CN110198685A - 具有增大的药物递送区域的可植入装置 - Google Patents
具有增大的药物递送区域的可植入装置 Download PDFInfo
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Abstract
公开了一种具有增大的药物递送区域的可植入装置，其中安装在球囊上的预卷曲支架组件还包括药物和相关联的聚合物基质的均匀的涂层，在球囊膨胀时形成得到环形圆筒形膜结构。由药物递送医疗装置形成的圆筒形膜能够实现血管腔区域的最大覆盖区域，从而防止管腔内有任何未治疗的区域。
Description
技术领域
本发明大体上涉及药物递送医疗设备。更具体地，本发明涉及具有增大的药物递送区域的均匀涂覆的可植入装置，所述可植入装置提供血管腔内的靶病变的最大覆盖区域。
背景技术
随着从裸金属支架到药物洗脱支架的稳定转变，对冠状动脉疾病(coronaryartery disease，CAD)的治疗已经取得了巨大的进步，药物洗脱支架(drug elutingstents，DES)以比裸金属支架高很多的速率减少了再狭窄率。这些药物洗脱支架主要用于重新打开堵塞的动脉以重新恢复血液流动，并在植入DES后将复发率最小化，除了它们所带来的优点之外，它们还有一些限制，并且有足够的改进空间。与DES相关联的限制具体地发生在某些适应症中，举几个例子，如糖尿病患者、急性心肌梗塞患者、分叉病变和慢性全闭塞(chronic total occlusion，CTO)等。例如，与糖尿病患者相关联的糖尿病足(膝盖以下患者)就受到与DES相关联的限制。
目前可用的DES是在支架的金属表面上进行涂覆的，因此当植入到血管壁中时，仅有12-20％的动脉管腔得到递送的药物，这代表支架与管腔的接触区域，从而使管腔的剩余区域不能被治疗并且缺乏药物。此外，具有较差生物利用度和较差亲脂性的药物加剧了血管壁中的扩散限制。由于未治疗的区域和扩散限制，在患者体内经常发生再阻塞，根据患者的身体状况和生理学，患者与患者之间的阻塞率和再阻塞率不同。例如，糖尿病患者比非糖尿病患者具有更高的阻塞率，糖尿病患者具有扩散的增殖性和连续性的疾病类型，其中缩窄的管腔直径和管腔长度还使药物的药物递送变得复杂，这是一个尚待解决的问题。
此外，从被递送的药物的生物利用度的观点来看，考虑到药物仅涂覆在支架上，由于所递送的药物仅限于所能覆盖的支架范围，因此递送的药物就会减少。药物的高生物利用度和扩大的扩散由于上述原因常常受到影响。例如，尽管通过现有DES递送的基于雷帕霉素类的药物被证明是安全的，但与其他药物相比，这些药物具有较差的保质期，因此加剧了局灶性再狭窄。
因此，本领域需要一种改进的和基于增大的区域的药物递送装置，所述药物递送装置有效地将药物递送到血管腔/动脉的整个区域，从而防止再狭窄和不受控的细胞生长的发生。
附图说明
图1表示在常规涂层构造中，在支架和球囊上的均匀的药物与聚合物基质涂层。
图2a表示使用膨胀的球囊得到的涂层结构的横截面，图2b表示在冠状动脉脉管系统中采用具有增大的药物递送区域的可植入装置后得到的涂层结构的横截面。
图3表示基于样品的HPLC分析结果的图。
图4表示基于对照溶液/标准溶液相对于样品的HPLC分析的图。
具体实施方式
在详细描述根据本发明的实施方式之前，应观察到实施方式主要存在于改进的药物递送可植入装置的部件与医疗设备上的均匀的药物涂层的组合中。因此，所描述的部件仅包括与理解本发明的实施方式相关的那些具体细节，以免使本公开的细节变得模糊，所述细节对于受益于本文描述的的那些本领域普通技术人员将变得显而易见。
