CN110201242A - 一种医疗装置 - Google Patents
一种医疗装置 Download PDFInfo
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- CN110201242A CN110201242A CN201910487518.5A CN201910487518A CN110201242A CN 110201242 A CN110201242 A CN 110201242A CN 201910487518 A CN201910487518 A CN 201910487518A CN 110201242 A CN110201242 A CN 110201242A
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Abstract
本发明涉及一种医疗装置,包括球囊,所述球囊包括多个褶,生物相容性基质,所述生物相容性基质放置于所述球囊和覆盖物之间,其中,所述覆盖物封闭所述生物相容性基质和所述球囊,并且其中,当所述球囊膨胀时所述封闭物的渗透性大于未扩展状态下所述封闭物的渗透性。本发明还涉及可膨胀的球囊,其被可扩展的覆盖物所封闭,所述覆盖物在扩展期间变得更加多孔/可渗透。所述球囊被含有药物活性剂的基质所包衣或者封闭。在所述球囊的扩展期间,药物活性剂通过可扩展的覆盖物被释放或者挤压至体腔(如动脉或者静脉)中。本发明还提供了通过将可膨胀的球囊递送到特定体腔来治疗疾病或病症的方法。
Description
本申请是申请日为2017年02月08日,申请号为201780010525.5,发明名称为“药物洗脱球囊”的中国发明专利申请的分案申请。
技术领域
本发明为可膨胀的球囊(inflatable balloon),其被可扩展的覆盖物(expandable cover)封闭,所述覆盖物在扩展期间变得更加多孔/可渗透。所述球囊被含有药物活性剂的基质包衣或者封闭。在所述球囊的扩展期间,所述药物活性剂通过所述可扩展的覆盖物(例如,膜)释放或者挤压进入体腔如动脉或者静脉中。本发明还提供了将可膨胀的球囊以及所述药物活性剂递送至体腔的方法。
背景技术
动脉粥样硬化涉及动脉壁增厚。病理上,动脉粥样硬化是由白细胞(也称为泡沫细胞)的侵入和积聚以及在动脉壁中形成纤维脂质斑块的内膜平滑肌细胞的增殖引起的。潜在池,动脉粥样硬化可以影响任何动脉血管,无论是在中央还是在外周,导致任何动脉变窄甚至完全阻塞。血管成形术是一种治疗性技术,涉及阻塞动脉的机械扩张。
经皮冠状动脉介入术(PCI)也被称为冠状动脉血管成形术,是用于治疗由于冠状动脉病变或梗阻而引起的心脏冠状动脉狭窄或狭窄部分的治疗方法。PCI中可以使用引导导管来为另一个导管或装置(微导管,支架,球囊等)提供支撑并使其更容易通过以进入目标部位。例如,引导导管可以通过主动脉插入并进入冠状动脉口。然后将引导导管插入到待治疗的动脉的开口或口中,并且使引导线或其他器械穿过引导导管的腔并插入到动脉中超过闭塞或狭窄处。在外周,使用经皮穿腔介入术或者PTA来治疗动脉如髂动脉、股动脉、腘动脉、肾动脉或者颈动脉的变窄或者狭窄。神经血管的血管成形术作为治疗中风的手段也越来越重要。
在某些情况下,可以在血管成形术期间将支架插入血管中以维持腔的开放。然而,支架的己知并发症是再狭窄,其中由于平滑肌细胞的侵入而导致血管变窄,并且响应于血管成形术的损伤而累积细胞外基质。为了预防再狭窄,支架可以包衣有各种不同的抗增殖药剂,例如西罗莫司(药物洗脱支架)。虽然药物洗脱支架已被证明在治疗冠状动脉闭塞方面非常有效,但是在支架植入之后,仍有小的、但是可测量的发生率出现由支架血栓形成所导致的严重并发症。Luscher等人Circulation 115:1051(2007)。支架血栓形成具有非常高的死亡率和发病率(出处同前)。
药物洗脱球囊(DEB)提供POBA(普通老年血管成形术球囊)或裸露或药物洗脱支架的替代品。重要的是,与其他干预方式相比,DEB可以提供几个明显的优势。Waksman等人Circulation:Cardiovascular Interventions2:352(2009)。例如,药物洗脱支架对长的弯曲血管、小血管(即直径小于2.5mm)或漫长的弥漫性钙化病变不起作用(出处同前)。考虑到药物从球囊表面到血管壁的转移的方法和机制,第一代DEB限于紫杉醇的递送。而且,长效抗增殖作用不需要紫杉醇的持续释放。药物洗脱球囊允许在短时间内快速输送相对大量的药物。药物洗脱球囊的其他优点包括(a)均匀的药物转移至整个血管壁;(b)在不超过一周的时间内迅速释放高浓度的药物;(c)没有异物(即支架)可减少慢性炎症和延缓引发血栓形成;(d)没有支架允许动脉的原始解剖结构保持完整,例如在分叉或小血管的情况下;和(e)局部给药,可降低对抗血小板治疗的依赖(出处同前)。
因此,持续需要开发药物洗脱球囊,其能够在一段持续的时间内有效地将药物递送至血管空间或任何其它体腔。
发明内容
本发明涉及可膨胀的球囊,其被可扩展的覆盖物封闭,所述覆盖物在扩展期间变得更加多孔或者可渗透。所述球囊可包括包衣(coating)。所述包衣可进一步包括至少一种药剂。所述包衣可为生物相容基质。在所述球囊的扩展期间,所述药物活性剂通过所述可扩展的覆盖物(例如,膜)释放进入体腔如动脉或者静脉中。本发明还提供了通过以下方法治疗病症或者疾病的方法:将可膨胀的球囊递送(或者插入)至体腔,随后将药物活性剂递送至所述体腔。
所述可膨胀的球囊可为定位在导管或其他柔性轴装置(catheter or otherflexible shaft device)上的血管成形术球囊。所述球囊包衣有至少一种药物活性剂。所述包衣可为任何生物相容基质的形式。例如,生物相容基质可以是半固体,如凝胶、带、管、螺旋切割管或其他形式的缠绕材料(wrapping)。所述药物活性剂可悬浮、包埋或者溶解在生物相容基质中。所述药物活性剂可与所述生物相容基质可溶混或者不可溶混。在一些实施方案中,所述药物活性剂可包封在一种或者多种粒子如一种或者多种微球、脂质体、纳米粒子(例如,纳米凝胶)或者其它粒子如环糊精(cyclodextran)中。所述凝胶可为水凝胶,其可被干燥,然后在所述球囊在体内或者体外扩展之前再水合。
在一些实施方案中,所述球囊和所述生物相容基质被贴合于所述球囊的可扩展的覆盖物封闭。当所述球囊在非扩展状态中时,所述可扩展的覆盖物可为半可渗透或者多孔的。在其它实施方案中,当所述球囊在非扩展状态中时,所述可扩展的覆盖物基本上为不可渗透或者非多孔的。
当所述球囊扩展时,所述可扩展的覆盖物向外部环境(例如血浆、血液、体液等)的渗透性或者多孔性增加。例如,在所述球囊膨胀期间,所述球囊的扩展拉伸或者径向扩展所述可扩展的覆盖物。随着所述球囊扩展,在所述可扩展的覆盖物中,孔或者通道可形成或者可增加尺寸和/或数目。在一些实施方案中,当包衣的球囊最初暴露于含水环境如血浆或者磷酸盐缓冲盐水一段限定的时间时,流体能够渗透所述可扩展的覆盖物并开始溶解所述生物相容基质。随着可扩展的球囊膨胀,所述生物相容基质的这种最初溶解促进所述包衣的扩展(流体化)。随着所述球囊扩展,血浆或者其它含水流体可继续扩散进入在所述可扩展的覆盖物和所述球囊之间的环形空间或者腔中。一旦膨胀,所述包衣继续溶解,从而将所述药物活性剂通过所述可扩展的覆盖物释放进入体腔如动脉或者静脉中。在一个实施方案中,所述包衣最初被脱水。一旦与血浆或者其它含水流体接触,那么所述包衣重新水合,然后溶解。所述药物活性剂的释放速率是可变的并且取决于一些不同因素,包括所述生物相容基质的重新水合过程和性质、所述球囊的扩展程度的速率和所述可扩展的覆盖物的多孔性/渗透性的程度。
所述可扩展的覆盖物可包括多个孔。
所述可扩展的覆盖物在扩展状态中的渗透性和/或多孔性大于所述可扩展的覆盖物在非扩展状态中的渗透性和/或多孔性。与所述可扩展的覆盖物在非扩展状态中的渗透性和/或多孔性相比,所述可扩展的覆盖物在所述扩展状态中的渗透性和/或多孔性可大至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少100%、至少120%、至少150%、至少200%、至少250%、至少300%,或者大约20%至大约400%、大约50%至大约300%,或者大约100%至大约200%。
在一个实施方案中,所述包衣为或者包含生物相容基质如水凝胶。
所述药剂可包封在所述生物相容基质中的多个微球、纳米粒子(例如,纳米凝胶)、脂质体,或者环糊精粒子中。在一些实施方案中,所述纳米粒子由纳米凝胶形成,所述纳米凝胶可由N-异丙基丙烯酰胺、N-乙烯基吡咯烷酮和聚乙二醇化马来酸及其组合形成。
在另一实施方案中,所述包衣为薄膜,其可由以下物质形成:羟丙基甲基纤维素(HPMC)、羧甲基纤维素(CMC)、羟丙基纤维素(HPC)、聚(乙烯基吡咯烷酮)(PVP)、聚乙烯醇(PVA)、聚(氧化乙烯)(PEO)、芽霉菌糖(pullulan)、壳聚糖、藻酸纳、角叉菜胶或者明胶。所述包衣可为带的形式,所述带可围绕所述球囊缠绕,例如,以螺旋构型。
在一个实施方案中,所述可扩展的覆盖物由聚合物如膨胀聚(四氟乙烯)(ePTFE)或者超高分子量聚乙烯形成。
在一些实施方案中,所述药物活性剂在所述球囊上的包衣中的总表面载荷为大约lμg/mm2至大约50μg/mm2。
当将所述可膨胀的球囊在水溶液中在37℃孵育大约1小时时,当所述球囊在非扩展状态中时,小于大约10%(w/w)的所述药物活性剂从在非扩展状态中的所述可膨胀的球囊中释放。在一些实施方案中,当将所述可膨胀的球囊在水溶液中在37℃孵育l小时时,当所述球囊扩展时,大于大50%(w/w)、大于大约60%(w/w)、大于大约70%(w/w)、大于大约80%(w/w)、大于大约90%(w/w),或者大于大约95%(w/w)的所述药物活性剂从在扩展状态中的所述可膨胀的球囊中释放。在一些实施方案中,当将所述可膨胀的球囊在水溶液中在37℃孵育l小时时,大约100%(w/w)的所述药物活性剂从在扩展状态中的所述可膨胀的球囊中释放。
当所述球囊扩展时,孔的直径为大约1μm至大约100μm或者大约25μm至大约80μm。
所述药物活性剂可为抗增殖剂如紫杉醇、依维莫司、他克莫司、西罗莫司、佐他莫司、biolimus和雷帕霉素或其混合物。
在一个实施方案中,所述可扩展的覆盖物为管状。
所述可膨胀的球囊可用于治疗疾病或者病症。所述方法可包括将所述可膨胀的球囊插入体腔中。体腔可为动脉如冠状动脉、腹股沟下动脉、主髂动脉、锁骨下动脉、肠系膜动脉、基底动脉和肾动脉。替代地,体腔可为尿道、膀脱、输尿管、食管、胃、结肠、气管、支气管或者肺泡。
在一些实施方案中,本公开提供可膨胀的球囊,其包含至少一个可膨胀的主体部分和至少一种药物活性剂。所述可膨胀的球囊的可膨胀的主体部分被覆盖物覆盖,其中至少当所述可膨胀的主体部分在扩展状态中时,所述覆盖物对于所述药物活性剂是可渗透的,其中所述药物活性剂驻留在所述主体部分和所述覆盖物之间。在使用所述可膨胀的球囊期间,所述药物活性剂从所述可膨胀的主体部分释放。
在一些实施方案中,所述覆盖物为可扩展的覆盖物,以及其中,当所述覆盖物在扩展状态中时,所述覆盖物的渗透性大于当所述覆盖物在非扩展状态中时所述覆盖物的渗透性。
