CN1899615A - 预防再狭窄的制剂 - Google Patents

预防再狭窄的制剂 Download PDF

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CN1899615A
CN1899615A CNA200610099823XA CN200610099823A CN1899615A CN 1899615 A CN1899615 A CN 1899615A CN A200610099823X A CNA200610099823X A CN A200610099823XA CN 200610099823 A CN200610099823 A CN 200610099823A CN 1899615 A CN1899615 A CN 1899615A
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乌尔里希·施佩克
布鲁诺·施勒
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Abstract

本发明涉及一种用于预防再狭窄的制剂。已知用于预防再狭窄的制剂尚不能在受损血管壁区域达到足够的活性剂浓度，原因是较高的剂量会引起不需要的副作用。本发明是加入至少一个亲脂性抗增生剂的制剂，其在丁醇和水之间的分配比为≥0.5。该亲脂性活性剂以足够的量被血管壁快速吸收。该制剂可为一种可以穿透毛细血管的液体，并且可含有造影剂，以便在通常需要进行造影放射照相的同时，不需要附加任何努力地将该活性剂转运至血管壁中。该制剂还可以包被于导管上。

Description

预防再狭窄的制剂
本申请是于2005年12月29日提交的申请号为200510135799.6，发明名称为“预防再狭窄的制剂”的分案申请。
本发明涉及一种预防再狭窄的制剂及其包被于血管造影术导管上的应用。
血管狭窄是发病和死亡的主要原因。在许多情况下，使用可膨胀的气囊导管可以将直径至少约达2mm的较大血管的局部狭窄或闭塞扩张恢复至其原始腔的大小。因使用很高的压力，可导致增厚的血管壁发生破裂，被挤压移位至周围组织中。在进行某些这样的操作中，植入管状穿孔的金属支架(斯滕特固定模)以保持血管开放。用此方法处理的血管壁经常在几周和几个月内出现厚度增加，类似于形成疤痕。结果，由于动脉硬化的进展，这些血管不久将再次狭窄(再狭窄)。再狭窄是一个严重的医学难题并造成医疗费用升高。
临床上被证实的预防再狭窄的方法是在手术后立即用高剂量X光(体外放射源或者管腔内放置的放射性同位素)对相关的血管壁区域进行辐射。
辐射主要的缺点是运用治疗性放射剂量时需要必要的安全措施。虽然在实验室和临床实践中试验了许多其他预防早期再狭窄的方法，但是至今仍无任何重要突破[Bult H.《再狭窄：药理学的一个挑战(Achallenge for pharmacology)》，Tips 21274-279，2000]。目前只有使用释放药物的斯滕特固定模才获得良好的效果。为了此方法的有效性，必须植入斯滕特固定模，而无斯滕特固定模植入的单独的血管扩张不可能预防再狭窄。
已经描述到有很多抑制有丝分裂、血管壁反应性增厚和再狭窄的药物。重要的作用原理是抑制血小板聚集、酶的抑制、有丝分裂的抑制、细胞生长抑制和类皮质激素。在体外和部分动物试验中取得了令人满意的结果，但是尚未在临床试验中得到证实。主要的解释是在相关的管壁区域中达不到足够的活性药物浓度。因为副作用限制了较高剂量的应用，口服和静脉内给药特别符合这种情况。作为替代方法，尝试使用特殊的导管给药，其中这些导管或者通过紧挨气囊的小孔将药物溶液直接推入血管壁中，或者阻断血管区域血液的供给排放，并使该管壁区域吸收接受所述药物溶液一段时间[Herdeg，C.