在本文献中，术语“包括(comprises)”、“包括(comprising)”或其任何其他变型旨在涵盖非排他性内含物，使得包括元素列表的过程、方法、物品或设备不只包括这些元素，而是可以包括其他未明确列出的元素，或这些过程、方法、物品或设备固有的元素。在没有更多约束的情况下，前面带有“包括……一种”的元素不排除在包括该元素的过程、方法、物品或设备中存在另外的相同的元素。
此外，在详细描述根据本发明的实施方式之前，应观察到用于描述本发明的所有科学和技术术语具有与本领域技术人员所理解的相同的含义。
本发明的各种实施方式提供了一种改进的可植入药物递送装置，所述改进的可植入药物递送装置能够将药物递送至整个血管腔区域，从而治疗整个管腔区域内的病变并增大药物递送的区域。更具体地，改进的可植入药物递送装置是安装在球囊组件上的涂覆的预卷曲支架组件，其中安装在球囊上的预卷曲支架的涂层包括一种或多种药物与一种或多种聚合物的基质的均匀的圆筒形涂层，在球囊上安装的预卷曲支架的球囊组件充气/膨胀时，所述涂层覆盖血管体腔的环形区域。
根据本发明，本发明提供了一种增大药物递送区域的可植入装置，所述增大药物递送区域的可植入装置将药物递送到冠状血管动脉和肢体血管动脉中的治疗部位。安装在球囊上的经涂覆的预卷曲支架构成单个整合的药物递送医疗设备。安装在球囊组件上的支架组件包括多个支柱部件，其中在多个支柱部件内限定有多个互连的空间区域，从而形成网状构造。将安装在球囊上的支架组件通过已知的方法进行卷曲，所述方法包括使用支架卷曲装备和手动卷曲方法的机构。
因此，安装在球囊上的预卷曲支架的涂层包括一种涂覆安装在球囊上的已预卷曲的支架的方法。所述涂层覆盖外表面，所述外表面包括支架组件的多个支柱部件的面对管腔表面，以及球囊组件的区域，所述球囊组件的区域径向地延伸并通过限定在多个支柱部件内的多个互连的空间区域而暴露，涂覆安装在球囊上的预卷曲的支架的外表面，其中球囊组件的多个部分暴露于所述涂层。
安装在球囊上的预卷曲支架上的涂层包括一种或多种药物与一种或多种聚合物的有机溶剂可溶性基质。
所述一种或多种药物选自以下的组，包括但不限于：抗再狭窄剂、抗增殖剂、抗炎剂、抗血栓药物以及抗氧化剂、免疫抑制剂、细胞抑制剂和细胞毒素剂。更具体地，所述一种或多种药物选自以下的组，包括但不限于：西罗莫司、他克莫司、紫杉醇、β-雌二醇、雷帕霉素、依维莫司、乙基雷帕霉素、佐他莫司、ABT-578、Biolimus A9以及雷帕霉素的类似物、丝裂霉素、筋霉素、新诺莫司(novolimus)、吡嘧司特钾、α-干扰素、生物活性RGD及其盐、酯或类似物。
在另一示例性实施方式中，所述药物可包括但不限于以下中的一种或多种：西罗莫司、他克莫司、紫杉醇、肝素、β-雌二醇、雷帕霉素、依维莫司、乙基雷帕霉素、佐他莫司、ABT-578、Biolimus A9、多西紫杉醇以及丝裂霉素。
所述一种或多种聚合物选自以下的组，包括但不限于：均聚物；乙交酯和丙交酯的共聚物；碳酸三亚甲基酯的共聚物；e-己内酯和聚二噁烷酮；聚乙醇酸(PGA)；聚(乳酸-共-乙醇酸)(PLGA)；聚(乙二醇)(PEG)；聚乳酸羟基乙酸(Polyglactin)；聚葡糖酸酯(Polyglyconate)；聚二氧杂环己酮；聚卡普隆(Polyglecaprone)；聚乙交酯；聚乳酸；聚羟基丁酸酯；聚(乙交酯-E-己内酯)；聚(乙交酯三亚甲基碳酸酯)；聚(L-乳酸L-赖氨酸)共聚物；基于酪氨酸的多芳基化合物；聚亚氨碳酸酯；聚碳酸酯；聚(D；L-丙交酯-氨基甲酸酯)；聚(酯酰胺)；聚对二氧环己酮；透明质酸；甲壳素；壳聚糖；聚L-谷氨酸；聚-L-赖氨酸；聚磷腈；聚[双(羧基苯氧基)磷腈]及其组合。在优选的实施方式中，聚-L丙交酯家族的生物可降解聚合物基质与一种或多种药物一起用于涂覆安装在球囊上的预卷曲支架。
