CN101297982A - 一种含有抗血栓形成轭合物的医疗装置用涂料 - Google Patents
一种含有抗血栓形成轭合物的医疗装置用涂料 Download PDFInfo
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- CN101297982A CN101297982A CNA2008101258072A CN200810125807A CN101297982A CN 101297982 A CN101297982 A CN 101297982A CN A2008101258072 A CNA2008101258072 A CN A2008101258072A CN 200810125807 A CN200810125807 A CN 200810125807A CN 101297982 A CN101297982 A CN 101297982A
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Abstract
本发明涉及一种制备梳型抗血栓形成轭合物的方法,其中基本上所有水溶性聚(乙烯醇)(PVA)的侧链用开环聚合反应延展以形成一种共聚物,并且其中基本上所有的末端轭合有一种抗血栓形成分子。另外,提供一种方法以将一种包含梳型抗血栓形成轭合物的涂层应用到一种可植入装置的至少一个部分中,以避免或减少装置表面的血栓形成。涂层的第一或底层通过用溶剂混合聚合材料和生物活性药剂制备,这样形成一种均相溶液。包含一种梳型抗血栓形成轭合物的第二或外层可通过使用,诸如,浸入涂布或喷雾涂布工艺而被涂在到内部的含药层上。在将微球或纳米球放置到医疗装置上之前,梳型抗血栓形成轭合物可任选地作为基质材料使用并包封一种药剂以形成微球或纳米球。
Description
技术领域
本申请涉及一种应用于关节表面的至少一段或者关节内的可植入物的材料。特别地,该发明涉及一种含有一种与抗血栓形成组合物轭合的梳型生物可吸收聚合物,其中一种抗再狭窄物质可包含于生物可吸收聚合物的聚合物基质中。该发明也涉及一种具有涂于其表面或包含于其中的轭合物的装置。
背景技术
狭窄症是脂肪,胆固醇,和其他物质随时间积聚而形成的血管压缩或狭窄。重症时,狭窄可以完全堵塞血管。介入疗法被应用于打开狭窄血管。介入疗法的一个例子是冠状动脉腔内血管成形术(PCTA)或者球囊冠状动脉腔内成形术。在这种治疗中,一个球囊导管被***并且在血管的狭窄部位膨胀以清除一个阻塞。大约三分之一进行了PTCA的患者患有再狭窄,其中血管在治疗的约六个月内再次阻塞。这样,再狭窄的血管可能不得不进行再次的血管成形术。为了避免额外的PTCA,诸如支架的可植入医疗器械在PTCA后或代替PTCA已被置于血管中。但是,再狭窄可能依然会随着支架的植入而产生。
再狭窄通过包括将支架***动脉的有效部位以替代,或者,伴随血管成形术的普通疗法而被抑制。支架是用金属或塑料制成的管,其可以具有固壁或网格壁。大多数使用中的支架是金属的并且是自膨胀或球囊膨胀的。进行支架***疗法的决定取决于血管狭窄的某些特征。其包括动脉的大小和狭窄的位置。支架的作用是支撑近期用血管成形术扩大的动脉,或者,如果没有使用血管成形术的话,支架被用来避免动脉的弹性回缩。支架典型地通过导管被植入。在球囊扩张支架的情况中,将支架折叠成小直径并且将其滑进球囊导管。然后导管***纵通过患者的血管***到达损伤部位或近期被扩大的位置。一旦入位,支架被扩展并且在部位中锁定。支架将永远留在动脉中,使其开放,改善通过动脉的血流,并且减轻症状(通常胸痛)。
支架在避免植入部位的再狭窄方面并不完全有效。再狭窄可在超过支架长度处和/或越过支架末端发生。医生最近已经应用涂上载有可以抑制平滑肌细胞增殖药物的薄聚合物膜的新型支架。该膜采用诸如溶剂蒸发术等的本领域公知方法在植入动脉前被涂在支架上。溶剂蒸发术将聚合物和药物在溶剂中混合。然后包含聚合物,药物,和溶剂的溶液可以通过浸入或喷涂被涂在支架的表面。然后将支架干燥,这当中溶剂被蒸发,并且聚合材料,与分散其中的药物一起,组成了支架上的一层薄膜层。
药物从聚合材料中的释放方式取决于聚合材料以及掺入其中的药物的性质。药物从聚合物扩散聚合物-液体界面,然后进入液体。释放也可以通过聚合材料的降解发生。聚合材料的降解可以通过水解或酶消化过程发生,从而导致掺入其中的药物释放入周围组织。
使用涂布支架一个重要的考虑是药物从涂布层的释放速率。我们期望在一个合理的时间段内有效治疗量的药物从支架中释放以使其在随后的生物学过程和血管成形术过程或支架植入过程中起作用。爆发释放,即植入后立即一个高释放速率,是不期望的并且是一个持久的问题。当典型地对患者无害时,爆发释放通过释放数倍于所需量的药物从而“浪费”有限的药物供给并且缩短了释放时间。几项技术已被研发以降低爆发释放。例如,在US专利6,258,121B1中,Yang等揭示了通过共混具有不同释放速率的两种聚合物并且将它们掺入同一个层来改变释放速率的方法。
