CN101068589A - 经皮给予活性物质的装置 - Google Patents
经皮给予活性物质的装置 Download PDFInfo
- Publication number
- CN101068589A CN101068589A CNA2004800338811A CN200480033881A CN101068589A CN 101068589 A CN101068589 A CN 101068589A CN A2004800338811 A CNA2004800338811 A CN A2004800338811A CN 200480033881 A CN200480033881 A CN 200480033881A CN 101068589 A CN101068589 A CN 101068589A
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- Prior art keywords
- microprojection
- skin
- active substance
- aforementioned
- described device
- Prior art date
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种用于经皮给予活性物质的装置，包括背衬层和与其连接的含有活性物质的贮库，其特征在于所述装置的面向皮肤的接触面具有多个微突出物，该微突出物适于穿入皮肤并有使该突出物难于从皮肤中拔出的结构。
Description
技术领域
本发明涉及能经皮给予活性物质的装置。本发明进一步涉及这种经皮给予活性物质或助剂的装置的用途。
背景技术
经皮治疗系统目前已被广泛用作治疗各种疾病的给药剂型。用这项技术，特别是活性物质尼古丁、硝酸甘油、东莨菪碱和雌二醇，而且许多更新的活性物质可以以控制的和暂时延长的方式发挥作用。当使用这种给药剂型时，对于大量活性物质，可以很大程度地抑制口服给药的情况下经常出现的生理首过效应，在这一点上该给药剂型具有特别的优势。这最终使更大量的活性物质能够到达其作用部位。
通常，经皮治疗系统(TTS)以以下方式构成，它们包括压敏粘合活性物质贮库或在任何情况下存在至少一种压敏胶层，以用于将该系统粘附到皮肤上。该系统和皮肤之间的粘合键是由所用的聚合物的自粘特性或由聚合物和助剂的适当的混合物产生的。
但是，只由表面张力现象造成的压敏胶在皮肤上的粘附不总是牢固的。由于这个原因，经常观察到关于TTS的粘附问题。不充分的粘附主要影响最长应用周期；通常，这种系统在皮肤上的可用性被限制到最长约7天。
用TTS释放活性物质通常通过活性物质经TTS的含聚合物层和软塑料层的扩散实现，在这种情况下，活性物质通过TTS的皮肤接触侧到达皮肤的表面。接下来，活性物质分子最初通过最外面的皮肤层(角质层)扩散，然后到达表皮较深的地方，在那里它们转移进入血液循环。
但是，只对于非常少量的活性物质，前述的活性物质的扩散转运才会以足以达到治疗目的速度发生。这主要是由角质层的天然屏障作用引起的。这种屏障作用使高分子活性物质(如肽、蛋白质、寡核苷酸和多核苷酸)或强极性活性物质的经皮给药显著地更加困难，或不可能。
所以，已有很多通过采用适当的方法克服角质层的屏障性质的尝试。例如，这可以通过采用化学渗透促进剂(如乙醇或其它醇)，电压差(如离子导入技术)，或甚至通过机械改性角质层而实现。为此，根据US 6 334 856，可以使用具有在一范围内布置的多个空心微针的装置。这些针确实具有非常尖的外形，但它们只穿入皮肤几百微米深。尽管这能够实现含有活性物质的液体的给药同时避免角质层的屏障性质，但是在很多情况下其不能提供液体形式的活性物质。其原因可能是，例如活性物质溶解度不够或活性物质溶液的稳定性不够。此外，由于可通过这些微针施用的液体体积很小，所以可施用的活性物质的量非常小(在几微克的范围内)。
US 6 083 196中描述了与US 6 334 856中所描述的装置非常相似的装置。该装置包括在其上排列有多个可以用于穿透皮肤的微突出物的载体膜。由于这种装置不能粘附到皮肤上，所以通过另外存在的固定装置(如以附加片的形式)的方式将该装置固定到皮肤上。