涂覆安装在球囊上的预卷曲支架的方法包括：将涂层溶液喷涂在安装在球囊上的预卷曲支架上，可植入装置安置在涂覆机中。涂覆机包括但不限于：喷嘴单元、保护管、心轴固定装置以及支托。所述喷嘴单元用于喷射涂层溶液，所述涂层溶液包括溶解在低沸点溶剂中的一种或多种药物与一种或多种可生物降解的聚合物基质。此外，将预处理的涂层溶液倒入与喷嘴单元相关联的进料杯中。
参考一涂层示例，将安装在球囊上的预卷曲支架(测量为2.25*20mm)安置在涂覆机中。制备一种或多种药物与一种或多种聚合物的涂层溶液，并在具有0.5-4.0psi惰性气体压力的特定条件下，使涂覆机以5-40转/分的速度旋转，来将1ml涂层溶液喷射在安装在涂覆机上的预卷曲支架系统上。在喷涂涂层溶液时，将涂层在室温下持续干燥5分钟的时间，从而使涂层溶液中的残留溶剂蒸发。
涂覆机可以具有可旋转的心轴。药物递送可插入医疗装置可以安装在可旋转的心轴上并与可旋转的心轴一起旋转。药物递送可插入医疗装置的外表面可暴露于喷嘴单元，从而涂覆支架组件的多个支柱部件的面对管腔表面，以及球囊组件的区域，所述球囊组件的区域径向延伸并通过限定在多个支柱部件内的多个互连的空间区域暴露，涂覆安装在球囊上的预卷曲支架的外表面。
在将安装在球囊上的可插入的涂覆的预卷曲支架定位在体腔内时，安装在球囊上的预卷曲支架内的球囊在6至9个大气压之间的标称压力范围内膨胀。在球囊膨胀时，支架从而膨胀，安装在球囊上的预卷曲支架的外表面上的涂层膨胀，并且产生用于处理体腔内靶病变的均匀的圆筒形膜结构的涂层。参考测量为2.25*20mm的支架的示例包括：在涂层上的药物浓度范围为从0.7微克每平方毫米到1.8微克每平方毫米，将药物递送到体腔内的靶部位处，从而表明药物递送区域增大。
球囊上的预卷曲支架组件还包括均匀的药物和相关联的聚合物涂层，均匀的药物涂层施加在支架和球囊的外表面上，从而提供对药物递送医疗设备外部的完全覆盖。在对安装在球囊上的经涂覆的预卷曲支架内的球囊充气时，在多个支柱部件上以及在多个支柱部件内限定的多个互连的空间区域上发现涂层。
在优选的实施方式中，安装在球囊上的预卷曲支架上的涂层包括从聚合物基质中洗脱的西罗莫司药物，所述聚合物基质选自聚-L丙交酯家族的共聚物的生物可降解基质。安装在球囊上的预卷曲支架内的支架组件是钴铬支架，其在预卷曲状态下的支架和球囊的面对管腔表面上具有涂层。在支架和球囊的面对管腔表面上的涂层包括：在多个支柱部件的面对管腔表面和侧表面上的涂层；以及通过在支架组件的多个支柱部件内限定的多个互连的空间区域暴露的球囊表面的径向延伸部分上的涂层。一旦在体腔内使用药物递送装置，聚-L丙交酯的生物可降解基质通过水解降解为天然存在的乳酸，所述天然存在的乳酸在六至8个月的周期内在体腔内最终代谢为二氧化碳和水。
由涂层溶液制备的预卷曲支架上的涂层包括：从聚-L丙交酯家族的共聚物的生物可降解基质中洗脱的西罗莫司药物。在一种实施方式中，将西罗莫司溶解在50ml的甲醇中，并且在西罗莫司完全溶解在甲醇中之后，还将选自聚-L丙交酯家族的共聚物的生物可降解基质的聚合物加入到含有西罗莫司和甲醇的溶液中。在下一步骤中，通过使用超声波清洁器将包含西罗莫司和所选聚合物的溶液进行脱气。
参考图1，以常规涂层构造示出了安装在球囊上的经涂覆的预卷曲支架。图2a表示使用膨胀的球囊得到的涂层结构的横截面，图2b表示在冠状动脉脉管系统中采用可植入装置后得到的涂层结构的横截面。
根据本发明的示例性实施方式，一种或多种药物和相关联的生物可降解的聚合物基质的均匀的涂层覆盖预卷曲在球囊上的支架的外表面，其中药物递送可植入装置部署在冠状动脉/脉管系统中。在靶部位处部署药物递送装置的常规过程中，其中球囊的膨胀在从45秒至60秒的范围内进行，在血管的湿润状态下产生具有均匀的圆筒形膜结构的药物和聚合物基质涂层。在冠状动脉血管或肢体血管应用中部署支架的期间，维持从45秒至60秒范围的常规的充气期。如图2a所描绘，与动脉壁的壁接触的黑色圆圈表示在经涂覆的球囊膨胀时的均匀的圆筒形膜结构，从而将药物递送到整个病变处以具有最大的覆盖区域。
