CN102526002A - 自行破坏的透皮治疗系统 - Google Patents
自行破坏的透皮治疗系统 Download PDFInfo
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Abstract
本发明涉及透皮治疗系统(TTS)，优选以透皮硬膏的形式，其含有活性物质、使该活性物质不能使用的化学剂、和媒质，该媒质在从患者的皮肤除去所述TTS时引起活性物质例如丁丙诺啡与化学剂例如高锰酸钾彼此接触并通过该接触破坏该活性物质。
Description
本分案申请是基于申请号为200780019411.3，申请日为2007年5月22日，发明名称为“自行破坏的透皮治疗系统”的原始中国专利申请的分案申请。
技术领域
本发明涉及一种在使用后自行破坏的、透皮治疗系统或也称为透皮硬膏(TTS)。本发明的TTS含有治疗活性物质，其优选由镇痛剂类构成。
背景技术
如此例如在长期治疗中具有活性物质丁丙诺啡和芬太尼的TTS是针对治疗慢性疼痛选择的药物剂型(Arzneiform)。通过透皮高活性镇痛剂的连续释放，连续地将镇痛剂供给疼痛患者，以避免血浆峰和血浆谷。
这具有这样的优点，即通过低的但是足够的所述活性物质的血浆浓度不但避免了由于过量给药的副作用，而且避免了由于给药不足的疼痛状态。例如商业产品 
还有 
或DurogesicSmat是本领域技术人员已知的，其长久以来在疼痛治疗中已证明是有效的。在疼痛治疗中TTS的缺点在于，为了在TTS的使用期间维持所谓的浓度梯度并由此维持所述活性物质的所期望的血浆水平(Plasmaspiegel)，在TTS中总是必须含有比实际释放给患者更多的活性物质。这导致的结果是，用过的(getragen)TTS对于例如毒品界(Drogenszene)的成员具有滥用可能，因为这类人群完全有能力收集使用过的TTS并用最原始的助剂提取，以便获得仍然含有的活性物质并滥用于满足毒瘾。
因此在过去从未间断尝试以阻止这种滥用，即建议患者剪碎用过 的硬膏并通过厕所冲走排入下水道。在这种方法中不利的是，无论立法者还是药物生产商都不能保证患者实际遵守这种措施。因此研发了TTS，其除了活性物质外还含有拮抗剂(例如WO 2004/098576、WO90/04965、WO 2004/037259)。经此应阻止或至少显著地增加了上述由用过的TTS获取或者提取镇痛性活性物质的难度。但是，该保护措施对于避免药物滥用被证明是不够的，因为仍然可用相对简单的手段将实际的活性物质通过分级沉淀从拮抗剂中分离。
在WO 02/094172中描述了一种用于避免滥用的计量给药系统，但是在所述系统中活性物质仍然是可活化的并不被破坏。同样在WO2005/070003中；在那里活性物质仅仅被吸收，这仍然存在从吸收剂/吸附剂的分离的可能性。最后在WO 2004/098568中也描述了一种“防滥用”的透皮计量给药系统。同样如在其余已知的这类系统中那样，在此活性物质也不被破坏，而仅仅通过拮抗剂中和其效果。
发明内容
因此，本发明的任务在于，提供一种TTS，其中在使用后可至少尽可能地避免所述的药物滥用。
通过提供一种TTS使所述任务得到了解决，优选以待贴敷到患者皮肤表面上的透皮硬膏的形式，即在使用后(即在TTS从患者的皮肤表面去除后)自动地-自行破坏。自行破坏的TTS主要意味着，将所包含的药物活性物质在使用后破坏、使其化学转化和/或使其不能使用。在此要确保的是这样的破坏过程不在TTS施用前或其施用期间启动。
本发明的主题由此是一种透皮治疗系统(TTS)，优选以透皮硬膏的形式，其至少含有治疗活性物质和物质或物质混合物(化学剂)，所述化学剂可优选通过化学反应破坏活性物质或使活性物质不能使用，其中活性物质和化学剂彼此分开地(优选空间上分开地)存在，且其中TTS至少包含一种媒质，其引起在从患者的皮肤除去所述TTS系统时活性物质与化学剂彼此接触并通过该接触破坏该活性物质或使其在其有效性方面不能使用。
