CN1206004C - 增强透皮物剂流量的装置 - Google Patents

增强透皮物剂流量的装置 Download PDF

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CN1206004C
CN1206004C CNB988119889A CN98811988A CN1206004C CN 1206004 C CN1206004 C CN 1206004C CN B988119889 A CNB988119889 A CN B988119889A CN 98811988 A CN98811988 A CN 98811988A CN 1206004 C CN1206004 C CN 1206004C
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CN1281375A (zh
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J·C·特劳特曼
黄锡礼
P·E·达多耶
H·L·基姆
M·G·朱克
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Alza Corp
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Abstract

一种装置(3)，它包括片件(6)和刚硬的支承件(15)，该片件(6)具有多个微突(4)，被用于穿剌皮肤；刚硬的支承件(15)与片件(6)接触，并延伸于整个片件(6)的宽度，用于将施加的力均匀地传递于整个片件(6)的长和宽，使微突(4)能重现地和准确地穿剌皮肤。

Description

增强透皮物剂流量的装置
技术领域
本发明涉及透皮物剂传递和采样。更具体的是，本发明涉及诸如肽和蛋白质的物剂经皮肤透皮传递，以及从机体透皮采样得到物剂，如葡萄糖，其它的机体分析物和一些滥用的物质如酒精和违禁药品。
技术背景
随着越来越多的医用肽和蛋白质能以量大、纯度高的形式为人所得，人们对透皮传递诸如肽和蛋白质的高分子量有利的物剂进入人体的兴趣不断上升。但肽和蛋白质的透皮传递仍面临着一些重大的问题。在许多场合下，这类物剂通过皮肤的传递速率或流量不足以产生理想的治疗效果，因为它们大体积/大分子量，导致不能由自然通途(孔，毛囊等)穿越皮肤。另外，多肽和蛋白质在穿越皮肤过程中，在到达靶细胞之前容易被降解。同样，水溶性小分子如盐的被动流动受到限制。
提高物剂透皮传递的一种方法基于电流通过体表的应用或称为“电转运”。“电转运”通常指有益的物剂，如物剂或物剂前体的通过诸如皮肤、粘膜、指甲等的体表。施加一个电位能诱导或增强物剂的转运，其导致施加电流来传递或增强物剂的传递。可以多种方式完成电转运物剂通过体表，一种广泛使用的电转运方式，离子电渗疗法，它涉及电诱导带电荷离子的转运。电渗透是另一种电转运方式，它涉及在电场的影响下带有物剂的溶液通过膜的迁移。还有一种电转运类型是电穿孔(Electroporation)，它涉及物剂通过由高电压电脉冲在膜上形成的孔。多个例子中，可能多种方式以不同的程度同时发生。因此，本文中所述术语“电转运”给予可能的最广泛的解释，包括电诱导的或增强的至少一种带电或不带电荷的物剂或其混合物的转运，不管实际上转运物剂的特殊机制如何。这与被动的或无电相助的穿越皮肤传递有关，电转运递送通常能提高物剂的传递，尤其是大分子量的物剂(例如多肽)的传递速率。然而，在穿越皮肤过程中进一步提高穿越皮肤传递速率和减少多肽降解是非常令人想望的。
提高物剂穿越皮肤传递速率的一种方法包括用一种皮肤渗透增强剂预处理皮肤或协同有益的物剂传递。本文广泛应用的术语“渗透增强剂”，描述当应用于传递物剂的体表时能提高物剂流量的物质。其机制可能包括减少体表对物剂通过的电阻，提高体表的选择通透性和/或渗透性，产生通过体表的亲水途径和/或电转运期间减少物剂的降解(例如皮肤酶参与的降解)。