药物涂层支架(DES)植入的一个潜在著的缺点是在植入或膨开后的不同时间可能发生血栓形成。血栓形成是血凝块在或临近于血管中的可植入装置的形成。凝块通常通过血液因子的聚集形成,主要是血小板和纤维蛋白,包括细胞因子。血栓形成,就像狭窄,常常在其发生处引起血管堵塞。狭窄和血栓形成都是两个需要医学介入的严重的潜在的致命状况。支架表面的血栓形成常常是致命的,并且在遭受血管中血栓形成的患者中间导致20-40%的死亡率。
尽管在降低再狭窄时有效,涂层的一些用于避免再狭窄的部分可能提高血栓形成的危险。药物涂层支架典型地与急性和亚急性血栓形成(SAT),或支架植入术后中期血栓形成(支架植入后30天)的升高不是密切相关的。但是,长期临床随访研究表明这些装置可能与升高的长期血栓形成(LST)发生率有关。尽管LST的升高已经被发现小于1%,但是高致死率通常与LST密切相关。避免其的一种方式包括在装置上的一层具有诸如肝素的抗凝剂的涂层。
对付支架血栓形成的一种方式是通过利用诸如肝素的抗凝剂。肝素是公知具有抗凝活性的物质。已经知道应用采用溶剂蒸发术将载有肝素的薄膜聚合物涂层涂在在支架表面上,例如,在US专利号5837313中,Ding等描述了一种制备肝素涂层组合物的方法。使用肝素的缺点是其与避免血栓形成的药物不能很好的共处。例如,如果肝素与一种抗血栓混合于一个聚合物涂层中,肝素的亲水活性将干扰所期望的抗血栓剂的释放曲线。例如,治疗药物通过溶剂处理被埋入聚合物涂层基质中。如果一种抗凝剂也被埋入聚合物基质,它将以无法控制的方式吸水。这可能在制造或者当被涂层装置被植入时发生并将可逆地影响药物的稳定性或有效性和/或干扰所期望的释放曲线。
但是,一些方法可以被用来在可植入医疗装置中混合抗血栓形成和治疗药物。US专利号5525348-Whitbourne公开了一种将药物(包括肝素)与季铵化合物或其他离子型表面活性剂配合在一起并且与水不溶性聚合物结合作为一种一种抗血栓形成涂层组合物的方法。该方法可能引入纤维素,或其衍生物等天然来源的聚合物,其在性质上是非均质的并且可能在植入部位引起的感染反应。这些从诸如肝素的抗血栓形成药剂到带相反电荷的载体聚合物的离子配合物可能也相反地影响涂层整合,并且如果存在额外药物,可能影响放置稳定性和这些药物的释放动力学。
一种稍微不同的方法在US专利号6702850,6245753和7129224-Byuu中被揭示,其中抗血栓形成药剂,例如肝素,在用于涂层形成前,被共价轭合到一个诸如丙烯酸的不可吸收的聚合物上。这些轭合物的疏水性进一步用诸如十八胺这样的具有长碳氢链的胺的疏水物质调节。这种方法具有一些潜在的缺点,例如肝素体内代谢后丙烯酸的已知毒性。疏水性胺的加入也提高了对组织相容性和每一步的置换反应的再产生的顾虑。另外,涂层的残余物质不是生物可降解的。
另一种抗血栓形成涂层方法在US专利号6559132-Holmer,6461665-Scholander以及6767405-Eketrop中被揭示,其中一个诸如壳聚糖的载体分子被轭合到一个活化的医疗装置的金属表面。然后,肝素被共价轭合到一个中间分子上。该过程可能被重复若干次直到一个得到理想的抗血栓层。任选地,该涂层能够在一个批量工艺模式中被到。但是,该方法不能轻易被应用到涂布了含有药物的聚合物涂层的医疗装置中。这些诸如西罗莫司的抗再狭窄药物中的一些可能在轭合过程中被破坏,特别是这些含有涉水过程的处理。
PCT申请WO2005/097223A1-Stucke等揭示了一种方法,其中一种与光敏交联物轭合的肝素,用诸如聚(甲基丙烯酸丁酯)和聚(乙烯基吡咯烷酮)的耐久聚合物分散或溶解在相同的涂层溶液中并且在溶液中或在涂层被应用后用紫外光交联。该方法的潜在缺点是功能紫外光可能在交联过程中对结合的药物带来不利影响,或者更糟的是,药物可能被交联到聚合物基质上,如果它们具有可能被紫外能量活化的功能基团的话。
另一种常用方法在US2005/0191333A1,US2006/0204533A1和WO2006/099514A2-全被Hsu,Li-Chien等,中被揭示,采用一种肝素与反离子(stearylkonium肝素)的低分子量配合物,或者一种高分子量聚电解质配合物,例如葡聚糖,果胶来形成一种抗血栓形成实体的配合物形式。这些抗血栓形成配合物进一步地分散于可能进一步地构成药物的聚合物基质中。这些方法创造了一种药物的多相基质以及肝素的亲水性品种,其中该亲水性品种在植入前或后吸水以逆转药物的稳定性和释放动力学。另外,肝素和类似物质的所需抗血栓形成功能应该更优选地处于表面,不能从涂布的医疗装置的表面洗出。
这样,仍然需要一种能够满足迫切需求的涂布材料,就像上述的,以涂布在医疗装置的至少一个表面,并且能够通过一种能相容浸透在涂层中的敏感的药学或治疗学意义上的物质的方法而被制备。这有助于满足一种对涂层的要求,就是当应用于药物涂层支架的外表面时,既能治疗再狭窄同时可避免血栓形成。
发明概述
提供一种在肝素和具有自由羧基末端基团的梳型生物可吸收聚合物之间的轭合物以及一种将该轭合物应用于其表面或埋于其结构中的装置。涂层最外面的层包含本发明的轭合物,其避免血栓形成,并且也用于调节包含在涂层内层中的药物的释放动力学。
