CN1225293C - 用于将液态药物皮内注射到人体的*** - Google Patents

用于将液态药物皮内注射到人体的*** Download PDF

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CN1225293C
CN1225293C CN00813342.5A CN00813342A CN1225293C CN 1225293 C CN1225293 C CN 1225293C CN 00813342 A CN00813342 A CN 00813342A CN 1225293 C CN1225293 C CN 1225293C
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CN1399567A (zh
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R·R·斯托特
R·A·米勒
J·M·博尼卡托
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Abstract

本发明提供了一种用于注射DNA为主剂的药物的***。该***包括带有约0.004英寸注射孔口的无针注射器(10)，用于提供DNA为主剂的药物，以3900到4300psi的初始压力，随后压力下降至约2800到3800psi水平，然后在注射结束后迅速切断压力。这种注射器包括环形基座(12)，用于保持注射器孔口与患者皮肤的距离。基座包括支撑部分(16)，注射器与其顶住安置，从而使孔口与患者皮肤距离约0.76-1.0英寸，基座远端的内径约为0.50-0.70英寸。

Description

用于将液态药物皮内注射到人体的***
发明背景
将注射剂送入人体的***已用了许多年。最常用的是与安瓿配合使用的皮下注射针。注射时，将针***组织达到所需的深度，然后操作者简单地推压安瓿内的柱塞来送递注射剂(injectate)。其它较少用的方法是无针注射***。这些***通常由装置和安瓿构成。该装置产生动力，安瓿中装有注射剂。安瓿通常在其远端有一个约为其内径1/100大小的环状开口。该装置将液体经此开口高速(足以穿透组织并射入注射剂)推出。注射时，操作者通常将安瓿的顶端抵住患者的皮肤，然后触发触发器。对无针注射***而言，注射深度是由装置而不是操作者控制的。
肠胃外(通过肠胃道以外的其它途径)注射可以按注射位点分成五种。它们是：皮内(ID)、皮下(SC)、肌内(IM)、静脉内(IM)/动脉内(IA)和骨髓内(IMED)。ID是将注射剂注入皮肤或皮内。SC注射是将注射剂注入脂肪组织内。IM注射是将注射剂注入肌肉中。IV/IA注射是将注射剂注入静脉或动脉。最后，IMED注射是将注射剂注入骨髓、脊髓或延髓。常规的针和安瓿***可以在这所有5个区域注射。无针***通常仅用于ID、SC和IM注射。本发明涉及ID注射。
针和安瓿***可有效地用于多种ID注射(如利多卡因)，因为当使用正确技术时，它可以注射预定量的液体(通常体积范围为0.1到0.3cc)。适当的ID注射后，在皮肤表面上会出现一个白色的凸起点。通常将这种凸起点称为疹块。用常规的针和安瓿注射***实施适当的ID注射可能会发生困难。安置针尖的空间非常小(约1mm)。这种空间通常称为皮内空间，如图1和图2中所示的2。针4的针体与靶表面必需呈一个很小的角度，通常为5°到15°，且保持特定的方向。关键是针尖穿过皮肤外层(通常称为表皮)，但针尖未穿透浅筋膜6(将皮肤层与下方脂肪层8分开的组织层)，否则所送递的注射剂9的体积不会完全占据皮内空间2。因此，用针和安瓿***进行的ID注射对使用者有严格的正确注射的要求。临床医生可以通过轻轻挤压凸起点确定是否进行了正确的ID注射；如果凸起点消失或变平，则该注射不是真正的皮内注射。如果针穿透了浅筋膜，注射剂将进入脂肪层。这是常规ID注射中经常发生的，仅需要重复上述过程直到进行了令人满意的注射。而这对患者而言可能是不舒服的，且也令临床医生失望。