，M.Oberhoff，D.I.Siegel-Axel，A.Baumbach，A.Blattner，A.Küttner，S.Schrder，K.R.Karsch：紫杉酚：预防再狭窄的化学疗法？体外和体内实验研究(Paclitaxel：Ein Chemotherapeutikumzur Restenoseprophylaxe？Experimentelle Untersuchungen invitro und in vivo).Z Kardiol 89 390-397，2000]。通过从包被的斯滕特固定模中缓慢释放活性剂可以使先前扩张的血管区域经较长一段时间有效地暴露于药物中。所有这些方法都仍然难以使需要治疗的血管区域足够长时间地暴露于足够的活性剂浓度之下。亲水性活性剂会很快从组织中冲掉[Baumbach，A.，C.Herdeg，M.Kluge，M.Oberhoff，M.Lerch，K.K.Haase，C.Wolter，S.Schrder，K.R.Karsch：《局部药物的传递：压力、物质特性和斯滕特固定模对药物转移进入动脉壁的影响(Local drug delivery：Impact of pressure，substance characteristics，and stenting on drug transfer intothe arterial wall)》。Cathet Cardiovasc Intervent 47 102-106，1999]。由于采用导管侵入性进入，重复给药是不可能的。亲脂性的活性剂不能在血管相容的水性介质中充分溶解，或者在溶液中保持为微胞或脂质体；这些微胞或脂质体只能被组织缓慢吸收。特殊导管可在一段时间内中断血流给药，或在高压下将活性剂溶液压入血管壁，这首先造成额外的组织损害，并增强了反应性增生。包被的、释放药物的斯滕特固定模难以以恒定的质量制备，由于其重量轻和丝织形状，只能含有极少量的活性剂，并不适于对斯滕特固定模周围几毫米处有再狭窄危险的重要血管区域进行近端和远端的治疗。如果先前已植入斯滕特固定模，其管腔内出现狭窄，可以通过给气囊导管的扩张去除狭窄。将第二个斯滕特固定模植入第一个斯滕特固定模的血管腔中以预防扩张造成的管壁增生是不可取的，因此，对于这种情况，没有任何预防再狭窄的有效方法。上述情况同样适用于当血管成形术后没有需要植入斯滕特固定模的指征时，或在没有明显的腔狭窄而出现血管增生时，这样既不需要血管扩张，也不需要植入斯滕特固定模。某些这样的血管壁改变可导致突发性的、大多为血栓形成的栓塞。在这种情况下，也需要一种不依赖斯滕特固定模植入而抑制血管壁病理性变化的方法。
目前在实验研究规模中获得某些成功的活性剂是肝素和水蛭素衍生物、前列腺环素、类皮质激素、雷帕霉素、秋水仙素和紫杉酚。
在多数情况下，将这些活性剂应用于斯滕特固定模；只要是使用溶液，均为含乙醇或Cremophor(聚二醇化物的商品名)添加剂的水溶液或者水溶性很差的紫杉酚(4，10β-二乙酰氧基-13α-((2R，3S)-3-苯甲酰氨基-2-羟基-3-苯基丙酰氧基)-2α-苯甲酰氧基-5β，20-环氧-1，7β-二羟基-11-紫杉烯-9-酮)(紫杉烯＝taxen)水溶液，使用Cremophor[聚(氧乙烯)-35-蓖麻油]会形成微胞，而使用乙醇可以大大避免微胞的形成。
已经有报道关于添加了有或无造影剂的在水性细胞抑制剂溶液中含较大颗粒的悬浮液或乳液，用于直接注射入肿瘤供血的血管。这些制剂用于闭塞肿瘤的血管，并同时进行细胞抑制的治疗。闭塞血管恰好是本发明的目的。
本发明的任务在于提供局部治疗潜在高增生组织的组合物，其使用方便，而且对患者没有损害。
根据现有技术的状况，本发明对此难题的解决，是通过在丁醇和水之间的分配比为≥0.5的含有至少一个抗增生的活性剂的制剂，加入到提高动脉和静脉显影的组合物中，或者包被导管而实现的。