所述装置为可膨胀的球囊,其可被直于导管或者其它柔性轴装直上。在一个实施方案中,所述导管的球囊段被包封、包衣或者以其他方式提供有至少一种治疗或者药物活性剂如依维莫司、他克莫司、西罗莫司、佐他莫司、biolimus、雷帕霉素或者等同活性药物成分,其被包封或者悬浮在生物相容基质中。
在一些实施方案中,可将所述药物活性剂包埋、层合、悬浮或者溶解在基质如凝胶中。所述凝胶或者基质可为水凝胶,其可被干燥并在所述球囊在体内扩展之前重新水合。在一个实施方案中,所述凝胶基质包含可水合的悬浮液。在一个实施方案中,所述凝胶基质可被脱水。
在一些实施方案中,所述球囊和所述基质被可扩展的覆盖物包封。
所述可扩展的覆盖物可为具有多个孔(具有平均尺寸)的聚合物膜(或者可扩展的膜)。在一些实施方案中,在所述膜的扩展状态中所述孔的平均尺寸大于在所述膜的非扩展状态中孔的平均尺寸。在一些实施方案中,所述膜在非扩展状态中是不可渗透或者半可渗透的。当所述球囊扩展时,覆盖物的渗透性可增加。例如,在所述球囊导管膨胀期间,所述球囊主体的扩展拉伸所述膜,以及孔或者通道可在覆盖物中或者穿过覆盖物形成,并随着所述球囊扩展增加直径。当膜扩展时,所述孔直径或者材料多孔性可为大约1μm至大约100μm,或者大约20μm至大约80μm或者大约1μm至50μm。当未扩展时所述膜可为疏水的和不可渗透的,而一旦所述球囊膨胀和在所述基质上施加压力,则所述基质被挤压通过所述膜。
在一些实施方案中,所述可膨胀的球囊包含纵向轴线和多个沿着所述球囊的纵向轴线折叠的褶。
所述球囊可包衣有至少一种药物活性剂。
所述覆盖物可形成为可扩展的管状套筒,其封闭所述球囊,同时在非膨胀状态中基本上贴合于所述球囊。在一些实施方案中,所述覆盖物包含管状套筒,其在所述球囊的至少所述可膨胀的主体部分上提供,以及所述覆盖物基本上贴合于在所述球囊的非膨胀状态中的所述球囊的主体部分。
在一些实施方案中,所述覆盖物可由编织物形成。
所述覆盖物可包括具有多孔性的多孔层(例如,弹性体多孔层)。在一个实施方案中,在所述层的扩展状态中所述层的多孔性大于在所述层的非扩展状态中所述层的多孔性。
当扩展时,所述可扩展的覆盖物的多孔性可大于在非扩展状态中所述可扩展的覆盖物的多孔性。所述可扩展的覆盖物可具有多个孔。与所述非扩展状态相比,在扩展之后,在所述扩展状态中所述可扩展的覆盖物的多孔性大大约20%至大约400%、大约50%至大约300%,或者大约100%至大约200%。
所述药物活性剂悬浮在基质中。所述基质可为凝胶如水凝胶。在所述球囊扩展期间,所述治疗剂被释放至体腔如血管或者其它体腔。
所述覆盖物可由聚合物如ePTFE或者超高分子量聚乙烯形成。
在一些实施方案中,可将所述药物活性剂悬浮或者包封在多个可生物降解的纳米尺寸和/或微米尺寸的微体中,例如尺寸为数纳米至数微米的珠、球或者腔室。这些可生物降解的微体可悬浮和分布(例如,均匀地)在(进一步的)基质中。在一个实施方案中,所述球囊的可膨胀的主体部分包衣有含有所述微体的所述基质。在一个实施方案中,所述覆盖物包衣有含有所述微体的所述基质。在一个实施方案中,所述微体悬浮在可溶膜中,所述可溶膜可围绕所述球囊的至少所述可膨胀的主体部分缠绕。所述膜可包括含有所述微体的水可降解基质。在一个实施方案中,所述膜为含有所述微体的溶剂浇铸(solvent cast)或者挤出的薄膜制剂。在一个实施方案中,所述膜包含由麦芽三糖单元组成的多糖聚合物,尤其是被称为芽霉菌糖的多糖聚合物。在一个实施方案中,所述膜含有5%至30%(w/w)的所述药物活性剂。在一个实施方案中,所述膜包含选自以下的一种或者多种辅剂:稳定剂、增稠剂,和渗透性增强剂。
具体地,所述(进一步的)基质可形成管、螺旋切割管状结构、带或者膜,其可围绕所述球囊的可膨胀的部分缠绕。所述膜可为水可溶胀的脱水膜,其在接触水时降解和溶解(在体内)。然后所述纳米/微米主体被放出或者挤压通过所述覆盖物并进入周围的体腔组织,具体为动脉或者静脉,同时所述球囊在体内膨胀,然后将基于药物组合物历经延长的时间段释放所述药物活性剂。通常,所述延长的时间段可为超过25天,具体为超过30夭。所述主体可包含多达5%w/w至30%w/w的活性药物成分。
所述膜可包含由麦芽三糖单元组成的多糖聚合物,尤其是被称为芽霉菌糖的多糖聚合物。芽霉菌糖为由麦芽三糖单元组成的多糖聚合物,也被称为α-1,4-;1,6-葡萄糖。麦芽三糖中的三个葡萄糖单元通过α-1,4糖苷键互相连接,而连续的麦芽三糖单元通过α-1,6糖苷键相互连接。芽霉菌糖是通过真菌出芽短梗霉菌从淀粉产生的。芽霉菌糖主要用于细胞抵抗干燥和掠食。这种多糖的存在也促进了分子进出细胞的扩散。
所述膜可包含一种或者多种选自以下的辅剂:稳定剂、增稠剂和渗透性增强剂。
在一些实施方案中,当所述球囊未膨胀时,在含水环境中在体温在大约1小时内,小于大约10%(w/w)的所述药物活性剂从所述球囊中释放。在一些实施方案中3当所述球囊膨胀时,在含水环境(如PBS)中在体温在大约1小时内,大于大约50%(w/w)、60%(w/w)、70%(w/w)或者80%(w/w)的所述药物活性剂从所述球囊中释放。
在一些实施方案中,所述药物活性剂包含抗增殖剂如依维莫司、他克莫司、西罗莫司、佐他莫司、biolimus、雷帕霉素、M-tor抑制剂活性剂,或者药学上的等同试剂。
在一些实施方案中,5%至30%w/w的所述药物活性剂存在于所述基质中。
本公开还提供了导管,其包含如本文中所述的可膨胀的球囊。
附图说明
图1显示引导线和在非扩展状态中的球囊。
图2显示在扩展状态中的球囊。
图3显示具有褶和可扩展的覆盖物的在非扩展状态中的球囊的横截面视图。
图4显示在扩展状态中挤出基质的球囊。
图5显示图4的放大图。
图6显示在扩展状态中挤出所述基质/凝胶的球囊的横截面视图。
图7显示凝胶基质,其形成围绕所述球囊以螺旋构型缠绕的薄膜。
图8显示由可扩展的覆盖物和在缠绕物中形成的凝胶基质封闭的在非扩展状态中的球囊的横截面视图。
图9显示作为螺旋缠绕物形成的,用可扩展的覆盖物封闭的基质,和通过所述孔/缝隙挤出所述凝胶的球囊的放大图。
具体实施方式
本公开提供了可膨胀的球囊,其被可扩展的覆盖物封闭,所述覆盖物在扩展期间变得更加多孔/可渗透。所述球囊用含有药物活性剂的基质包衣或者封闭。在所述球囊扩展期间,所述药物活性剂通过可扩展的膜释放进入体腔如动脉或者静脉中。本发明还提供了通过将所述可膨胀的球囊递送至动脉、静脉或者体腔治疗疾病或者病症的方法。
所述可膨胀的球囊可为置于导管或者其它柔性轴装置上的血管成形术球囊。所述球囊包衣有至少一种药物活性剂。所述包衣可为任何生物相容基质的形式(本文中使用的包衣是指(放置)在所述球囊和所述可扩展的覆盖物之间的包衣、覆盖层、封闭物或者布置物)。例如,所述生物相容基质可为半固体如凝胶。掺入药物活性剂的包衣也可使用带围绕所述球囊缠绕,从而封闭所述球囊,所述带可为螺旋、螺旋切割管或者螺旋切割缠绕材料的形式。可将所述球囊用所述生物相容基质缠绕l、2、3、4、5、6、7、8、9、10…n次。所述药物活性剂可悬浮、包埋或者溶解在生物相容基质如凝胶中。所述药物活性剂可与所述生物相容基质可溶混或者不可溶混。在一些实施方案中,所述药物活性剂可包封在粒子如脂质体、纳米粒子或者其它粒子如环糊精中。所述凝胶可为水凝胶,其可被干燥,然后在所述球囊在体内或者体外扩展之前重新水合。
本文中使用的术语"药物活性剂"可与术语"药剂"或者"药物"互换。
所述球囊和所述生物相容基质被贴合于所述球囊的可扩展的覆盖物封闭(本文中使用的封闭的、封闭着或者封闭是指包围、覆盖、封闭或者包封)。所述可扩展的覆盖物可完整地封闭整个球囊或者仅封闭所述球囊的部分。在
所述可扩展的覆盖物和所述球囊之间存在环形空间或者腔,其可被密封,即,不与导管流体连通,或者替代地,环形空间或者腔可与导管流体连通。优选地,当所述球囊在非扩展状态中时,所述可扩展的覆盖物为半可渗透或者多孔的。当所述球囊扩展时,所述可扩展的覆盖物向外部环境(例如,血浆、血液、体液等)的多孔性或者渗透性增加。例如,在所述球囊导管膨胀期间,
所述球囊的扩展拉伸或者径向扩展所述可扩展的覆盖物。作为这种扩展的结果,孔或者通道可在所述可扩展的覆盖物中形成;随着所述球囊扩展,这些孔或者通道的尺寸或者数目增加。当包衣的球囊最初暴露于含水环境(例如,血浆或者磷酸盐缓冲盐水)限定的时间段时,流体能够渗透所述可扩展的覆盖物并开始溶解所述基质。随着可扩展的球囊膨胀,这种最初溶解促进所述包衣的扩展(流体化)。随着所述球囊扩展,血浆或者其它含水流体能够继续扩散进入在所述可扩展的覆盖物和所述球囊之间的环形空间或者腔。一旦膨胀,所述包衣继续溶解,从而将所述药物活性剂通过所述可扩展的覆盖物释放进入体腔如动脉或者静脉(本文中使用的释放是指单独的或者包封在微球、脂质体、纳米粒子(例如,纳米凝胶)、环糊精或者其它粒子中的或者与所述生物相容基质结合的药物活性剂释放、挤出、挤压、爆发或者扩散通过所述可扩展的覆盖物)中。在一个实施方案中,所述包衣最初被脱水。一旦与血浆或者其它含水流体接触,那么所述包衣变得充分重新水合,然后溶解。所述药物活性剂的释放速率是可变的,以及取决于一些不同变量,包括所述生物相容基质的重新水合过程和性质、所述球囊扩展的程度的速率和所述可扩展的覆盖物的多孔性/渗透性的程度。
可用本发明的球囊治疗的疾病包括但不限于冠状动脉疾病和外周动脉疾病以及其他疾病。可用本发明的球囊或者方法治疗的疾病或者病症的非限制性实例包括动脉粥样硬化、冠状动脉的动脉粥样硬化疾病(CAD)、外周动脉的动脉粥样硬化疾病(PAD)、动脉变窄等。
动脉粥样硬化是世界上死亡和残疾的主要原因之一。动脉粥样硬化涉及在动脉的腔表面沉积脂肪斑块。脂肪斑块在动脉的腔表面上的沉积导致动脉的横截面积变窄。最终,这种沉积阻断了远离病变的血流,从而引起由动脉供应的组织的缺血性损伤。冠状动脉为心脏提供血液。冠状动脉的动脉粥样硬化疾病(CAD)是美国最常见的、严重的、慢性的、危及生命的疾病之一。根据疾病控制中心的统计,每年有37万人死于CAD,73.5万美国人患有心脏病或心肌梗死(https://www.cdc.gov/heartdisease/facts.htm.2017年2月5日检索)。冠状动脉腔的变窄导致心肌被破坏,首先是心绞痛,随后是心肌梗塞,最后导致死亡。
动脉变窄可发生在冠状动脉以外的血管中,包括颈动脉、主髂动脉、腹股沟下动脉、远侧股深动脉、远侧腘动脉、胫骨动脉、锁骨下动脉和肠系膜动脉。外周动脉的动脉粥样硬化疾病(PAD)的患病率取决于受影响的特定解剖部位以及用于诊断闭塞的标准,但是估计美国有850万人患有PAD(https://www.cdc.gov/dhdsp/data statistics/fact sheets/ fs pad.htm,2017年2月5日检索)。传统上,医生已经使用间歇性跛行的测试来确定PAD是否存在。