发明内容
所以，本发明的目的是提供一种经皮给予活性物质的装置，该装置特别适于给予高分子或强极性活性物质，并且其消除或减少了现有技术的上述缺点。更具体而言，本发明因此能够经皮给予不是以液体形式存在的活性物质，而且即使没有额外的自粘方式也能使该装置粘附到皮肤上。
通过根据权利要求1的装置令人惊奇地达到了这个目的，该装置与所述权利要求的前序部分一致，具有经皮治疗系统的一般特征，并且其中面向皮肤的接触表面具有多个适于穿入皮肤的钉形或针形微突出物。这些微突出物具有能使该突出物更难于从皮肤中拔出的结构。
因此根据本发明的装置的微突出物的特征在于，将该微突出物插入皮肤所需的力小于后来从皮肤拔出所需的力。
由于微突出物穿透皮肤，克服了角质层的屏障，并且贮库中所含的活性物质从贮库扩散到所述装置的皮肤接触侧后，通过避开所述屏障而能够达到表皮较深的地方。根据本发明的系统使活性物质能够应用到较深的皮肤层，即那些位于角质层的屏障层之下的皮肤层。
由于上述使微突出物更难于从皮肤中拔出的结构，可以在皮肤上的应用部位固定所述装置，而无需另外的手段来达到这种固定。尽管与粘合键相似，但这是一种基于机械固着的固定。
为了促进穿入皮肤，该微突出物优选指向其末端(即面向皮肤)。它们优选为针形结构且向其末端逐渐变细。如果微突出物的横截面或直径适当小，则即使微突出物不是尖的或逐渐变细的，穿透皮肤也是可能的。微突出物具有基本的圆形、椭圆形、三角形、四边形或多边形、或不规则的横截面。由于非常窄的横截面，用近似具有锯条或锯齿边缘形状的微突出物不可能实现在皮肤上充分的固定，所以应该避免。
微突出物的厚度优选在5～100μm的范围内，特别优选在10～50μm的范围内。对于针形突出物而言，在尖端处的厚度优选为1～10μm，且相对的一端厚度优选为5～100μm。
微突出物的适当长度取决于所述装置的整个厚度、特别是活性物质贮库的厚度，也取决于所需的穿透深度。微突出物的长度优选在50～500μm范围内，特别优选在100～300μm范围内。关于此点，另外优选微突出物从装置的面向皮肤的表面(例如，聚合物基层)突出不到300μm，特别是不到200μm。
上述能使得更难于从皮肤拔出并用于固定装置的结构被布置在突出物的外周线。在个别突出物上也可以存在多个(两个或多个)固定结构，并且它们可以沿着其整个长度分布。但是，至少从装置的皮肤接触侧的表面突出的突出物的区域具有这种结构。
可以通过给微突出物的纵向周线提供底切(undercuts)来实现所述固定结构。特别优选这些结构的外形为阻碍从皮肤拔出的倒钩形。各个微突出物可以具有一个，或优选具有多个这样的倒钩。
根据本发明进一步的实施方案，微突出物或至少其中一部分数量的微突出物以螺旋形状形成并且被旋转布置。通过采用旋转移动，从而可以促进穿入皮肤并且实现在皮肤上的固定。该旋转驱动可以例如以微机械手段、特别以微机械致动器(micromechanical actuator)提供。
通常，所述装置的所有微突出物基本具有相同的形状；然而，本发明也包括其中存在两组或多组不同形状的微突出物的该装置的实施方案。
微突出物的数量优选为1～103/mm2，特别优选10～100/mm2。微突出物与背衬层固定连接，或/和它们被插入和固定于所述装置的含有活性物质的贮库中，该贮库优选为聚合物基质的形式。作为可选择的办法，微突出物可以布置在活性物质渗透膜或层压到活性物质贮库面向皮肤的表面的薄膜上面或里面，从而最好使微突出物的尖端指向外侧，即面向皮肤。所述的膜或薄膜还可以具有压敏粘合特性。
特别地，如果微突出物固定在作为背衬层的半刚性支撑膜上，则具有如下另外的优点，在自发皮肤运动的情况下，由于皮肤的相对运动通过背衬层或支撑膜传递到微突出物，所以引起根据倒钩原理制成的微突出物更深地穿入皮肤。
根据进一步的实施方案，具有倒钩状结构的微突出物还可以具有在面向皮肤一端具有开口的空心针的形式的内部空腔或管道。该空腔或管道与填充液体的贮库相连，空心针被浸入该贮库中或被插入其中。
作为可选择的方法，微突出物还可以由能够使活性物质从贮库通过微突出物扩散到皮肤中的可扩散的材料制成，因此与在空心针的情况下相同，在这种情况下也可以使活性物质直接释放到皮肤中。
