸丁酯、甲基丙烯酸甲酯，甲基丙烯酸缩水甘油酯、乙酸乙烯酯或乙烯吡咯酮。
对于大部分的活性物质而言，硅氧烷粘着剂的溶解性相对而言是比较低的。(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚碱与盐酸盐，其饱和浓度分别约为5％(重量)，然而盐类是实际上不溶于此体系的。因此，只有活性物质碱适合与硅氧烷粘着剂结合。若有一个适当的物质，其可以提高活性物质的溶解度，混入硅氧烷粘着剂中，则硅氧烷粘着剂对活性物质在这样的基质中溶解成游离碱基的能力则可被提高至40％(重量)，且不会伤害基质的物理特性。这些适合的物质有亲水性聚合物或甘油或甘油衍生物(例如甘油的脂肪酸酯)，所述亲水性聚合物例如是可溶的聚乙烯吡咯酮、乙烯吡咯酮和乙酸乙烯酯的共聚合物、聚乙二醇、聚丙二醇、或乙烯及乙酸乙烯酯的共聚合物，其中聚乙烯吡咯酮被证实是相当的适合。
约1.5至5％(重量)的聚乙烯吡咯酮于一个抗胺性的硅氧烷粘着剂中，可增加(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的溶解度至约为10至15％(重量)。这足以于20平方厘米大的药贴片，每平方米50克重的基质中溶解10毫克的活性物质。由于使用经皮肤药贴片治疗时，必须假设，所使用的活性物质，于施药期间只有约为50％是可用的，因此每天使用的至40平方厘米含有约1至10毫克活性物质的药贴片才能达到有效治疗血浆的浓度。
聚乙烯吡咯酮散布于硅氧烷粘着剂中的另一个好处是，可减少已知是来自于硅氧烷粘着剂中所谓的冷流。冷流在此的意思是，基质表现的像是一个非常粘稠的液体，因此，经由流动的缘故，会趋向造成一个较大的面积。这样会造成，当使用一段时间后，基质面会比药贴片支持层的面积来得大，而且在药贴片中，基质容易和包装物质粘住。聚乙烯吡咯酮的优点已于EP0 524776中提及。
根据本发明制造的药贴片，是先将(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚或盐酸盐溶解于或悬浮于乙醇中或是其他适当的有机溶剂中，然后加入至正在搅拌中的粘着剂溶液中。若粘着剂有适当的溶剂体系，则活性物质也可以直接加入至粘着剂溶液中。额外的辅助物质也可以被加入至粘着剂溶液中、活性物质溶液中或是加入至含有粘着剂的活性物质溶液中。此辅助物质有益地被加入至活性物质溶液中，例如，一个碱性的物质适合将活性物质的盐酸盐转换成游离的活性物质碱。特别优选使用碱金属氢氧化物，如氢氧化钠或氢氧化钾，或碱金属硅酸盐，如三硅酸钠或三硅酸钾或偏硅酸钠或偏硅酸钾作为碱性物质。在反应后，可以随意决定要不要过滤此溶液，在那些反应物中，除了活性物质碱外，大部分已经作用完毕了。上述的反应物，在氢氧化钠或氢氧化钾的例子中分别使用的是氯化钠或氯化钾，而在硅酸钠或硅酸钾的例子中分别使用的是氯化钠或氯化钾及聚二氧化硅。反应后含有活性物质的粘着剂溶液将被涂抹至一个适当的膜片上，而在干燥的过程中有机溶剂会挥发掉。然后药贴片的支持层会被压制到基本上不含有溶剂的基质层上，最后药贴片通过用来完成。
渗透能力可用渗透加强剂来加强，而渗透加强剂可以选用脂肪醇、脂肪酸、脂肪酸酯、脂肪酸酰胺、甘油或其衍生物(例如甘油脂肪酸酯)、N-甲基-吡咯酮、萜烯，如苎烯、α-蒎烯、α-萜品醇、香芹酮、香芹醇、氧化苎烯、氧化蒎烯、1，8-桉叶油素。
最终药贴片的生产以及渗透速率的详细内容会在实施例以及渗透力实验中加以说明，在实施例1至3中所提及的聚丙烯酸酯粘着剂，会让人了解以及聚丙烯酸酯粘着剂可能被其他的丙烯酸酯所取代，以适合医学上的用途。
完成后的药贴片使用法拉兹扩散细胞(Franz diffusion cell)以及人类的表皮来研究其渗透力。结果列在图1。可以看到所有的药贴片都可以经由皮肤提供全身足够量的活性物质。本发明亦证明，在使用游离碱基的例子中与使用盐类的例子相比，其活性物质的释放明显被改善了。同时也可以看到，以硅氧烷粘着剂为主的药贴片，虽然其含活性物质的量较少，但其经由皮肤传送的活性物质的量，却和以聚丙烯酸酯为主的粘着剂差不多。