本发明还提供了通过将药物活性剂从可膨胀的球囊通过可扩展的覆盖物释放进入不同于血管空间的体腔中来治疗任何体腔的方法。例如,可用本发明的球囊治疗泌尿生殖系统(包括尿道、膀脱、输尿管、阴茎和阴道)、胃肠系统(如食道、胃、小肠或结肠),和呼吸系统(包括气管、支气管和肺泡)。也可以治疗冠状动脉以外的血管空间,包括主动脉,腔静脉(下腔和上腔)或神经血管动脉,例如颈动脉,基底动脉。本发明的包衣的球囊也可用于在体内潜在空间内产生腔体,例如,肌肉、血管内膜或纤维化组织。然后将药物活性剂释放到由潜在空间产生的新的体腔中,例如在肌肉内。
可用本发明的包衣的球囊治疗的其它疾病包括炎性疾病和癌症。可用本发明的包衣的球囊治疗的癌症包括但不限于膀胱癌、肺癌、耳癌、鼻癌和喉癌、白血病、结肠癌、黑色素瘤、胰腺癌、乳腺癌、前列腺癌、乳腺癌、定向造血干细胞癌、卵巢癌、基底细胞癌、胆道癌;膀胱癌;骨癌;乳腺癌;宫颈癌;绒毛膜癌;结肠和直肠癌;结缔组织癌,消化系统癌症;子宫内膜癌;食管癌;眼癌;头和颈的癌症;胃部癌症;上皮内肿瘤;肾癌;喉癌;白血病,包括急性髓细胞样白血病、急性淋巴样白血病、慢性髓细胞样白血病、慢性淋巴样白血病;肝癌;淋巴瘤,包括霍奇金和非霍奇全淋巴瘤;骨髓瘤;纤维瘤、神经细胞瘤;口腔癌(例如,唇癌、舌癌、口癌,和咽癌);卵巢癌,胰腺癌;前列腺癌;视网膜母细胞瘤;横纹肌肉瘤;直肠癌;肾癌;呼吸系统癌症;肉瘤;皮肤癌;胃癌;睾丸癌症;甲状腺癌;子宫癌症;泌尿系统癌症,以及其它癌和内瘤。
炎性疾病包括但不限于类风湿性关节炎、系统性红斑狼疮(SLE)、克罗恩氏病或其他胶原血管疾病。也可用本发明的球囊治疗由细菌、病毒或朊病毒引起的感染疾病。
所述可扩展的覆盖物的结构优选是弹性柔顺的并且可扩展的。所述可扩展的覆盖物可按以下形式构造:织物、片材、管、膜、浇铸物、套管、胶带或任何其它期望的结构构造,其允许所述可扩展的覆盖物贴合于所述球囊。所述可扩展的覆盖物还包含多个洞、孔、缝隙或者穿孔。替代地,所述洞、孔、缝隙或者穿孔可由原纤维的多孔网络形成,或者可由各种密度的原纤维物质形成。可使用各种类型的可扩展的覆盖物,包括弹性体的那些以及其中所述孔当所述球囊膨胀(和/或所述覆盖物扩展)时打开,并当所述球囊变瘪(和/或所述覆盖物未扩展)时收缩。所述可扩展的覆盖物可包括例如有机硅、乳胶、聚氨酯,和当材料拉伸时发生塑性变形由此打开孔的那些其它材料(参见下文材料的讨论)。当所述可扩展的覆盖物在非扩展状态中时,所述洞、孔、缝隙或者穿孔基本上关闭,使得历经限定的时间段通过所述药物活性剂从所述球囊的释放(例如,进入含水环境中)测得的所述可扩展的覆盖物的渗透性小于大约50%(w/w)、小于大约25%(w/w)、小于大约15%(w/w)、小于大约10%(w/w),或者小于大约5%(w/w),如下所述。本文中使用的w/w是指在任何时间t释放的药物活性剂的重量除以在球囊上包被的药物活性剂的总重量,%w/w是指w/w×100。
所述药物活性剂向血管空间中的体内释放可通过以下方法在体外模拟:在包含缓冲剂如磷酸盐缓冲盐水(PBS)的含水浴中孵育包衣有药物活性剂并用可扩展的覆盖物封闭的球囊。然后测定在所述球囊扩展之后所述药物活性剂向所述含水浴(例如,所述缓冲剂)的释放。测量药物活性剂的释放特征,绝对w/w以及动力学参见下面的讨论)。所述药物活性剂在含水环境中的浓度可使用任何手段测量,包括但不限于高压液相色谱法(HPLC)或者特异性免疫测定。例如,测定当在大约4℃、大约20-25℃或者大约37℃在含水环境如PBS、血浆、血液、体液或者其它含水介质中孵育时,在大约l小时内通过所述可扩展的覆盖物释放的药物活性剂的量。可使用各时间点评价当所述球囊在非扩展状态或者扩展状态中时药物活性剂的释放,包括但不限于,在大约30秒内、在大约1分钟内、在大约2分钟内、在大约3分钟内、在大约4分钟内、在大约5分钟内、在大约6分钟内、在大约8分钟内、在大约9分钟内、在大约10分钟内、在大约15分钟内、在大约20分钟内、在大约25分钟内、在大约30分钟内、在大约35分钟内、在大约40分钟内、在大约45分钟内、在大约50分钟内、在大约55分钟内、在大约1小时内、在大约2小时内、在大约3小时内、在大约4小时内、在大约5小时内、在大约6小时内、在大约7小时内、在大约8小时内、在大约1-10分钟内、在大约10-100分钟内或者在大约50-200分钟内。
在将可扩展的球囊推进至目标部位之后,操作者(例如,介入心脏病学家)通过使球囊膨胀而展开所述球囊。当所述可扩展的覆盖物由于所述球囊扩展而扩展时,所述可扩展的覆盖物的多孔性或者渗透性增加。如前面所讨论,然后血浆或者其它含水流体可扩散进入在所述可扩展的覆盖物和所述球囊之间的环形空间或者腔。然后所述包衣(全部或者部分)溶解,从而将所述药物活性剂通过所述可扩展的覆盖物释放进入体腔如动脉或者静脉中。在一个实施方案中,首先将所述包衣在施用至所述球囊期间脱水,然后在与含水环境如血浆接触之后重新水合。当所述可扩展的覆盖物在扩展状态中时,通过所述药物活性剂向含水环境中的释放测得的所述可扩展的覆盖物的渗透性为大约100%(w/w)、95%(w/w)、90%(w/w)、80%(w/w)、70%(w/w)、60%(w/w)、50%(w/w)、40%(w/w)、30%(w/w)或者20%(w/w)。对所述药物活性剂的测定可如上所述在4℃、20-25℃或者37℃在含水环境如PBS中实施1小时或者上面阐述的时间段。
可将任何希望的量的药物活性剂施用至所述球囊。例如,在球囊(例如,所述覆盖物和/或基质)上包覆或者浸渍的所述药物活性剂的量可为大约10至50,000μg,包括10、20、30、40、50、60、70、80、90、100、500、1000、10,000、20,000、30,000、40,000和50,000μg。所述药物活性剂在球囊上的总表面载荷可为大约1μg/mm2至大约200mm2,包括大约1、2、3、4、5、6、7、8、9、10、20、30、40、50、100、150或者200mm2。在球囊上在生物相容基质中存在的活性剂的量可为2μg/mm2至10μg/mm2、2.5μg/mm2至5μg/mm2、1μg/mm2至2μg/mm2、2μg/mm2至15μg/mm2、5μg/mm2至25μg/mm2或者25μg/mm2至40μg/mm2。因为所述包衣可以以任何形式(例如,带或者缠绕材料)施加,所以在所述球囊和可扩展的覆盖物之间的环形空间或者腔也可改变。因此,所述药物活性剂的量可显著改变,所述药物活性剂的载荷高达10,000-50,000μg。
所述可扩展的覆盖物的渗透性可为所述可扩展的覆盖物的多孔性的函数。与当所述可扩展的覆盖物在非扩展或者压缩状态中时所述可扩展的覆盖物的渗透性或者多孔性相比,当所述可扩展的覆盖物在扩展状态中时所述可扩展的覆盖物的渗透性或者多孔性可大大约20%至大约400%,大约50%至大约300%,或者大约100%至大约200%。这里为了计算%范围,将在所述扩展状态中的渗透性或者多孔性分别除以在所述非扩展状态中的渗透性或者多孔性,然后乘以100。差值百分比还包括10%、20%、30%、40%、50%、60%、70%、80%、90%、100%、150%、200%、250%、300%、400%、500%、600%、700%、800%等。
"多孔性"是指材料中空隙空间的量度,并且测量为空隙空间占固体材料的百分比,范围为0-100%。多孔性可根据以下方程测定:多孔性=(1-d1/d2)×100,其中d1是由材料重量和材料体积(由样品尺寸的测量结果确定)确定的材料密度,以及d2是样品的固体部分的密度(参见例如,美国专利7,445,735和EP 0464163B1)。样品的团体部分的体积可以例如使用Quantachrome stereopycnometer(Quantachrome Corp.)来测量。所述可扩展结构的孔的平均直径可以通过使用Autoscan水银孔隙度计(Quantachrome Corp.)的压汞孔隙率测定法测定。汞侵入/挤压是基于在严格控制的压力下将汞(非润湿液体)压入多孔材料中。由于汞不会浸湿大多数物质,并且不会通过毛细管作用自发地渗透到孔中,所以必须通过施加外部压力将其压入样品的空隙中。填充空隙所需的压力与孔的大小成反比。只需要少量的力或压力来填充大的空隙,而需要更大的压力来填充非常小的孔的空隙。参见美国专利7,445,735。除了汞以外,还可以使用其他合适的非润湿液体进行孔隙率测量。其他可用于测量孔隙率的方法包括椭偏孔隙度测定法,水饱和法,水蒸发法和氮气吸附法。当扩展时在所述可扩展的覆盖物中的孔的直径可为大约1μm至大约100μm、大约10μm至大约100μm、大约20μm至大约80μm、大约40μm至大约60μm或者大约20μm至大约50μm。
所述药物活性剂可历经一段时间t均匀递送至体腔。所述药物活性剂可遵循零级动力学通过所述可扩展的覆盖物释放,无爆发效应。本文中使用的术语"零级动力学"是指释放特征,其中所述药物活性剂以与时间和掺入球囊中的药物活性剂的浓度无关的速率释放。零级释放确保稳定量的药物活性剂历经希望的时间长度释放,从而使潜在的波峰/波谷波动和副作用最小化,同时最大化药物活性剂浓度保持在治疗窗内的时间量。释放速率可以使用标准方法来计算,
其中药物流量为J,以及药物浓度随时间的变化可表示为:
所述术语"药物"、"药物活性剂"或者"药剂"在这里可互换使用。释放速率也可受扩散或者侵蚀驱动。Fu等人,Drug Release Kinetics and Transport Mechanisms of Non-degradable and Degradable Polymeric Delivery Systems.Expert Opin Drug Deliv.2010 Apr;7(4): 429--444。替代地,药物活性剂的释放可以作为立即释放到体腔中的爆发起作用。
所述可扩展的覆盖物的厚度可为大约0.1μm至大约300μm或者大约1μm至大约150μm。本文中包括其它范围,例如50、100、150、200、250或者300μm。当所述可扩展的覆盖物受到拉伸或伸长并且经历塑性和/或弹性变形时,其可变形而不会开裂。在所述球球囊变瘪之后,所述可扩展的覆盖物恢复到未扩展状态,而不会破裂、撕开、翻转或者反卷至自身上。所述可扩展的覆盖物可包括任何适合的材料,包括合成和非合成材料。所述可扩展的覆盖物也可包括合成和非合成材料的混合物。合成材料的实例包括高密度,高分子量聚乙烯(HDHMWPE)、超高分子量聚乙烯(UHDHMWPE)、膨胀聚(四氟乙烯)(ePTFE)、乙烯-乙酸乙烯醋、乳胶、氨基甲酸酯、含氟聚合物、聚乙烯醇(PVA)-交联的水凝胶、聚硅氧烷、苯乙烯-乙烯/丁烯-苯乙烯嵌段共聚物、脂族聚酯及其混合物和共聚物、聚二甲基硅氧烷(PDMS)(有机硅)或者聚氨酯泡沫体,例如,HYPOLTM。所述可扩展材料可以编织成具有聚合物学丝网格的编织物,例如聚合物复丝纱线的管状相互交织的套管。参见美国专利5,957,9740。
在一个实施方案中,所述可扩展的覆盖物由医用级有机硅构成。在另一实施方案中,所述覆盖物为弹性体。在第二实施方案中,弹性体为高强度热塑性弹性体。这种高强度热塑性弹性体可为苯乙烯嵌段共聚物、聚烯烃共混物、弹性体合金、热塑性聚氨酯、热塑性共聚酯,或者热塑性聚酰胺。所述高强度热塑性弹性体可由聚酯-聚醚共聚物或者聚酰胺-聚醚共聚物形成。所述高强度热塑性弹性体也可为尼龙。非合成材料的实例包括但不限于胶原、纤维蛋白、弹性蛋白、胞外基质组分及其混合物。