微突出物可以由对本领域的技术人员公知的生物相容性和皮肤友好的材料制成，特别是塑料和金属。合适的单独或结合的塑料材料的例子包括：丙烯腈-苯乙烯共聚物、聚甲基丙烯酸甲酯、PVC、聚四氟乙烯、聚酰胺、聚氨酯和聚苯乙烯。合适的金属材料的例子包括：不锈钢、钛和钛合金、铝和铝合金、钴、铬和钼的合金。微突出物可以以对本领域的技术人员公知的方式通过注模法、压模法、加热成型、深冲压、挤压、蚀刻技术等制成。
然而，本发明也包括其中活性物质释放不直接由微突出物实现，而由活性物质贮库面向皮肤的表面实现的实施方案。在这种情况下，微突出物的作用限于穿透皮肤屏障和将装置固定在皮肤上。
根据另一实施方案，所述装置在皮肤侧上具有粘性聚合物基质，其优选与微突出物的平面同延布置。这种方法使装置能够在皮肤上更牢固地固定。在这种情况下，微突出物优选从聚合物基质层的平面突出平均小于300μm，特别优选小于200μm。该粘性聚合物基质可以同时构成活性物质贮库并且包含一种或多种活性物质，任选与一种或多种助剂结合。作为可选择的方法，粘性聚合物基质可以不含有活性物质，活性物质存在于一个或多个另外的层中。
适合作为用于制备所述的聚合物基质、含有活性物质的贮库或压敏胶层的原料具体为以下单独或结合使用的聚合物：聚(甲基)丙烯酸酯、聚异丁烯、多萜、乙烯-乙酸乙烯酯共聚物、合成橡胶、苯乙烯-异戊二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯-苯乙烯嵌段共聚物、热融粘合剂、橡胶与树脂的混合物、硅氧烷压敏胶、聚乙酸乙烯酯、聚乙烯吡咯烷酮、聚乙烯醇、聚乙二醇、纤维素衍生物(如羟丙基甲基纤维素)。基于上述聚合物的压敏胶组成原则上对本领域的技术人员是公知的。聚合物基质，各个活性物质贮库，可以进一步包含一种或多种已知的助剂，特别选自软化剂、乳化剂、渗透促进剂、增稠剂、增溶剂、稳定剂、填充剂和载体物质的组。
所述的聚合物基质优选具有10～90wt％的聚合物含量，特别优选30～70wt％；助剂的含量优选在0.1～30wt％之间，特别优选在1～10wt％之间。活性物质含量优选在0.1～20wt％的范围内，特别优选在0.5～10wt％的范围内。微突出物的重量百分比在计算中没有考虑。
最为适合作为背衬层或支撑层的是具有特别高强度特征的聚酯膜，例如聚对苯二甲酸乙二醇酯和聚对苯二甲酸丁二醇酯；和另外其它皮肤友好的塑料材料，例如，聚氯乙稀、乙烯乙酸乙烯酯、乙酸乙烯酯、聚乙烯、聚丙烯和纤维素衍生物。
根据本发明的装置面向皮肤的表面优选覆盖有可剥离的保护膜，其可在使用前被剥下。与用于背衬层相同的材料可以用于可剥离保护膜，条件是该层经过适当的表面处理，例如硅化或氟硅化。但是同样也可以使用其它可剥离的保护层，例如聚四氟乙烯处理的纸、玻璃纸、聚氯乙稀等。
根据本发明的装置方便地适于经皮给予用于人或动物的治疗性或预防性处理，也包括用于免疫目的的药学活性物质或疫苗。它们特别适于有效口服剂量(人)小于10mg/天的较高分子或强极性活性物质的给药。
根据本发明的装置特征在于，一方面安全并长时间地粘附到皮肤上；另一方面它们能够经皮给予用别的办法不适于经皮给予的活性物质。
因此这些装置优选包含一种或多种选自肽(特别是肽类激素，例如胰岛素、缩宫素、加压素，生长因子，免疫调节剂、抗生素)、蛋白质(例如酶、干扰素、白细胞介素、抗体)、高活性遗传设计的活性物质、寡核苷酸(如反义寡核苷酸)和多核苷酸(质粒)的组的活性物质，或/和它们包含一种或多种活性疫苗，优选自包括活性细菌、灭活细菌、毒性减弱或遗传改性病毒、灭活病毒、细菌类毒素(bacterial toxoid)、蛋白质、糖蛋白、遗传设计的抗原、及寡核苷酸和多核苷酸的组。
此外，根据本发明的装置还可以用于给予其它药学活性物质。适于这种情况的活性物质特别为选自下面组的那些活性物质：降低或调节血压的物质、作用于心脏的物质(特别是β-阻滞剂和抗心率不齐药物)、止痛剂、类固醇激素、麻醉剂、食欲抑制剂、抗过敏药、抗组胺药、抗动脉硬化活性物质、抗关节炎药/抗风湿药、抗生素、抗胆碱能药、抗惊厥药、抗抑郁药、抗糖尿病剂、止泻药、抗利尿剂、抗雌激素药、抗真菌药/杀真菌活性药、抗真菌活性剂、降脂药、激素、非甾体抗炎药、抗偏头痛药、抗恶心药、抗肿瘤药、抗帕金森药、抗精神病药、解痉药/抗痉挛药、抗血栓药、抗病毒剂、抗焦虑剂、支气管扩张剂、钙通道阻滞剂、胆碱能药物、胆碱酯酶抑制剂、CNS兴奋剂、多巴胺受体激动剂、免疫调节剂、免疫抑制剂、离子交换树脂、单胺氧化酶抑制剂、镇静药/安眠药、溶血栓药、血管扩张药、维生素。
