CN1282262A - 用于电传递装置的多层式速度控制膜 - Google Patents
用于电传递装置的多层式速度控制膜 Download PDFInfo
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- CN1282262A CN1282262A CN98812304A CN98812304A CN1282262A CN 1282262 A CN1282262 A CN 1282262A CN 98812304 A CN98812304 A CN 98812304A CN 98812304 A CN98812304 A CN 98812304A CN 1282262 A CN1282262 A CN 1282262A
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Abstract
本发明公开的技术涉及一种改进的电传递装置。这种改进涉及一种膜组件,它包括与一种或两种高孔隙度膜粘合或封接的一种低孔隙度膜。所述的高孔隙度可保护低孔隙度膜避免受到体表上和/或药物储蓄器中的可导致不需要的被动流动和/或不充分的电离子透入流动的成分或污染物的破坏。结果是具有所述膜组件的电传递装置可以更可靠、更准确和更精确地通过电传递经体表而递送药物和/或治疗剂。
Description
发明领域
本发明涉及给患者递送药物和治疗剂的电传递装置。本发明还涉及用于电传递装置的速度控制膜。
发明背景
电传递装置和透皮贴片是能够满足面向健康保健工业的许多需求的药物递送系统。例如，已经进行许多尝试来控制和提高递送速度、减少药物和治疗剂的降解并降低感染的风险。然而，这类目的已经变得更难以达到，因为所递送的药物和治疗剂的分子大小增加了。这类药物和治疗剂包括肽类、多肽类和蛋白质类。
电传递装置一般包括至少两个电极和一个电能源。每一个电极均与皮肤、指甲、粘膜或身体的其它膜表面的一些部分电连通并以物理方式与其接触。一般将一个电极称作活性或供体电极，而将另一个电极称作反或反向电极。供体电极还包括一个含有所递送的药物或治疗剂的供体储蓄器，而反电极包括通常一个含有一种电解质的逆向储蓄器。在联合使用的情况下，所述的电极闭合通过患者体表的电路。
所述的药物或治疗剂是一种带电荷的分子或离子，它经所施加的电流通过体表传送。药物或治疗剂的电荷决定供体电极是阴极还是阳极。例如，当所述的药物带正电时，所述的供体电极是阳极，而反电极是阴极。另一方面，当所述的药物带负电时，所述的供体电极是阴极，而反电极是阳极。
所述的储蓄器一般是小药袋、空腔、多孔海绵或衬垫的形式或者是预先成型的凝胶或聚合物复合体形式。供体储蓄器与各个电极保持电连通。半透膜一般具有有限数量的微小孔以控制药物递送速度。
公知的电传递装置还可以包括可控制药物递送速度的半透膜。这种膜位于供体储蓄器与体表之间。这种膜还以电或离子传递的方式与供体储蓄器和体表连通。也将膜用于逆向储蓄器中以控制药物或治疗剂的被动递送。
然而，存在一种对更精确和确切控制被动药物／治疗剂流动的半透膜的需求。现有技术的膜的缺陷在于具有小的孔径大小(约0．09微米直径)和低的孔隙度(约4×105通道／cm2或0．003％体积)的膜可防止被动流动、但是在层压和装配后没有足够的电流。现有技术的装置的缺陷还在于所述的膜可以被来自操作装置过程中的皮肤或药物储蓄器的油和其它污染物所破坏或损害。这种污染可以导致膜中阻塞，影响药物递送的速度。例如，如果所述的膜失去了阻力，那么所述的药物可以以显著的量被动地流入体表。膜还可以具有阻碍药物递送的过大的阻力而降低功效并耗尽电源能量。如果所述的药物是一种止痛药诸如一种类阿片(opiod)，那么这种药物递送速度的控制的丧失是严重的缺陷。
当膜与体表接触时，膜孔可以受到有害的影响。皮肤上的身体的油、污垢颗粒和其它污染物会转入半透膜而阻塞膜中的孔。供体和／或逆向储蓄器中的疏水成分还可以阻塞膜孔或导致阻塞。这类对半透膜的破坏危害药物递送速度的控制、准确度和精确度。
现有技术的装置还存在进一步的缺陷，因为当所述的膜被固定在供体和／或逆向储蓄器上时，膜孔可以被改变。在可导致膜孔阻塞和膜孔变形的加热和／或加压条件下使用粘合剂和／或层压板来固定半透膜。这类破坏可有害地影响药物／治疗剂的被动和／或离子电渗流动。
发明概括
本发明具有优于这类现有技术装置之处，因为除其它原因外，还使用了一种半透膜组件。仅用于电传递装置的这种膜组件基本上不受皮肤油和其它污染物或储蓄器内疏水成分的影响。本发明还包括将膜固定到贮库的方法，其没有与在加热和加压条件下使用粘合剂和层压板将所述的膜固定在储蓄器上相关的难题。