所述包衣可为任何生物相容基质的形式。所述包衣可直接施用在所述球囊的外表面上,或者可施用在所述可扩展的覆盖物的内部或者内表面上。替代地,所述药物活性剂可在所述球囊的外表面和所述可扩展的覆盖物的内部或者内表面之间被布置在生物相容基质中。也可将所述包含药物活性剂的包衣围绕所述球囊使用带缠绕,从而封闭所述球囊,所述带可为以下形式:螺旋、螺旋切割管或者螺旋切割缠绕材料。可将所述球囊用所述生物相容基质缠绕1、2、3、4、5、6、7、8、9、10…n次。可将所述含有所述药物活性剂的生物相容基质使用标准技术施用至所述球囊或者可扩展的覆盖物,以覆盖所述球囊或者所述可扩展的覆盖物的整个或者仅部分表面。所述包衣可形成一种或多种药物活性剂和生物相容基质如凝胶的均匀混合物的单一层,或者以限定的几何图案如点阵图案存在。
所述包衣可围绕所述球囊形成单一层或者多个层如连续缠绕材(continuouswrapping)。可将所述球囊用包含至少一种药物活性剂的液体溶液浸渍或者喷雾。在施用每一层之后,可将所述球囊在施用下一层之前干燥。包含所述药物活性剂的层的厚度可为大约0.1μm至大约150μm、大约1μm至大约100μm、大约10μm至大约50μm,或者大约20μm至大约30μm。替代地,可将所述药物活性剂/生物相容基质组合物的多个层施用在所述球囊的表面上或者在这些或者其它厚度范围内覆盖。例如,可将两种或者更多种药剂的不同层在所述球囊或者可扩展的覆盖物上包衣,使得特定药物活性剂能够首先释放至体腔中,然后随后释放第二药物活性剂。
所述生物相容基质可包括水溶性材料或者水可溶胀的材料。所述药物活性剂可均匀地或者不均匀地(例如,微粒如脂质体或者纳米粒子)分散在所述生物相容基质中。所述生物相容基质可包含水溶性材料,其可在施用后脱水,然后在操作者插入体腔后再水合。"水溶性材料"是指与水或其他水性生理流体(例如血浆或间质液)接触时溶解、水解、分解、溶解或崩解的物质。随着所述球囊扩展,所述可扩展的覆盖物也扩展,伴随着对血浆或者其它生理流体的渗透性增加。水溶性材料在所述药物活性剂包衣中溶解,以及所述药物活性剂释放至体腔中。所述生物相容基质溶解所需要的时间长度可不同,并且小于大约4小时、2小时、小于大约1小时、小于大约30分钟、小于大约10分钟、小于大约5分钟、小于大约1分钟、小于大约30秒或者小于大约5秒。
所述生物相容基质可包括水不溶性和水溶性材料的混合物。这种组合的实例包括虫胶和聚乙烯基吡咯烷酮,以及乙基纤维素和羟丙基甲基纤维素。所述生物相容基质也可包括水可溶胀材料。水溶性或者水可溶胀材料可包括多糖,例如葡聚糖、藻酸盐、直链淀粉、支链淀粉、角叉菜胶、羧甲基纤维素、胶凝糖、瓜尔胶、多糖结合疫苗、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、支链淀粉、淀粉衍生物、透明质酸、淀粉衍生物、黄原胶(xantan)、木糖葡聚糖、基于壳聚糖的水凝胶、肽多糖,和蛋白多糖(progeoglyeans)。水溶性或者水可溶胀材料也可包括简单碳水化合物,例如葡萄糖、麦芽糖、乳糖、果糖、蔗糖、半乳糖、萄糖胶、半乳糖胺、胞壁酸、葡糖醛酸酯(glucruronate)、葡糖酸盐、岩藻糖、海藻糖、合成聚合物,例如聚乙烯醇、聚乙烯基吡咯烷酮、聚乙二醇、丙二醇、聚氧基亚乙基衍生物、多肽,例如弹性蛋白、聚乙烯基胺或者聚(L-赖氨酸)、未交联水凝胶、交联的水凝胶、聚丙烯酸或者任何其它交联的水可溶胀聚合物。水凝胶材料的实例包括呈羧甲基纤维素(CMC)、羟丙基甲基纤维素(HPMC)、支链淀粉、淀粉衍生物、透明质酸,或者它们的组合(W02007US0074123)。
所述包含药剂的生物相容基质也可包括任何希望的生物相容的非毒性材料。这种生物相容材料的实例包括聚(丙交酯-共聚-乙交酯)、聚酯如聚乳酸、聚乙醇酸、聚酸酐、聚已酸内酯、聚羟基丁酸戊酯,或者其混合物或者共聚物。在一个实施方案中,所述生物相容基质可进一步包括天然存在物质,例如胶原蛋白、纤连蛋白、玻连蛋白、弹性蛋白、层粘连蛋白、肝素、纤维蛋白、纤维素、碳或细胞外基质组分。可以在基质中使用的聚合物包括聚(丙交酯-共聚-乙交酯);聚DL-丙交酶,聚-L-丙交酯和/或其混合物,并且可以具有各种特性粘度和分子量。在一个实施方案中,可以使用聚(DL丙交酯-共聚-乙交酯)。聚-DL-丙交酯材料可以是均匀组合物的形式,并且当溶解和干燥时,它可以形成药物物质可以被捕获以递送到组织的通道的格子。在又一实施方案中,所述包衣组合物包含不可吸收的聚合物,例如乙烯乙酸乙烯酯(EVAC)、聚甲基丙烯酸丁酯(PBMA)和甲基丙烯酸甲酯(MMA)。
可以与本发明的方法一起使用的生物可吸收聚合物的其它实例包括脂族聚酯、生物玻璃纤维素、乙交酯的几丁质胶原共聚物、丙交酯共聚物、弹性蛋白、原弹性蛋白、纤维蛋白、乙交酯/1-丙交酯共聚物(PGA/PLLA)、乙交酯/三亚甲基碳酸酯共聚物(PGA/TMC)、水凝胶丙交酯/四甲基乙交酯共聚物、丙交酯/三亚甲基碳酸酯共聚物、丙交酯/-ε-己内酯共聚物、丙交酯/-σ-戊内酯共聚物、L-丙交酯/dl-丙交酯共聚物、甲基丙烯酸甲酯-N-乙烯基吡咯烷酮共聚物、改性蛋白质、尼龙2PHBA/γ-羟基戊酸酯共聚物(PHBA/HVA)、PLA/聚氧化乙烯共聚物、PLA-聚氧化乙烯(PELA)、聚(氨基酸)、聚(三亚甲基碳酸酯)、聚羟基脂肪酸酯聚合物(PHA)、聚(草酸亚烷基酯)、聚(亚丁基二羟乙酸酯)、聚(羟基丁酸酯)(PHB)、聚(n-乙烯基吡咯烷酮)、聚(原酸酯)、聚烷基-2-氰基丙烯酸酯、聚酸肝、聚氰基丙烯酸酯、聚(α-羟基酸/α-氨基酸)(polydepsipeptides)、聚二氢吡喃、聚-dl-丙交酯(POLLA)、聚酰胺酯、草酸的聚酯、聚乙交酯(PGA)、聚亚氨基碳酸酯、聚丙交酯(PLA)、聚原酸酯、聚对二氧杂环己酮(PDO)、多肽、聚偶磷氮、多糖、聚氨酯(PU)、聚乙烯醇(PVA)、聚-β-羟基丙酸酯(PHPA)、聚-β-羟基丁酸酯(PBA)、聚-σ戊内醋、聚-β-链烷酸、聚-β-苹果酸(PMLA)、聚-ε-己内国旨(PCL)、假-聚(氨基酸)、淀粉、三亚甲基碳酸酯(TMC)和基于酪氨酸的聚合物。参见美国专利7,378,144。
用于受控药物递送的聚合物也可用于所述包衣。这种聚合物的实例包括聚酸肝和聚酯、以下物质的聚合物和共聚物:乳酸、羟乙酸、羟基丁酸、扁桃酸、己内酯、葵二酸、1,3-二(对-羧基苯氧基)丙烷(CPP)、二-(对-羧基苯氧基)甲烷、十二烷二酸(DD)、间苯二酸(ISO)、对苯二甲酸、己二酸、富马酸、壬二酸、庚二酸、软木酸(辛二酸)、衣康酸、联苯基-4,4'-二羧酸和二苯甲酮-4,4'-二数酸。聚合物可以是芳族的、脂族的、亲水的或疏水的。
形成所述生物相容基质的聚合物可包括由麦芽三糖单元组成的多糖聚合物,其也被称为芽霉菌糖。芽霉菌糖为多糖聚合物,其由麦芽三糖单元组成,其也被称为α-1,4-;α-1,6-糖苷键。麦芽三糖中的三个葡萄糖单元通过α-1,4糖苷键连接,而连续的麦芽三糖单元通过α-1,6糖苷键相互连接。芽霉菌糖可通过真菌出芽短梗霉菌从淀粉产生。
所述药物活性剂可分散在由非水凝胶聚合物制成的具有多个空隙的海绵状膜或者层之中和/或之上。替代地,所述海绵状膜或者层也可以由基于聚合物的原纤维网络或支架构成,从而在该纤维或原纤维节点网络内存在空隙空间。可将所述药物活性剂注入所述海绵膜或者层的空隙中,所述海绵膜或者层位于所述球囊的外表面上,并位于或者被布置在所述球囊的外膜和所述可扩展的覆盖物的内壁之间。当所述球囊径向扩展时,所述海绵膜或者层围绕所述球囊的周边拉伸并变得较薄,从而打开和扩大所述空隙。结果,将所述药物活性剂通过海绵膜或者层的空隙排出或者"挤出"。所述海绵膜或者层可通过以下方法制备:将非水凝胶聚合物溶解在溶剂和可洗脱的微粒材料中。在海绵膜或者层组合物固化之后,使其暴露于溶剂,例如,水或者PBS,这导致所述微粒材料从聚合物洗脱,从而留下在其中具有多个空隙的海绵膜或者层。然后将所述海绵包衣暴露于生物活性材料以用这种材料加载所述海绵膜或者层。这种材料可以通过扩散或其他方式装载到包衣中。用于形成海绵膜或层的非水凝胶聚合物是生物相容的。非水凝胶聚合物是这样的聚合物,当在这种聚合物膜的顶部加一滴水时,该液滴不会扩散。这样的聚合物的实例包括但不限于聚氨酯,聚异丁烯及其共聚物,有机硅和聚酯。其它合适的聚合物包括聚烯烃、聚异丁烯、乙烯-α烯烃共聚物、高密度高分子量聚乙烯(HDHMWPE)、丙烯酸类聚合物和共聚物、乙烯基卤化物聚合物和共聚物如聚氯乙烯、聚乙烯醚如聚乙烯基甲基醚、聚偏二卤化物如聚偏二氟乙烯和聚偏二氯乙烯、聚丙烯腈、聚乙烯基酮、聚乙烯基芳族化合物如聚苯乙烯、聚乙烯酯如聚乙酸乙烯酯;乙烯基单体的共聚物、乙烯基单体与烯烃的共聚物如乙烯-甲基丙烯酸甲酯共聚物、丙烯睛-苯乙烯共聚物、ABS树脂、乙烯-乙酸乙烯酯共聚物、聚酰胺如尼龙66和聚己内酯、醇酸树脂、聚碳酸酯、聚氧乙烯、聚酰亚胺、聚醚、环氧树脂、聚氨酯、人造三醋酸纤维素、纤维素、乙酸纤维素、丁酸纤维素、乙酸丁酸纤维素、玻璃纸、硝酸纤维素、丙酸纤维素、纤维素醚、羧甲基纤维素、胶原蛋白、几丁质、聚乳酸、聚乙醇酸和聚乳酸-聚环氧乙烷共聚物。参见美国专利6773447、美国专利公开200400063590。
所述生物相容基质还可以包含有机凝胶,例如聚(乙烯)、L-丙氨酸、脱水山梨糖醇单硬脂酸酯、Eudragit或卵磷脂有机凝胶。Gup也等人,World J.Pharmacy& Pharmaceutical Sciences 3(9):150-163(2014)。替代地,所述凝胶可包括溶胶-凝胶。Niederberger等人,Metal Oxide Nanonparticles in Onganic solvents‘Synthesis, Formulation.Assembly and Applications.Springer(2009)。
所述生物相容基质可包括薄膜。Karki等人,Thin films as an emergingplatform for drug delivery.Asian J.Pharmaceutical Sciences 574(2016)。薄膜包含具有或不具有增塑剂的薄而柔软的聚合物层(出处同上)。在某些实施方案中,薄膜比其他常规剂型更快地溶解,即快速溶解(出处同上)。薄膜也可以是粘膜粘附的(出处同上)。薄膜可以以任何形状或尺寸形成。在一些实施方案中,所述薄膜的厚度可为大约500μm至大约1,500μm;以及当干燥时,薄膜的厚度可为大约3μm至大约250μm。薄膜可包括聚合物,其包括但不限于羟丙基甲基纤维素(HPMC)、羧甲基纤维素(CMC)、羟丙基纤维素(HPC)、聚(乙烯基吡咯烷酮)(PVP)、聚(乙烯醇)(PVA)、聚(氧化乙烯)(PEO)、芽霉菌糖、壳聚糖、藻酸纳、角叉菜胶、明胶,或其组合。
