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CN205006935U - 血管介入装置和导管 - Google Patents

血管介入装置和导管 Download PDF

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CN205006935U
CN205006935U CN201520484174.XU CN201520484174U CN205006935U CN 205006935 U CN205006935 U CN 205006935U CN 201520484174 U CN201520484174 U CN 201520484174U CN 205006935 U CN205006935 U CN 205006935U
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catheter
antimicrobial coating
antimicrobial
vascular
adapter
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乔纳森·K·伯克豪斯
悉达·K·舍伍古尔
托尼·F·亚当斯
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M25/0045—Catheters; Hollow probes characterised by structural features multi-layered, e.g. coated
    • A61M2025/0046—Coatings for improving slidability
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M2025/0056—Catheters; Hollow probes characterised by structural features provided with an antibacterial agent, e.g. by coating, residing in the polymer matrix or releasing an agent out of a reservoir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M2025/006—Catheters; Hollow probes characterised by structural features having a special surface topography or special surface properties, e.g. roughened or knurled surface

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Abstract

血管介入装置包括为导管提供抗扭结特性的抗菌涂层。抗菌涂层可以沿导管的长度延伸，以便当导管被插入到病人的血管时提供抗菌保护。抗菌涂层还可以增加导管的有效直径，以使得导管变成扭结的可能性最小化。