已作多个努力企图机械破坏皮肤以增强穿越皮肤的流量，如授予Ganderton等的美国专利3814097，授予Gross等的5279544，授予Lee等的5250023，授予Gerstel等的3964482，授予Kravitz等的美国专利Re 25637和PCT申请WO 96/37155。尽管Gerstel揭示了其它形状的应用，但这些典型的装置通常利用管状或圆柱形结构穿剌皮肤的外层。这些参考文献中揭示的穿剌元件一般从薄的平面元件如垫片或金属薄片垂直伸展。该平面元件的柔韧性和穿剌元件的管状导致多个缺点。例如制造困难，当在该装置的顶端施压时该平面元件会弯曲，不能均匀地穿过皮肤，穿剌皮肤较差而导致电转运的透皮流量低，由于物剂集中流过少数通道而增加了剌激。
皮肤穿刺元件业已常用于免疫领域。例如，美国专利3,072,122(Rosenthal)揭示了将标准规格的金属薄片压成接种尖端。这些尖端的长度为1-4毫米，其长度足以引起流血。金属片装在塑料手柄上，它很刚硬，足以能将尖端压入病人的皮肤。这些尖端一般用干燥的抗原性物质涂覆来进行接种。
发明的叙述
本发明提供了适用于提高穿越皮肤流量的一种装置。该装置具有多个微突，这些微突均一并可靠地剌入体表(如皮肤)从而增强物剂的传递或采样。本发明的装置易大批生产，从而降低了成本。本装置能通过多个微突穿剌皮肤的角质层而形成管道，通过这些通道能输入(即传递)物质，例如物剂，或能提取(即采样)物质，例如机体分析物。本发明的主要优点是该装置通过其多个微突保证了均一的穿剌(即产生相同大小和深度的通道)。而且，本发明可重现地使不同病人被均一的穿剌。
一方面，本发明由刚硬的结构组成，该刚硬结构连接并延伸于整个有多个微突供穿刺皮肤的柔性的装置。这种刚硬结构把施加于结构顶端的力基本上均匀地传送到整个柔韧性装置上，由此产生微突的均匀移位。要达到这一目的就得使力加到带微突的易弯曲的该装置的能变形元件上时大大减少扩散。这刚硬的结构提供了确切可信的传递，把外加负荷传递给微突以便较容易地、完全和可重复地进行皮肤穿剌。用微突改善对皮肤的穿剌，因为这种坚固的结构特别有利于提高流量。这些微突的均匀分布的位移使所有的微突近乎全部剌入，结果产生相当数目的物剂通道和与皮肤的电连接(假如用电转运)，以便物剂不断地和可重复地流过皮肤。
在本发明的这一个方面，该柔性的皮肤穿剌装置由相当薄的柔韧薄片组成，在使用中这块薄片适合于与被穿剌的体表基本平行地放置。薄片上具有多个开口，这些开口允许物剂在与这薄片相连的贮器(一般位于这薄片的远体表面)和通过微突剌入体表产生的孔之间通过。薄片也有多个微突(也被称之为微刃)从这薄片的近体表面几乎垂直地延伸出来。在本发明的这个方面，坚固的支承件结构连接并在整个薄片上延伸是为了增加结构的刚性和更均匀地分布力量于装置上，以达到更一致地迫使微突进入(即穿剌)体表。可任意选择地，虽然最好是该坚固的结构为物剂贮器形成一个空穴，该贮器能充满所包含/采样的物剂。
该发明的第二方面，柔性的皮肤穿剌装置由相当薄的柔韧薄片组成，该薄片具有一定空穴或空间的结构可容纳包含物剂或所收集物剂的贮器。使用中，与被穿剌的体表甚至垂直地安置薄片，如此能使薄片有一边接触体表，在该边具有从其延伸的多个微突。本发明的这一方面，刚硬的支承件结构连接和延伸越过整个薄片的远机体边缘，以便在那里增添结构上的刚性和更均匀地分布所加的力于装置上，以达到更一致地迫使这些微突进入(即穿剌)体表。
本发明的装置能用于物剂传递，物剂采样或两者兼用。尤其，本发明的装置能用于穿越皮肤的物剂传递，穿越皮肤的分析物采样或两者兼用。本发明使用的传递装置包含(但不限于)电转运装置，被动装置，渗透装置和加压驱动装置。本发明使用的采样装置包括(但不限于)反向电转运装置，被动装置，负压驱动装置和渗透装置。