所述生物相容基质可以包含生物粘附剂。所述生物胶粘剂可分布在整个生物相容基质中或者仅围绕含有药剂的粒子分布(参见下文药物活性剂的讨论,所述药物活性剂可掺入微球体、脂质体、纳米凝胶和其他类型的基于颗粒的药物递送媒介物中,其掺入所述基质中)。在一些实施方案中,所述生物胶粘剂粘附至血管或体腔壁。例如,所述生物胶粘剂可包括藻酸盐-儿茶酚混合物。Kastrup等人,PNAS 109:21444-21449(2012)。在一些实施方案中,所述生物胶粘剂可以包含一种或多种水解胶体乳化剂。可以使用的水解胶体乳化剂的非限制性实例包括纤维素乳化剂和丙烯酸乳化剂,包括例如具有含大约10至大约50个碳原子的烷基的那些乳化剂。在一些实施方案中,所述丙烯酸乳化剂为羧酸和丙烯酸酯的共聚物(描述在例如美国专利3,915,921和4,509,949中),包括交联的那些。这种交联乳化剂的实例是"丙烯酸盐(酯)/丙烯酸C10-30烷基酯交联聚合物",一种丙烯酸和丙烯酸(ClO-30)烷基酯的交联的聚合物。丙烯酸盐(酯)/丙烯酸ClO-30烷基酯交联聚合物可得自Noveon,Inc.(先前的B.F.Goodrich)和在商品名下出售。丙烯酸盐(酯)/丙烯酸C10-30烷基酯交联聚合物具有小的亲油部分和大的亲水部分,因此使其可以用作形成水包油乳液的主要乳化剂。此外,丙烯酸盐(酯)丙烯酸C10-30烷基酯交联聚合物能够在与基质(即生物膜或粘膜)接触时释放分散相的化合物,并且不会再湿润(油相在与水接触时不会再乳化)。关于在美国药典中列出的丙烯酸盐(酯)/丙烯酸C10-30烷基酯交联聚合物的另外的信息提供在Noveon出版物TDS-114、117、118、124、232-3和237以及PDSPemulen 1622中。
可以使用烷基链氰基丙烯酸酣如氰基丙烯酸甲基-、乙基-、异丙基-、丁基-和辛基酯作为生物胶粘剂。参见美国专利8,613,952;此外,参见Mizrahi等人,Acta Biomaterialia 7:3150-3157(2011)。其它可能的生物胶粘剂包括但不限于基于氨基甲酸乙酯的材料以及包含贻贝粘附蛋白的胶粘剂。Mehdizadeh等人,Macromol Biosci.13(3):271-288(2013)。
在一些实施方案中,所述生物胶粘剂可通过组合以下物质制备:(i)具有一个或多个第一化学反应性氨基的生物聚合物;(ii)具有至少两个第二化学反应性基团的生物相容性交联剂,所述第二化学反应性基团可以与所述生物聚合物的所述一个或多个第一化学反应性氨基发生化学反应;和(iii)生物相容性流变改性剂。参见美国专利公开20160166728。
所述生物相容基质可根据常规的药物复配技术与药学上可接受的赋形剂(例如载体、佐剂和/或稀释剂)混合。赋形剂用于改性、维持或保存包括例如组合物的pH、渗透压、粘度、透明度、颜色、等渗性、气味、无菌性、稳定性、溶解或释放速率、吸附或渗透。适合的赋形剂包括但不限于氨基酸(如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸);抗菌剂;抗氧化剂(如抗坏血酸、亚硫酸钠或亚硫酸氢钠);缓冲剂(如硼酸盐、碳酸氢盐、TrisHCl、柠檬酸盐、磷酸盐、其他有机酸);填充剂(如甘露醇或甘氨酸)、螯合剂(如乙二胺四乙酸(EDTA)、乙二醇四乙酸(EGTA));络合剂(如咖啡因、聚乙烯吡咯烷酮、β环糊精或羟丙基β环糊精);填料;单糖;二糖和其他碳水化合物(如葡萄糖、甘露糖或糊精);蛋白质(如血清白蛋白、明胶或免疫球蛋白);着色剂;调味剂和稀释剂;乳化剂;亲水聚合物(如聚乙烯吡咯烷酮);低分子量多肽;成盐抗衡离子(如钠);防腐剂(如苯扎氯铵、苯甲酸、水杨酸、硫柳汞、苯乙醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯己定、山梨酸或过氧化氢);溶剂(如甘油、丙二醇或聚乙二醇);糖醇(如甘露醇或山梨糖醇);悬浮剂;表面活性剂或润湿剂(如普朗尼克(pluronics)、PEG、脱水山梨糖醇酯、聚山梨醇酯如聚山梨醇酯20、聚山梨酸酯80、曲通、氨丁三醇、卵磷脂、胆固醇、泰洛沙班);增强稳定剂(蔗糖或山梨糖醇);张力增强剂(例如碱金属卤化物(在一方面中,氯化纳或氯化钾、甘露醇、山梨糖醇);递送煤介物;稀释剂;赋形剂和/或药物辅剂(Remington's Pharmaceutical Sciences,18th Edition,A.R.Gennaro,ed.,Mack PubIishing Company,1990)。
可将所述药物活性剂掺入微球、脂质体、纳米凝胶和其它类型的基于粒子的药物递送媒介物中,所述微球、脂质体、纳米凝胶和其它类型的基于粒子的药物递送媒介物掺入在所述生物相容基质中。Hoare等人,Polymer 49:1993-2007(2008)。例如,可将聚(乳酸-共聚-乙醇酸)纳米颗粒掺入至可交联的基于透明质酸的水凝胶基质中(出处同上)。
脂质体是由同心双层(薄片)形成的脂膜包围的中心水性腔组成的微小脂质囊泡。脂质体能够包含亲水性物质(在水性内部)或疏水性物质(在脂质膜中)。脂质体可以是具有单一脂质双层的单层囊泡("UMV"),或具有一系列脂质双层的多层囊泡("MLV")(也称为"寡层囊泡")。多层囊泡的直径通常在0.2μm至10μm的范围内。参见例如,WO 98/006882。脂质体的双层最通常包含磷脂,但也可包含脂质,包括但不限于脂肪酸、脂肪酸盐和/或脂肪醇。除其他因素外,脂质体的性质取决于组分的性质。因此,如果要获得具有某些特性的脂质体,则必须考虑其极性基团的电荷和/或其脂肪酸链的长度和饱和度。另外,可以修饰脂质体的性质,例如将胆固醇和其他脂质掺入膜中,改变脂质双分子层的数量,或共价连接天然分子(例如蛋白质、多糖、糖脂、抗体、酶)或合成的分子(如聚乙二醇)到表面。在可以用于获得脂质体的水性介质中存在许多磷脂组合,任选地与其他脂质或胆固醇组合。根据制备方法和使用的脂质,可以获得不同大小、结构和性质的囊泡。
例如,脂质体可以由磷脂的同源群体(例如中性磷脂)或不同类型的磷脂的混合物形成。用于制造递送载体的磷酯的实例包括但不限于磷脂酰胆碱(PC)、磷脂酰甘油(PG)、磷脂酰乙醇胺(PE)、磷脂酰丝氨酸(PS)、磷脂酸(PA)、磷脂酰肌醇(PI)、卵磷脂酰胆碱(EPC)、卵磷脂酰甘油(EPG)、卵磷脂酰乙醇胺(EPE)、卵磷脂酰丝氨酸(EPS)、卵磷脂酸(EPA)、卵磷脂酰肌醇(EPI)、大豆磷脂酰胆碱(SPC)、大豆磷脂酰甘油(SPG)、大豆磷脂酰乙醇胺(SPE)、大豆磷脂酰丝氨酸(SPS)、大豆磷脂酸(SPA)、大豆磷脂酰肌醇(SPI)、二棕榈酰磷脂酰胆碱(DPPC)、1,2-二油酰-sn甘油-3-磷脂酰胆碱(DOPC)、二肉豆寇酰磷脂酰胆碱(DMPC)、二棕榈酰磷脂酰甘油(DPPG)、二油磷脂酰甘油(DOPG)、二肉豆寇酰磷脂酰甘油(DMPG)、十六烷基磷酸胆碱(HEPC)、氢化大豆磷脂酰胆碱(HSPC)、二硬脂酰磷脂酰胆碱(DSPC)、二硬脂酰磷脂酰甘油(DSPG)、二油酰磷脂酰乙醇胺(DOPE)、棕榈酰硬脂酰磷脂酰胆碱(PSPC)、棕榈酰硬脂酰磷脂酰甘油(PSPG)、单油酰磷脂酰乙醇胺(MOPE)、1-棕榈酰-2-油酰-sn-甘油-3-磷脂酰胆碱(POPC)、聚乙二醇二硬脂磷脂酰乙醇胺(PEG-DSPE)、二棕榈酰磷脂酰丝氨酸(DPPS)、1,2-二油酰-sn-甘油-3-磷脂酰丝氨酸(DOPS)、二肉豆蔻酰磷脂酰丝氨酸(DMPS)、二硬脂酰磷脂酰丝氨酸(DSPS)、二棕榈酰磷脂酸(DPPA)、1,2-二油酰基-sn-甘油基-3-磷脂酸(DOPA)、二肉豆蔻酰磷脂酸(DMPA)、二硬脂酰基磷脂酸(DSPA)、二棕榈酰磷脂酰肌醇(DPPI)、1,2-二油酰-sn-甘油-3-磷脂酰肌醇(DOPI)、二肉豆蔻酰磷脂酰肌醇(DMPI)、二硬脂酰磷脂酰肌醇(DSPI),及其混合物。
替代地,可将所述药物活性剂掺入纳米凝胶中。Vinogradov等人,Expert opin.Drug Deliv.-4(1):5-17(2007)。纳米凝胶是由聚乙二醇(PEG)片段交联的带电聚离子片段的聚合物网络。参见美国专利6,696,0890多种不同的药物活性剂可以掺入纳米凝胶中(出处同上)。
药物活性剂可以是纳米颗粒悬浮液、固体脂质纳米颗粒、PLGA纳米颗粒或的形式,以及可以掺入或包封在生物相容性基质中。Hoare等人,Hydrogels in drug delivery:Progress and Challengenes.Polymer 49:1993-2007(2008)。
纳米凝胶可以是由交联的亲水聚合物网络(水凝胶)组成的纳米粒子。纳米凝胶最通常由化学或物理交联的生物相容的合成聚合物或生物聚合物组成。在又一实施方案中,所述纳米凝胶是可生物降解的。获得纳米凝胶的方法以及用于获得生物相容和/或生物可降解的纳米凝胶的方法在本领域中是已知的(参见美国专利7,727,554)。一方面,纳米凝胶包含可生物降解的连接基(例如,其中酶(例如生理晦)可降解交联剂,从而降解纳米凝胶)。参见美国专利公开20160250152。纳米凝胶(例如生物可降解的纳米凝胶)可以使用聚合物(例如,N-异丙基丙烯酰胺、N-乙烯基吡咯烷酮、聚乙二醇化的马来酸或其组合)和二硫化物交联剂合成。使用例如上述聚合物形成的纳米凝胶可以具有大约50nm的直径并具有持续的药物释放性质。纳米凝胶可由N-烷基丙烯酰胺形成。在一个具体方面,N-烷基丙烯酰胺为聚-N-异丙基丙烯酰胺。
所述纳米凝胶可进一步包含乙烯基单体和聚亚烷基二醇。例如,乙烯基单体可以是乙烯基吡咯烷酮,聚亚烷基二醇可以是聚乙二醇。所述纳米凝胶可进一步包含丙烯酸钠。在具体方面,所述纳米凝胶包含大约500至大约1000mgN-烷基丙烯酰胺。在另一方面,所述纳米凝胶可包括大约100至大约200mg乙烯基聚合物和大约50至大约100mg聚亚烷基二醇。在又一方面,所述纳米凝胶包含大约200mg丙烯酸钠。所述纳米凝胶粒子的尺寸可为大约10nm、20nm、40nm、60nm、80nm、100nm、120nm、140nm、160nm、180nm、200nm、220nm、240nm、260nm、280nm、300nm、320nm、340nm、360nm、380nm、400nm、420nm、440nm、460nm、480nm、500nm、520nm、540nm、560nm、580nm、600nm、620nm、640nm、660nm、680nm、700nm、720nm、740nm、760nm、780nm、800nm、820nm、840nm、860nm、880nm、900nm、920nm、940nm、960nm、980nm或者大约1000nm的粒子直径。在另一方面,所述纳米凝胶的ζ电位为大约一10mV、-15mV、-20mV、-25mV、-30mV、-35mV,或者-40mV。所述纳米凝胶具有大约2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%或者25%的药物活性剂的负载能力(1oadingpotentia1)。
在某些实施方案中,药物活性剂可以被包封在粒度为50-1000μm的含有纤维素醚的环糊精颗粒中。环糊精是脱水葡萄糖单元的低聚物,其通过α-1,4键连接成环形分子。根据单元的数量,将这些坏糊精称为α(6单位)、β(7单位)和γ(8单位)环糊精。这些通常由淀粉通过酶促过程产生。环糊精的环状结构使分子水平上形成封闭的络合物成为可能。