正如优选实施方案中所示，本发明的另一个优点在于低孔隙度膜在结构上得到一种或多种、优选两种高孔隙度保护层的支撑。此外，这种膜组件所实现的稳态药物递送比可比较的常规电传递系统快。例如，这种膜组件的流动阻力一般比具有类似厚度和结构完整性的可比较的单一低孔隙度层低。结果是本发明提高了结构完整性而基本上不会影响实现稳态药物递送／流动所需的时间。
本发明的另一个方面是一种在速度控制的膜内减少由身体的油、粘合剂、颗粒污染物和／或疏水成分所导致的阻塞作用的方法。这类阻塞作用可以有害地影响或危害电传递装置内这类膜的被动流动。
本发明的另一个方面是一种电传递装置，它包括位于供体储蓄器与体表之间的速度控制的膜组件。这种组件包括与储蓄器邻接的低孔隙度层和位于低孔隙度层和体表之间的高孔隙度层。在本发明的另一个方面中，高孔隙度层与供体储蓄器邻接，而低孔隙度层位于高孔隙度层与体表之间。
本发明的另一个方面是一种电传递装置，它包括第二层高孔隙度保护层，由此将低孔隙度层夹在高孔隙度层之间。通过层压将所述的高孔隙度层固定在所述装置和／或低孔隙度膜上而基本上不会改变低孔隙度的控制速度层的孔隙度。照此，当将膜组件固定在供体储蓄器上时，显著量的孔阻塞是可以耐受的。结果是低孔隙度层的准确度和精确度没有被明显破坏。高孔隙度层保护了低孔隙度层不与导致阻塞和其它破坏的身体的油和颗粒污染物接触。
优选的情况是，本发明的高孔隙度膜具有的孔隙度足以使得药物递送速度基本上高于治疗药物的递送速度。更优选的情况是，孔隙度大于或等于约10％，且更优选的情况是大于或等于约20％。
优选的情况是，本发明低孔隙度、速度控制的膜具有的孔隙度足够低，使得药物递送速度基本上等于治疗药物的递送速度。更优选的情况是，所述的孔隙度小于或等于约1％，且更优选的情况是小于或等于约0．1％。
本发明的另一个方面是用于装配膜组件的低和高孔隙度的制造方法。例如，通过在所加工的低孔隙度基体上以石印方式(lithographically)沉积一种薄膜来制备这种膜。优选的情况是，以照相平版印刷(photolithographically)方式在低或高孔隙度的合适的预先成型的基体的任一主要相对表面上形成低或高孔隙度的膜。通过使用粘合剂或通过使用加压和／或加热密封可以将高孔隙度膜固定在低孔隙度膜上。优选的情况是，基本上仅将高孔隙度膜的周边以粘合方式进行固定或层压。优选的情况是，将低孔隙度的膜夹在高孔隙度层之间以保护低孔隙度层不被破坏。
附图的简要说明
下文将参照优选的实施方案和附图来进一步具体地描述本发明，在附图中：
附图1是具有典型膜组件的典型电传递装置的截面示意图；
附图2是典型膜组件的截面示意图；
附图3是另一种典型膜组件的截面示意图；
附图4是用加热和／或加压层压和封接的典型膜组件的截面示意图，且；
附图5是用自粘膜或以粘合方式封接的典型膜组件的截面示意图。
发明详述
本发明的优选实施方案涉及一种用于电传递装置的速度控制的膜组件。在电传递装置中将该膜组件进行设计并装配以便改进药物和／或治疗剂流动的准确度和精确度。通过使所述的组件包括高和低孔隙度层来改进流动的准确度和精确度。在一个实施方案中，高孔隙度层位于供体储蓄器和与体表邻接的低孔隙度层之间。
在装配或操作前高孔隙度层具有的孔隙度足够高，使得在达到孔阻塞时，高孔隙度层的多孔性高于低孔隙度层。这类阻塞可以在装配过程中由粘合剂或层压板或在装配或操作过程中与污染物接触而产生。结果是药物／治疗剂的递送速度基本上不受电传递装置装配或操作过程中高孔隙度膜受破坏的影响。
在本发明的另一个实施方案中，速度控制的膜组件包括位于低孔隙度层与体表之间的高孔隙度膜。在装配或操作前，这种高孔隙度层具有的孔隙度足够高，使得在装置装配或操作过程中达到孔阻塞或破坏时，高孔隙度层的多孔性高于低孔隙度层。高孔隙度层保护低孔隙度层不被破坏。例如，高孔隙度层可以受到身体表面上的油或颗粒污染物破坏。可以形成阻塞和／或孔可以被阻塞或以其他方式被阻塞。当固定和装配所述的膜时，这类破坏也可以发生。
在本发明的另一个优选的实施方案中，速度控制的膜组件包括位于低孔隙度膜和体表之间的第一层高孔隙度膜以及位于低孔隙度膜与供体储蓄器之间的第二层高孔隙度膜。结果是低孔隙度膜受到保护而避免受到药物／治疗剂储蓄器内的组分和污染物的破坏和避免受到体表上油和颗粒污染物的破坏。这种低孔隙度膜也可以受到保护而在装配过程中避免受到粘合剂和层压板的破坏。
优选的情况是，速度控制的膜组件使用了两种高孔隙度膜来保护低孔隙度膜。该组件可更准确和可靠地以更精确的流量递送药物和／或治疗剂。象其它的实施方案一样，在装配或操作前，高孔隙度层具有的孔隙度足够高，使得在装配或操作装置期间带来孔阻塞或破坏时，每一高孔隙度层的多孔性高于低孔隙度层。