因此，根据本发明的体系，使用约20平方厘米大小的药贴片可经由皮肤传送每日所需的多巴胺激动剂，其结构如上所述。由于药贴片易于制造，且可经由整个基质表面传送活性物质至皮肤，且适合活性物质盐以及活性物质碱，其相较于WO 94/07468中所描述的习知的体系有相当多的改善。
实施例1：含有(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的聚丙烯酸酯体系
在乙酸乙酯中将66克、50％的Eudragit E100溶液加入至264克、含有50％固体含量的聚丙烯酸酯粘着剂的溶液中；在加入36克的油醇之后，搅拌使其均匀。
之后，将89.65克的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚溶解于200毫升的甲基乙基甲酮中，接着将其加入至上述的正在搅拌的溶液中。在搅拌均匀后，将其用适当的医生用刀涂抹至硅氧烷化的聚酯簿膜上，调整此潮湿薄膜的厚度，使其于50℃下干燥30分钟后重量为60克/平方米。
然后此干燥后的基质薄膜被覆以13μm厚的聚酯薄膜制成薄膜。再将所得到的药贴片薄片打印成希望的大小，然后用包装袋装起来。
在药贴片基质中的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚碱基的浓度是30.8％。
适合的聚丙烯酸酯粘着剂，例如有Durotak 387-2051、Durotak 387-2287、Durotak 387-2353、Durotak 387-2516，以上的产品皆来自于National Starch & Chemical公司。
于活体外实验下，其渗透人类表皮的速度如图一所示。
实施例2：含有(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的硅氧烷体系
将18克的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚溶解于40克的乙醇中，然后将其加入至24克的25％Kollidon 90F的溶液中，搅拌均匀。随后将251克、含有70％固体含量的抗胺硅氧烷粘着剂溶液加入至上述的混合溶液中，然后再次搅拌均匀。
接着用适当的医生用刀将上述的混合物涂抹至有粘性的聚酯薄膜上(Scotchpak 1022)，使其于50℃干燥下干燥30分钟，去除掉溶剂后的重量为50克/平方米。
然后此干燥后的基质薄膜被覆以13μm厚的聚酯薄膜，再将所得的药贴片冲切成所需的大小，然后用包装袋装起来。
在药贴片基质中的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚碱基的浓度是9％。
适当的抗胺硅氧烷粘着剂，例如有BIO-PSA Q7-4301及BIO-PSA Q7-4201，此二者皆来自于Dow Corning公司。
于活体外实验下，其渗透人类表皮的速度如图一所示。
实施例3：含有(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚盐酸盐的聚丙烯酸酯体系
将10克的盐酸盐加入至70克的聚丙烯酸酯粘着剂中(Durotak 387-2287，50％固体含量，National Starch & Chemical公司)，接着加入4克的油酸，将此混合物涂抹至硅氧烷化的聚酯薄膜上，去除掉溶剂后的重量为60克/平方米。溶剂将于40至80℃的温度间干燥15至20分钟后被去除。此干燥后的基质层被覆以12至30μm厚的聚酯薄膜，最后将此药贴片打印成薄膜。
实施例4：