本发明的这套装置能被重复使用，以保持体表的微伤口/微裂缝。这些微突产生的微伤口/微裂缝，在通过皮肤传递或采样的长时间内开放。病人或医疗技师都能很容易地做到这点，他们可定期地重复加压于该装置的远皮肤侧，使微突穿剌皮肤的角质层，克服由于机体的自然愈合过程导致的最初切口可能的封闭。
附图简述
在图中，相同的标号表示相同的构件
图1是沿图2中1-1线得到刚硬的支承件和皮肤穿剌元件的放大剖面图；
图2是图1中刚硬的支承件的顶视图；
图3是根据本发明的皮肤穿剌装置底部的一个实施方案的放大透视图，透明的联系介质从其流出；
图4，6和7是刚硬的支承件的其它实施方案的顶视图；
图5是刚硬的支承件和皮肤穿剌部件的另外的实施方案的分解透视图；
图8是依照本发明的支承件和皮肤穿剌部件另一种实施方案的侧面图；
图9是本发明的支承件的另一种实施方案的顶视图；
图10是本发明支承件的又一种实施方案的透视分解图；
图11是本发明支承件的另一种实施方案的截面透视分解图；
图12是依照本发明另一个实施方案，带有支承件的手持装置的透视图；
图13是依照本发明的一种实施方案的电转运物剂传递/采样系统的透视分解图；
图14是图13的电转运物剂传递/采样系统的底视图；
图15是图13的电转运物剂传递/采样系统的右视图；
图16是图13的电转运物剂传递/采样系统的后视图；
图17是图15的装配好的电转运物剂传递/采样系统沿线17-17的剖面图；
图18是依照本发明一种实施方案的被动物剂传递/采样系统的剖面图。
实行本发明的方法
现在回头详细说明这些附图，在图1中显示的本发明的装置2包括皮肤穿剌片件6和支承件15。使用装置2，能增强物剂的穿越皮肤传递或采样。本案中的术语“物质”、“物剂”和“药物”可互换使用，广泛地包括人类和灵长类等哺乳动物，鸟类，有价值的家养，运动场或农场动物，或供实验用的动物，诸如大小白鼠、豚鼠等产生局部或全身效应的生理或药理活性物质。这些术语也包括象葡萄糖这样的物质，在组织中，间质液和/或血液中发现的其它分析物质，乙醇，合法的物质和违禁的物剂等，这些物质能够通过皮肤采样。
物剂穿越皮肤流动(例如传递物剂和采样分析)的主要屏障是最外层(即角质层)。表皮内层一般包含二层，通常称为颗粒层、表皮生发层和生发层。要通过颗粒层、表皮生发层和生发层转运或吸收一种物剂，应基本上没有或者没有阻力。装置2包括刚硬的支承件15和柔软的片件6(见图3，图中的装置2为显示其微突而处倒置位置)，它具有多个向外延伸的微突4。装置2被压到皮肤的一个区域，通过这里物剂被透皮传递或采样。微突4在皮肤上形成裂缝并至少能穿过角质层，这样，物剂很少有阻碍或没有阻碍地通过皮肤而被传递。典型情况下，微突穿剌皮肤可深达500μm深度，一般也可达50至300μm。为了穿剌皮肤或体表，微突4可以是微刀片状(图1和3)、针状(未显示)或其它各种形状。当用压力加到支承件15的顶部时，微突4穿剌表皮的角质层，以增加物剂通过体表给药或采样。本案中所用的术语“体表”通常指人或动物的皮肤、粘膜和指甲，和植物的外表面。微突4穿剌体表使物剂从系统很好地传导进入体表，反之亦然。
在图1-3中所显示的实施方案中，片件6与多个开口8构成一体，每个开口8至少有一个微突4沿着其边缘。微突4在角质层中割开一个微小裂缝，从而增加了从由多个空穴7容纳的物剂贮器27透皮释放的物剂，或收集在由多个空穴7容纳的收集贮器27里物剂的透皮流量。
片件6可以由金属、硅或塑料构成，以金属如不锈钢和钛为佳。由于片件6相当的薄，因而是柔软的和易弯曲的，例如当片件6由金属如不锈钢或钛构成，它将只有大约5μm至10μm厚度，一般大约为25-50μm。