Description

血管介入装置和导管
技术领域
本实用新型总体涉及包括抗菌涂层的血管介入装置。具体而言，本实用新型针对血管介入装置上用于提供抗扭结(kinkresistance)特性的抗菌涂层。
背景技术
在诸如导管那样的血管介入装置中包括用来使得由于使用血管介入装置而引起的感染的出现最小化的抗菌涂层，正在变得越来越常见。例如，导管常常包括抗菌润滑剂，它在导管插入到病人的血管期间提供润滑性，然后在导管被插入时提供抗菌保护。
当前的抗菌涂层的使用所存在的问题是当过量的抗菌剂进入到血流中或分布到限定的位置时引起的毒性的风险。为了在大部分持续时间期间(例如，在导管插入的全部时间内)得到抗菌保护，在导管上必须存在大剂量的抗菌润滑剂。由于大剂量的润滑剂的使用，将出现分布太高浓度的抗菌剂的风险。
导管的使用所存在的另一个问题是扭结。例如，当外周静脉导管被插入到病人的血管时，典型地，它将在导管离开导管座的离开点上被弯曲(例如，由于导管座被平坦地放置在病人的皮肤上)，也有可能在导管进入病人的皮肤或血管的进入点上被弯曲。这种弯曲常常会导致扭结，这种扭结将限制或阻止流体流过导管。
实用新型内容
本实用新型延伸到包括为导管提供抗扭结特性的抗菌涂层的血管介入装置。抗菌涂层可以沿导管的长度延伸，以便当导管被插入到病人的血管时提供抗菌保护。抗菌涂层还可以增加导管的有效直径，以使得导管变成扭结的可能性最小化。
在一个实施例中，本实用新型被实施为血管介入装置。血管介入装置包括导管座；从导管座向远端延伸的导管；以及抗菌涂层。抗菌涂层被施加到导管的至少一部分，并且抗菌涂层包括基底材料，所述基底材料在抗菌涂层被插入到病人的皮肤内时释放一种或多种抗菌剂。基底材料也为导管提供抗扭结特性。
在某些实施例中，抗菌涂层可以靠近导管座和/或它可包括增加的直径部分。在某些实施例中，增加的直径部分靠近导管座。
在某些实施例中，抗菌涂层的长度可被配置成使得当导管被插入到静脉时抗菌涂层的远端被放置在靠近静脉的内膜层。在某些实施例中，这个长度可以是在7毫米与12毫米之间。
在某些实施例中，基底材料可以是亲水性的，以便当抗菌涂层被放置在病人的皮肤内时增强抗菌剂的释放。在某些实施例中，基底材料可以是UV固化的丙烯酸酯-聚氨酯(acrylate-urethane)，或热固化的聚氨酯。在某些实施例中，基底材料可以具有稍微超过导管硬度的硬度。
在某些实施例中，血管介入装置还可以包括施加到导管上的抗菌润滑剂。在某些实施例中，抗菌润滑剂可被施加到不包括抗菌涂层的导管的一部分上。
在另一个实施例中，本实用新型被实施为血管介入装置。血管介入装置包括导管座；从导管座向远端延伸的导管；以及抗菌涂层。抗菌涂层从导管座向导管的远端延伸，并且在靠近导管座处具有增加的直径部分。
在另一个实施例中，本实用新型被实施为导管，包括被施加到导管的一部分上的抗菌涂层。抗菌涂层具有近端和远端。近端包括增加的直径部分。且抗菌涂层还包括基底材料，所述基底材料在抗菌涂层被放置到病人的皮肤内时释放一种或多种抗菌剂。
本实用新型内容被提供来以简化的形式介绍下面在详细说明中进一步描述的一组选择的概念。本实用新型内容不打算限定要求保护的事物的关键特性或基本特性。
本实用新型的附加特性和优点将在随后的详细说明中阐述，并且从说明中本实用新型的附加特性和优点在某种程度上明显或可以通过本实用新型的实施而获知。本实用新型的特性和优点可以借助于在所附权利要求中具体地指出的教导和组合而被实现和得到。从以下的详细说明和所附权利要求，本实用新型的这些和其它特性将变得更明显，或可以通过如在此后阐述的本实用新型的实施而获知。
附图说明
为了描述得到本实用新型的上述的和其他的优点和特性的方式，可以通过参考在附图中显示的具体实施例，呈现对于以上概略描述的本实用新型的更具体的说明。应当看到，这些附图仅仅描绘本实用新型的典型实施例，所以不应当看作为限制它的范围，本实用新型将通过使用附图以附加的特异性和细节进行描述和说明，在附图中：
图1是包括对于导管的抗扭结特性起作用的抗菌涂层的血管介入装置的立体图；
图1A是图1的血管介入装置的立体图，其显示了沿导管的长度的抗菌涂层；
图2显示了血管介入装置的一部分的截面图；
图3显示了图2的血管介入装置当被插入到病人的血管时的截面图；
图3A是抗菌涂层与皮肤的真皮层(常驻细菌的主要来源)接触时的详细截面图；
图4是在其导管的远端部分上加上抗菌润滑剂的血管介入装置的截面图；
图5是当抗菌涂层沿导管的全部长度延伸时的血管介入装置的截面图。
具体实施方式
图1显示了包括按照本实用新型的一个或多个实施例的抗菌涂层103的示例性血管介入装置100。血管介入装置100包括导管座102和从导管座向远端延伸的导管101。虽然血管介入装置100被显示为包括伸长管，但按照本实用新型的血管介入装置不一定必须包括伸长管。而且，血管介入装置100可以是外周静脉导管的例子。然而，按照本实用新型的抗菌涂层可被施加到其它类型的导管上，包括中心静脉导管和外周插入的中心导管。简而言之，按照本实用新型的一个或多个实施例，任何装置，只要其包括被插入到病人的血管的可弯曲的部件，该装置就可以包括施加于上述部件上的抗菌涂层。