涂层的第一或子层通过将聚合材料和生物活性药物用溶剂混合而制备,从而形成一种均相溶液。该聚合材料能够从合成材料的大范围中选择,但是在一个特别具体的实施方式中,应用了一种聚(丙交酯-乙交酯(PLGA)。选择该生物活性物质是基于所希望的治疗结果。例如,一种诸如紫杉醇的抗癌药物,一种诸如雷帕霉素的免疫抑制剂,和/或诸如***的抗感染药物,可被包括在内层中。在制备时,该溶液能通过浸入或喷雾过程而置于装置中。在干燥过程中,溶剂蒸发,然后一种荷载有生物活性药物的聚合材料的薄层被留下来涂布于支架上。应该说明的是本发明不限于仅仅一个内层或每层都有生物活性药物。加入一种或更多不同生物活性药物到每一层中和/或具有荷载有一种生物活性药物的不止一个内层也被包括于本发明的范围之内。
第二或外层包含抗血栓形成肝素-生物可吸收聚合物轭合物。该涂层可以用于使用中的内部药物包含层,例如,一个浸入涂布或喷雾涂布过程。在本发明的一个特别的具体实施方式中,外层包含能够溶于包含乙酸乙酯(EA)和异丙醇(IPA)的混合溶剂***的抗血栓形成肝素-生物可吸收聚合物轭合物。该溶液随后被喷到已用包含上述药物层涂布的装置的表面。干燥后,该抗血栓形成肝素生物可吸收聚合物轭合物保留在涂层的外层,并允许内层的药物从那里流出。
使用一种取决于装置特性的适当的手段将被涂布的装置插进身体的受害区域,例如,诸如冠状动脉的血管。一旦到位,该装置将撑开血管。该生物活性药物将从第一层中释放,从而提供所需治疗结果,例如抑制平滑肌细胞增殖。最外层的抗血栓形成肝素生物可吸收聚合物轭合物部分水合并且避免装置周围的血液凝固,从而抑制血栓形成和亚急性装置血栓形成。另外,最外层的抗血栓形成肝素生物可吸收聚合物轭合物可额外地降低或避免生物活性药物从内部药物包含层的爆发释放,从而允许在一个相对延长的时间段里的释放发生。
任选地,利用在聚合物基质中的梳型聚合物和肝素轭合物作为治疗药物的载体制备颗粒。在具体实施方式中,该药物某种程度上与梳型聚合物的疏水核密切相关。将药物和轭合物共溶于溶剂,该溶剂随后蒸发从而产生其核心有药物的颗粒。这些颗粒适合于放置在装置结构内。例如,一种装置可能具有诸如含有颗粒于其中的坑,缺口,褶皱或通道。这样就允许具有不同性质的颗粒被放置在装置的多个部位。此外,具有至少两种不同药物的颗粒能被置于相同的结构特征中。药物随着颗粒降解从结构特征中释放。同时,肝素的存在将避免装置安置部位的血栓形成。
附图说明
本发明的特征和优点通过下述的详细的说明对于那些本领域普通技术人员来说时显而易见的,其中:
图1是作为构成梳型聚合物的引发剂的内酯二聚物(交酯)与聚乙烯醇(PVA)的开环聚合反应的图式表征。
图2是肝素到PVA-引发PLA梳型生物可降解聚合物的共轭反应的图式表征。
图3是本发明存在于应用于装置表面的外层的具有生物可降解梳型聚酯肝素轭合物的涂层的图解。
图4是显示了本发明的生物可降解梳型聚酯肝素轭合物第一次与药物结合形成纳米颗粒或微球的示意图。
图5是具有选择性置入装置的结构特征中的颗粒的可展开医疗装置的等轴视图。
图6是在第一多元孔中具有针对本发明的颗粒的可展开医疗装置的横断图。
发明的具体描述
一种或多种聚合物组合物被用于医疗装置以提供一种涂布于其上的涂层或者被荷载进医疗装置的结构特征中。该聚合物组合物表现出多种功能。例如,一层可包含一种允许附加层粘着于其上的基本涂层。一种在其聚合物基质中能携带生物活性药物的附加层。任选地,可以使用单一涂层,其中的聚合物组合物可以使得涂层表现出多样的功能,例如允许涂层粘附于装置并包含一种避免血栓形成的药物。其他功能包括包含避免再狭窄的药物。
药物的化学性质能够限制涂层携载的药物的数量。例如,抗血栓形成药剂倾向于亲水而抗增殖剂倾向于疏水。这样,在聚合物涂层的基质中包载入疏水药物以限制其暴露于水中并且控制其从基质中的流出是被期望的。本发明通过提供的介于诸如肝素的抗凝剂和具有一个自由羧基末端基团的生物可吸收聚合物之间的轭合物支持具有不同的密切相关的活性的两种药物。该构型将导致亲水性肝素药物实质上被定位远离处于聚合物基质中的疏水性物质。这样,当应用于医疗装置时,具有轭合物的涂层确保了抗血栓形成药剂大量地被定位远离处于聚合物基质中的任何疏水性药物。
下面的定义为了更容易地理解本发明而提供并且在任何情况下也不应被认为作为发明的说明书的限制。
如本处所用,“支架”意味着用任何生物可相容材料制成的普遍管状结构,其可被***导管以保持管腔开放并且避免由于狭窄或外压而关闭。
如本处所用,“生物活性药物”意味着一种药物或其他物质,其对于活体具有治疗活性,包括但不限于抗血栓形成药,抗癌药,抗凝血药,抗血小板药,血栓溶解药,抗增殖药,抗感染药,抑制再狭窄的药物,平滑肌细胞抑制剂,抗菌药,及其类似物,和/或其混合物和/或任何在给活体提供治疗价值的表现功能中可以协助另一种成份的成份。