依照本发明，比片件6更坚硬的刚硬结构的支承件15被安置在整个片件6上(图1和2)。当装置2被用于体表，并施加下压力(即直接朝体表穿剌)引起微突4穿剌体表时，支承件15防止片件6变形或弯曲。支承件15应当足够刚硬，使在手工用手指或手把装置2对着皮肤压下时，其下垂低于300μm，低于50μm为更佳。支承件15可以是各种不同形状，例如，但不限于，图1，2，4-8和13中所显示的实施方案。在图1和2中显示的实施方案中，支承件15是刚硬的结构，它形成了延伸跨越整个支承件的厚度的多个空穴7，空穴7共同容纳贮器27(图1)供被释放的物剂或被采集来的物剂放置。在空穴7之间是多个支承件或横梁5，它们与整个片件6连接并沿整个片件6的长或宽延伸。横梁5将加于装置3顶部的力均匀地传递到整个片件6，因而每个微突4移位(进入皮肤)的距离相同。当使用透皮电转运装置时，片件6和/或支承件15被最佳的惊人地与电转运装置的电极分开或者被绝缘，这是为了避免物剂贮器短路。这可以用非导电材料，电绝缘材料或在片件6和/或支承件15上加涂层而达到目的。
更可取的是支承件15也有低的可压缩性，在手指或手把装置对着皮肤加压的过程中，最理想的支承件15被压缩的距离少于200μm，更好的是少于50μm。最好是在用手指或手把装置压向皮肤的过程中，支承件15显示的可压缩性低于约250μm并兼有柔性。
支承件15可以用具有前述高度刚性的任何材料制成，优选的是还有前面提到的压缩性低。合适的材料包括金属、合金、陶瓷、玻璃、刚性塑料和加强材料(例如碳纤维强化材料)。
图2和图4-13说明了各种实施方案的支承件。在图2，4-7和13中所显示的实施方案，支承件15被边缘的(例如环状的)围壁53构成，它至少有一个横梁5延伸在整个支承件15上，这样就产生多个容纳物剂贮器的空穴7，并将施加的力充分均匀地分散到整个片件6上(即不使片件6弯曲)。图4，5，6和13中的横梁通常沿对角线延伸于由支承件15的外壁所限定的整个空间。本案所用的对角线，表示与下述横梁不同的实施方案(即不指横梁连接直线形的两个不相邻的顶点，或者通过多面体两条不相邻的边)，正如这些图中所示的实施方案的情况。如图中所见，横梁包括倾斜的(图6)和不倾斜的(图7)横梁以及蜂窝状的结构(图2)。横梁的数目依赖于各种因素，例如片件6和支承件15的相对的结构完整性或柔性，整个支承件15的距离，物剂贮器接触皮肤面积的大小，以及物剂贮器的容积。一般，当使用非常薄的金属制成片件6时，在支承件15上相邻横梁5之间的最大距离，与片件6上的相邻微突4之间的距离相比，将不大于约4倍，而最好不大于约2倍。图7描述支承件15可由经多个横梁5与外环壁53连接的多个内环壁55构成。
图5描述片件6可供选择的实施方案，其微突4从薄的片状部件6的机体接触边缘49向外延伸。在这个实施方案中，使用过程中，片件6的平面大致沿与体表垂直的方向伸展。片件6具有螺旋状形态，它限定了空穴51供放置含有物剂或接受物剂的贮器(图5未示)。片件6的形状也可以是卷绕形、折叠形(未显示)和曲线形(未显示)以及其它形状，通常从它的平面状态沿着它的长度形成具有多个空穴51的结构。较好的实施方案是空穴51与支承件15的空穴7连通。
在图1和5中显示出与片件6的远皮肤侧面/边缘接触的支承件15的表面通常是平坦的(即成平面)。然而，与片件6连接的支承件15的表面最好具有凸面或曲线形(例如圆柱形状)表面54(如图8所示)。凸面或圆柱形表面54的曲率半径最好大于约5cm，大于约10cm更佳。
图9描述了支承件15的另外的实施方案，在该实施方案中，支承件15由多个具有波形结构的长条组成，并且均对片件6的平面垂直定向。片件6的结构与图3相同，其上有开口8，并与微突4联系(图9未示)。波形长条91，93在其连接点95处最好被固定在一起，如薄片91，93由金属或塑料制成时用焊接固定。相邻的长条91，93的波形结构形成空穴93，在这中间容纳适当的贮器材料。这样，长条91和93的高度将部分地由装入空穴97的贮器材料的厚度的支配。