抗菌涂层可包括具有抗致病菌的特性的、可被施加到导管的表面上的任何材料，这些材料具有足够的刚度，以使得导管被弯曲时变为扭结的可能性最小化。例如，在某些实施例中，抗菌涂层可包括基底材料基质和一种或多种抗菌剂。在某些实施例中，基底材料基质可以是UV固化的、亲水的材料，包含具有控制释放(洗脱)特性的抗菌剂。替换地，基底材料可被涂覆抗菌涂层，当遇到流体时，抗菌剂将从抗菌涂层洗脱。
例如，在某些实施例中，基底材料可以是水软化的UV固化的丙烯酸酯-聚氨酯，或热固化的聚氨酯。在许多实施方案中，水软化材料比非软化材料更优选，因为这样的材料当被插入到病人体中和被暴露到流体时变为更加柔软。导管常常由这样的水软化材料形成。因此，使用由水软化材料组成的抗菌涂层，可以使涂层的特性与导管匹配，以使得涂层对于导管的性能和对于病人的舒适度的任何负面影响最小化。例如，在某些实施例中，抗菌涂层的硬度可以仅仅稍微超过导管的硬度。这种增加的硬度使得导管变为扭结的可能性最小化，而同时因为导管基本上保持弹性，从而在导管使用期间最少地影响病人的舒适度。
可被使用来构成本实用新型的抗菌涂层的材料的例子包括：在标题为“VascularAccessDeviceAntimicrobialMaterialsAndSolutions”的美国专利No.8,512,294；标题为“AntimicrobialCompositions”的美国专利申请No.12/397,760；标题为“AntimicrobialCoatingCompositions”的美国专利申请No.12/476,997；标题为“SystemsAndMethodsForApplyingAnAntimicrobialCoatingToAMedicalDevice”的美国专利申请No.12/490,235；和标题为“AntimicrobialCoatingForDermallyInvasiveDevices”的美国专利申请No.12/831,880中公开的那些材料。这些专利文件的每个专利文件引用在此以供参考。
在一个具体的实施例中，被使用来形成抗菌涂层的抗菌剂可以是包括醋酸氯己定(CHA)和/或葡萄糖酸氯己定(CHG)的氯己定。然而，可以使用能从基底材料或从基底材料的涂层洗脱的任何其他的抗菌剂。
图1A显示了导管101和抗菌涂层103的详细的视图。如图所示，抗菌涂层103可以从导管座102沿导管101的一部分延伸。在这个例子中，抗菌涂层103沿导管101的一半长度延伸。然而，在某些实施例中，抗菌涂层103可以沿导管101的较长的或较短的长度延伸，包括延伸到远端。
在图1A上能最清楚地看到，抗菌涂层103的近端可以具有朝导管座102方向增加的直径。导管101在从导管座102离开时最可能扭结。因此，朝导管座102方向增加抗菌涂层103的直径提供附加的抗扭结性，否则在那里最可能会发生扭结。在某些实施例中，诸如在图1A上显示的，抗菌涂层的直径的增加可以逐渐增加到使得抗菌涂层103可以具有与导管座102的突出部分相同的直径的程度。
虽然在图1和1A上抗菌涂层103被显示为仅仅延伸到导管座102，但在某些实施例中，抗菌涂层可以最接近地延伸到导管座的一部分上。另外，在某些实施例中，抗菌涂层在它接触到导管座的位置上的直径可被配置成小于导管座在该位置的直径。而且，在某些实施例中，直径不是逐渐增加的，而是可以在离导管座的某个距离上从较小的直径提高到较大的直径。因此，本实用新型囊括抗菌涂层在接近导管座时的直径的许多不同类型的增加。
图1A还显示抗菌涂层103的直径在其远端处减小到最小的量。在抗菌涂层的远端处具有最小的直径可以使得当导管101被插入时病人的任何不舒适感最小化。
图1A还显示，在某些实施例中，抗菌润滑油104可被施加到不包括抗菌涂层的导管的任何部分。然而，本实用新型囊括其中只有抗菌涂层被施加到导管的实施例，而不管抗菌涂层是否仅仅沿导管的一部分长度延伸。
图2提供血管介入装置100的截面图，其更好地显示抗菌涂层103的直径的增加。如图所示，朝向抗菌涂层103的远端，该涂层的直径是最小的。在某些实施例中，在该远端处它的直径可以是在10与100微米之间。然后，随着抗菌涂层103到达导管座102，直径逐渐增加，而形成增加的直径部分103a。该增加的直径部分103a可以在导管从导管座102离开时为导管提供增加的抗扭结性。例如，因为所述部分103a的增加的直径，导管将不可能在它从导管座离开时造成扭结的位置处充分弯曲。换句话说，增加的直径部分103a将倾向于使得导管101在它从导管座102离开时更加逐渐地弯曲，而不是在出口点处急剧地弯曲。同样地，抗菌涂层103的其他的(较小直径)部分可以为导管101提供附加的刚度，以使得可能导致扭结的任何急剧弯曲的可能性最小化。