正如附图1中所示，在本发明的一个优选的实施方案中，电传递装置10包括供体电极12和反电极14。供体和反电极12、14分别与供体和逆向储蓄器16、18邻接。供体储蓄器16中含有待递送的药物或治疗剂，且逆向储蓄器18中含有一种生物相容性电解质盐。或者，可以同时从供体和逆向电极中或以一种交替的方式递送药物和／或治疗剂。在这种情况中，将速度控制的膜组件与反电极和储蓄器一起使用。
绝缘器20将供体电极12和供体储蓄器16与反电极14和逆向储蓄器(是任选的)隔离开。所述的绝缘器20可防止供体电极12或储蓄器16与反电极14或储蓄器18之间的直接离子或电子传递。所述的绝缘器20可防止装置10短路。所述的绝缘器20可以由充分不透水和离子的材料来制备以确保通过体表100、200、300的治疗剂离子传递。优选的情况是，所述的绝缘器20由聚异丁烯或乙烯乙酸乙烯酯或能够与聚合物储蓄器形成充分牢固键以实现结构完整性的材料来制备。
正如附图1中所示，电传递装置10还包括由电绝缘或非电导材料构成的裱褙层22。电源24可对电极12、14提供电能。所述的电源24可以是电池组或其系列。所述的裱褙层22优选由具有可忽略导电性的材料制备以使装置10绝缘。所述的裱褙层22可防止因外部水分所造成的短路且在结构上可支撑装置10的邻接的元件。
电极12、14由电导材料诸如一种金属构成。优选的情况是，电极12、14由箔或筛制备；或者使用化学方法诸如沉积、涂抹／镀层、压延加工、薄膜蒸发或通过在粘合剂基质内包埋金属粉末制备。典型的金属包括银、锌、氯化银、铝、铂、不锈钢、金和钛。最优选的实施方案包括由银构成的阳电极和由氯化银构成的阴电极。
电极12、14还可以由分散在聚合物基质内的导电填料构成。例如，优选导电填料是粉状石墨、碳纤维或电极领域公知的其它填料。优选聚合物基质是电极领域中公知的疏水聚合物以便将与可存在于各个储蓄器中的任何水的任何相互作用或反应降到最低限度。反和供体电极12、14可以由不同的金属构成或具有不同的半池反应。电极12、14还可以产生至少一部分所需的电能。典型的原电池对是银氯化银电极组件，其中标准电化学反应和各个的还原电势是本领域公知的。例如，参见CRCHandbook of Physics and Chemistry第67版D151-D158页(1987)，将该文献引入本文作为参考。
电传递装置10还包括与电源24的异名极连接的电子控制电路(未显示)。电源24优选是3伏锂钮状电池组或薄膜电池组。粘合层28最好在周边使装置10与体表100粘合。所述的装置10还可以包括可拆卸的衬垫(未显示)，它可保护粘合层28直到将装置10施用到体表并开始操作为止。
供体和逆向储蓄器16、18能够吸收并包含适合于离子电渗递送的组合物。例如，储蓄器可以是由棉花或其它天然或合成的吸附剂织物或材料构成的网、衬垫或海绵。优选的情况是，所述的储蓄器16、18还包括亲水性聚合物和水介质。更优选的情况是，储蓄器16、18包括固体聚合物基质，这种基质部分由结构上明显、不溶性亲水性聚合物组成。
包含有所递送治疗剂的基质可以是交联的(诸如一种硅橡胶基质)或预制的并且用药物溶液吸附的(诸如使用纤维素、织物纤维、衬垫或海绵作为基质)。或者，储蓄器16、18可以包括凝胶基质，诸如一种可在水中膨胀的或可溶的亲水性聚合物。还可以使用所提及的聚合物的混合物。所述的聚合物可以是线性的或交联的。优选的情况是，储蓄器中总聚合物含量在约2％至50％重量之间。合适的亲水性聚合物包括那些本文所提及的对应于膜层的聚合物。
可选择的是，储蓄器16、18可以包括一种疏水性聚合物以增进结构刚性。优选的情况是，疏水性聚合物是可热熔的以增进储蓄器16、18至绝缘器20或其它邻接元件的层压。典型的疏水性聚合物包括那些本文所提及的对应于膜层的聚合物。
所述的基质可以是通过将药剂或电解质(和其它成分)与一种惰性聚合物混合而制备的聚合物基质结构。供体储蓄器16含有所递送的药剂且逆向储蓄器18含有一种电解质，诸如水溶性生物相容性盐。优选的情况是，储蓄器的组成包括约25-90％重量的基质。还可以包含疏水性聚合物以维持可促进药剂流动的开孔(或微孔性)聚合物结构。
储蓄器16、18还可以包含至少一种任选的材料，包括染料、色素、惰性填料和／或一种流变剂(诸如矿物油和硅石)。逆向储蓄器18中还可以包含至少一种任选的成分，包括碱金属盐(诸如NaCl)、碱土金属盐(诸如其氯化物、硫酸盐、硝酸盐、碳酸盐或磷酸盐)、有机酸盐(抗坏血酸盐、柠檬酸盐或乙酸盐)、含有氧化还原物质的电解质(诸如Cu2+、Fe2+、Fe3+、醌、氢醌、Ag1+、和(IO3)1-、和其它生物相容性盐和缓冲液。更优选的情况是，所述的电解质盐是增进生物相容性的氯化钠。