图10，又描述了支承件15的另一种实施方案，该实施方案中支承件15由波形薄片101构成，波形薄片101加工成与片件6的远皮肤侧面接触。如有必要，覆盖波形薄片101远皮肤侧面的覆盖薄片(图10未示)，或沿着波形薄片101侧边的轨道(图10未示)能提供额外的刚性并在向薄片101的远皮肤侧面施力时，阻止薄片101沿波纹折叠弯曲或折叠的任何趋势。在波形薄片101上可以有多个开口，因此，物剂通过波形薄片101的流动成为可能。开口的大小和数量(图10未示)不是决定性的，只要波形薄片101的结构完整性和刚性不受损害即可。这将有可能在与薄片101的远皮肤侧面相邻的空穴104安置额外的贮器材料。如在其它实施方案中一样，贮器材料能被装进波形物和下面的片件6之间形成的空穴103中(图10未示)。
图11揭示一种波纹片101可选择的实施方案，其波纹折叠不完全相互平行。与图10的装置相似，为了提高波纹片101结构的刚性，如有必要，图11装置也在波形片101的远皮肤侧面上附有覆盖薄片，或者选用围绕波形片101的环状轨道。比图10更进一步，可如图11的装置为让物剂通过那里传递，在波形片101上存在了多个开口(图11未示)，这种开口有可能利用空穴104来容纳物剂贮器材料。
图1-2，4-7，9-11和13中描述的支承件15的共同特征是支承件15包含一些空穴(如空穴7，97和103)，贮器材料能被装载入这些空穴内。另一方面，片件6的某些实施方案如图5中所示，有其自身的空穴51容纳贮器材料。在这种情况下，以及在把含有物剂/采样的贮器放在预处理的皮肤上之前将这片件6应用于皮肤作为预处理的情况下，用不着把该支承件15完整地作为片件6的一个部件，或者将它固定附着在这片件6上。
图12描述支承件115，它是用于把片件6压向皮肤的手持装置112的头部，该头部115由金属板构成，板有足够的厚度(如0.5em或更厚)使其具有足够的刚性。支承件115与装置112用螺纹113相连。以使微突4剌穿皮肤，表面111对着片件6压下。表面111可有凸曲率(如图12所示和联系图8的讨论)也可只是平坦表面(即平面)。任选的是，为了使支承件115以预定的力量压紧片件6的远皮肤侧，装置112可以由弹簧支承。
虽然已经初步描述了本发明的支承件15借助于片件6和微突4对身体组织(如皮肤)的初次应用与穿剌，但是，本领域技术人员将意识到该刚硬的支承件15也可用于重复使用片件6(即以后的使用)和接着的微突4穿剌，其部位可以是与第一次相同的体表处或在新的体表部位。用微突4在原来的体表位置上(即微突4初次剌破的体表位置)再次剌破皮肤，对于使微突4产生的微切口/微裂缝保持开放是有益的。这样，穿越皮肤的物剂流量能继续不受阻碍。穿越皮肤的物剂传递/采样装置，正如图13-18显示的，在穿越皮肤传递或采样过程中，一般适合粘附于皮肤。在微突4初次产生通过角质层的微切口/微裂缝之后，皮肤立即开始愈合过程，最后，微裂缝将由于愈合过程继续而关闭。因此，为了保持微裂缝开放和使得穿越皮肤的物剂流量不受阻碍，使用手指对着皮肤再使用片件是令人满意的。这能用本发明的支承件结构很容易地完成。当穿越皮肤传递/采样装置被粘附到皮肤时，为了引起微突4再次剌破角质层，病人或技师可简单地定时重复用手指或手对装置的远皮肤侧面施压。
微突或微刃4通常由一片材料构成，而且对于至少穿剌皮肤的角质层是足够尖锐，有足够长度。在一个实施方案中，微突4和片件6对物剂通过基本上是不渗透的或不能渗透的。每个微突的宽度可以是任何宽度范围。在一批微突插入以后，微突和体表的相交处的微突宽度一般至少约为25μm。所需要的刀刃长度由被穿剌的体表的差异确定，至少相当于角质层的天然厚度，因为本发明的主要特征之一是微突至少要穿过角质层进入表皮层。通常，微突要有一定的长度和结构，要使其穿剌的深度达到大约25-400μm，应用最多的穿剌深度在大约50-200μm之间。微突4能够倾斜(即能形成一角度)使边缘64(图3)进一步减少按压微突进入皮肤组织所需要的穿剌力。每个微突4的前沿都处于适合穿剌皮肤的相同角度或不同角度。或者，每个微突的前沿可以形成曲线，例如形成凸形或凹形或被分成任何数目的倾斜片断，例如第一段比较垂直，第二段与垂直成圈套的角度。