具体实施方式
现在将参照图1～3的示意说明解释本发明。这里说明的实施方案只是作为实施例。
图1和2各显示根据本发明的用于经皮给予活性物质的装置1的纵剖面，该装置处于用于皮肤7的状态。8指插入脂质基质的角状头(corneocytes)。
图1显示具有背衬层或支撑膜2和含有活性物质的聚合物基质3的装置1。在该基质中有多个微突出物4，显示了其中的两个。
微突出物4在它们基本为圆柱形针杆的末端具有穿入皮肤7的尖端6。微突出物4的另一端与背衬层2相连，以使微突出物4与背衬层2的平面近似垂直排列。
微突出物具有倒钩形固定结构5。微突出物的横截面为圆形，固定结构5的横截面也一样。
图2显示图1中描述的装置的修改，其中微突出物4的固定结构5具有螺旋形状。微突出物通过微机械驱动装置(未显示)被旋转式地引导并被旋转。其它的附图标记与图1具有相同的含义。
图3显示(剖面)可以作为驱动装置用于根据本发明的装置中，如根据图2的装置中的微机械致动器。
当微齿条10沿着箭头的一个方向移动时，微齿轮11被驱动。如图2中所示，齿轮的轮轴12可以在它的末端(面向皮肤)区域具有螺旋固定结构。
通过使用多个齿条10和齿轮11，可以实现多个螺旋微突出物4，5的单向驱动。在这种情况下，进一步可以通过相应的一个齿条10同时驱动两个或多个齿轮11。
Claims (17)
1、用于经皮给予活性物质的装置，具有背衬层和与其连接的含有活性物质的贮库，其特征在于该装置面向皮肤的接触面具有多个微突出物，该微突出物适于穿入皮肤并具有使该突出物较难于从皮肤中拔出的结构。
2、根据权利要求1所述的装置，特征在于将该微突出物插入皮肤所需的力小于后来从皮肤中拔出所需的力。
3、根据权利要求1或2所述的装置，其特征在于微突出物为针形。
4、根据权利要求1～3的任一项所述的装置，其特征在于该装置包括多个纵向周线具有一个或多个底切的微突出物，从而形成所述的结构。
5、根据权利要求1～3的任一项所述的装置，其特征在于该装置具有多个其中所述的结构形成为倒钩的微突出物，所述的微突出物各具有一个或多个这种倒钩。
6、根据权利要求1～3的任一项所述的装置，其特征在于该装置具有多个微突出物，该多个微突出物被螺旋成形并可旋转地布置，从而在采用旋转移动时，便于穿入皮肤并实现在皮肤中的固定。
7、根据权利要求6所述的装置，其特征在于旋转驱动通过微机械致动器实现。
8、根据前述权利要求的任一项所述的装置，其特征在于微突出物，或至少几个微突出物，固定在含有活性物质的贮库中。
9、根据前述权利要求的任一项所述的装置，其特征在于微突出物，或至少几个微突出物，与背衬层相连。
10、根据前述权利要求的任一项所述的装置，其特征在于微突出物，或至少几个微突出物，形成为空心针。
11、根据前述权利要求的任一项所述的装置，其特征在于在该装置皮肤侧上具有粘性聚合物基质，该粘性聚合物基质优选被布置为与微突出物的平面范围相同。
12、根据权利要求11所述的装置，其特征在于微突出物从聚合物基质层的平面突出平均不到300μm。
13、根据权利要求11或12所述的装置，其特征在于所述的粘性聚合物基质同时构成活性物质贮库并包含一种或多种活性物质，任选与一种或多种助剂组合。
14、根据前述权利要求的任一项所述的装置，其特征在于该装置包含选自肽、蛋白质、寡核苷酸和多核苷酸的组的一种或多种活性物质。
15、根据前述权利要求的任一项所述的装置，其特征在于该装置包含优选选自包括细菌、病毒、细菌类毒素、寡核苷酸和多核苷酸、及遗传工程抗原的组的一种或多种疫苗。
16、根据前述权利要求的任一项所述的装置用于经皮给予人或动物体活性物质或疫苗的用途。
17、根据权利要求16所述的用途，其特征在于活性物质或疫苗选自包括肽、蛋白质、寡核苷酸、多核苷酸、细菌、病毒、灭活病毒、细菌类毒素、寡核苷酸和多核苷酸、及遗传工程抗原的组。