可在本发明中使用的药物活性剂包括:(i)药剂,诸如(a)抗血栓形成剂(诸如肝素、肝素衍生物、尿激酶和PPack(右旋苯丙氨酸脯氨酸精氨酸氯甲基酮);(b)抗炎剂,诸如地塞米松、泼尼松龙、皮质酮、布地奈德、雌激素、柳氮磺吡啶和氨水杨酸;(c)抗肿瘤剂/抗增殖剂/抗缩瞳剂如西罗莫司(或其类似物、biolimus、依维莫司或者佐他莫司)、紫杉醇、5-氟尿嘧啶、顺铂、长春碱、长春新碱、埃博霉素、内皮他汀、血管他汀、血管肽素、能够阻断平滑肌细胞增殖的单克隆抗体、胸苷激酶抑制剂、雷帕霉素、40-0-(2-羟基乙基)雷帕霉素(依维莫司)、40-0-苄基-雷帕霉素、40-0(4'-羟甲基)苄基-雷帕霉素、40-0-[4'-(1,2-二羟基乙基)]苄基-雷帕霉素、40-稀丙基-雷帕霉素、40-0-[3’-(2,2-二甲基-1,3-二氧戌环-4(S)-基-丙-p-2’-烯-1’基)]-20雷帕霉素、(2’:E4’S)-40-0-(4’,5’.:二羟基戌-2'-烯-1’-基)雷帕霉素、40-0(2-羟基)乙氧基羰基曱基-雷帕霉素、40-0-(3-羟基丙基)-雷帕霉素、40-0-((羟基)己基-雷帕霉素、40-0-[2-(2-羟基)乙氧基]乙基-雷帕霉素、40-0-[(3S)-2,2二甲基二氧戌环-3-基]曱基-雷帕霉素、40-0-[(2S)-2,3-二羟基丙-1-基]-雷帕霉素、40-0-(2-乙酰氧基)乙基-雷帕霉素、40-0-(2-尼古丁酰氧基)乙基-雷帕霉素、40-0-[2-(N-25吗啉代)乙酰氧基乙基-雷帕霉素、40-0-(2-N-咪唑基乙酰氧基)乙基-雷帕霉素、40-0[2-(N-曱基-N'-哌嗪基)乙酰氧基]乙基-雷帕霉素、39-0-去甲基-3.9、40-0,0亚乙基-雷帕霉素、(26R)-26-二氢-40-0-(2-羟基)乙基-雷帕霉素、28-0甲基雷帕霉素、40-0-(2-氨基乙基)-雷帕霉素、40-0-(2-乙酰氨基乙基)-雷帕霉素、40-0(2-烟酰胺基乙基)-雷帕霉素、40-0-(2-(N-曱基-咪唑-2’基曱酰胺基)乙基)-30雷帕霉素、40-0-(2-乙氧基羰基氨基乙基)-雷帕霉素、40-0-(2-甲苯基亚磺酰氨基乙基)-雷帕霉素、40-0-(2-甲苯基磺酰氨基乙基)-雷帕霉素、40-0-[2-(4’,5’-二乙酯基-1’,2’,3’-三唑-1’-基)-乙基]雷帕霉素、42-Epi-(四唑基)雷帕霉素(他克莫司)、以及42-[3-羟基-2-(羟甲基)-3-甲基丙酸酯]雷帕霉素(他克莫司),(W02008/086369)(在各种实施方案中,大环内酯免疫抑制药物可以是至少50%、75%、90%、98%或99%结晶;(d)麻醉剂,诸如利多卡因、布比卡因和罗哌卡因;(e)抗凝剂,诸如D-苯丙-脯-精氨酸氯甲基酮、含RGD多肽的化合物、肝素、水蛭素、抗凝血酶化合物、血小板受体拮抗剂、抗凝血酶抗体、抗血小板受体抗体、阿司匹林、前列腺素抑制剖、血小板抑制剂和蜱抗血小板肽;(f)血管细胞生长促进剂,诸如生长因子、转录激活因子和翻译促进剂;(g)血管细胞生长抑制剂,诸如生长因子抑制剂、生长因子受体拮抗剂、转录阻抑物、翻译阻抑物、复制抑制剂、抑制性抗体、定向抑制生长因子的抗体、由生长因子和细胞毒素组成的双功能分子、由抗体和细胞毒素组成的双功能分子;(h)蛋白激酶和酪氨酸激酶抑制剂(例如,酪氨酸磷酸化抑制剂、染料木黄酮、喹恶啉类);(i)前列环素类似物;(j)胆固醇降低剂;(k)血管生成素;(l)抗微生物剂,诸如三氯生、头抱菌素类、氨基糖苷类和呋喃妥因;(m)细胞毒性剂、细胞生长抑制剂和细跑增殖效应物;(n)血管扩张剂;以及(o)干扰内源性血管活性机制的制剂,(ii)基因治疗剂,其包括反义DNA和RNA,以及编码以下的DNA:(a)反义RNA,(b)tRNA或rRNA以替换有缺陷或不足的内源性分子,(c)包括生长因子的血管生成因子如酸性和碱性成纤维细胞生长因子、血管内皮生长因子、表皮生长因子、转化生长因子a和P、源于血小板的内皮生长因子、源于血小板的生长因子、胂瘤坏死因子a、肝细胞生长因子和胰岛素样生长因子,(d)细胞周期抑制剂,其包括CD抑制剂,以及(e)胸苷激酶(“TK”)和用于干扰细胞增殖的其他药剂。
可以使用的其他药物活性剂包括:阿卡波糖、抗原、(β-受体阻断剂、非甾体抗炎药(NSAID)、强心苷、乙酰水杨酸、病毒抑制剂、阿柔比星、阿昔洛韦、顺铂、放线菌素、α-和β-拟交感神经药、奥美拉唑、别嘌呤醇、前列地尔、前列腺素、金刚烷胺、氨溴素、氨氯地平、甲氨蝶呤、S-氨基水杨酸、阿米替林、阿莫西林、阿那曲唑、阿替洛尔、硫唑嘌呤、巴柳氮、倍氯米松、倍他司汀、苯扎贝特、比卡鲁胺、地西泮和地西泮衍生物、布地奈德、丁苯羟酸、丁丙诺啡、美沙酮、钙盐、钾盐、镁盐、坎地沙坦、卡马西平、卡托普利、头抱菌素、西替利嗪、鹅去氧胆酸、熊去氧胆酸、茶碱和茶碱衍生物、胰蛋白酶、西咪替丁、克拉霉素、克拉维酸、克林霉素、氯丁替诺、可乐定、磺胺甲基异恶唑、可待因、咖啡因、维生素D和维生素D的衍生物、考来烯胺、色甘酸、香豆素和香豆素衍生物、半胱氨酸、阿糖胞苷、环磷酰胺、环孢素、环丙孕酮、阿糖胞苷(cytabarine)、达哌唑、去氧孕稀、地奈德、双肼屈嗪、地尔硫卓、麦角生物碱、茶苯海明、二甲基亚砜、二甲硅油、多潘立酮和多潘立酮衍生物、多巴胺、多沙唑嗪、多柔比星、多西拉敏、达派唑、苯二氮卓类、双氯芬酸、糖苷类抗生素、地昔帕明、益康唑、ACE抑制剂、依那普利、麻黄碱、肾上腺素、促红细胞生成素和促红细胞生成素衍生物、吗啡烷类、钙拮抗剂、依利替康、莫达非尼(modafmil)、奥利司他、肽抗生素类、苯妥英、利鲁唑、利塞膦酸盐、西地那非、托吡酯、大环内酯类抗生素、雌二醇和雌二醇衍生物、孕激素和孕激素衍生物、睾酮和睾酮衍生物、雄激素和雄激素素衍生物、乙水杨胺、依托酚那酯、依托贝特、非诺贝特、乙羟茶碱、依托泊苷、泛音洛韦、法莫替丁、非洛地平、非诺贝特、芬太尼、芬替康唑、回旋酶抑制剂、氟康唑、氟达拉滨、氟桂利嗪、氟尿嘧啶、氟西汀、氟比洛茶、布洛芬、氟他胺、氟伐他汀、促滤泡素、福莫特罗、磷霉素、呋塞米、夫西地酸、戈洛帕米、更昔洛韦、吉非贝齐、庆大霉素、银杏、圣约翰草、格列本脲、作为口服抗糖尿病药的尿素衍生物、高血糖素、葡糖胺和葡糖胺衍生物、谷胱甘肽、甘油和甘油衍生物、下丘脑激素、戈舍瑞林、回旋酶抑制剂、胍乙啶、卤泛群、氟哌啶醇、肝素和肝素衍生物、透明质酸、肼屈嗪、氢氯噻嗪和氢噻嗪衍生物、水杨酸类、羟嗪、伊达比星、异环磷酰胺、丙咪嗪、吲哚美辛、吲哚拉明、胰岛素、干扰素类、碘和碘衍生物、异康唑、异丙肾上腺素、葡糖醇和葡糖醇衍生物、伊曲康唑、酮康唑、酮洛芬、酮替芬、拉西地平、兰索拉唑、左旋多巴、左美沙酮、甲状腺激素类、硫辛酸和硫辛酸衍生物、赖诺普利、利舒脲、洛非帕明、洛莫司汀、洛哌丁胺、氯雷他定、马普替林、甲苯达唑、美贝维林、美克洛嗪、甲芬那酸、甲氟喹、美洛昔康、甲吲洛尔、甲丙氨醋、美罗培南、美沙拉嗪、甲琥胺、安替比林甲胺甲烷、二甲双胍、甲氨蝶呤、哌甲酯、甲泼尼龙、美噻吨、甲氧氯普胺、美托洛尔、甲硝唾、米安色林、咪康唑、米诺环素、米诺地尔、米索前列醇、丝裂霉素、咪唑斯汀、莫昔普利、吗啡和吗啡衍生物、月见草、纳布啡、纳洛酮、替利定、萘普生、那可汀、那他霉素、新斯的明、尼麦角林、尼可刹米、硝苯地平、尼氟酸、尼莫地平、尼莫唑、尼莫司汀、尼索地平、肾上腺素和肾上腺素衍生物、诺氟沙星、甲哌氯丙嗪砜、那可汀、制霉菌素、氧氟沙星、奥氮平、奥沙拉嗪、奥美拉唑、奥莫康唑、昂丹司琼、奥沙西罗、苯唑西林、奥昔康唑、羟甲唑啉、泮托拉唑、对乙酰氨基酚、帕罗西汀、喷昔洛韦、口服青霉素类、喷他佐辛、喷替茶碱、己酮可可碱、奋乃静、哌替啶、植物提取物、安替比林、非尼拉敏、巴比妥酸衍生物、保泰松、苯妥英、匹莫齐特、吲哚洛尔、哌嗪、吡拉西坦、哌仑西平、吡贝地尔、吡罗昔康、普拉克索、普伐他汀、哌唑嗪、普鲁卡因、丙嗪、丙哌维林、普萘洛尔、异丙安替比林、前列腺素类、丙硫异烟胺、丙羟茶碱、喹硫平、喹那普利、喹普利拉、雷米普利、雷尼替丁、瑞普特罗、利血平、利巴韦林、利福平、利培酮、利托那韦、罗匹尼罗、罗沙替丁、罗红霉素、鲁斯可皂苷元、芦丁和芦丁衍生物、沙巴达、沙丁胺醇、沙美特罗、东茛菪碱、司来吉兰、舍他康唑、舍吲哚、舍曲林、硅酸盐类、西地那非、辛伐他汀、谷留醇、索他洛尔、司谷氨酸、司帕沙星、大观霉素、螺旋霉素、螺普利、螺内酯、司他夫定、链霉素、疏糖铝、舒芬太尼、舒巴坦、磺胺类、柳氮磺吡啶、舒必利、舒他西林、舒噻美、舒马普坦、氯琥珀胆碱、他克林、他克莫司、他林洛尔、他莫昔芬、牛橫罗定、他扎罗汀、替马西泮、替尼泊苷、替诺昔康、特拉唑嗪、特比萘芬、特布他林、特非那定、特利加压素、特他洛尔、四环素类、四氢唑林、可可碱、茶碱、布替嗪、甲疏咪唑、吩噻嗓类、塞替派、噻加宾、硫必利、丙酸衍生物、噻氯匹定、噻吗洛尔、替硝唑、噻康唑、硫鸟嘌呤、噻克索酮、替罗拉胺、替扎尼定、妥拉唑林、甲苯磺丁脲、托卡朋、托萘醋、托哌酮、拓扑替康、托拉塞米、抗雌激素药、曲马多、曲马唑啉、群多普利、反苯环丙胺、曲匹地尔、曲唑酮、曲安西龙和曲安西龙衍生物、氨苯蝶啶、三氟哌多、曲氟尿苷、甲氧苄啶、曲米帕明、曲吡那敏、曲普利啶、曲磷胺、曲金刚胺、氨丁三醇、三苯乙醇、曲克芦丁、妥洛特罗、酪胺、短杆菌素、乌拉地尔、熊去氧胆酸、鹅去氧胆酸、伐昔洛韦、丙戊酸、万古霉素、维库氯铵、万艾可、文拉法辛、维拉帕米、阿糖腺苷、氨己稀酸、维洛沙嗪、长春碱、长春胺、长春新減、长春地辛、长春瑞滨、长春西汀、维喹地尔、华法林、尼可占替诺、希帕胺、扎鲁司特、扎西他滨、齐多夫定、佐米曲普坦、唑吡坦、佐匹克隆、佐替平等。参见例如美国专利6,897,205、6,838,528和6,497,7290。
在某些实施方案中,可以将间质干细胞颗粒如外泌体掺入到生物相容基质中或以其他方式包衣在球囊上。参见美国专利公开2015190430。间质干细胞颗粒可产生于或者来自于间质干细胞(MSC)。这样的方法可以包括从间质干细胞条件培养基(MSC-CM)中分离所述颗粒。例如,间质干细胞颗粒可以基于分子量、大小、形状、组成或生物学活性来分离。可将条件培养基在分离和使用期间、之前或之后进行过滤或浓缩或过滤和浓缩两者。MSC衍生的外泌体可用于治疗心血管疾病,包括心肌梗塞、再灌注损伤和肺动脉高压。Huang等人,Exosomes in Mesenchymal Stem Cells,a New Therapeutic Strategy forCardiovascular Diseases?Int J Biol Sci.11⑵:238-245(2015)。
或者,可以将多种DNA或RNA载体掺入生物相容基质中。例如,重组病毒包括本领域中的重组腺伴随病毒(AAV)、重组腺病毒、重组慢病毒、重组逆转录病毒、重组痘病毒和其它已知病毒,以及可使用质粒、粘粒和噬菌体。基因递送病毒构建物的选择在本领域中是众所周知的(参见例如,Ausubel等人,Current Protocols in Molecular Biology,JohnWiley&Sons,New York,1989;Kay,M.A.等人,2001Nat.Medic.7(1):33-40;以及WaltherW.和Stein U.,2000Drugs,60(2):249-71)。另外,递送载体如基于纳米颗粒和脂质的mRNA或蛋白质递送系统可以用作AAV载体的替代物。替代递送载体的其他实例包括慢病毒载体,基于脂质的递送系统,基因枪,流体动力学,电穿孔或核转染显微注射以及生物射弹。Nayerossadat等人(Adv Biomed Res.2012;1:27)和Ibraheem等人(Int J Pharm.2014Jan1;459(l-2):70-83)详细讨论了各种基因递送方法。