代表性抗癌药包括阿西维辛,阿柔比星,阿考达唑,阿克罗宁,阿多来新,阿拉诺新,阿地白介素,别嘌呤醇钠,六甲密胺,氨鲁米特,氨萘非特,聚肌胞,安沙可林,雄激素,anguidine,阿非科林甘氨酸盐,亮氨酸溶肉瘤素,门冬酰胺酶,5-阿扎胞苷,硫唑嘌呤,卡介苗(BCG),贝克叶酸拮抗剂(Baker’s Antifol)(可溶),β-2’-硫代鸟嘌呤脱氧核甙,盐酸比生群(bisantrene hcl),博莱霉素硫酸盐,白消安,丁硫氨酸亚砜胺,ceracemide,卡贝替姆,卡铂,卡莫司汀,苯丁酸氮芥,chloroquinoxaline-磺胺,氯脲菌素,色霉素A3,顺铂,克拉屈滨,皮质激素,短小棒状杆菌,CPT-11,克立那托,安西他滨,环磷酰胺,阿糖胞苷,溴茴丙烯酸钠,马来酸dibis,氮烯咪胺,更生霉素,柔红霉素HCl,deazauridine,右丙亚胺,去水卫矛醇,地吖醌,二溴卫矛醇,didemnin B,二乙基二硫代氨基甲酸酯,肌苷二醛,二氢-5-氮杂胞苷,多柔比星,棘霉素,依达曲沙,依地福新,eflomithine,Elliott’s溶液,依沙芦星,表柔比星,依索比星,磷雌氮芥磷酸盐,***,依他硝唑,ethiofos,鬼臼乙叉甙,fadrazole,法扎拉滨,芬维A胺,非格司亭,非那雄胺,黄酮乙酸,氟尿苷,氟达拉滨磷酸盐,5-氟尿嘧啶,氟他胺,硝酸镓,吉西他滨,乙酸戈舍瑞林,hepsulfam,环己烷双乙酰胺,高三尖杉酯碱,硫酸肼,4-羟雄烯二酮,hydrozyurea,盐酸伊达比星,异环磷酰胺,干扰素α,干扰素β,干扰素γ,白介素-1α和β,白介素-3,白介素-4,白介素-6,4-甘薯苦醇,异丙铂,异维A酸,亚叶酸钙,醋酸亮丙瑞林,左旋咪唑,柔红霉素脂质体,脂质体包封多柔比星,洛莫司汀,氯尼达明,美坦生,盐酸氮芥,美法仑,美诺立尔,merbarone,6-巯嘌呤,美司钠,卡介苗的甲醇提取残渣,甲氨蝶呤,N-甲基甲酰胺,米非司酮,米托胍腙,丝裂霉素-C,米托坦,盐酸米托蒽醌,单核细胞/巨噬细胞集落刺激因子,***隆,萘福昔定,新制癌菌素,乙酸奥曲肽,奥马铂,奥沙利铂,紫杉醇,pala,喷司他丁,哌嗪双酮,哌泊溴烷,吡柔比星,吡曲克辛,盐酸吡罗蒽醌,PIXY-321,普卡霉素,卟菲尔钠,泼尼莫司汀,丙卡巴肼,孕激素,吡唑呋喃菌素,雷佐生,沙格司亭,司莫司汀,锗螺胺,螺莫司汀,链黑霉素,链佐星,磺氯苯脲,苏拉明钠,他莫昔芬,多烯紫杉醇,替加氟,替尼泊苷,terephthalamidine,替罗昔隆,硫鸟嘌呤,塞替派,胸苷注射液,甲酰胺基噻唑,托泊替康,托瑞米芬,维A酸,盐酸三氟拉嗪,曲氟尿苷,三甲曲沙,肿瘤坏死因子,尿嘧啶氮芥,长春碱硫酸盐,长春新碱硫酸盐,长春地辛,长春瑞滨,长春利定,Yoshi864,佐柔比星,及其混合物。
代表性抗感染药包括经典非甾体类抗炎药(NSAIDS),例如阿斯匹林,双氯芬酸,吲哚美辛,舒林酸,酮洛芬,氟比洛芬,布洛芬,萘普生,吡罗昔康,替诺昔康,托美丁,酮咯酸,oxaprosin,甲灭酸,非诺洛芬,萘丁美酮(瑞力芬),扑热息痛(),及其混合物;COX-2抑制剂,诸如尼美舒利,NS-398,flosulid,L-745337,塞来考昔,罗非昔布,SC-57666,DuP-697,帕瑞考昔钠,JTE-522,伐地考昔,SC-58125,艾托考昔,RS-57067,L-748780,L-761066,APHS,依托度酸,美洛昔康,S-2474,及其混合物;糖皮质激素,诸如氢化可的松,可的松,***,***龙,甲基***龙,甲***,曲安西龙,帕拉米松,氟泼尼龙,倍他米松,***,氟氢可的松,去氧皮质酮,及其混合物;及其混合物。
如本处所用,“有效量”意味着无毒但足以提供所需局部或全身效果并且以一个合理的有益/危险比例参与任何医学治疗的的药理活性药物的量。
图3表明本发明涂层应用表面2的具体实施方式。表面2位于,例如,一个可植入医疗装置。涂层包含一个荷载有一种能够诸如避免平滑肌细胞增殖和迁移的生物活性药物的聚合膜的第一或内部层4。第一层或涂层可包含不止一种生物活性药物。
药物置入聚合物基质的一种方式包括使用一种药物和聚合物溶于其中的溶剂或溶剂混合物。随着混合物的干燥,溶剂被去除从而将药物包裹在聚合物基质中。可以被用来制造内部/第一聚合层的代表性聚合物包括聚氨酯,聚乙烯对苯二酸盐(PET),PLLA-聚-乙醇酸(PGA)共聚物(PLGA),聚己酸内酯(PCL)聚-(羟丁酸酯/羟戊酸酯)共聚物(PHBV),聚(乙烯基吡咯烷酮)(PVP),聚四氟乙烯(PTFE,),聚(2-甲基丙烯酸羟乙酯)(聚-HEMA),聚(聚醚聚氨酯脲),硅酮,丙烯酸脂类,环氧化合物(epoxides),聚酯,聚氨酯,parlenes,聚磷腈聚合物,氟聚合物,聚酰胺,聚烯烃,以及其混合物。可用来制造内部/第一聚合层的代表性生物可吸收聚合物包括聚己酸内酯(PCL),聚-D,L-乳酸(DL-PLA),聚-L-乳酸(L-PLA),聚(羟基丁酸酯),聚二氧环己酮,聚原酸酯,聚酸酐,聚(乙醇酸),聚磷酸酯,聚磷酸酯氨基甲酸酯(polyphosphoester urethane),聚(氨基酸),聚(三亚甲基碳酸酯),聚(亚胺碳酸酯),聚亚烷基草酸盐,聚磷腈,以及脂肪族聚碳酸酯。