最近几年，针对新型疫苗和治疗的开发进行了一些努力。称为“脱氧核糖核酸(DNA)-为主剂(based)的注射剂”的术语就指这种新型的注射剂。DNA定义为遗传信息的载体。疫苗指用于活性免疫预防(预防疾病)的任何制剂。治疗指用各种方法对疾病或紊乱的处理。DNA为主剂的注射剂有望成为是一种令人激动的新型预防和治疗疾病的工具。
简单地说，DNA为主剂的ID注射，其总体目的是预防或治疗疾病。在细胞水平上，该目的是实现转染和表达。转染指细胞受到核酸(来自逆转录病毒的)的感染，导致在转染的细胞内进行病毒复制。表达指细胞产生抗原的能力。抗原是在潜伏期后(几天到几周)，由于与适当细胞进行接触的结果，引发敏感状态和/或免疫应答的任何物质，该物质与敏化对象的抗体和/或免疫细胞以可显示的方式发生体内或体外反应。注射要成功，必须转染和表达都发生。一旦成功地发生了转染和表达，注射剂中所含的遗传“信息”就被送递进入免疫***。已经表明，为了让DNA为主剂的ID注射有效，注射后短时间内(确切的为几天)需要将遗传信息送递到体免疫***。已经发现，用常规的ID注射用针和安瓿注射***可能会减少或完全不发生转染。无针注射***(除本文所述的以外)也有缺陷，它们不能够有效的送递DNA为主剂的ID注射剂(本文以后将具体描述)。本发明的目的是开发一种无针注射***，特别适用于DNA为主剂的ID注射剂。
发明概述
本发明提供了一种用于将DNA为主剂的皮内药物注射进人体的***。该***包括带有约0.004英寸注射口的无针注射器，以3900到4300psi的初压提供DNA为主剂的药物，然后压力迅速降至约2800到3800psi水平，再迅速切断压力终止注射。注射器包括适用于将注射孔与患者皮肤保持一点距离的环形接合器。该接合器有一个安置注射器装于其上的基座(adapter)，使孔口与患者的皮肤相距0.76到1.0英寸，基座远端的内径约为0.50到0.70英寸。
附图简述
图1用已有技术的针和安瓿注射***进行DNA为主剂的ID注射的剖面图，在将针***人皮层之前；
图2是与图1相应的DNA为主剂的ID注射剖面图，但此时针已***皮层，正在注射注射剂；
图3是本发明优选实施例的侧面剖视图，基座安置在位而装置的其它部分搁在患者的皮肤上；
图4相应于图3的侧面剖视图，但在进行注射；
图5该优选实施例皮内注射器基座的等角视图；
图6是图3-5皮内注射器基座的正侧图；
图7是沿图6中沿7-7线的侧面正视图；
图8是已有技术弹簧动力无针注射***的典型压力曲线图；
图9是已有技术弹簧动力无针注射***在前20毫秒的典型压力曲线图：
图10是本发明优选实施例的典型压力曲线图。
发明详述
本文所述的无针注射***可以有效地给予与针和安瓿***注射剂相同体积范围的ID注射剂，而无需特别的技术或训练。为了增加ID注射的效率，将ID基座开发成附着于本发明优选实施例安瓿的远端，本文将美国专利No.5,399,163和待批的美国专利申请No.08/858,249这两者所公开的无针注射***全部纳入作为参考。对这两个***而言，身体的实际注射部位可以是许多不同部位(如前臂的中间或膝盖周围)。
在本发明的优选实施例中，将图中12所示的皮内基座与美国专利No.5,399,163或待批美国专利申请No.08/858,249中所述的无针注射***结合使用，该***的安瓿部分示于10。皮内注射器基座12的横截面为环形。它使安瓿14的远端与皮肤的距离约为0.76-1.0英寸，较佳地约为0.79英寸，此价值的内径约为0.50-0.70英寸，较佳地约为0.60英寸。与传统的针和安瓿***以及其它无针注射***相比，本***增加了DNA为主剂的ID注射的效率。
本发明的优选实施例还可使用在ID位点注射预定量的DNA为主剂的注射剂的方法。用本发明优选实施例的无针注射***可以确保DNA为主剂的注射剂在整个皮内空间中适当散布，从而将注射剂产生的理想的免疫应答达到最大程度。本发明优选实施例的目的是将DNA为主剂的注射剂送递到ID位点，使得人体的免疫***能激活达到现有的针和安瓿***或其它无针***所不能实现的程度。