如同WO 97/48440中阐明的，先用照相制板术，再用化学蚀刻术，然后用微冲压术能生产片件6，在此引证并包括这些揭示。图5所描述的片件6的具体实施方案需要使平面的片件6形成所期望的空穴形状的附加步骤(即螺旋形，蛇形，同心圆等等)。利用已知的金属片弯曲，辊压，折叠和/或成形的技术能达到目的。
通常，冲压以后微突4与片件6的表面48成大约90度的角(图3)，但是能安排它们从垂直位置成向前和向后的任何角度以利于穿剌角质层。
从具有足够强度和制造微突能力的材料，例如玻璃，陶瓷，坚硬的聚合物，加强的(如碳纤维加强固)聚合物、金属和金属合金，制造片件6和微突4。金属和金属合金的例子包括，但不限于不锈钢，铁，钢，锡，锌，铜，金，铂，铝，锗，锆，钛和钛合金。每一片件和每个微突都可具有一薄层金、铂、铱钛或铑镀层。玻璃的例子包括二氧化硅和Corning公司(美国纽约)供应的“PHOTOCERAM”这样的反玻璃化的玻璃。聚合物的例子包括，但不限于聚苯乙烯，聚甲基丙烯酸甲酯，聚丙烯，聚乙烯，“Bakelite”(“酚醛塑料”)，醋酸纤维素，乙基纤维素，苯乙烯/丙烯腈共聚物，苯乙烯/丁二烯共聚物，丙烯腈/丁二烯/苯乙烯(ABS)共聚物，聚氯乙烯和丙烯酸共聚物，它包括聚甲基丙烯酸酯的聚丙烯酸酯。
片件6的任何实施方案的微突4和开口8的数目，随所期望的流速，被采样或递送的物剂，所用的传递或采样的装置(即电转运，被动扩散，渗透，压力驱动等)和本领域普通技术人员会了解的其它因素而有差异。一般，单位面积微突数(即微刃密度)越大，则皮肤内物剂流量(每个微裂缝)越不集中，因为有较多通过皮肤的通道。因此，单位面积微突数较少会使通过皮肤的物剂的传递更集中在较少的通道内。皮肤通道内较高浓度的物剂可导致较高发生率和/或严重性的皮肤反应(例如剌激性)。因此，较大的微刃密度能减少皮肤反应的发生率和/或严重性。
可预先安置一种可供选择的联系介质(未显示)在具有如WO 98/28037所说的图1-3中所显示的该结构的片件6的皮肤接触面48上，现引证其揭示内容包括于此。这种联系介质，如果使用，是作为物剂的管道，作为包含物剂的贮器或收集物剂的贮器与皮肤之间的桥梁而起作用，由此允许物剂无阻碍地经那里被传递。
可与本发明一起使用的一种穿越皮肤传递/采样的装置，依赖于通过体表的电流或“电转运”的应用。在本领域中的那些工作将正确地评价本发明能与各种电转运系统联合使用，因为在这方面本发明不局限于任何方式。电转运系统的例子可以参考Theeuwes等的US专利5147296，Theeuwes等的5080646，Theeuews等的5169382，Phipps等的5423739，Haak等的5385543，Gyory等的5310404和Gyory等的5169383，其中任何被揭示的电转运系统都能用于本发明。
图13-17阐明一代表性的电转运传递/采样装置10，按照本发明，该装置10可以与支承件15和皮肤穿剌装置2合用。装置10包含一个上罩16，一个电路板组件18，一个下罩20，供体电极22，反电极24，供体贮器27，反贮器28和与皮肤相容的胶合剂30。上罩16有侧翼31，该侧翼协助保持装置10在病人皮肤上。印刷电路板组件18包含一个与分立组件40和电池(组)32匹配的集成电路19。借助通过开口13a和13b的支柱33(图17中仅显示一个)把电路板组件18附着在罩子16上，为了把电路板组件18热固定在罩16上，支柱的末端被加热/熔化。借助粘合层30把下罩20附着在上罩16上，粘合层30的上表面34既附着于下罩20又附着于包括侧翼31的底表面的上罩16。在电路板组件置18下表面上显示出(部分地)钮扣小电池32。根据需要也可应用其它类型的电池启动装置10。