第二或外部层6可包括一种具有高度抗凝活性的抗血栓形成肝素-生物可吸收聚合物轭合物。该抗血栓形成肝素-生物可吸收聚合物轭合物的第二层可额外地具有防止分散在第一或内部4层中的生物活性药物的爆发释放的功能,从而造成可含有多于一种生物活性药物的层4的一个相对更长的释放阶段。另外,轭合物6定位亲水性肝素8大量地远离疏水性内部层4。
为了解释本发明的目的,该涂层被用于诸如支架和/或支架-移植物的医疗装置。大体上,支架用诸如那些用不锈钢或钴铬合金制造的金属做成。但是,支架可以,也用聚合物材料做成。也可以理解任何接触有机液体,或其类似物的基质,医疗装置,或其部分,也可用本发明涂布。例如,诸如腔静脉滤器和吻合装置的其他装置可用包含有药物于其中的聚合物材料制造。这里所描述的支架或其他医疗装置的任何一种可被用于局部或区域药物给药。球囊可膨胀支架可被用于任何尺寸的血管或导管,并且特别适于在冠状动脉中的应用。另一方面,自膨胀支架特别适于在诸如在颈动脉中的压伤恢复起关键作用的血管中的应用。
第一4和第二6涂层或层覆盖至少整个支架表面2的一部分是期望的但并不是必需。第一层4的应用通过溶剂蒸发法或其他诸如溶剂塑模喷雾涂布法的已知方法完成。溶剂蒸发法包括用诸如四氢呋喃(THF)的溶剂混合聚合材料和生物活性药物,然后搅拌以形成混合物。第一层的代表性聚合材料包含聚氨酯和代表性生物活性药物包含雷怕霉素。该混合物通过将溶剂到喷支架上;或将支架浸入溶剂而涂于支架的表面2上。支架涂上混合物后进行干燥,在此过程总,溶剂蒸发并且聚合材料和生物活性药物在支架上形成一个薄膜。任选地,大多数生物活性药物加入到第一层4。
支架涂层的第二或最外层6包含抗血栓形成肝素-生物可吸收聚合物轭合物。抗血栓形成肝素生物可吸收聚合物轭合物可在有机溶剂或大多数有机溶剂的混合物中溶解。肝素8可包含未分级肝素,分级肝素,低分子量肝素,脱硫肝素和多种哺乳动物来源的肝素。代表性抗血栓形成药剂可包括:维生素K拮抗剂诸如醋硝香豆素,氯茚二酮,双香豆素(双香豆素),二苯茚酮,乙基双香 豆素乙酯,苯丙香豆素,苯茚二酮,噻氯香豆素,华法林;肝素类抗血小板聚集抑制剂诸如抗纤维蛋白酶III,Bemiparin,Dalteparin,达那肝素,依诺肝素,肝素,那屈肝素,Parnaparin,瑞维肝素,舒洛地希,Tinzaparin;其他血小板聚集抑制剂诸如阿昔单抗,乙酰水杨酸(阿司匹林),阿洛普令,贝前列素,地他 唑,Carbasalate钙,氯克罗孟,氯吡格雷,双嘧达莫,依替巴肽,吲哚布芬,伊洛前列素,吡考他胺,Prasugrel,依前列醇,噻氯匹定,替罗非班,Treprostinil,三氟柳;酶的抗凝血剂诸如阿替普酶,安克洛酶,复合纤溶酶链激酶,纤维蛋 白酶,Drotrecogin alfa,纤溶酶,蛋白C,瑞替普酶,沙芦普酶,链激酶,替奈 普酶,尿激酶;直接血栓形成抑制剂诸如阿加曲班,比伐卢定,达比加群,地 西卢定,来匹卢定,美拉加群,Ximelagatran;以及其他抗血栓形成剂诸如达比 加群,去纤苷,皮肤素硫酸盐,Fondaparinux,Rivaroxaban。
如图1和2所示,代表性抗血栓形成肝素-生物可相容共聚物轭合物的制备如下。首先,如图1所示,一种d,l-丙交酯的环二聚物,在约140C的高温度下,在辛酸亚锡(Sn(Oct)2催化剂和作为开环引发剂的预定数量的聚(乙烯醇)(PVA,足以水解至被水溶)存在下聚合。开环共聚反应形成终产物,其包含带有羟基末端基团的聚酯的均聚物。每一种聚合物的分子量由环二聚物和PVA引发剂的比例来确定。环二聚物和PVA引发剂的比例越高,PVA-PLA共聚物的分子量越高。
本发明的一个具体实施方式中最终的PVA-PLA共聚物的一端的羟基基团可进一步转化为可随后与肝素分子的轭合反应中应用的羧基。尽管任何肝素份子,重组肝素,肝素衍生物或肝素类似物(具有1000-1000000道尔顿的优选分子量)可用在偶连反应以制造最终的抗血栓形成肝素可吸收聚合物轭合物,但是优先应用一种脱硫肝素以升高反应的偶连效率。
当抗血栓形成肝素-生物可吸收聚合物轭合物制备出来以后,应用溶剂蒸发法或其他适当方法将包含抗血栓形成肝素生物可相容共聚物轭合物的第二层直接涂布在第一层上。在溶剂从可植入医疗装置的表面蒸发后,一种包含抗血栓形成肝素-生物可吸收聚合物轭合物的薄膜在装置的最外表面形成。任选地,在加入药物洗脱医学装置前,梳型抗血栓生物可相容共聚物可加工成包含药物的微球或纳米球形式。
下面实施例说明了轭合物的产生和根据本发明原理的用途。
I.实施例1梳型生物可降解PLA通过内酯二聚物(丙交酯)以聚(乙烯醇,PVA)作为引发剂的开环聚合反应的制备。
如图1所示,将定量的d,l-丙交酯(来自Purac,USA)移入一个装有磁性搅拌棒的干燥的圆底玻璃反应器。将定量的聚(乙烯醇),(例如完全水解的聚乙烯醇(Elvanol)70-03,来自Du Pont,公司)以及辛酸亚锡(Sigma,St.Lois,USA)加入到玻璃反应器。然后将玻璃反应器用塞子密封并且在氩气和真空之间循环三次以去除反应器中的空气和氧气。然后密封反应器在真空下被逐渐加热到140C并且用磁性搅拌棒搅拌下保存。反应终止时,将聚合物溶于二氯甲烷并在甲醇中沉淀然后在真空和低温下干燥。