低孔隙度膜30位于供体储蓄器16与体表100之间。高孔隙度膜31位于低孔隙度膜30和供体储蓄器16之间。孔基本上均匀地分布在膜30、31的整个厚度范围内并从表面至表面延展。可以将电传递装置10用于通过体表100传递药物和／或治疗剂。
传递药物所接触的表面积可以在约1-200cm2的范围内。更优选的情况是，该面积在约2-30cm2的范围内。所述面积范围的下限端值可以受到可得到的电源强度和所需流速限制，而上限端值受到体表可得到的量、给定体表曲面的持续粘合利用度和患者舒适程度的限制。
电传递装置10还包括一种优选采用和成形的控制器(未显示)以便使患者启动和关闭装置10。还可以将所述的控制器按照药物治疗方法的要求来设计程序，或设计成周期性自动启动和关闭的程序以便例如与身体的天然或昼夜节律的模式相适应。优选的情况是，一种微处理机可控制作为时间函数的电流，和／或产生电流波形诸如脉冲、正弦、斜上、斜下、尖峰等。
通过本领域一般公知的方法可以熔融混合、溶剂铸造或挤压本发明的结构元件。
附图2中所示的是本发明的另一个优选的实施方案。电传递装置10包括位于低孔隙度的速度控制的膜42与体表200之间的高孔隙度膜44。优选的情况是，高孔隙度膜具有的孔隙度足以使药物的递送速度基本上高于治疗药物的递送速度。更优选的情况是，所述的孔隙度大于或等于约10％，且更优选的情况是，所述的孔隙度大于或等于约20％。优选的情况是，低孔隙度的速度控制膜42具有的孔隙度足够低而使药物递送速度基本上等于治疗药物递送速度。更优选的情况是，所述的孔隙度小于或等于约1％，且更优选的情况是小于或等于约0．1％。高孔隙度层44保护低孔隙度层42免受体表200上的油和颗粒污染物的破坏。当将组件40固定在体表200上时，层44还可保护层42免受传递离子的粘合剂的破坏。
附图3中所示的是本发明的另一个优选的实施方案，它包括两层高孔隙度层52、56。膜52位于低孔隙度膜54与供体或逆向储蓄器16、18之间。另一层高孔隙度膜56位于低孔隙度膜54与体表300之间。优选的情况是，高孔隙度层56具有的孔隙度大于或等于约10％，且更优选的情况是大于或等于约20％。膜56保护低孔隙度膜54免受阻塞或另外的破坏。这类破坏可由从体表传递的油、颗粒或其它污染物所产生。
当将组件50固定在体表300上时，层56还可保护膜54免受传递离子的可涂布在层56上的粘合剂的影响。结果是阻塞的孔、阻塞和其它影响递送速度的破坏的风险得到了显著降低或消除。高孔隙度膜52可保护低孔隙度膜54免受供体和／或逆向储蓄器16、18中的成分和／或污染物的破坏。
附图4中所示的是本发明另一个优选的实施方案。将控制速度的膜组件60优选地通过沿其周边68层压而固定在装置10上。组件60包括位于两层通过加热和／或加压熔融而沿其周边68固定的封接的高孔隙度层62、66之间的低孔隙度层。由此所述的低孔隙度层64在外层62、66之间是安全的。
本发明的高孔隙度膜具有优选的孔径大小、孔径分布和孔空间分布。例如，优选的情况是，将所述的高孔隙度膜中的孔以空间方式充分分布以避免任何明显的药物／治疗剂递送不均匀。优选的情况是，高孔隙度层中的孔径大小足够大以便使药物递送速度超过治疗药物的递送速度。优选的情况是，孔的大小分布足够狭窄以便允许足够均匀和有治疗作用的药物递送速度。
本发明的速度控制的低孔隙度膜也具有优选的孔径大小、孔径分布和孔空间分布。优选的情况是，低孔隙度膜中孔的孔径大小足够大以便基本上允许有治疗作用的药物递送速度，并且足够小以便防止任何明显的被动药物或治疗剂的递送。优选的情况是，低孔隙度层中孔的大小分布足够狭窄以便防止明显的不均匀的药物流动。优选的情况是，低孔隙度层中孔的空间分布足够均匀以便防止明显的不均匀的药物流动。
优选的情况是，低孔隙度膜中孔洞的最宽的平均部分在约1毫米至所递送药物或治疗剂的分子大小之间。孔的形状优选基本上是圆柱形，它具有的平均半径在约0．01微米至所递送药物或治疗剂的分子大小之间，且更优选在约0．01至5微米之间，且甚至更优选在约0．01至200微米之间。优选的情况是，在高孔隙度层膜中，孔洞的平均孔半径或最宽平均部分大于5微米。
优选的情况是，本发明的膜组件通过能够得到依据孔隙度和孔分布、均匀性、大小、形状和尺寸的高准确度和精确度的石印工艺来制成。制备低孔隙度膜的一个优选的方法是用一种电阻材料或能量灵敏材料包敷低孔隙度基体。可以将高孔隙度基体用于形成高孔隙度膜。或者，可以通过激光钻孔形成孔。
通过曝露于一种合适的能源来固化电阻材料。通过对屏蔽能源的未固化的电阻材料施用溶剂而将膜从基体中取出。也将溶剂处理步骤称作化学浸蚀。可以用一个预先形成的罩防护预先选择的电阻材料部分。