本发明可以与任何球囊导管支架递送系统一起使用,包括以下文献中描述的球囊导管支架递送系统:美国专利6,168,617、6,222,097;6,331,186;6,478,814;7,169,162或者20090254064。
所述可扩展的覆盖物可封闭整个球囊或者仅封闭所述球囊的部分。在所述可扩展的覆盖物和所述球囊之间存在环形空间或者腔,其可被密封,即,不与导管流体连通,或者替代地,可与导管轴流体连通。例如,所述球囊导管系统可允许流体释放进入在所述球囊和所述可扩展的覆盖物之间的空间或者环形腔中。在该实施方案中,所述环形腔或者空间与沿着导管轴延伸的流体递送腔和在所述可膨胀的球囊和所述可扩展的覆盖物之间的环形腔或者空间连通。经过导管轴中的流体递送腔的流体可释放至环形腔或者空间中,从而在插入至体腔中之前或者期间水合所述脱水的生物相容基质。
球囊导管如在美国专利公开20040006359中描述的那些也可用于本发明方法。
可在球囊已经被压实以插入之后或插入之前将包衣施加至球囊。球囊通过例如卷曲或折叠而被压实。参见美国专利5,350,361、7,308,748或者7,152,452。所述球囊通过诸如导管的递送装置递送到介入部位。在通过本领域众所周知的方法递送和/或移除期间,可将球囊递送、移除和可视化,参见例如美国专利6,610,013或7,171,255。本发明的球囊可以包括:顺应性球囊(当加压时扩展例如16-40%)、半顺应性球囊(当加压时扩展例如7-16%)和非顺应性球囊(当加压时扩展例如2-7%)。各种特性(例如最大的膨胀度,即从标称直径到爆裂的膨胀度)是不同的,并且是本领域公知的。也用于血管成形术的切割球囊可以与本发明的方法和装置一起使用。使球囊膨胀至由操作者根据球囊的部位和类型确定的设定膨胀压力。球囊的“额定破裂压力”或“RBP”是球囊可膨胀而不失败的最大保证压力。
球囊可以在施加药物活性剂之前或之后被涂覆润滑剂包衣,以降低药物活性剂或生物相容性基质与球囊之间的摩擦系数,即粘连。润滑剂包衣可以是亲水或疏水包衣。降低医疗器械中使用的摩擦系数的润滑剂的实例包括:有机硅;水和卵磷脂的胶体溶液;作为电连接器润滑剂的聚苯醚;和固体润滑剂二硫化钼、PTFE或粉状石墨和氮化硼。摩擦系数可以降低到0.001或更低。或者,具有非粘性表面的聚合物可以通过使用表面改性化合物如含氟聚合物和共聚物等生产,所述表面改性化合物具有乙烯基末端或者侧基用于化学溶剂耐性和非粘性表面。具有亲水表面的聚合物可以通过使用表面改性化合物如聚乙烯吡咯烷酮、PVA、PEG等来生产。另外,通过使用表面改性化合物如聚乙烯吡咯烷酮、PVA、PEG、等可以生产具有低表面摩擦的聚合物。
在一个实施方案中,将球囊1.1置于引导线1.2上(图1)。引导线1.2可以具有位于所述球囊两端的标记带1.3、1.4。所述球囊可为扩展的或者膨胀的2.1(图2),从而允许释放或者挤出生物相容基质或者水凝胶2.2。在引入血管中之后,所述球囊可以定位在动脉粥样硬化斑块附近。将所述球囊在膨胀之前以折叠或者打褶的(或者未膨胀)状态引入血管或者体腔中,3.1、3.2、3.3、3.4(引导线3.5)(图3)。将所述球囊完全封闭或者包封在可扩展的覆盖物3.6中。随着所述球囊膨胀,褶展开并且在完全扩展之后球囊完全展开(膨账)。在所述非扩展状态中,所述球囊的褶围绕位于引导线上的球囊的主体缠绕。所述球囊可含有3、4、5、6、7、8、9、10...n个褶;与膨胀的球囊的打褶尺寸比率可为2、3、4、5、6、7、8、9、10、20或者30。
在扩展之后,在所述可扩展的覆盖物中的缝隙或者孔扩大4.1(图4),从而允许将所述生物相容基质挤出进入体腔中4.2。这种挤出在特写视图中显示为5.1(图5)。所述球囊在扩展之后的横截面视图在图6中示出。所述球囊6.1包围引导线6.2。扩大的缝隙/孔显示为6.3。通过这些缝隙或者孔,将所述生物相容基质6.4挤出。
所述生物相容基质可由螺旋缠绕物7.1形成,所述螺旋缠绕物包围、封闭或者包封所述球囊7.2(图7)。用打褶的球囊8.2的可扩展的覆盖物8.3的缠绕在图8中示出。将围绕球囊9.2螺旋缠绕的基质9.1用含有缝隙/孔9.4的可扩展的覆盖物9.3封闭,可将所述基质通过所述缝隙/孔挤出(图9)。
可以使用本发明的医疗装置和方法治疗的受试者是哺乳动物,包括但不限于人、马、狗、猫、猪、啮齿动物、猴等。
以下是本发明的实例,不应被解释为限制。
实施例
实施例1:球囊包衣(紫杉醇)
(a)在氯仿中的90%紫杉醇(paclitaxel)/%Mpeg-PLGA:将紫杉醇在氯仿中混合至1.5%的w/v浓度(15mg/mL)。将聚合物在氯仿中混合至1.5%的w/v浓度(15mg/mL)。然后两种溶液分别以90:10的比例混合。
(b)在氯仿中的90%紫杉醇/10%Mpeg-PDLA:将紫杉醇在氯仿中混合至1.5%的w/v浓度(15mg/mL)。将聚合物在氯仿中混合至1.5%的w/v浓度(15mg/mL)。然后两种溶液分别以90:10的比例混合。
(c)在蒸馏(DI(去离子水))水中的90%紫杉醇/10%碘海醇(Iohexol):将紫杉醇在丙酮中混合至1.5%的w/v浓度(15mg/mL)。将碘海醇在去离子水中混合至1.5%的w/v浓度(15mg/mL)。然后将两种溶液以90:10或者95:5的比例组合(如果适用的话)。
(d)在DI水中的90%紫杉醇/10%尿素(Urea):将紫杉醇在氯仿中混合至1.5%的w/v浓度(15mg/mL)。将尿素在去离子水中混合至1.5%的w/v浓度(15mg/mL)。然后两种溶液分别以90:10的比例混合。
(e)球囊的包衣:将3.0mm×15mm球囊用上面列出的制剂包衣。将球囊用以下的目标剂量包衣:1μg/mm2、2μg/mm2和3μg/mm2。在包衣之后立即将包衣的球囊折叠并上鞘。
(f)溶解性研究:玻璃载玻片将被涂上各种制剂。然后将所述包衣被从载玻片上刮下到坩埚中。然后在分析天平(T/N 1160)上称量涂层。将磷酸盐缓冲盐水(PBS)加入到预先称重的涂层中以制成10mg/mL的溶液。然后将溶液涡旋3分钟并过滤。使用3mL注射器和13mm0.45μm PTFE过滤器将lmL溶液取出并过滤到试管中。然后将1mL甲醇加入到过滤的PBS中并“涡旋”20秒以溶解存在的任何紫杉醇。然后分析1mL样品的药物(紫杉醇)含量。
实施例2:球囊包衣(西罗莫司)
(a)在氯仿中的90%西罗莫司/10%Mpeg-PLGA:将西罗莫司在氯仿中混合至1.5%的w/v浓度(15mg/mL)。将聚合物在氯仿中混合至1.5%的w/v浓度(15mg/mL)。然后两种溶液分别以90:10的比例混合。
(b)在氯仿中的90%西罗莫司/10%Mpeg-PDLA:将西罗莫司在氯仿中混合至1.5%的w/v浓度(15mg/mL)。将聚合物在氯仿中混合至1.5%的w/v浓度(15mg/mL)。然后两种溶液分别以90:10的比例混合。
(c)在蒸馏(DI)水中的90%西罗莫司/10%碘海醇:将西罗莫司在丙酮中混合至1.5%的w/v浓度(15mg/mL)。将碘海醇在去离子水中混合至1.5%的w/v浓度(15mg/mL)。然后将两种溶液以90:10或者95:5的比例组合(如果适用的话)。
(d)在DI水中的90%西罗莫司/10%尿素:将西罗莫司在氯仿中混合至1.5%的w/v浓度(15mg/mL)。将尿素在去离子水中混合至1.5%的w/v浓度(15mg/mL)。然后两种溶液分别以90:10的比例混合。
(e)球囊的包衣:将3.0mm×15mm球囊用上面列出的制剂包衣。将球囊用目标剂量如1μg/mm2、2μg/mm2和3μg/mm2包衣。在包衣之后立即将包衣的球囊折叠并用可扩展的覆盖物上鞘。
(f)溶解性研究:将玻璃载玻片涂上各种制剂。然后将涂层从载玻片上刮下到坩埚中。然后在分析天平(T/N 1160)上称量涂层。将磷酸盐缓冲盐水(PBS)加入到预先称重的涂层中以制成10mg/mL的溶液。然后将溶液涡旋3分钟并过滤。使用3mL注射器和13mm 0.45μmPTFE过滤器将1mL溶液提取并过滤到试管中。然后将1mL甲醇加入到过滤的PBS中并涡旋20秒以溶解任何存在的西罗莫司。然后分析1mL样品的药物(西罗莫司)含量。
实施例3:洗脱特征(Elution Profile)
(a)洗脱特征动力学:在有和没有可犷展的覆盖物的情况下,将包衣的球囊置于不同的1mL PBS等分试样中,在37℃保存一系列确定的时间,例如30秒、1、2、3、4、5、10、15、30、60和120分钟,以随时间产生洗脱特征。然后通过高压液相色谱(HPLC)分析PBS的等分试样以建立在每个时间点在溶液中的西罗莫司浓度。包含已知量的西罗莫司的校准标准品将被用于确定西罗莫司洗脱的量。累加西罗莫司存在的多个峰(也存在于校准标准品中)以给出在该时间段洗脱的西罗莫司的量(以绝对量和作为洗脱累积量)。然后使用Waters HPLC系统进行高压液相色谱(HPLC)分析。
实施例4:临床模拟试验
(a)体外质量损失测试:将按照实施例2制备的具有可扩展的覆盖物的包衣的球囊在微量天平上称重,然后固定到球囊导管上。将一段光学透明的管填充磷酸盐缓冲盐水(PBS),并浸入37℃的水浴中以模拟在受试者体腔内展开的生理条件。将包衣的球囊插入到所述管中,并且使球囊膨胀至比球囊的额定破裂压力(例如5-15atm)低至少大约25%至大约70%,持续30秒、1、2、3、4、5、10、15、30、60或者120分钟。所述球囊将变瘪,然后从所述管除去。在干燥后,将球囊进一步干燥并在微量天平上称重。在展开前和展开后重量的比较表明多少涂层从球囊中释放、解离和/或转移。
(b)体外测试远端流量:将实施例2中制备的包衣的球囊固定到包含100μm孔径的多孔过滤器的引导线上。将一段管填充PBS并浸入37℃的水浴中。将用可扩展的覆盖物封闭的包衣的球囊插入所述管中。将开始PBS通过TYGON管的流动,远端过滤器将被展开并且球囊将被膨胀至比球囊的额定破裂压力(例如,5-15atm)低至少大约25%至大约70%,持续30秒、1、2、3、4、5、10、15、30、60或者120分钟。所述球囊将变瘪并从所述管除去。所述过滤器将在除去球囊之后被展开5分钟,并且PBS的流动将停止,邻近环氧密封切割所述管,过滤器缩回并从所述管除去。将分析过滤器的含量以确定含有西罗莫司的颗粒的存在。
实施例5:在尤卡坦小型猪(Yucatan Minswine)动脉中扩展包衣的球囊
包衣的球囊将被准备,然后固定到球囊导管。简而言之,将球囊在包衣组合物中浸涂(例如,如实施例1或实施例2中所述)。然后将球囊干燥、折叠并固定到球囊导管上。