将20克的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚盐酸盐与8.0克的偏硅酸钠或9.1克的三硅酸钠于35毫升的乙醇中于室温下一起搅拌48小时。将此活性物质溶液随意的过滤一下，加入6.0克、25％(重量)溶于乙醇中的聚乙烯，比咯酮溶液(Kollidon F90，Bayer公司)，以及25克、70％溶于庚烷中的抗胺硅氧烷粘着剂溶液(Q7-4301，Dow Corning公司)，一起加入上述的混合物中，然后以机械搅拌均匀。
为了制造药贴片基质，上述的混合物接着被涂抹至一个适当且有粘性的薄膜上，而此溶剂于50C下干燥20分钟而去除。干燥后的基质薄膜的涂层重量约为50克/平方米。
此干燥后的基质薄膜被覆以23μm厚的聚酯薄膜。每一张药贴片再冲切成最后的薄片。如果活性物质溶液有经过过滤，此药贴片最后的成份与实施例的所述相同。
实施例5：
将25克的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚盐酸盐与14.7克的偏硅酸钠或16.8克的三硅酸钠于40毫升的乙醇中于室温下一起搅拌48小时。将此活性物质溶液随意的过滤一下，然后加入92克油醇，63.2克、52％的聚丙烯酸酯粘着剂溶液(Durotak 387-2287，National Starch & Chermical公司)以及22.8克、40％(重量)Eudragit E100溶液(Rhm-Pharma公司)，接着将混合物以机械搅拌均匀。
为了制造药贴片基质，上述的混合物接着被涂抹至一个适当且有粘性的薄膜上，而此溶剂于50℃下干燥20分钟而去除。干燥后的基质簿膜的涂层重量约为80克/平方米。
此干燥后的基质簿膜被覆以23μm厚的聚酯薄膜。每一张药贴片再打印成最后的薄片。
实施例6：
将20克的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚盐酸盐，加入至含有等分子的碱基，乙醇化的氢氧化钠或氢氧化钾溶液中(2.27克的氢氧化钠，3.19克的氢氧化钾)。最好溶液的浓度为1.5摩尔/升。活性物质盐的转换于几分钟内发生，在这段时间里大部分的氯化钠会形成并沉淀。而活性物质则完全的溶解。
可随意地加入发泡剂至活性物质溶液中以去除可能过多的碱基。将此活性物质溶液随意的过滤一下；加入6.0克、25％(重量)溶于乙醇中的聚乙烯吡咯酮溶液(Kollidon F90，Bayer公司)及250克、70％溶于庚烷中的抗胺硅氧烷粘着剂溶液(Q7-4301，Dow Corning公司)，然后将此混合物以机械搅拌均匀。
为了制造药贴片基质，上述的混合物接着被涂抹至一个适当且有粘性的簿膜上，而此溶剂于50℃下干燥20分钟而去除。干燥后基质薄膜的涂层重量约为50克/平方米
此干燥后的基质簿膜被覆以23μm厚的聚酯薄膜。每一张药贴片再冲切成最后的薄片。如果活性物质溶液有经过过滤，药贴片上最后的成份与实施例2所述相同。
实施例7：
其与实施例6类似，将25克的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚盐酸盐与2.84克的氢氧化钠或3.99克的氢氧化钾在乙醇溶液中反应。如在实施例6中，随意地加入发泡剂至活性物质溶液中，再过滤，然后加入9.2克的油醇，63.2克、52％聚丙烯酸酯粘着剂溶液(Durotak 387-2287，National Starch &Chemical公司)，以及22.8克、40％(重量)Eudragit E100溶液(Rhm-Pharma公司)，然后将此混合物以机械搅拌均匀。
为了制造药贴片基质，上述的混合物接着被涂抹至一个适当且有粘性的簿膜上，而此溶剂于50℃下干燥20分钟而去除，干燥后的基质薄膜的涂层重量约为80克/平方米。
此干燥后的基质薄膜被覆以23μm厚的聚酯薄膜；再将每一张药贴片再冲切成最后的薄片。

Claims (16)