各种实施方式包括用于处理体腔内的多个病变的方法，所述多个病变与多个医疗状况相关联。所述医疗状况可以是以下中的一者或多者：再狭窄、阻塞的体腔、动脉粥样硬化、心肌梗塞以及体腔中的斑块积聚。体腔可以是例如血管、尿道、食道、输尿管以及胆管。在优选的实施方式中，安装在球囊上的经涂覆的预卷曲支架处理糖尿病患者的冠状动脉/肢体动脉中的病变。
在一种实施方式中，安装在球囊上的预卷曲支架的外表面上的涂层确保支架组件的内表面上没有涂层，因此多个支柱部件的管腔表面没有任何涂层。在多个支柱部件的管腔表面下的球囊的部分也没有涂层，从而加速再内皮化过程，特别是在冠状动脉或肢体动脉中。
与管腔接触的均匀的圆筒形膜结构有利地保留在冠状动脉或肢体动脉的管腔中，从而提供一种环形构造。这种环形构造有利于药物的爆裂释放以及药物适当的从数天到数月的持续释放，从而帮助具有再狭窄或狭窄的再次发生的医疗状况的糖尿病患者，并进一步防止管腔中的细胞不受控的生长。
在一示例中，安装在球囊上的经涂覆的预卷曲支架包括大小为3.00×20mm的预卷曲支架。按照精确的称重天平称重，涂层溶液中使用的西罗莫司的量/重量为5mg。涂层溶液包括：将5mg西罗莫司溶解在添加有25ml甲醇的琥珀色的100ml标准容量瓶中。将所得涂层溶液在超声波清洁器中进行持续2分钟时间的超声处理，在超声处理之后对涂层溶液进行脱气。在涂层溶液脱气后，涂层溶液的理论标准溶液浓度为50μg/ml，并且还制备了对照/标准以用于比较分析。
因此，将安装在球囊上的预卷曲支架浸入含有涂层溶液的琥珀色的10ml标准容量瓶中。使用具有0.45滤膜的针筒过滤器过滤涂层溶液，并将所述涂层溶液装入HPLC小瓶以用于进一步分析。分析用的HPLC系统包括UV-VIS检测器和色谱柱：BDS HYPERSIL C18，其中尺寸为250×4.6mm，并且所使用的颗粒大小为5μm。另外，操作参数包括：流速为1ml/min、在277nm处为λ最大值、自动进样体积为20μl、柱温为40℃(±2℃)、样品温度为15℃(±1℃)以及运行时间为12分钟。
图3示出了基于样品的HPLC分析结果的图。参考图3，在注射涂层溶液后药物的平均覆盖面积为878217。
图4示出了基于对照溶液/标准溶液的HPLC分析的图。参考图4，相对于对照溶液/标准溶液的平均覆盖面积为3147981。
对于样品相对于标准溶液/对照溶液，使用以下公式计算在安装在球囊上的预卷曲支架上涂覆的药物量：
因此，对于测量为3.00×20mm的预卷曲支架，使用样品的平均覆盖面积和标准溶液/对照溶液的平均覆盖面积计算的药物含量为136.56μg。
在另一实施方式中，具有安装在球囊上的预卷曲支架组件的增大药物递送区域的均匀预涂覆的可植入装置用于治疗急性心肌梗塞(acute myocardial infraction，AMI)患者以及含有血栓的病变(thrombus containing lesion，TCL)患者。治疗AMI患者和TCL患者的现有方法包括通过提供链激酶来溶解血栓的溶栓。在另一种方法中，使用血栓抽吸导管从病变中吸出血栓，然后植入DES。尽管这些方法在植入后成功去除血栓，但由于病变内部的支架血栓或残物，通常会造成无法流动或流动缓慢的情况。考虑到植入DES时存在急性血栓形成复发的高趋势，需要在植入DES后避免亚急性或晚期血栓。因此，在采用根据本发明的药物递送可植入装置时，均匀的圆筒形膜结构的适度拉伸强度阻止了管腔内的急性、亚急性以及晚期血栓形成的发生，进一步消除了流动缓慢和无法流动的状况。