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| DE10353629A DE10353629A1 (de) | 2003-11-17 | 2003-11-17 | Vorrichtung zur transdermalen Verabreichung von Wirkstoffen |
| DE10353629.9 | 2003-11-17 | ||
| PCT/EP2004/012458 WO2005049128A1 (de) | 2003-11-17 | 2004-11-04 | Vorrichtung zur transdermalen verabreichung von wirkstoffen |
Publications (2)
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| CN101068589A true CN101068589A (zh) | 2007-11-07 |
| CN101068589B CN101068589B (zh) | 2010-05-12 |
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| EP (1) | EP1684846B1 (zh) |
| JP (1) | JP4763612B2 (zh) |
| CN (1) | CN101068589B (zh) |
| AT (1) | ATE389432T1 (zh) |
| CA (1) | CA2546688C (zh) |
| DE (2) | DE10353629A1 (zh) |
| ES (1) | ES2304628T3 (zh) |
| PL (1) | PL1684846T3 (zh) |
| PT (1) | PT1684846E (zh) |
| WO (1) | WO2005049128A1 (zh) |
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| CN103203072A (zh) * | 2013-03-25 | 2013-07-17 | 清华大学 | 金属微针阵列柔性贴片、经皮给药器件及经皮给药贴片 |
| CN105727438A (zh) * | 2016-04-18 | 2016-07-06 | 朱志飞 | 螺旋微针祛皱装置及祛皱方法 |
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| AU2015271878B2 (en) * | 2010-04-28 | 2017-05-11 | Sorrento Therapeutics, Inc. | Device for delivery of rheumatoid arthritis medication |
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| CN104039382B (zh) | 2011-10-27 | 2018-01-12 | 金伯利-克拉克环球有限公司 | 高粘度生物活性剂的经皮递送 |
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| DE102017117784A1 (de) | 2017-08-04 | 2019-02-07 | Lts Lohmann Therapie-Systeme Ag | Applikatorsystem enthaltend ein Mikronadelarray aufweisend einen Wirkstoff für die Wundheilung |
| DE102017118419A1 (de) | 2017-08-11 | 2019-02-14 | Lts Lohmann Therapie-Systeme Ag | Mikronadelarray aufweisend einen Farbumschlag-Indikator |
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2003
- 2003-11-17 DE DE10353629A patent/DE10353629A1/de not_active Withdrawn