图3示意了抗菌涂层103如何为导管101提供抗扭结性。如图所示，导管座102通常平坦地放在病人的皮肤300上。因为这样做，导管101将在从它在导管座102离开的离开点到它进入病人的皮肤300的进入点之间向下成角度。抗菌涂层103，更具体地，增加的直径部分103a使得导管101在插入点与导管座102之间更逐渐地弯曲，由此，使得扭结的可能性最小化。
图3还显示其中抗菌涂层103的长度被配置成使得涂层延伸通过皮肤300的真皮层和到达静脉301的入口的例子。这样，抗菌剂可以从抗菌涂层103被释放，直接到达真皮层，并在插入点处进入皮肤300和进入静脉301。这些部位，特别是真皮层，是可能进入静脉301的病菌的主要来源。为此，抗菌涂层103的长度可被配置成保证抗菌剂导向这些部位。
图3A提供图3的一部分的详细的图，以便显示在导管101被插入的位置的皮肤300的真皮层302。如图所示，抗菌涂层103具有足够的长度来保证抗菌涂层与真皮层接触。通过采用洗脱抗菌剂的抗菌涂层(例如，亲水的抗菌涂层)，抗菌剂可以以控制的方式被分布到真皮层(及其周围区域)，以使得来自抗菌剂的毒性的可能性最小化。
如上所述，当抗菌润滑剂被使用来对于这些真皮层提供抗菌保护时，将有很大的毒性风险，因为很难保证抗菌剂被定位到真皮层以及不会在毒性水平下被引入到病人的血管。与此相反，通过采用包括洗脱抗菌剂的基底材料的抗菌涂层103，抗菌剂可被精确地分布到真皮层302，并且以提供长期抗菌保护的速率被释放。换句话说，抗菌涂层103可以限制在装置的整个寿命内洗脱的特定的抗菌剂的总量，以及把抗菌剂集中在最大受益的区域中。
为了保证当血管介入装置100被使用时抗菌涂层103的适当的布置，抗菌涂层103可被配置成具有适当的长度。例如，在皮肤的外层与静脉的内膜层之间的组织的深度通常是在3mm与6mm之间。另外，典型地，4mm到6mm的导管保持在皮肤的外面。因此，在某些实施例中，抗菌涂层103的长度可以从导管座延伸7mm到12mm，以保证涂层的远端即使不是在静脉的内膜层之外，也至少被放置于静脉的内膜层处。
当然，在其他的实施例中，可以使用抗菌涂层的其他的长度。简而言之，当特定的血管介入装置被使用时，可以至少部分根据当使用特定的血管介入装置时保持在皮肤的外面的导管的典型的长度来选择抗菌涂层的长度。例如，许多导管包括表示导管应当被插入多深的标线或其它指示。在某些实施例中，抗菌涂层103的长度可以基于在导管座与这种类型的指示之间的导管的长度。同样地，抗菌涂层的长度也可以基于从皮肤的外层与导管被插入到的静脉的内膜层的距离(即，长度可以基于其中导管将典型地被插入的期望位置)。
本实用新型的抗菌涂层对于被使用来抽血的血管介入装置可以是特别有利的。通过以前主要被使用来注入流体到病人血管的血管介入装置来抽取血液样本，正变得越来越常见。当流体被注入时，不必太关心扭结，因为流体的压力趋向于打开可能在导管中出现的任何扭结。然而，当这些同样的装置被使用来抽取血液时，因为减小的压力以及当抽血时所使用的流体速率，而更可能出现扭结。所以，本实用新型的抗菌涂层对于阻止在血液抽取期间的扭结可以是特别有利的。
图4显示图3上所描绘的血管介入装置的替换实施例。图4与图3的不同之处在于，抗菌润滑剂310已被施加到导管101上的、不包括抗菌涂层103的部分。在某些实施例中，抗菌润滑剂310也可以至少部分延伸到抗菌涂层103。抗菌润滑剂310可以为导管101提供润滑作用，有助于插入，以及也可以在插入点提供附加的抗菌保护。例如，在导管101被插入时，抗菌润滑剂310可以沾在皮肤的真皮层上，提供立即的和集中的抗菌保护。然后，抗菌涂层103一旦位于真皮层内时，就可以不断以控制释放和目标对准的方式提供抗菌保护。抗菌润滑剂310也可以有助于阻止在导管101上和在导管101中形成血块，特别是在导管101的一个或多个远端开口处。
图5显示图3上所示的血管介入装置的另一个替换实施例。图5与图3的不同之处在于抗菌涂层103延伸到导管101的远端。在这样的情形下，也可以使用抗菌润滑剂，虽然图上未显示出。
按照本实用新型的一个或多个实施例，可以通过把未固化的基底材料分布在靠近导管座的导管上，而将抗菌涂层施加到血管介入装置。这种基底材料可以在缓慢地旋转导管(例如，在20与120转/分钟之间)的同时被施加。导管可以不断地旋转，而同时使用模具来把基底材料涂覆在导管的想要的长度上。在某些实施例中，可以使用蛤壳形模具。然后，抗菌涂层可被固化。在某些实施例中，在抗菌涂层进行固化的同时，可以不断旋转导管。
本实用新型可以以其它具体的形式被体现，而不背离它的精神或基本特征。所描述的实施例在所有的方面都应当被看作为说明性的，而不是限制性的。因此，本实用新型的范围由所附权利要求指明，而不是由以上的说明指明。来自权利要求的等价性的意义和范围内的所有的改变都应当被包括在权利要求的范围内。