所述化学剂可以为物质或物质混合物，所述物质或物质混合物还可以以固体、溶液、凝胶、分散体或其它的表现形式存在。优选所述化学剂是物质，其与所述活性物质化学地反应并经此将所述活性物质破坏，特别是化学的氧化剂例如无机试剂，如高锰酸盐，例如高锰酸钾、二氧化锰、二氧化铅、四乙酸铅、铈(IV)盐、铬酸盐、铬酸、四氧化锇、硝酸、亚硝酸盐(如亚硝酸钾)、二氧化硒、过氧化氢和其它的过氧化-化合物、溴、氯、次卤化物(Hypohalogenide)、或硫；优选高锰酸钾、过氧化氢和亚硝酸钾；有机氧化剂，如二甲亚砜、N-溴丁酰亚胺、醌、超化合价的碘化合物，过酸和过酸酯、还有酶。在给定的活性物质的情况下优选基于其与活性物质的化学反应能力选择所述化学剂。
所述活性物质优选涉及选自镇痛剂类例如麻醉剂的活性物质。优选提到的是吗啡衍生物、海洛因和丁丙诺啡，或芬太尼和其衍生物舒芬太尼和阿芬太尼。原则上所有其它的活性物质/化学剂-组合也是可使用的，只要对于该组合而言通过TTS的施用是适合的给药剂型。所述媒质，其引起在从患者的皮肤除去所述硬膏/TTS时活性物质与化学剂彼此接触和/或彼此进行化学反应，可同样以各种形式出现。必须确保的是，在每次除去TTS时，不取决于剥离方向，所述媒质均满足其功能。在此，将所述媒质调整到这样的形式，所述化学剂存在于其中(例如作为在包(Beutel)中的溶液)。优选所述媒质固定于TTS的外覆盖层内部，例如通过与覆盖层内侧的粘合。取决于化学剂的表现形式，本发明媒质的实例向本领域技术人员展示了化学剂及其在TTS中的适应形式(Unterbringungsform)的选择。
此外，用于本发明的TTS或者透皮硬膏的制备使用本领域技术人员对这样的系统已知的材料。
本发明的TTS优选具有层构造，为此在实施例中示例性地说明一种可能的变化方案。所述TTS可以基质-硬膏(Matrix-Pflaster)的形式存在，其中所述活性物质包含于由一层或多层组成的基质中，其借助粘合剂层直接平铺于皮肤上。在同样可能的构造中作为膜硬膏 (Membranpflaster)在活性物质-储层(Wirkstoff-Reservoir)和皮肤之间存在粘合性膜，其控制进入最上皮肤层(表皮)中的活性物质释放。
对于本发明的TTS的制备，本领域技术人员可由此原则上地动用由现有技术已知的TTS或者透皮硬膏的材料、制备方法和构造，其根据本发明额外地具有适宜的媒质/化学剂-组合(参见例如Transdermale Pflaster；Spektrum der Wissenschaft 10/2003，42；Transdermal Controlled Systemic Madications，Y.W.Chien，Drugsand the Pharmaceutical Sciences，Vol.31；Polymers inTransdermal Drug Delivery Systems，S.Kandavilli et.Al.，Pharmaceutical Technology，May 2002，62-80)。用于这样的医学应用的塑料的适用性的前提条件除了有利的材料性能外(例如机械强度和可加工性)外，出于卫生的原因还有其良好的可消毒性。满足这些要求的例如有聚乙烯、聚丙烯、聚氯乙烯、聚苯乙烯、聚甲基丙烯酸酯、聚酰胺和聚碳酸酯。
本发明将通过以下的实施例更详尽地得到说明而非受限于此。还可将特定的、在该实施例中描述的本发明TTS的具体实施方式单独地或以彼此组合的形式同样概括化为本发明优选的特征。
具体实施方式
实施例1