由此本发明提供用于肠胃外、局部治疗过度增生性组织的制剂，其特别是在紧急治疗期间用于抑制病理性血管壁变化，用于预防再狭窄和用于局部肿瘤治疗，而无额外的血管壁损害或血流限制/栓塞；其含有亲脂的，抗过度增生的活性剂，并且其不含形成微胞的、延缓其快速和足量地被管壁吸收的物质，其中有机溶剂含量低于10％或经干燥除去，且活性剂在丁醇/水体系中具有分配比为≥0.5和/或结合细胞成分。
本发明的原理是基于以下惊人的观察：只要不被增溶剂封闭在向外亲水的微胞中，足够浓缩的溶液、凝胶或其他基质中的活性剂会被血管壁足量而快速地吸收。当活性剂是亲脂性的(丁醇与水性缓冲液(pH 7)的分配比≥0.5，优选≥1，特别优选≥5，或者辛醇与水性缓冲液(pH 7)的分配比≥1，优选≥10，特别优选≥50)，或可逆地(＞10％、优选＞50％、特别优选＞80％)和/或不可逆地与细胞成分(例如紫杉酚、普罗布考(4，4’-(亚异丙基二硫)双(2，6-二-叔丁基苯酚))、卟啉衍生物)结合时，在血管扩张和视需要斯滕特固定模植入期间给药时，药物在相关血管区域中的留滞时间足以产生治疗作用。通过阻止和减轻血管损伤所致的初期反应性增生，可以在数月中防止的血管壁的急剧增厚。令人惊奇的是，本发明的制剂证明不需要使被治疗的组织较长时间的暴露，或者不需要在额外损伤血管壁下直接渗入。
在血管成形术和斯滕特固定模植入期间，多次重复地将造影剂选择性地注入相关血管以确定狭窄的位置、程度和形态，以确定扩张导管的准确位置，评价扩张的成功与否，以及可选择性地植入一个适宜强度和长度的斯滕特固定模。通过将活性剂或其适于此目的的制剂加入用于诊断的造影剂中，则在每次注射造影剂的同时就将该活性剂传递至血管壁上，不需要作别的努力或对血管造成损伤。在此治疗的是用以诊断显影的整个血管区域，包括狭窄前的区域和其远端的区域。主要优点是：经扩张的狭窄和选择性斯滕特固定模植入部位的前后临界区域，均不会排除在治疗之外。
如果不需要或不希望注射造影剂，同样可以使用在其他的水性载体中的亲脂性活性剂溶液。条件是这些溶液所含活性剂的浓度高于其在水性介质中的饱和浓度。可以通过添加不产生或极少产生微胞的有机溶剂(例如乙醇和DMSO)达到此目的，和/或通过在不利于储存和给药条件(例如加热，与浓缩活性剂溶液的有机溶剂混合)下溶解这些活性剂，而形成足够稳定的过饱和溶液而达到此目的。
在某些情况下，水溶性低的亲脂性活性剂在造影剂溶液中的溶解性或过饱和溶液的稳定性得到惊人提高。造影剂所致的另一个令人惊奇的作用是增强了活性剂的管壁粘附性和血吸收性，以及在敏感的血管区域对某些极度系统毒性的物质具有良好的局部耐受性。
即使活性剂与造影剂不相容，或活性剂在造影剂中不能足够溶解，还可以通过诊断导管将该活性剂溶液直接注入或注射入相应的血管中。在此优选相近于通过导管使用造影剂给血管显影的容积[Elke M：造影剂在应用辐射学的诊断中(Kontrastmittel in derradiologischen Diagnostik)，113-119页，第3版，Georg ThiemeVerlag Stuttgart New York，1992]。
造影剂是血管耐受的溶液、悬浮液或乳液，其可以用于增强X光照片、超声波检测、光学成像或磁共振成像中血管或血流的显像。这些造影剂包括例如Visipaque 320(碘克沙醇)、Ultravist 370(碘普胺)、Omnipaque 350(碘海醇)或Solutrast 370(碘帕醇)或Magnevist(马根维显，钆-DPTA)或Gadovist 1M(钆布醇，Gd-DO3A-butrol)。