1.一种含有D2激动剂的经由皮肤治疗帕金森氏症的体系，其包含有一个不会和基质成分起化学作用的支持层，一个含有有效量的(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的自粘性基质层及一个使用前须撕除的保护箔片或膜片，其特征在于，基质是一个以丙烯酸酯或硅氧烷为基础的非水溶性聚合物粘着体系，使(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的溶解度≥5重量％；其中上述以硅氧烷为基础的聚合物粘着体系是抗胺的硅氧烷粘着剂。
2.根据权利要求1所述的经由皮肤治疗的体系，其中其含有小于0.5重量％的无机的硅酸盐微粒。
3.根据权利要求1所述的经由皮肤治疗的体系，其中其含有小于0.05重量％的无机的硅酸盐微粒。
4.根据权利要求1所述的经由皮肤治疗的体系，其中以丙烯酸酯为基础的聚合物粘着剂包含下列单体之中的至少两种：丙烯酸、丙烯酰胺、丙烯酸己酯、丙烯酸2-乙基己酯、丙烯酸羟乙酯、丙烯酸辛酯、丙烯酸丁酯、丙烯酸甲酯、丙烯酸缩水甘油酯、甲基丙烯酸、甲基丙烯酰胺、甲基丙烯酸己酯、甲基丙烯酸2-乙基己酯、甲基丙烯酸丁酯、甲基丙烯酸甲酯，甲基丙烯酸缩水甘油酯、乙酸乙烯酯或乙烯吡咯酮。
5.根据权利要求1所述的经由皮肤治疗的体系，其中以硅氧烷为基础的聚合物粘合剂包含亲水性聚合物或甘油或甘油衍生物以增加(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚的溶解度。
6.根据权利要求4或第5所述的经由皮肤治疗的体系，其中(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚在以丙烯酸酯为基础的聚合物粘着剂中的浓度为10至35重量％或在以硅氧烷为基础的聚合物粘着剂中的浓度为5至40重量％。
7.根据权利要求6所述的经由皮肤治疗的体系，其中其包含有可促进(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]氨基]-1-萘酚渗透进入人类皮肤的物质。
8.根据权利要求7所述的经由皮肤治疗的体系，其中促进渗透性的物质可选自脂肪醇、脂肪酸、脂肪酸酯、脂肪酸酰胺、甘油或甘油衍生物、N-甲基-吡咯酮、萜烯或萜烯衍生物。
9.根据权利要求8所述的经由皮肤治疗的体系，其中促进渗透性的物质是油酸或油醇。
10.根据权利要求5所述的经由皮肤治疗的体系，其中亲水性聚合物是聚乙烯吡咯酮、乙烯吡咯酮与乙酸乙烯酯的共聚合物、聚乙二醇、聚丙二醇、或乙烯与乙酸乙烯酯的共聚合物。
11.根据权利要求10所述的经由皮肤治疗的体系，其中所述亲水性聚合物是可溶性的聚乙烯吡咯酮，其以1.5至5％(重量)的浓度存在于含有活性物质的基质层中。
12.根据权利要求1所述的经由皮肤治疗的体系，其中基质含有惰性的填料以改进成分间的凝聚力。
13.一种用于制备经由皮肤治疗体系的方法，其包括下列步骤：
i)将溶于乙醇中的(-)-5，6，7，8-四氢-6-[丙基-[2-(2一噻吩基)乙基]氨基]-1-萘酚盐酸盐的悬浮液与溶于乙醇中的碱性物质相混合，以便盐酸盐转变成游离的碱基，
ii)过滤反应后产生的悬浮物，
iii)加入聚乙烯吡咯酮及粘着剂溶液，及
iv)将产物干燥。
14.根据权利要求13所述的方法，其中所述碱性物质为氢氧化钠、或氢氧化钾。
15.根据权利要求13所述的方法，其中碱所述性物质为偏硅酸钠、偏硅酸钾、三硅酸钠或三硅酸钾。
16.根据权利要求13所述的方法，其中在干燥产物前，将此混合物涂在一个惰性的支持层或保护的箔片或膜片上以产生均匀的薄膜。
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US10322093B2 (en) 2019-06-18
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