装置10一般由电池32，电子电路系统19，40，电极22，24，反贮器28，安置供体贮器27的支承件15和皮肤穿剌装置2组成。所有这些部件被合并成整套装在一起的统一体。下罩20包括电极22，24和贮器27，28。电路板组件18的输出(图13未示)用导电胶带42，42’通过下罩20中形成的凹陷25，25’的开口23，23’与电极24和22进行电连接。电极22和24’依次与贮器27和28的顶端面44’，44直接进行机械和电相接。反贮器28的底面46通过粘合层30的开口29与病人的皮肤接触。供体贮器27的底面46’通过皮肤穿剌装置2中的多个开口8与病人的皮肤接触，如图1所示。供体贮器27中的物剂一般是溶液状态，最好是水溶液，该水溶液可包含于诸如海绵的固体固体基质中，海绵是亲水性聚合物基质(例如水凝胶)，它允许物剂通过、自由流动。贮器基质充满开口8而使物剂贮器与体表相接触，如图1所示。如上述讨论，可把一层联系介质放在片件6的近皮肤侧面，微刃4通过那里。可任意选择的联系介质提供了供体贮器27和皮肤之间更均一的物剂流动通道。通常，因为扩散或因为贮器和联系介质有相同的物质，物剂最初存在于贮器和联系介质内。
装置10借助四周的粘合层30(粘合层有上粘合面34和与机体接触的粘合面36)粘附于病人的体表(例如皮肤)，且可任意将这里讨论的任何实施方式中装置2上的元件固定。而且，为了帮助维持界面与皮肤的接触，联系介质65可任意选择有点粘的或是粘的。粘合面36覆盖了除装置2和反电极贮器28所占地位以外装置10的整个下侧面。粘合面36具有粘合性，该性质保证装置10在使用者正常活动期间保持在机体上，然而，在预定的(如24小时)使用期以后允许适当地移动。上粘合面34粘附在下罩20上，并且将电极和物剂贮器保持在罩的凹陷25，25’之内并维持装置2与下罩20相连，下罩20与上罩16相连。
在物剂传递/采样装置的一个实施方式中，为了在装置不用时保持粘合层30的完整性，在装置10上有一剥离层衬垫(未示)。使用时，在装置用于皮肤之前剥去剥离层。装置10也有一个按钮开关12，当按下开关钮时，装置10开动了，通过LED14变亮可使使用者知道。在预定的传递时间内，由电转运传递物剂通过病人的皮肤(如臂上)。
本发明的其它实施方式中，把支承件15预先安排在部件6的顶面上，使用被动的透皮传递或采样装置。本领域的技术人员将能了解，本发明能与各种被动的透皮系统连用，因为本发明在这方面并不受限制。例如被动系统的例子，可能必须参考，但并不限于Campbell等的US专利4379454，Gale等的4588580，Gampbell等的4832953)，Gale等的4698062，Campbell等的4867982和Hunt等的5268209，本发明可与这些专利中揭示的任何系统合用。图18中阐明了被动透皮传递/采样装置的一个例子。具有装在其外环形壁53内的片件6边缘的支承件15被装在能被应用于体表的泡沫衬垫或嵌条57中。片件6的边缘不需要被装在外环形壁内，因为如前面实施方式所叙，片件6能被连接在支承件15上。延伸在整个环形壁53和横梁5上的是一刚硬的顶盖59。顶盖59非常坚硬，以致当力量向它施加时不变形，并能更均匀地传递所加的力以及更均匀地传递整个片件6的长和宽上，使微突4位移。虽然并不要求，但最好被动传递/采样装置在泡沫衬垫57接触机体的面上，四周有粘合剂，在部件2接触机体的面上有一粘合的界面凝胶(未示)。
本领域中的人员将会了解，本发明也能与各种渗透和压力驱动系统结合使用，因为本发明在这方面不限于特殊装置。渗透和压力驱动装置的例子，可能必须参考Eckenhoff的US专利4340480，Theeuwes等的4655766，Eckenhoff的4753651，Gross等的5279544，Theeuwes的4655766，Gross等的5242406，和Eckenhoff的4753651，其中任一个都可与本发明结合使用。