Claims (20)

1.一种血管介入装置，其特征在于，包括：
导管座；
从所述导管座向远端延伸的导管；以及
被施加到所述导管的至少一部分上的抗菌涂层，所述抗菌涂层包括基底材料，所述基底材料在所述抗菌涂层被插入到病人的皮肤内时释放一种或多种抗菌剂，且所述基底材料为导管提供抗扭结特性。
2.如权利要求1所述的血管介入装置，其特征在于，所述抗菌涂层靠近所述导管座。
3.如权利要求1所述的血管介入装置，其特征在于，所述抗菌涂层包括增加的直径部分。
4.如权利要求3所述的血管介入装置，其特征在于，所述增加的直径部分靠近所述导管座。
5.如权利要求4所述的血管介入装置，其特征在于，所述增加的直径部分的直径向着所述导管座增加。
6.如权利要求1所述的血管介入装置，其特征在于，所述抗菌涂层的远端靠近所述导管的远端。
7.如权利要求6所述的血管介入装置，其特征在于，所述抗菌涂层的远端与所述导管座相隔一定距离，所述距离基于当所述导管被插入静脉时在静脉的内膜层与所述导管座之间应当存在的导管的期望长度。
8.如权利要求1所述的血管介入装置，其特征在于，所述抗菌涂层的长度在7毫米与12毫米之间。
9.如权利要求1所述的血管介入装置，其特征在于，所述基底材料是亲水性的。
10.如权利要求1所述的血管介入装置，其特征在于，所述基底材料是UV固化的丙烯酸酯-聚氨酯或热固化的聚氨酯。
11.如权利要求1所述的血管介入装置，其特征在于，所述导管包括材料并且所述基底材料的硬度大于导管的所述材料的硬度。
12.如权利要求1所述的血管介入装置，其特征在于，在所述抗菌涂层的远端处的抗菌涂层的厚度在10微米与100微米之间。
13.如权利要求1所述的血管介入装置，其特征在于，还包括：施加到所述导管上的抗菌润滑剂。
14.如权利要求13所述的血管介入装置，其特征在于，所述抗菌润滑剂被施加到不包括所述抗菌涂层的导管的一部分上。
15.一种血管介入装置，其特征在于，包括：
导管座；
从所述导管座向远端延伸的导管；以及
在所述导管上的抗菌涂层，所述抗菌涂层从所述导管座向所述导管的远端延伸，且所述抗菌涂层在靠近所述导管座处具有增加的直径部分。
16.如权利要求15所述的血管介入装置，其特征在于，所述抗菌涂层包括基底材料，所述基底材料在所述抗菌涂层被放置在病人的皮肤内时洗脱一种或多种抗菌剂。
17.如权利要求16所述的血管介入装置，其特征在于，所述抗菌涂层的硬度超过所述导管的硬度。
18.如权利要求15所述的血管介入装置，其特征在于，所述抗菌涂层的远端与所述导管座相隔一定长度，所述长度对应于当所述导管被插入静脉时在静脉的内膜层与所述导管座之间期望存在的导管的长度。
19.一种导管，其特征在于，包括：
被施加到所述导管的一部分上的抗菌涂层，所述抗菌涂层具有近端和远端，所述近端包括增加的直径部分，且所述抗菌涂层包括基底材料，所述基底材料在所述抗菌涂层被放置到病人的皮肤内时释放一种或多种抗菌剂。
20.如权利要求19所述的导管，其特征在于，还包括：
导管座，所述导管从所述导管座延伸，且所述导管位于所述导管座内以使得所述抗菌涂层的近端靠近所述导管座。
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EP3679956A1 (en) 2020-07-15
CN106535952A (zh) 2017-03-22
EP3166654A1 (en) 2017-05-17
CN110841172B (zh) 2022-02-18
BR112017000463B1 (pt) 2020-11-17
BR112017000463A2 (pt) 2017-11-07
AU2018256507B2 (en) 2020-01-02
US20190167855A1 (en) 2019-06-06
MX2017000034A (es) 2017-05-01
ES2787205T3 (es) 2020-10-15
EP3166654B1 (en) 2020-02-26
US20160008517A1 (en) 2016-01-14
US11219705B2 (en) 2022-01-11
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MX377838B (es) 2025-03-11
AU2015288075B2 (en) 2018-08-30
CA2954385C (en) 2022-03-15
CA2954385A1 (en) 2016-01-14
SG10202002835WA (en) 2020-05-28
AU2018256507A1 (en) 2018-11-22
WO2016007439A1 (en) 2016-01-14
AU2015288075A1 (en) 2017-02-23
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US10232088B2 (en) 2019-03-19
CN106535952B (zh) 2019-12-13

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