向1.14kg自交联的聚丙烯酸酯(由单体2-乙基己基丙烯酸酯、醋酸乙烯酯、丙烯酸丁酯和丙烯酸构成)在有机溶剂(乙酸乙酯、庚烷和异丙醇/甲苯)中的溶液中加入100g的乙酰丙酸、150g的油烯基油酸酯、100g聚乙烯吡咯烷酮、150g乙醇、200g乙酸乙酯和100g丁丙诺啡碱并搅拌该混合物约2小时直至均化。在均化后将该混合物涂抹到100μm的聚酯薄膜的经硅化处理侧并在烘箱中通过在60或者80℃下10分钟的干燥除去所述溶剂。在涂层中的涂抹厚度如此选择，即在除去溶剂后得到约80g/m2的单位面积重量。在除去溶剂后将由经硅化的聚酯薄膜和含活性物质的聚合物层组成的层合物(Laminat)用 吸收性材料(例如吸水纸 
或纤维网(Vlies))覆盖。随后将整个层合物剪碎成边长5×5cm的方形。将该5×5cm尺寸的经硅化的聚酯薄膜除去，并将所述由含丁丙诺啡的粘合剂层和纤维网构成的层合物以这样的方式平铺到另一个聚酯薄膜的经硅化处理侧，即使得所述聚酯薄膜全方位突出于用吸收性硬纤维网覆盖的含活性物质的粘合剂层。现在将一个由硬塑料材料制成的五角星放置到纤维网上。放置一个包到所述吸收性纤维网上，所述包用高锰酸钾溶液填充，其被这样塑形，即其在总面积上小于含活性物质的聚合物层。在不限制本发明的情况下，所述包可具有4×4cm的尺寸。在第二个加工步骤中首先制备由经硅化的纸、无活性物质的压敏层(Haftkleberschicht)和聚酯薄膜构成23μm的层合物。除去经硅化的纸并覆盖中间产物(其由硅化的聚酯薄膜、具有吸收性纤维网和星的含活性物质的聚合物层构成的方形构成，其由用高锰酸钾溶液填充的4×4cm尺寸的聚乙烯包覆盖)，并现在以这样的方式冲裁所述TTS，即使得所述无活性物质的压敏层全方位地突出于所述含活性物质的压敏层。
如果现在使用该TTS，必须首先除去经硅化的聚酯层(释放衬垫(Releaseliner))，这是容易地实现的。如果将所述TTS粘贴到患者的皮肤上，则这样使所述包(用高锰酸钾水溶液填充)保持完好。但是如果在2-7天的使用期间后将所述TTS从患者的皮肤上除去，则至少一个五角星的角由于刚性钻穿所述具有高锰酸钾溶液的包并将其强制性地破坏。通过所述星的几何形状确保所述包在每种情况下被戳破，无论在何种方向将所述TTS由患者除去。通过吸收性纤维网，高锰酸钾溶液在短时间内分布到所述TTS表面上。经此启动氧化过程，其在例如丁丙诺啡的情况下导致其氧化性破坏。即便将所述使用过的TTS在TTS-除去后直接引入提取过程，也不能阻止该破坏过程，相反，所述破坏过程由此加速，即不仅鸦片丁丙诺啡而且氧化剂高锰酸钾被引入到溶液中。经此确保的是所述活性物质不能被滥用。
在实施例中所描述的透皮硬膏由此具有如下(层-)构造(1-6)
6 具有无活性物质的压敏层的聚酯薄膜
5 塑料星
4 高锰酸钾溶液(包)
3 纤维网
2 含活性物质的压敏层
1 经硅化的聚酯薄膜(释放衬垫)
0 皮肤。
Claims (13)
1.透皮治疗系统TTS，其含有活性物质、导致该活性物质不能使用的化学剂和媒质，其中活性物质和化学剂是在空间上彼此分开的，所述媒质固定于TTS的外覆盖层内部，将所述媒质调整到这样的形式，所述化学剂作为溶液存在于包中，所述媒质还包括吸收性材料和塑料星，无论在何种方向将所述TTS从患者的皮肤除去，所述星的几何形状确保所述包在每种情况下被戳破，引起活性物质与使该活性物质不能使用的化学剂彼此接触并通过该接触破坏该活性物质。
2.根据权利要求1所述的透皮治疗系统，其特征在于，所述TTS为透皮硬膏。
3.根据权利要求1所述的透皮治疗系统，其特征在于，所述吸收性材料是吸水纸或纤维网。
4.根据权利要求1所述的透皮治疗系统，其特征在于，所述化学剂是氧化剂。
5.根据权利要求1所述的透皮治疗系统，其特征在于，所述化学剂是高锰酸钾。