本发明对通常通过体表和膜(包括皮肤)传递各类药物是有用的。一般，它包括所有治疗领域中的药物。本发明也用于天然存在的，化学合成的或重组生产的蛋白质，肽类及其片段的穿越皮肤传递。另外，本发明可另外用来配合疫苗，包括寡核苷酸类药物，聚核苷酸类药物的核苷酸类药物和基因的传递。这些物质一般分子量至少有300道尔顿左右，有的分子量至少大约300至40,000道尔顿。如以上提及的，本发明装置2也可与采样装置联用，包括，但不限于，逆向电转运(即在不带电荷的物质如葡萄糖采样的情况下，反向离子电渗和/或电渗透)，渗透和反向被动扩散。例如可以参考Eckenhoff等的US专利4756314，Schoendorfer的5438984，Glikfeld等的5279543和Guy等的5362307。
本领域中的一般技术人员将会了解，本发明可以其它特殊的形式实施，而不偏离本发明和它的基本特征。因此这里揭示的实施方案，应该认为在所有方面都是说明性而不具有限制性。由所附的权利要求书而不是前面的阐述表明本发明的范围。

Claims (7)

1.一种用于通过体表导入或取出物剂的装置(2)，包括有多个微突(4)的部件(6)和结构支承件(15)，微突(4)从部件(6)的近体表侧部件(48)延伸出来，支承件(15)与部件(6)的至少一部分接触，并延伸跨越所述的部分，支承件(15)的刚性比部件(6)的大，所述装置(2)的特征在于：
微突(4)的长度足以刺入体表，其刺入深度小于500微米，
结构支承件(15)具有多个空穴(7)，含有物剂或接受物剂的贮器(27)在空穴里。
2.如权利要求1所述的装置，其中支承件(15)对垂直于体表的施加力，其刚性比部件(6)的大。
3.如权利要求1所述的装置，其中支承件(15)在人工用手指或手对皮肤压下装置(2)的情况下具足够刚性，下垂小于300μm。
4.如权利要求3所述的装置，其中支承件(15)在所述按压情况下下垂小于50μm。
5.如权利要求1所述的装置，其中支承件(15)在人工用手指或手对着皮肤按压装置(2)的情况下，支承件基本上是不可压缩的，压缩度小于250μm。
6.如权利要求5所述的装置，其中支承件(15)在所述按压情况下压缩小于50μm。
7.如权利要求1所述的装置，其中部件(6)包括一薄片，使用中薄片与体表近似平行，薄片上有多个开口(8)和从薄片的近机体表面(48)延伸出来的多个微突(4)，所述的微突(4)适合于穿刺体表。
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DE69839969D1 (de) 2008-10-16
PT1037687E (pt) 2008-12-17
WO1999029298A3 (en) 1999-08-12
AU1997499A (en) 1999-06-28
US6322808B1 (en) 2001-11-27
ES2314995T3 (es) 2009-03-16
ATE406935T1 (de) 2008-09-15
CN1281375A (zh) 2001-01-24
EP1037687A2 (en) 2000-09-27
KR20010032929A (ko) 2001-04-25
KR100557261B1 (ko) 2006-03-07
EP1037687B8 (en) 2008-10-22
US6953589B1 (en) 2005-10-11
CA2313700C (en) 2009-11-24
EP1037687B1 (en) 2008-09-03
DK1037687T3 (da) 2009-01-26
AU757230B2 (en) 2003-02-06

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