II.实施例2梳型抗血栓形成(Ahrombotic)肝素-生物可吸收聚合物轭合物的制备
如图2所示,梳型PLA,诸如根据上述实施例1所制备的,溶于无水二甲基甲酰胺(DMF),随后溶解无水丁二酸和二环己基碳二亚胺(DCC)。所得溶液在室温真空下保存5小时。副产物,二环己基脲(DCU),以及未反应的DCC和NHS过滤除去。所得中间体在甲醇中再沉淀并在真空烘箱中干燥。然后将羧酸末端修饰的中间体加入到N-羟化丁二酰亚胺(NHS)的二甲基甲酰胺溶液中活化并且室温下与肝素反应4小时,从而制成最终的本发明梳型生物可降解聚合物-肝素轭合物的梳型轭合物。将最终轭合物沉淀和冻干。
III.实施例3药物涂层支架用包含一种梳型可吸收聚合物-肝素轭合物的最外层的涂布
如图3所示,钴铬支架的表面10用包含聚合物溶液的药物喷雾涂布,该溶液可包含诸如,含有PLGA和雷怕霉素的乙酸乙酯(EA)。PLGA和雷怕霉素的重量比为2∶1。在含药层20干燥后,含有梳型可吸收聚合物-肝素轭合物的涂层溶液被喷雾涂布到第一含药层20上。该层干燥后,种含有梳型可吸收聚合物-肝素轭合物的薄膜30就会在最外层形成。
诸如上述的那些涂层可以是薄的,典型的是5-8微米厚。诸如支架的装置的表面区域,相对地是非常大的,以致于该有益药物的整体容量具有非常短的扩散路经从而释放到周围组织中。所得累积药物释放曲线以巨大的初始爆发释放为特征,随后快速接近一条渐近线,而不是所希望的“均匀的,延长释放,”或者线性释放。经常希望变化治疗剂从诸如支架的装置中的洗脱方式。另外,也希望变化装置不同位置的药量。这可以通过将药物放进装置的结构部分中完成。
如图5所示,一种可膨胀装置具有多个便于装置上至少一种药物的放置的结构部分。图5中表示的可膨胀医疗装置10可从一管状材料切割以形成圆柱形可膨胀装置。该可膨胀医疗装置10包括用多个桥接部件14连接的多个圆柱形部分12。桥接部件14允许装置穿过血管的曲折(torturous)路经到达展开部位时可轴向弯曲并且允许装置必须匹配管腔的曲率时可轴向弯曲。网状的拉长的撑杆18是用用韧性铰链20内部连接并且圆周撑杆22包括圆柱形管12。在医疗装置10膨胀时韧性铰链20变形然而撑杆18并未变形。可膨胀的医疗装置的例子的详细细节在US专利号6241762中描述,在此全部引入参考。
拉长的撑杆18和圆周撑杆22包括诸如开口30的结构部分,其中的一些为了传递到在可膨胀医疗装置植入的管腔中而选择性地用一种药物填满。开口30的深度用撑杆22的厚度确定。其他结构部分可包括凸起或韧窝,狭缝,拉长开口,加入的材料和任何可采集或包含需要置入可膨胀装置的材料部分。另外,装置10的其他部分,诸如桥接部分14,可包括结构部分。在图5所示的特殊例子中,开口30被提供于装置10的非变形部分,诸如撑杆18,以使开口是非变形的并且药物在装置膨胀时没有断裂,去除,或其他破坏的危险的情况下被递送。一个将有益药物荷载入开口30的方式的一个例子进一步描述在US专利6764507中描述,在此全部引入参考。
为了便于一种或多种药物在图5所示的装置的结构部分中的放置,颗粒40能通过使用图4所示的作为治疗药的一种载体的梳型聚合物和肝素轭合物而被制造。在该具体实施方式中,药物42某种程度上与梳型聚合物44的疏水性核心46相关。使用溶剂将药剂42和轭合物共溶,该溶剂随后蒸发制备出其核心带有药物的颗粒。这些颗粒适于放置在如图5所示的装置的结构中。例如,装置可带有于其中颗粒的诸如井,缺口,褶皱或通道的结构部分。这样允许具有不同性质的颗粒置于装置的不同位置。另外,具有至少两种药物的颗粒能被置于相同的结构部分中。随着颗粒的降解药物结构部分中释放。相似地,肝素的存在将避免在装置放置部位的血栓形成。
图6公开了图5装置10中的开口50的横断图。多个颗粒40被置于两层52到54之间。在组成和厚度上变化层52和54以控制颗粒40在水性环境中的暴露。这将控制药物从颗粒40的核心中的释放。另外,颗粒能被混入单个材料中并且置于装置10的开口50中。
为了在装置的特征部分上或其中放置,从而给出了如下的纳米颗粒和微粒的形成的方法的例子。
IV.实施例4应用梳型可吸收聚合物-肝素和紫杉醇的纳米颗粒的形成
在温和搅拌下,将20mg的紫杉醇和200mg的聚(丙交酯-至-乙交酯),PLGA50/50,溶解在16ml的二氯甲烷中。将得到的溶液转移到250ml的包含4%的聚乙烯醇(PVA)水性溶液中,聚乙烯醇为乳化剂。混合溶液在输出功率为50mW的脉冲模式超声波发生器中超声90秒。在室温下将乳剂搅拌过夜一除去溶剂。所形成纳米球包含紫杉醇,其是12000rpm下离心30分钟而收集得到的,将纳米球用去离子水洗涤4词以除去过量的乳化剂。然后,产品在使用前冻干。
V例5应用梳型可吸收聚合物-肝素和紫杉醇的微粒的形成