尤卡坦小型猪的一段切除的冠状动脉将被定位并填充PBS。然后将冠状动脉浸入37℃的水浴中以模拟在受试者中展开的生理条件。包衣的球囊将被插入管中,并且球囊将被膨胀至比球囊的额定破裂压力(例如,5-15atm)低至少大约25%至大约70%,持续30秒、1、2、3、4、5、10、15、30、60或者120分钟。所述球囊将变瘪并从动脉除去。将暴露于展开的球囊的动脉切片从动脉切片的其余部分切下,放入组织匀浆器中,用二氯甲烷提取均化的材料以制成25mL总体积的冲洗液,将其收集在烧瓶中进行分析。将进行如上所述的HPLC分析以确定在每个时间点从球囊通过可扩展的覆盖物转移到冠状动脉的西罗莫司的量。
西罗莫司也将从所述球囊通过以下方法提取:将西罗莫司置于含1mL甲醇的5mL玻璃试管中并涡旋大约20秒。球囊将从试管中取出,并使用3mL注射器和0.45微米过滤器将试管的内容物过滤到lmL自动进样器小瓶中。西罗莫司浓度将通过HPLC测定。
实施例6:所述球囊和包衣的光学显微镜检查和扫描电子显微镜检查(SEM)
包衣的球囊将使用例如实施例1或实施例2中所述的包衣组合物制备。所述球囊将被可扩展的覆盖物覆盖并在37℃浸渍在PBS中。如上所述,包衣的球囊将被插入管中,并且球囊将被膨胀至比球囊的额定破裂压力(例如,5-15atm)低至少大约25%至大约70%,持续大约30秒、1、2、3、4、5、10、15、30、60或者120分钟。所述球囊将变瘪并从管除去。SEM和光学显微术将在球囊和可扩展的覆盖物上进行,以确定与包衣的转移、解离和移位有关的球囊和可扩展的覆盖物的表面发生的物理变化。
实施例7:活性药剂在应用部位的体内分析
一组10只新西兰白兔将用Seldinger操作使用包衣有西罗莫司制剂的球囊制备,总西罗莫司负载量大约为20-60μg。然后将所述包衣的球囊通过所述可扩展的覆盖物封闭,然后置于冠状动脉中。所述覆盖的和包衣的球囊导管将在荧光透视检查的帮助下定位。六只动物将使用包衣中没有西罗莫司的包衣的球囊进行操作。在展开和移除球囊后,2个对照动物将在展开1小时后处死,并收集血清和组织样品。其余3只对照动物将在展开56天后处死。在研究过程中,每五天从对照和药物处理动物收集血清样品。药物处理的动物(各3只)将在展开后1小时、24小时、7天、14天、28天、42天和56天被处死。如上所述,通过HPLC对组织和血清样品进行西罗莫司浓度分析。本发明的范围不受上文具体示出和描述的限制。本领域技术人员将认识到,对于所描绘的材料、构造、结构和尺寸的示例,存在合适的替代方案。在本发明的描述中引用和讨论了许多参考文献,包括专利和各种出版物。提供这样的参考文献的引用和讨论仅仅是为了阐明本发明的描述,而不是承认任何参考文献是在此描述的本发明的现有技术。在本说明书中引用和讨论的所有参考文献通过引用整体并入本文。在不脱离本发明的精神和范围的情况下,本领域普通技术人员将会想到在此描述的变型,修改和其他实施方案。尽管已经示出和描述了本发明的具体实施例,但是对于本领域技术人员来说显而易见的是,可以在不脱离本发明的精神和范围的情况下进行改变和修改。在前面的描述和附图中阐述的内容仅作为说明而不是作为限制来提供。
Claims (30)
1.一种医疗装置,包括球囊,所述球囊包括多个褶,生物相容性基质,所述生物相容性基质放置于所述球囊和覆盖物之间,其中,所述覆盖物封闭所述生物相容性基质和所述球囊,并且其中,当所述球囊膨胀时所述覆盖物的渗透性大于未扩展状态下所述覆盖物的渗透性。
2.根据权利要求1所述的医疗装置,其中,所述生物相容性基质包含至少一种药剂。
3.根据权利要求2所述的医疗装置,其中,所述药剂包封在微球、脂质体、纳米颗粒、纳米凝胶或其混合物中。
4.根据权利要求2所述的医疗装置,其中,所述药剂包含至少一种抗增殖剂,所述至少一种抗增殖剂选自由以下组成的组:依维莫司、他克莫司、佐他莫司、biolimus、雷帕霉素,或其混合物。
5.根据权利要求1所述的医疗装置,其中,所述生物相容性基质封闭所述褶。
6.根据权利要求5所述的医疗装置,其中,所述球囊膨胀时所述生物相容性基质穿过所述覆盖物被挤出。
7.根据权利要求6所述的医疗装置,其中,所述球囊是顺应性的、半顺应性的或非顺应性的。
8.根据权利要求6所述的医疗装置,还包括所述覆盖物中的多个洞、孔、缝隙或其组合。
9.根据权利要求8所述的医疗装置,其中,当所述球囊膨胀时,所述生物相容性基质通过所述覆盖物中的孔被挤出。
10.根据权利要求1所述的医疗装置,其中,所述生物相容性基质形成封闭所述褶的管。
11.根据权利要求2所述的医疗装置,其中,所述生物相容性基质中的所述药剂的总表面载荷为约1μg/mm2至约200μg/mm2。
12.根据权利要求11所述的医疗装置,其中,当所述球囊未膨胀时,在将所述医疗装置在37℃下在水溶液中孵育约10分钟后,释放小于约10%(w/w)的所述药剂。
13.根据权利要求11所述的医疗装置,其中,当所述球囊膨胀时,在37℃下在水溶液中孵育约10分钟后,释放大于约75%(w/w)的所述药剂。
14.根据权利要求13所述的医疗装置,其中,所述药剂遵循零级动力学释放到所述水溶液中。
15.根据权利要求1所述的医疗装置,其中,所述覆盖物的厚度范围为约0.1μm至约300μm。
16.根据权利要求1所述的医疗装置,其中,所述生物相容性基质是薄膜。
17.根据权利要求2所述的医疗装置,其中,所述生物相容性基质包括葡聚糖、藻酸盐、直链淀粉、支链淀粉、角叉菜胶、羧甲基纤维素、胶凝糖、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、支链淀粉、透明质酸、黄原胶、木糖葡聚糖、基于壳聚糖的水凝胶、肽多糖、蛋白多糖、葡萄糖、多糖、麦芽糖、乳糖、果糖、蔗糖、半乳糖、萄糖胶、半乳糖胺、胞壁酸、葡萄糖醛酸酯、葡萄糖酸盐、岩藻糖、海藻糖、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、丙二醇、聚氧基亚乙基衍生物、弹性蛋白、聚乙烯基胺或者聚(L-赖氨酸)、羧甲基纤维素(CMC)、羟丙基甲基纤维素(HPMC)、支链淀粉、透明质酸、芽霉菌糖或其组合。
18.根据权利要求17所述的医疗装置,还包括生物胶粘剂。
19.根据权利要求18所述的医疗装置,其中,所述生物相容性基质由芽霉菌糖形成。
20.根据权利要求19所述的医疗装置,其中,所述生物相容性基质形成为带,所述带围绕所述褶缠绕1至10次。
21.根据权利要求20所述的医疗装置,还包括至少两个不同的带,其中,每个带包含至少一种药剂。
22.根据权利要求21所述的医疗装置,其中,所述药剂包括至少一种抗增殖剂,所述至少一种抗增殖剂选自由以下组成的组:依维莫司、他克莫司、佐他莫司、biolimus、雷帕霉素,或其混合物。
23.根据权利要求1所述的医疗装置,其中,所述覆盖物由聚合物形成。
24.根据权利要求23所述的医疗装置,其中所述覆盖物由以下形成:高密度、高分子量聚乙烯(HDHMWPE),超高分子量聚乙烯(UHDHMWPE),聚(四氟乙烯),聚(四氟乙烯)(PTFE),乙烯乙酸乙烯酯,乳胶,氨基甲酸酯,含氟聚合物,聚乙烯醇(PVA)-交联的水凝胶,聚硅氧烷,苯乙烯-乙烯/丁烯-苯乙烯嵌段共聚物,其混合物、共聚物或其组合。
25.根据权利要求24所述的医疗装置,其中,所述覆盖物由超高分子量聚乙烯制成。
26.根据权利要求24所述的医疗装置,其中,所述覆盖物形成围绕所述球囊密封的管。
27.根据权利要求1所述的医疗装置,其中,至少一个标记带定位于所述球囊的两端。
28.一种医疗装置,所述装置包括球囊,所述球囊包括多个褶和放置于所述球囊和覆盖物之间的生物相容性基质,其中,所述生物相容性基质包括至少一种药剂,所述至少一种药剂选自由以下组成的组:抗依维莫司、他克莫司、西罗莫司、佐他莫司、biolimus、雷帕霉素,或其混合物;所述至少一种药剂包封在微球体、脂质体、纳米颗粒或纳米凝胶中,并且其中,所述覆盖物形成封闭所述球囊的管,所述管围绕所述球囊密封,并且其中,当所述球囊膨胀时所述覆盖物的渗透性大于未扩展状态下所述覆盖物的渗透性。
29.根据权利要求28所述的医疗装置,所述生物相容性基质包括:葡聚糖、藻酸盐、直链淀粉、支链淀粉、角叉菜胶、羧甲基纤维素、胶凝糖、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、支链淀粉、透明质酸、黄原胶、木糖葡聚糖、基于壳聚糖的水凝胶、肽多糖、蛋白多糖、葡萄糖、多糖、麦芽糖、乳糖、果糖、蔗糖、半乳糖、萄糖胶、半乳糖胺、胞壁酸、葡萄糖醛酸酯、葡萄糖酸盐、岩藻糖、海藻糖、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、丙二醇、聚氧基亚乙基衍生物、弹性蛋白、聚乙烯基胺或者聚(L-赖氨酸)、羧甲基纤维素(CMC)、羟丙基甲基纤维素(HPMC)、支链淀粉、透明质酸、芽霉菌糖或其组合;所述生物相容性基质中的生物胶粘剂和所述可扩展的覆盖物由以下形成:高密度、高分子量聚乙烯(HDHMWPE),超高分子量聚乙烯(UHDHMWPE),聚(四氟乙烯),聚(四氟乙烯)(PTFE),乙烯乙酸乙烯酯,胶乳,氨基甲酸酯,含氟聚合物,聚乙烯醇(PVA)-交联的水凝胶,聚硅氧烷,苯乙烯-乙烯/丁烯-苯乙烯嵌段共聚物,其混合物、共聚物或其组合。
30.根据权利要求29所述的医疗装置,其中,所述球囊是是顺应性的、半顺应性的或非顺应性的。
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CN202111436665.3A Pending CN114225119A (zh) | 2016-02-08 | 2017-02-08 | 包含包衣的可膨胀的球囊 |
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EP (4) | EP3413964A4 (zh) |
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EP3868435A1 (en) | 2021-08-25 |
JP2021184843A (ja) | 2021-12-09 |
CN108601930B (zh) | 2021-12-14 |
WO2017139357A1 (en) | 2017-08-17 |
JP7027319B2 (ja) | 2022-03-01 |
EP3413964A4 (en) | 2019-12-04 |
US20210196932A1 (en) | 2021-07-01 |
EP3871731A1 (en) | 2021-09-01 |
EP3413964A1 (en) | 2018-12-19 |
CN108601930A (zh) | 2018-09-28 |
JP2023109865A (ja) | 2023-08-08 |
JP2019510536A (ja) | 2019-04-18 |
EP3868434A1 (en) | 2021-08-25 |
CN114225119A (zh) | 2022-03-25 |
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