典型的石印法包括电子束石印法、X射线石印法和离子束石印法。更优选的情况是，将照相平版石印法用于制备本发明的低和高孔隙度膜层。其它可用于本发明的石印工艺包括那些公开在《聚合物科学和工程学百科全书》(Encyclopedia of Polymer Science and Engineering)，KirkOthmer’s第11卷(1988)中的方法，将该文献中的相关部分引入本文作为参考。
优选的情况是，本发明的膜层由对能源敏感的或电阻材料制成。例如，当使用石印法时，优选使用正象和负象电阻材料。这类材料公开在《聚合物科学和工程学百科全书》(Encyclopedia of Polymer Scienceand Engineering)，Kirk Othmer’s第9卷97-139页(1987)中，将该文献引入本文作为参考。
典型的材料包括亲水性和疏水性聚合物。典型的亲水性聚合物包括共聚多酯类(诸如购自DuPont De Nemours＆Co．Wilmington，DE的HYDRELTM)、聚乙烯吡咯烷酮类、聚乙烯醇类、聚环氧乙烷类(诸如购自UnionCarbide Corp．的POLYOXTM)、购自BF Akron的Goodrich的CARBOPOLTM、OH、聚环氧乙烷类或聚乙二醇类与聚丙烯酸的混合物(诸如POLYOXTM与CARBOPOLTM的混合物)、聚丙烯酰胺类、KLUCELTM、交联葡聚糖(诸如SEPHADEX，它购自Pharmacia Fine Chemicals，AB of Uppsala，Sweden)、淀粉接枝的聚(丙烯酸钠-共-丙烯酰胺(诸如购自Grain Processing Corp．of Muscatine，Iowa的WATER LOCKTM)、纤维素衍生物(诸如羟乙基纤维素、羟丙基甲基纤维素、低取代的羟丙基纤维素和交联的羧甲基纤维素钠诸如购自FMC Corp．of Philadelphia，PA的Ac-Di-Sol)、水凝胶(诸如购自National Patent Development Corp．的聚羟乙基甲基丙烯酸酯)、天然树胶、脱乙酰壳多糖、果胶、淀粉、瓜尔胶、刺槐豆胶、它们的混合物和组合物、及其等效材料。其它合适的材料公开在《常用聚合物手册》(Handbook of Common Polymers)J．R．Scott＆W．J．Roff，(CRCPress，1971)中，将该文献中的相关部分引入本文作为参考。
用于制备本发明高和／或低孔隙度膜的典型的疏水性聚合物包括：聚碳酸酯类、聚异丁烯类、聚乙烯类、聚丙烯类、聚异戊二烯类、聚烯烃类、橡胶类、KRATONTM、聚乙酸乙烯酯类、乙烯乙酸乙烯酯共聚物、聚酰胺类、尼龙类、聚氨基甲酸乙酯类、聚氯乙烯类；醇的丙烯酸或甲基丙烯酸酯类，所述的醇有诸如正丁醇、1-甲基戊醇、2-甲基戊醇、3-甲基戊醇、2-乙基丁醇、异辛醇、正癸醇及其组合；与一种或多种烯属不饱和单体共聚合的这样的醇的丙烯酸或甲基丙烯酸的酯类，所述的单体诸如丙烯酸、甲基丙烯酸、丙烯酰胺类、甲基丙烯酰胺类、正烷氧基甲基丙烯酰胺类、正烷氧基甲基甲基丙烯酰胺类、正叔丁基丙烯酰胺类、衣康酸、烷基上带有10-24个碳的正支链的烷基马来酰胺酸类、乙二醇二丙烯酸酯及其混合物和组合。还优选的情况是，用于制备低和／或高孔隙度膜的亲水性或疏水性聚合物是可热熔的。
除这类材料外，速度控制的低孔隙度膜优选由聚碳酸酯或尼龙树脂制成。优选的情况是，由聚碳酸酯制成的低孔隙度膜具有的孔径大小约为0．01-14微米且孔密度约为6×108-1×105孔／cm2。优选的情况是，由尼龙制成的低孔隙度膜具有的孔径大小约为0．22-5．0微米且孔密度约为1×10-3-1×10-6孔／cm2；更优选地，约为1×10-3-1×10-4孔／cm2。
一个典型的实施方案包括三层膜组件，该膜组件包括由位于两层高孔隙度膜之间的尼龙制成的低孔隙度膜，所述的高孔隙度膜由聚碳酸酯制成。所述的低孔隙度膜具有的孔径大小约为1．0微米，而高孔隙度层具有的孔径大小约为5．0微米。低和高孔隙度膜优选具有基本上相同的孔密度、孔径分布和孔空间分布。用一种粘合剂或更优选通过对外层施用加热和加压层压而将所述聚碳酸酯膜的周边封接。
例如，作为本领域中所公知的，通过γ-照射聚碳酸酯膜可以制成低孔隙度膜。正如本领域中所公知的，然后将照射过的膜以化学方式用例如氢氧化钠浸蚀。
本发明的电传递装置用于给患者体表诸如皮肤、粘膜或指甲递送治疗剂和／或药物。对于给定的一组操作参数(例如孔隙度、电流、接触面积、分子大小、流速等)，存在于储蓄器中的所述的药物或治疗剂的浓度足以通过皮肤递送具有治疗作用的剂量或浓度。