一种增加DNA为主剂的ID注射效果的方法是增加将遗传信息送递到免疫***的速度。这可以以许多种方式完成。其中两种方法是：1)通过以足够的压力将注射剂在靶位点尽可能大的面积增加被转染的细胞数量，以确保转染；2)进行会导致发生一定局部组织破坏而促进免疫应答的ID注射。本发明的优选实施例确实能增加将遗传信息送递到免疫***的速度。它是通过上述两种方法得以实现的。
图3和4显示用本发明优选实施例进行ID注射的剖面图，将DNA为主剂的注射剂送递通过皮肤组织的许多层。这种散布方式在充足的压力下将注射剂注入到很大的面积上以增加转染。这与用常规安瓿和针注射(参见图2)产生的注射液集中进入或填塞不同。其二，由此散布方式在皮肤层中造成局部组织破坏。此局部组织破坏与以前所述的细胞转染不同，因为转染是在细胞层次上发生的，而本文中的组织破坏表现为皮肤的许多层的分离，而未透入其下的浅筋膜6或肌肉组织8(参见图4)。所以，这种局部组织破坏就激活了免疫应答。
注射剂在皮内空间中的适当分布取决于三种因素：1)安瓿远端必须与皮肤保持合适的距离(即0.76-1.0英寸)；2)与皮肤接触的基座的直径应在一定的范围内(即0.50-0.70英寸)；3)必须以适当的压力和在适当的一段时间内送递注射液。如图3和4所示，基座12的近端16套在安瓿14的远端18。基座12的近端16增大，从而产生一个台肩即或支撑部分22(见图6-7)。一些轴向肋条(axial rib)24与支撑部分22配合，确保基座适当地安置在安瓿14上。在其远端基座12还有扩大的凸缘即接触圈26起稳定作用。接触圈26的外径通常为0.70到0.90英寸，或至少比基座12的内径大大约0.20英寸。
必须将安瓿顶部与皮肤保持上述距离的原因是为了确保穿透适当的深度。合适的基座尺寸对确保这种装置不会干扰ID疹块的形成是非常重要的。基座尺寸的下限由所形成疹块直径的最大预计值决定，而上限由物理限制条件如注射位点确定之。
在此优选实施例中，将注射剂28从安瓿14的孔口压送出来，通过表皮5.然后进入皮内空间2。通常在注射位点上形成疹块(见30所示的虚线)。此疹块以虚线显示，因为通常是在注射后才形成的。
如图10所示，安瓿内注射剂的压力应在5毫秒内，较佳地为1毫秒或更短时间内，迅速上升至峰压3900-4300psi，较佳地约为4100psi。注射的这个阶段称为穿透阶段。在穿透阶段中皮肤组织被穿透。低于此峰压的注射不足以持续地刺穿皮肤层。而高于这个范围的注射压力则会穿透得太深。要瞬间到达所需水平的穿透并避免注射剂从组织返回出来(称为“射回”的现象)，需要压力快速上升。
随后，安瓿内的注射剂压力降至2800-3800psi。注射的这个阶段(称为送递阶段)是将预定量DNA的ID注射剂送递到皮内空间。就是这个阶段是本发明所述无针注射***的优点。与针和安瓿注射***相比，注射剂散布在相当大的面积上。这基本上是由本发明优选实施例中所用的CO2气源造成的。与适当的压力调节阀和质量流量控制器结合使用的CO2气体，在整个注射过程中提供了稳定的能源。这个能量转化成在安瓿中的大(在1200和2500psi间)而稳定(没有明显的压力波动)送递压力。这种大而稳定的送递压力的另一结果是表现皮肤许多层的分离的局部组织的破坏而未穿透浅筋膜6(见图2)。
最后，在注射结束时，安瓿内的冲杆将到达安瓿的底部。这是唯一终止注射的机制。因此，在送递所有的注射剂以前注射器冲杆的推动力都保持很高，而且由于冲杆与安瓿的冲击作用，注射剂的剩余压力在不到10毫秒内就跌至大气压力。这种特性的作用是将全部溶液送递到所需的深度，并防止注射剂从组织返回出来(称为“射回”的现象)。