本发明的各种实施方式有利地提供药物和相关联的聚合物基质涂层的环形适度拉伸强度膜结构，提供在没有再狭窄的情况下的管腔内的病变的最大覆盖，并且防止血管腔区域内的急性、亚急性以及晚期血栓的形成。因此，本发明结合了药物洗脱支架的益处以及药物洗脱球囊的益处，并增加了体腔内的药物的可用性。
本领域技术人员将认识到，本文描述的上述优点和其他优点仅仅是示例性的，并不意味着完全呈现了本发明的各种实施方式的所有优点。
在前述临时说明书中，已经描述了本发明的特定实施方式。然而，本领域普通技术人员认识到，在不脱离本发明的范围的情况下，可以对本发明进行各种修改和改变。因此，临时说明书应被视为说明性而非限制性的意义，并且所有这些修改旨在包括在本发明的范围内。
Claims (11)
1.一种涂覆安装在球囊上的预卷曲支架的方法，所述方法包括：
将支架组件卷曲在球囊组件上以形成安装在球囊上的预卷曲支架，所述支架组件包括多个支柱部件，其中所述多个支柱部件内限定有多个互连的空间区域；以及
涂覆安装在球囊上的所述预卷曲支架的外表面，其中所述球囊组件的多个部分暴露于所述涂覆，形成均匀的圆筒形涂层。
2.根据权利要求1所述的方法，其中，通过喷涂的方法涂覆安装在球囊上的所述预卷曲支架。
3.根据权利要求1所述的方法，其中，所述喷涂包括沿轴向方向和旋转方向涂覆一种或多种药物与聚合物的有机溶剂可溶性基质。
4.根据权利要求1所述的方法，其中，所述涂层包括组合物，所述组合物包括一种或多种药物与一种或多种聚合物的基质。
5.根据权利要求1所述的方法，其中，所述涂层溶液包括溶解在快速蒸发溶剂中的一种或多种药物与一种或多种聚合物。
6.根据权利要求1所述的方法，其中，涂覆安装在球囊上的所述预卷曲支架的外表面使得安装在球囊上的所述预卷曲支架的内表面不具有涂层。
7.一种安装在球囊上的经涂覆的预卷曲支架，安装在球囊上的所述经涂覆的预卷曲支架包括一种或多种药物与一种或多种聚合物的基质的均匀的圆筒形涂层，在安装在所述球囊上的所述预卷曲支架的球囊组件充气/膨胀时，所述均匀的圆筒形涂层覆盖血管体腔的环形区域。
8.根据权利要求6所述的安装在球囊上的所述经涂覆的预卷曲支架，其中，所述均匀的圆筒形涂层处理了所述体腔内的病变。
9.根据权利要求6所述的安装在球囊上的所述经涂覆的预卷曲支架，其中，所述药物选自以下中的至少一种：抗再狭窄剂、抗增殖剂、抗炎剂、抗血栓形成剂、抗氧化剂、免疫抑制剂、细胞抑制剂以及细胞毒素剂。
10.根据权利要求6所述的安装在球囊上的所述经涂覆的预卷曲支架，其中，所述药物选自以下中的至少一种：西罗莫司、他克莫司、紫杉醇、β-雌二醇、雷帕霉素、依维莫司、乙基雷帕霉素、佐他莫司、ABT-578、Biolimus A9以及雷帕霉素的类似物、丝裂霉素、筋霉素、新诺莫司、吡嘧司特钾、α-干扰素、生物活性RGD及其盐、酯或类似物。
11.根据权利要求6所述的安装在球囊上的所述方法经涂覆的预卷曲支架，其中，所述至少一种聚合物是以下中的至少一种：均聚物；乙交酯和丙交酯的共聚物；碳酸三亚甲基酯的共聚物；e-己内酯和聚二噁烷酮；聚乙醇酸(PGA)；聚(乳酸-共-乙醇酸)(PLGA)；聚(乙二醇)(PEG)；聚乳酸羟基乙酸；聚葡糖酸酯；聚二氧杂环己酮；聚卡普隆；聚乙交酯；聚乳酸；聚羟基丁酸酯；聚(乙交酯-E-己内酯)；聚(乙交酯三亚甲基碳酸酯)；聚(L-乳酸L-赖氨酸)共聚物；基于酪氨酸的多芳基化合物；聚亚氨碳酸酯；聚碳酸酯；聚(D；L-丙交酯-氨基甲酸酯)；聚(酯酰胺)；聚对二氧环己酮；透明质酸；甲壳素；壳聚糖；聚L-谷氨酸；聚-L-赖氨酸；聚磷腈；聚[双(羧基苯氧基)磷腈]及其组合。