在温和搅拌下将20mg的紫杉醇和200mg的聚(丙交酯-至-乙交酯),PLGA50/50,溶解在16ml的乙酸乙酯(EA)中。80ml水(注射级水)加热至50C并通过磁性搅拌盘搅拌保存。加入定量的乳化剂(PVA,0.4g)形成一种水性溶液。然后,该溶液连续搅拌下冷至室温。乙酸乙酯(3.2ml)在温和搅拌下加入到该水性溶液中。然后,在500rpm搅拌下,紫杉醇和PLGA溶液缓慢的注入乳化水性溶液中。乳液室温下进一步搅拌4小时以固化微球。然后,最终的微球通过过滤收集并用WFI水洗两次。最终得到的微球在后续使用前冻干过夜。
图4显示了根据上述实施例制备的放置在图5所示装置的一个开口中的颗粒。这些颗粒采用诸如静电雾化沉积处理法的干粉沉积方法从而放置在这些开口中。这些包含颗粒的装置可进一步加工以调节药物的释放动力学,该工艺使用一种诸如溶剂喷雾工艺的处理方式以进一步调节释放动力学,开口也可用额外的覆盖物覆盖以调节药物的释放动力学。
尽管本发明用上述特别优选的具体实施方式已被描述,对于那些本领域技术人员来说,在不偏离本发明的精神和重要属性的情况下,很多的改进和变化可以用于这些设计。相应地,参考应该用于附加权利要求,而不是上述的规格,就像发明的范围所表示。提供的说明书是为了说明目的并且没有想要限制发明,其也没有想要以任何方式限制使用的范围,领域或者构成任何排除的明确词语。
Claims (64)
1、一种包含一种梳型生物可兼容和生物可吸收共聚物的轭合物材料,其中基本上所有侧链都与一种抗血栓形成药剂共轭。
2、权利要求1的轭合物材料,其中抗血栓形成药剂是肝素。
3、权利要求2的轭合物材料,其中肝素是低分子量肝素。
4、权利要求2的轭合物材料,其中肝素是脱硫肝素。
5、权利要求1的轭合物材料,其中梳型生物可相容和生物可吸收共聚物包含聚乙烯醇和生物可降解聚酯。
6、权利要求5的轭合物材料,其中聚乙烯醇被充分水解以在生理条件下为水溶性。
7、权利要求6的轭合物材料,其中聚乙烯醇的分子量等于或小于50000道尔顿。
8、权利要求5的轭合物材料,其中生物可降解聚酯选自由聚己酸内酯(PCL),聚-D,L-乳酸(DL-PLA),聚-L-乳酸(L-PLA),聚(乙醇酸)(PGA),聚(乳酸-共-乙醇酸)(PLGA),聚(羟基丁酸酯),聚(羟基丁酸酯-共-戊酸酯),聚二氧环己酮,聚原酸酯,聚酸酐,聚(乙醇酸-共-三亚甲基碳酸酯),聚磷酸酯,聚磷酸酯氨基甲酸酯,聚(氨基酸),聚(三亚甲基碳酸酯),聚(亚胺碳酸酯),聚亚烷基草酸盐,聚磷腈,以及脂肪族聚碳酸酯,以及聚(醚-共-酯)所组成的组。
10、权利要求1的轭合物材料,其中梳型生物可兼容共聚物包括PVA和l,l-聚乳酸,乙交酯和己内酯的三元共聚物并且该抗血栓形成药剂包括肝素分子。
11、权利要求1的轭合物材料,其中梳型生物可兼容共聚物包括PVA和d,l-聚乳酸,乙交酯和己内酯的三元共聚物并且该抗血栓形成药剂包括肝素分子。
12、涂层,其包含:
应用于表面的第一生物可吸收聚合物;
在第一生物可吸收聚合物中的药剂;以及
含有梳型生物可相容和生物可吸收共聚物,其中基本上所有侧链连接到抗血栓形成药剂的轭合物材料,并且该轭合物涂在第一生物可吸收聚合物的顶部。
13、权利要求12的涂层,其中轭合物的该抗血栓形成分子基本上位于第一生物可吸收聚合物层的远端。
14、权利要求12的涂层,其中该抗血栓形成分子包括肝素。
15、权利要求12的涂层,其中该药剂选自由雷怕霉素,紫杉醇和pimecrolimus所组成的组的抗狭窄药剂
16、权利要求12的涂层,其中第一生物可吸收聚合物包含第一共聚物,并且第二生物可吸收聚合物包含PVA,其中基本上其所有侧链都通过第二生物可吸收共聚物来扩展。
17、权利要求16的轭合物材料,其中第一和第二共聚物相同并且选自由聚己酸内酯(PCL),聚-D,L-乳酸(DL-PLA),聚-L-乳酸(L-PLA),聚(乙醇酸)(PGA),聚(乳酸-共-乙醇酸)(PLGA),聚(羟基丁酸酯),聚(羟基丁酸酯-共-戊酸酯),聚二氧环己酮,聚原酸酯,聚酸酐,聚(乙醇酸-共-三亚甲基碳酸酯),聚磷酸酯,聚磷酸酯氨基甲酸酯,聚(氨基酸),聚(三亚甲基碳酸酯),聚(亚胺碳酸酯),聚亚烷基草酸盐,聚磷腈,以及脂肪族聚碳酸酯,以及聚(醚-共-酯)所组成的组。
18、权利要求12的涂层,其中第一生物可吸收聚合物是均聚物。
19、权利要求12的涂层,其中梳型生物可相容和生物可吸收共聚物包含PVA和选自包含聚己酸内酯(PCL),聚-D,L-乳酸(DL-PLA),聚-L-乳酸(L-PLA),聚(乙醇酸)(PGA),聚(羟基丁酸酯),聚二氧环己酮,聚原酸酯,聚酸酐,聚磷酸酯,聚(氨基酸),聚(三亚甲基碳酸酯),聚(亚胺碳酸酯),聚亚烷基草酸盐,聚磷腈,以及脂肪族聚碳酸酯生物可吸收均聚物。
20、权利要求12的涂层,其中第一生物可吸收聚合物包含均聚物并且第二生物可吸收聚合物包含PVA,其中基本上其所有的侧链第二生物可吸收共聚物来扩展。
21、权利要求12的涂层,其中该涂层用于可植入医疗装置。
22、权利要求21的涂层,其中该医疗装置包括支架。
23、一种形成抗血栓形成轭合物的方法,包括:
提供至少在环状内酯分子上;然后
通过使用作为至少一个环状内酯分子的开环聚合反应的引发剂的PVA形成生物可吸收共聚物;并且
随后用二羧酸酐和肝素连接生物可吸收共聚物的步骤。
24、权利要求23的方法,其中至少一种环内酯分子包括丙交酯。