如本文所用，对“药剂”给出了其在本领域中最宽的合理的解释，且它包括产生所需和一般有益效果的药物。例如，“药剂”包括来自所有治疗种类的治疗用化合物和分子，所述的所有治疗种类包括但不限于抗感染药(诸如抗菌素和抗病毒药)、止痛药(诸如芬太尼、舒芬太尼、丁丙诺啡和止痛药组合)、麻醉药、抗关节炎药、止喘药(诸如特布他林)、抗惊厥药、抗抑郁药、抗糖尿病药、止泻药、抗组胺药、消炎药、抗偏头痛药(antimigranes)、抗运动病制剂(诸如东莨菪碱和奥丹西隆)、抗肿瘤药、抗帕金森神经功能障碍病药、止痒药、精神抑制药、退热药、解痉药(包括胃肠和泌尿)、抗胆碱能药、拟交感神经药、黄嘌呤及其衍生物、心血管制剂(包括诸如硝苯地平这样的钙通道阻断剂、β-激动剂(诸如多巴酚丁胺和羟苄羟麻黄碱)、β-阻断剂、抗心律失常药、抗高血压药(诸如阿替洛尔)、ACE抑制剂(诸如赖诺普利)、利尿药、血管舒张药(包括一般性、冠状、外周和大脑血管舒张药)、中枢神经系统刺激剂、咳嗽感冒制剂、减充血剂、诊断试剂、激素(诸如甲状旁腺素)、安眠药、免疫抑制剂、肌肉松弛药、抗副交感神经药、拟副交感神经药、前列腺素、蛋白质、肽、精神刺激剂、镇静药和安定药。
更优选的情况是，本发明的电传递装置可递送药物和／或治疗剂包括巴氯芬、丙酸倍氯米松、倍他米松、丁螺环酮、色甘酸钠、地尔硫、多沙唑嗪、氟哌利多、恩卡胺、芬太尼、氢化可的松、吲哚美辛、酮基布洛芬、利多卡因、甲氨蝶呤、甲氧氯普胺、咪康唑、咪达唑仑、硝苯乙吡啶、炎痛喜康、哌唑嗪、东莨菪碱、舒芬太尼、特布他林、睾丸素、丁卡因和维拉帕米。
在一个典型的实施方案中，本发明的电传递装置还可递送肽类、多肽类、蛋白质和其它大分子。本领域中公知这类分子因其大小而难以经皮或经粘膜递送。例如，这类分子可以具有的分子量在300-40，000道尔顿的范围且包括但不限于LHRH及其类似物(诸如buserelin、性瑞林、促黄体激素释放因子、naphrelin和亮丙瑞林)、GHRH、GHRF、胰岛素、促胰岛素、肝素、降钙素、奥曲肽、内啡肽、TRH、NT-36或N-[[(S)-4-氧代-2-氮杂环丁烷]羰基]L-组氨酰基-L-脯氨酰胺]、liprecin、垂体激素(诸如HGH、HMG、HCG、醋酸去氨加压素)、卵泡类黄体素、α-ANF、生长因子释放因子(GFRF)、β-MSH、生长抑素、缓激肽、生长激素、血小板衍生的生长因子、天冬酰胺酶、硫酸博来霉素、木瓜凝乳蛋白酶、缩胆囊素、绒毛膜促性腺激素、促肾上腺皮质素(ACTH)、红细胞生成素、依前列烯醇(血小板凝聚抑制剂)、胰升糖素、hirulog、玻璃酸酶、干扰素、白细胞介素-2、人尿促性激素(诸如尿促卵泡素(FSH)和LH)、催产素、链激酶、组织纤溶酶原激活物、尿激酶、加压素、去氨加压素、ACTH类似物、ANP、ANP清除抑制剂、血管紧张肽Ⅱ拮抗剂、抗利尿激素激动剂、抗利尿激素拮抗剂、缓激肽拮抗剂、CD4、ceredase、CSF’s、脑啡肽、FAB片段、IgE肽抑制剂、IGF-1、神经营养因子、集落刺激因子、甲状旁腺素和激动剂、甲状旁腺素拮抗剂、前列腺素拮抗剂、pentigetide、蛋白质C、蛋白质S、凝乳酶抑制剂、胸腺素α-1抗胰蛋白酶(重组)和β-TGF。
本发明的电传递装置尤其对递送高效药物和具有危险性副作用的药物、诸如麻醉药具有优点。例如，这种膜组件可以通过消除或基本上降低所述药物或治疗剂的被动流动而防止或显著降低过量给药(非故意或故意)的风险。
正如附图5中所示，可以沿周边界面68用一种粘合剂将所述的膜组件60封接。当所述膜加热和／加压封接不良时或当所述的膜不自粘时，粘合剂是特别优选的。优选的粘合剂包括购自New Jersey的HerculesCorporation的STAYBELITETM酯No．5和10；或REGAL-REZTM或PICCOTACTM。
正如附图5中所示，通过使用沿周边界面68自粘的上部和下部高孔隙度膜62、66也可以封接所述的膜组件60。当封接时，在高孔隙度膜62、66内包含低孔隙度膜64。优选的自粘材料包括聚苯乙烯丁二烯、聚(苯乙烯-异戊二烯-苯乙烯)嵌段共聚物、聚异丁烯共聚物和公开在美国专利4，391，278、4，474，570和4，702，732中的聚合物，将这些文献引入本文作为参考。
由于已经一般性地描述了本发明并详细地描述了本发明的优选实施方案，所以显而易见的是可以对本发明进行修改或以相当的技术内容将其替换而不会脱离本发明的范围。
Claims (17)
1．一种用于通过体表递送治疗剂的电传递装置，包括：
一个控制器；
一个电源；
一个反电极组件；和
至少一个供体电极组件，它包括一个电极、一个包含所述治疗剂的供体储蓄器和一个膜组件，所述的膜组件包括：