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| US20060036311A1 (en) * | 2002-08-23 | 2006-02-16 | Yasuhide Nakayama | Stent and process for producing the same |
| US20060043650A1 (en) * | 2004-08-26 | 2006-03-02 | Hossainy Syed F | Methods for manufacturing a coated stent-balloon assembly |
| DE102007034991A1 (de) * | 2007-07-26 | 2009-01-29 | Biotronik Vi Patent Ag | Verfahren zur Herstellung eines gecrimpten Stents, Verwendung einer Polymerbeschichtung und Medizinprodukte |
| CN101589971A (zh) * | 2009-06-30 | 2009-12-02 | 北京中孵友信医药科技有限公司 | 第三代pci治疗性球囊支架系统、制备方法及应用 |
| US20130261723A1 (en) * | 2012-03-30 | 2013-10-03 | Abbott Cardiovascular Systems Inc. | Treatment Of Diabetic Patients With A Drug Eluting Stent And A Drug Coated Balloon |
| CN103990186A (zh) * | 2014-05-28 | 2014-08-20 | 中国中医科学院西苑医院 | 一种具有防治再狭窄药物涂层的支架及其制备方法 |
| CN106334220A (zh) * | 2016-10-20 | 2017-01-18 | 浙江归创医疗器械有限公司 | 医疗器械上药物涂层的涂覆工艺 |
Also Published As
| Publication number | Publication date |
|---|---|
| BR112019013660A2 (pt) | 2020-01-21 |
| RU2019120256A3 (zh) | 2022-02-01 |
| EP3661464A1 (en) | 2020-06-10 |
| JP2020534876A (ja) | 2020-12-03 |
| US20200368050A1 (en) | 2020-11-26 |
| CA3049312A1 (en) | 2019-02-14 |
| WO2019030770A1 (en) | 2019-02-14 |
| IL268309A (en) | 2019-09-26 |
| ZA201903981B (en) | 2022-03-30 |
| BR112019013660B1 (pt) | 2024-01-02 |
| AU2018313122A1 (en) | 2019-07-11 |
| IL268309B (en) | 2022-02-01 |
| RU2019120256A (ru) | 2020-12-28 |
| EP3661464A4 (en) | 2021-04-21 |
| JP7170647B2 (ja) | 2022-11-14 |
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