25、权利要求23的方法,其中至少一种环内酯分子包括乙交酯。
26、权利要求23的方法,其中至少一种环内酯分子包括己内酯。
27、权利要求23的方法,进一步包括提供第二内酯分子的步骤。
28、权利要求23的方法,其中二羧酸酐耦合物质是琥珀酸酐。
29、权利要求23的方法,其中二羧酸酐耦合物质是富马酸酐。
30、权利要求23的方法,其中二羧酸酐耦合物质是癸二酸酐。
31、一种通过使用作为治疗药剂的载体的聚合物抗血栓形成轭合物制备大量颗粒的方法,包括:
在至少一种溶剂中溶解治疗药剂和聚合抗血栓形成轭合物以形成第一溶液;
用包含水和至少一种表面活性剂的第二水性溶液混合第一溶液以形成乳液;
从乳液中去除溶剂以形成大量颗粒。
32、权利要求31的方法,其中轭合物包括梳型生物可相容和生物可吸收共聚物,其中大体上所有侧链连接抗血栓形成药剂。
33、权利要求31的方法,其中抗血栓形成药剂是肝素。
34、权利要求33的方法,其中肝素是低分子量肝素。
35、权利要求33的方法,其中肝素是脱硫肝素。
36、权利要求31的方法,其中梳型生物可相容和生物可吸收共聚物包括聚乙烯醇和生物可降解聚酯。
37、权利要求36的方法,其中聚乙烯醇被充分水解以在生理条件下可溶于水。
38、权利要求37的方法,其中聚乙烯醇的分子量等于或小于50000道尔顿。
39、权利要求36的方法,其中生物可降解聚酯选自由聚己酸内酯(PCL),聚-D,L-乳酸(DL-PLA),聚-L-乳酸(L-PLA),聚(乙醇酸)(PGA),聚(乳酸-共-乙醇酸)(PLGA),聚(羟基丁酸酯),聚(羟基丁酸酯-共-戊酸酯),聚二氧环己酮,聚原酸酯,聚酸酐,聚(乙醇酸-共-三亚甲基碳酸酯),聚磷酸酯,聚磷酸酯氨基甲酸酯,聚(氨基酸),聚(三亚甲基碳酸酯),聚(亚胺碳酸酯),聚亚烷基草酸盐,聚磷腈,以及脂肪族聚碳酸酯,以及聚(醚-共-酯)所组成的组。
40、权利要求31的方法,其中梳型生物可兼容共聚物包括PVA-PLA共聚物并且抗血栓形成药剂包括肝素分子,轭合物具有如下结构:
其中n是2-1000的整数;和m是100-5000的整数;LA是乳酸的重复单元;SA是琥珀酸;HP是肝素。
41、权利要求31的方法,其中梳型生物可相容共聚物包括PVA和l,l-聚乳酸,乙交酯和己内酯的三元共聚物并且该抗血栓形成药剂包括肝素分子。
42、权利要求31的方法,其中梳型生物可兼容共聚物包括PVA和d,l-聚乳酸,乙交酯和己内酯的三元共聚物并且该抗血栓形成药剂包括肝素分子。
43、权利要求31的方法,其中多数颗粒包括微粒。
44、权利要求31的方法,其中多数颗粒包括纳米颗粒。
45、一种装置,包括:
可从第一直径膨胀到第二直径的框架,其中该框架具有内表面和外表面,表面之间的距离决定框架的壁厚;
延框架配置的多个结构部分;以及
分布于多个结构部分的大量聚合物抗血栓形成轭合物颗粒。
46、权利要求45的装置,其中多个结构特征包括配置在框架表面的脊。
47、权利要求45的装置,其中多个结构特征包括多个形成在框架中的坑。
48、权利要求47的装置,其中坑从外表面延伸到内表面。
49、权利要求47的装置,其中多个坑中填满颗粒。
50、权利要求45的装置,其中多个聚合物抗血栓形成轭合物颗粒作为治疗药剂的载体。
51、权利要求50的装置,其中抗血栓形成轭合物包括梳型生物可相容和生物可吸收共聚物,其中基本上所有侧链连接抗血栓形成药剂。
52、权利要求51的装置,其中抗血栓形成药剂是肝素。
53、权利要求52的装置,其中肝素是低分子量肝素。
54、权利要求53的装置,其中肝素是脱硫肝素。
55、权利要求51的装置,其中梳型生物可相容和生物可吸收共聚物包括聚乙烯醇和生物可降解聚酯。
56、权利要求55的装置,其中聚乙烯醇充分地水解以在生理条件下溶于水。
57、权利要求56的装置,其中聚乙烯醇的分子量等于或小于50000道尔顿。
58、权利要求55的装置生物可降解聚酯选自由聚己酸内酯(PCL),聚-D,L-乳酸(DL-PLA),聚-L-乳酸(L-PLA),聚(乙醇酸)(PGA),聚(乳酸-共-乙醇酸)(PLGA),聚(羟基丁酸酯),聚(羟基丁酸酯-共-戊酸酯),聚二氧环己酮,聚原酸酯,聚酸酐,聚(乙醇酸-共-三亚甲基碳酸酯),聚磷酸酯,聚磷酸酯氨基甲酸酯,聚(氨基酸),聚(三亚甲基碳酸酯),聚(亚胺碳酸酯),聚亚烷基草酸盐,聚磷腈,以及脂肪族聚碳酸酯,以及聚(醚-共-酯)所组成的组。
60、权利要求55的装置,其中梳型生物可相容共聚物包括PVA和l,l-聚乳酸,乙交酯和己内酯的三元共聚物并且该抗血栓形成药剂包括肝素分子。
61、权利要求55的装置,其中梳型生物可兼容共聚物包括PVA和d,l-聚乳酸,乙交酯和己内酯的三元共聚物并且该抗血栓形成药剂包括肝素分子。
62、权利要求55的装置,其中大多数颗粒包括微粒。
63、权力要求55的装置,其中大多数颗粒包括纳米颗粒。
64、权利要求55的装置进一步包括应用于框架表面的抗血栓形成涂层。
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