一个具有第一种平均孔径大小、孔隙度、孔径大小分布和空间孔分布的第一种膜，该膜被固定到
一个具有第二种平均孔径大小、孔隙度、孔径大小分布和空间孔分布的第二种膜，
其中第一种孔隙度低于第二种孔隙度，且
其中第一种平均孔径大小、孔径大小分布和空间孔分布基本上相同于第二种平均孔径大小、孔径大小分布和孔分布。
2．一种用于通过体表递送治疗剂的电传递装置，包括：
用于控制电流的部件；
一个电源；
一个反电极组件；和
至少一个供体电极组件，它包括一个电极、一个包含所述治疗剂的供体储蓄器和一个膜组件，所述的膜组件包括：
一个用于限制治疗剂流量的第一种部件；它被固定于
用于限制治疗剂流量的第二种部件，其中第一种限制部件所限制的治疗剂流量大于第二种限制部件。
3．权利要求1的电传递装置，进一步包括一个固定在第一种膜上的第三种膜，该膜具有的第三种平均孔径大小、孔隙度、孔径大小分布和空间孔分布基本上分别与第二种平均孔径大小、孔隙度、孔径大小分布和空间孔分布相等。
4．权利要求2的电传递装置，进一步包括一个用于限制治疗剂流量的第三种部件，它所限制的治疗剂流量基本上与第二种限制部件的相同。
5．权利要求1或3的电传递装置，其中第一种孔隙度足够高，使得至少允许治疗剂流量在此流过，且
第二种和第三种孔隙度足够高，使得允许大于治疗剂的流量在此流过。
6．权利要求1或3的电传递装置，其中所述的第一种孔隙度小于或等于约1．0％，且
第二种和第三种孔隙度大于或等于约10％。
7．权利要求1或3的电传递装置，其中第一种孔隙度小于或等于约0．10％，且
第二种和第三种孔隙度大于或等于约20％。
8．权利要求2或4的电传递装置，其中第一种限制部件至少允许一种治疗剂流量，且
第二种和第三种限制部件允许大于治疗剂的流量。
9．权利要求1或3的电传递装置，其中第一种、第二种和第三种膜通过加热和／或加压封接被固定、通过一种粘合剂被固定或自粘。
10．权利要求2或4的电传递装置，其中第一种、第二种和第三种限制性部件通过固定法被固定。
11．权利要求1或2的装置，进一步包括在供体和反电极组件之间的绝缘部件、包封所述装置的裱褙层、供体储蓄器内的聚合物基质；且反电极组件包括反电极、逆向膜组件和包含有聚合物基质的逆向储蓄器，
其中电源是锂或薄膜电池组；
其中控制器或控制部件是微处理器；
其中逆向和／或供体储蓄器进一步包括一种选自由染料、色素、惰性填料、流变剂、碱金属盐、碱土金属盐及其组合组成的组的材料；
其中所述的供体电极是阳极并含有银，且
其中反电极是阴极并含有氯化银。
12．权利要求1或2的装置，它具有的体表接触面积为2-30cm2，其中第一种孔径大小约为0．22-5．0微米且第一种孔隙度约为1×10-3-1×10-6孔／cm2。
13．权利要求12的装置，其中第一种孔隙度约为10-3-1×10-4孔／cm2。
14．权利要求1或3的装置，其中第一种、第二种和第三种平均孔径大小足够大，从而允许肽、多肽或蛋白质通过，且
其中第一种、第二种和第三种孔径大小和孔的空间分布足够狭窄，从而允许一种均匀的治疗剂流量。
15．权利要求1或3的装置，其中第一种平均孔径大小在约1mm至所述治疗剂分子大小之间，且
其中所述的孔基本上是圆柱形。
16．权利要求15的装置，其中第一种平均孔径大小在约0．01至200微米之间。
17．权利要求15的装置，其中第一种平均孔径大小约为1．0微米且第二种和第三种平均孔径大小约为5．0微米。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6804797P | 1997-12-18 | 1997-12-18 | |
| US60/068,047 | 1997-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1282262A true CN1282262A (zh) | 2001-01-31 |
Family
ID=22080088
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|---|---|---|---|
| CN98812304A Pending CN1282262A (zh) | 1997-12-18 | 1998-12-14 | 用于电传递装置的多层式速度控制膜 |
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| US (1) | US6163720A (zh) |
| EP (1) | EP1039949B1 (zh) |
| JP (2) | JP4038019B2 (zh) |