图10显示了用本发明优选实施例进行1/4cc ID注射的典型压力曲线图。术语“压力曲线”是指安瓿中的注射剂压力与时间的变化图。用安装在安瓿上的压力传感器收集数据，此时传感元件与注射剂接触(恰在喷嘴开始部位的上游)而不干扰注射。传感器的分辨率为0.20psi，线性为2％满刻度。传感器与PC-基的数据采集***相连，后者是由个人计算机、应用软件、数据采集板、信号调节单元和电源构成的。认为每秒10,000份样品的扫描率足以对此压力变化的事件进行分析。此图显示在约1毫秒内安瓿中的注射压力上升至峰压4300psi。在峰压后，紧接着在大约1毫秒的时间压力下降800psi(跌至约3500psi)。然后安瓿的压力回复到其最初的峰值压力。这种现象可能是由安瓿的一定塑性导致的。即，这种安瓿虽然要设计成钢性容易承受压力，但并不是完全的钢性结构，在施加很大的压力时它略微胀大。这种胀大意味着事实上安瓿的直径有1毫秒的时间稍微地增加。显然，有某些原本是用来使液体增压的能量用来引起这种胀大。同时，安瓿冲杆从初始的冲击状态转化成稳定状态(如上述的穿透和送递阶段所述)，液体被注射出安瓿顶端的小孔口，而安瓿回复到其公称尺寸。这使压力反弹会其初始水平。这种现象可以说明在峰压后压力的迅速下跌和反弹。随后压力波动的幅度非常小(约100psi)，它可能是由上述相同的现象但较小的程度上导致的。虽然这种现象不是设计时的意图，但它对ID注射并没有可测的影响，因此视为是允许的。在约20毫秒后压力曲线开始变得真正平稳，且持续保持直到注射结束。
在用机械或气压作为能源的无针注射***中，发现压力波动的情况对DNA为主剂的ID注射是有影响的。这些类型的装置通常是用于SC注射的。通常，这些装置用压缩弹簧驱动冲杆进行注射。图8显示机械弹簧动力无针注射***的压力曲线图。用上述同样***采集数据。在这些***中，与本发明的优选实施例一样，安瓿中的压力在不到1毫秒内迅速上升至其约4100的高峰。但在随后的9毫秒左右内，可以看到明显的压力振荡。有一点竟跌至约2800psi(见图9)。这种压力振荡将转化成脉动的液体流，这对要使用的DNA ID注射有3个影响：1)不能将所有液体送递到所需的深度(即会穿透浅筋膜)；2)散布方式不是最佳；3)会在所有组织层而不是仅在靶层(即皮内空间)中发生组织破坏。用弹簧作动力的另一缺点是注射结束时安瓿压力通常非常低(约700psi)。这种压力太低不能确保所有注射剂都注入皮内空间。
不脱离本发明的精神和范围，可以对本发明进行改变和修饰。这些改变和修饰都在本发明的权利要求范围内。

Claims (3)

1.一种用于将液态药物皮内注射到人体的***，其特征在于，所述的***包括：
带有约0.004英寸注射孔口的无针注射器，它以3900到4300psi的初始压力，随后迅速下降至2800到3800psi水平，然后在注射结束后迅速切断压力的条件，提供液态的药物，所述的注射器包括适用于保持注射器孔口与患者皮肤距离的可拆卸的皮内环形基座，所述的基座包括与注射器顶住安置的支撑部分，从而使孔口与患者皮肤的固定距离为约0.76-1.0英寸，靠近皮肤的基座远端的内径约为0.50-0.70英寸。
2.如权利要求1所述的***，其特征在于，所述的皮内基座通常为圆柱状，且基座的远端具有朝基座外面径向伸出的凸缘。
3.如权利要求1所述的***，其特征在于，所述凸缘的外径至少比所述基座内径大0.20英寸。
CN00813342.5A 1999-08-20 2000-08-18 用于将液态药物皮内注射到人体的*** Expired - Fee Related CN1225293C (zh)

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US09/378,294 US6319224B1 (en) 1999-08-20 1999-08-20 Intradermal injection system for injecting DNA-based injectables into humans
US09/378,294 1999-08-20

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