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2004
- 2004-11-04 JP JP2006538740A patent/JP4763612B2/ja not_active Expired - Fee Related
- 2004-11-04 WO PCT/EP2004/012458 patent/WO2005049128A1/de active IP Right Grant
- 2004-11-04 PT PT04797585T patent/PT1684846E/pt unknown
- 2004-11-04 EP EP04797585A patent/EP1684846B1/de not_active Not-in-force
- 2004-11-04 PL PL04797585T patent/PL1684846T3/pl unknown
- 2004-11-04 CN CN2004800338811A patent/CN101068589B/zh not_active Expired - Fee Related
- 2004-11-04 ES ES04797585T patent/ES2304628T3/es active Active
- 2004-11-04 CA CA2546688A patent/CA2546688C/en active Active
- 2004-11-04 AT AT04797585T patent/ATE389432T1/de not_active IP Right Cessation
- 2004-11-04 DE DE502004006613T patent/DE502004006613D1/de active Active
- 2004-11-04 US US10/579,809 patent/US20070081977A1/en not_active Abandoned
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103203072A (zh) * | 2013-03-25 | 2013-07-17 | 清华大学 | 金属微针阵列柔性贴片、经皮给药器件及经皮给药贴片 |
| CN103203072B (zh) * | 2013-03-25 | 2015-05-20 | 清华大学 | 金属微针阵列柔性贴片、经皮给药器件及经皮给药贴片 |
| CN105727438A (zh) * | 2016-04-18 | 2016-07-06 | 朱志飞 | 螺旋微针祛皱装置及祛皱方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2007520258A (ja) | 2007-07-26 |
| ES2304628T3 (es) | 2008-10-16 |
| WO2005049128A1 (de) | 2005-06-02 |
| DE10353629A1 (de) | 2005-06-16 |
| CA2546688C (en) | 2012-03-13 |
| DE502004006613D1 (de) | 2008-04-30 |
| US20070081977A1 (en) | 2007-04-12 |
| PL1684846T3 (pl) | 2008-08-29 |
| CA2546688A1 (en) | 2005-06-02 |
| EP1684846A1 (de) | 2006-08-02 |
| CN101068589B (zh) | 2010-05-12 |
| PT1684846E (pt) | 2008-06-25 |
| JP4763612B2 (ja) | 2011-08-31 |
| EP1684846B1 (de) | 2008-03-19 |
| ATE389432T1 (de) | 2008-04-15 |
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