| KR (1) | KR100584630B1 (zh) |
| CN (1) | CN1282262A (zh) |
| AT (1) | ATE223244T1 (zh) |
| AU (1) | AU1827599A (zh) |
| CA (1) | CA2315228C (zh) |
| DE (1) | DE69807746T2 (zh) |
| ES (1) | ES2181315T3 (zh) |
| WO (1) | WO1999030774A1 (zh) |
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- 1998-12-03 US US09/204,820 patent/US6163720A/en not_active Expired - Lifetime
- 1998-12-14 KR KR1020007006591A patent/KR100584630B1/ko not_active IP Right Cessation
- 1998-12-14 JP JP2000538749A patent/JP4038019B2/ja not_active Expired - Fee Related
- 1998-12-14 WO PCT/US1998/026612 patent/WO1999030774A1/en active IP Right Grant
- 1998-12-14 AU AU18275/99A patent/AU1827599A/en not_active Abandoned
- 1998-12-14 DE DE69807746T patent/DE69807746T2/de not_active Expired - Lifetime
- 1998-12-14 CN CN98812304A patent/CN1282262A/zh active Pending
- 1998-12-14 AT AT98963197T patent/ATE223244T1/de not_active IP Right Cessation
- 1998-12-14 EP EP98963197A patent/EP1039949B1/en not_active Expired - Lifetime
- 1998-12-14 ES ES98963197T patent/ES2181315T3/es not_active Expired - Lifetime
- 1998-12-14 CA CA002315228A patent/CA2315228C/en not_active Expired - Fee Related
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2007
- 2007-06-19 JP JP2007161218A patent/JP4139844B2/ja not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| DE69807746D1 (de) | 2002-10-10 |
| JP4038019B2 (ja) | 2008-01-23 |
| JP2007283118A (ja) | 2007-11-01 |
| JP2002508229A (ja) | 2002-03-19 |
| WO1999030774A1 (en) | 1999-06-24 |
| CA2315228A1 (en) | 1999-06-24 |
| KR20010024727A (ko) | 2001-03-26 |
| EP1039949A1 (en) | 2000-10-04 |
| DE69807746T2 (de) | 2003-01-02 |
| AU1827599A (en) | 1999-07-05 |
| ATE223244T1 (de) | 2002-09-15 |
| KR100584630B1 (ko) | 2006-05-30 |
| CA2315228C (en) | 2007-09-18 |
| ES2181315T3 (es) | 2003-02-16 |
| JP4139844B2 (ja) | 2008-08-27 |
| EP1039949B1 (en) | 2002-09-04 |
| US6163720A (en) | 2000-12-19 |
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