6.根据权利要求1所述的透皮治疗系统，其特征在于，在从患者的皮肤除去TTS后活性物质和化学剂化学地相互反应。
7.根据权利要求2所述的透皮治疗系统，其特征在于，所述透皮硬膏具有如下构造：1)经硅化的聚酯薄膜、2)含活性物质的压敏层、3)纤维网、4)高锰酸钾溶液包、5)塑料星和6)具有无活性物质的压敏层的聚酯薄膜。
8.根据权利要求1至7任一项所述的透皮治疗系统，其特征在于，所述活性物质是镇痛剂。
9.根据权利要求1至7任一项所述的透皮治疗系统，其特征在于，所述活性物质是麻醉剂。
10.根据权利要求1至7任一项所述的透皮治疗系统，其特征在于，所述活性物质是吗啡衍生物、海洛因或丁丙诺啡。
11.根据权利要求1至7任一项所述的透皮治疗系统，其特征在于，所述活性物质是芬太尼、舒芬太尼或阿芬太尼。
12.根据权利要求1至7任一项所述的透皮治疗系统，其特征在于，所述塑料星是由硬塑料材料制成的五角星。
13.根据权利要求1至7任一项所述的透皮治疗系统，其特征在于，所述活性物质是丁丙诺啡且所述化学剂是高锰酸钾。
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| Publication number | Publication date |
|---|---|
| CN102526002B (zh) | 2014-07-02 |
| AU2007267464A1 (en) | 2007-12-06 |
| KR20090012252A (ko) | 2009-02-02 |
| JP5689943B2 (ja) | 2015-03-25 |
| WO2007137732A3 (de) | 2008-06-19 |
| EP2029122B1 (de) | 2015-04-22 |
| AU2007267464B2 (en) | 2012-07-26 |
| KR101410202B1 (ko) | 2014-06-19 |
| US8075912B2 (en) | 2011-12-13 |
| EP2907510A1 (de) | 2015-08-19 |
| DE102006025282A1 (de) | 2007-12-20 |
| BRPI0711858B1 (pt) | 2020-04-22 |
| WO2007137732A2 (de) | 2007-12-06 |
| PL2029122T3 (pl) | 2015-10-30 |
| EP2029122A2 (de) | 2009-03-04 |
| BRPI0711858A2 (pt) | 2011-12-13 |
| JP5415941B2 (ja) | 2014-02-12 |
| CA2650833C (en) | 2014-07-15 |
| ES2536507T3 (es) | 2015-05-26 |
| MX2008015276A (es) | 2008-12-12 |
| BRPI0711858B8 (pt) | 2021-05-25 |
| CA2650833A1 (en) | 2007-12-06 |
| JP2014055162A (ja) | 2014-03-27 |
| ZA200809004B (en) | 2009-10-28 |
| CN101453997A (zh) | 2009-06-10 |
| JP2009538842A (ja) | 2009-11-12 |
| US20110159076A1 (en) | 2011-06-30 |
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