作为活性剂考虑所有用于抑制细胞生长、细胞增殖和增生性增殖的适宜物质，只要它们符合上述关于亲脂性和/或与组织成分结合的条件。由于一些活性剂不具有足够的亲脂性或者结合能力，也可以使用它们的药物活性衍生物或药物活性剂的前体，这样它们直到组织中才释放真正的活性剂。优选的是类紫杉(Taxoide)的细胞抑制剂，例如紫杉酚和多西他赛((2R，3S)-N-(叔丁氧基羰基)-2-羟基-3-苯基-β-丙氨酸-(4-乙酰氧基-2α-苯甲酰氧基-5β，20-环氧-1，7β，10β-三羟基-9-氧代-11-紫杉酚-13α-基-酯)，或者作为强亲脂性物质的实例是大环内酯类抗肿瘤药(Epothilone)。这些是亲脂性且不溶于水的，以致可优选例如NicollaouKC，Riemer C，Kerr MA，Rideout D，Wrasidlo W.在《紫杉醇的设计、合成和生物活性(Design，synthesis and biological activityof protaxols)》，《自然(Nature)》，1993；364：464-466或USP 457,674，《Novel Taxoids》中描述的较亲水的衍生物，只要它们的分子量不超过大约10KD。
其他可用的活性剂选自类皮质激素、有丝分裂抑制剂例如秋水仙碱、抗生素例如阿奇霉素或罗红霉素(Gupta等，1998)或抗氧化剂例如普罗布考，以及肝素和水蛭素衍生物或前列腺环素。另外，免疫抑制剂例如雷帕霉素也可用作活性剂。
其他亲水性细胞抑制剂的亲脂性衍生物的实例可见于Brunner H，Schellerer K-M，Treittinger B.的《作为有效的细胞抑制剂和射线损害抗肿瘤剂的铂(II)络合物中血卟啉型配体的合成和体外实验(Synthesis and in vitro testing of hematoporphyrin type ligandsin platinum(II)complexes as potent cytostatic and phototoxicantitumor agents)》Inorganica Chimica Acta，1997；264：67-79，形式为铂络合物与卟啉的轭合物。
本发明含有细胞抑制剂作为活性剂的制剂，也适于治疗肿瘤疾病。用于局部治疗是有利的，将患者的紧张度降至最低。
除了亲脂性物质外，对血管壁，特别是对发生病理变化的血管壁，具有特异亲和力的活性剂或结合底物的活性剂也是适宜的。这些物质对血管壁具有特异亲和力，在数分钟内不会被血流冲走。已经知道静脉内给药后低浓度磁铁矿沉积在动脉硬化改变的血管壁中(SchmitzSA等，Watanabe可遗传高脂血兔动脉粥样硬化斑的超顺磁性氧化铁增强的MRI(Superparamagnetic iron oxide-enhanced MRI ofatherosclerotic plaques in Watanabe hereditable hyperlipidemicrabbits)，Invest Radiol，2000；35：460-471)。但是，令人惊奇的是这些磁铁矿在短时间流过用气囊扩张的血管后，可以达到治疗的足够浓度。为了使这些磁铁矿可用于治疗，必须用药物将它们包被，这些药物例如为Lübbe AS，Bergemann C，Huhnt W，Fricke T，RiessH，Brock JW，Huhn D.在《用磁性药物定位的临床前试验：耐受性和效力(Preclinical Experiences with magnetic drug targeting：Tolerance and efficacy)》(Cancer Research，1996；56：4694-4701)中所述的药物。
将活性剂尽可能多地溶解在未稀释的造影剂中。也可将它们制备为独立的溶液，在使用前用造影剂对它们进行稀释。在此活性剂溶液和造影剂溶液的混合比应当不大于2∶1，优选小于1∶1，特别优选小于0.2∶1。该活性剂应当溶解于耐受性好的水性介质或可以与水混合的介质中。而且，还可以使用具有良好耐受性(至少在用造影剂溶液或另一种水性介质稀释后)的有机溶剂，例如乙醇、DMSO、DMF等。制备的注射溶液将尽可能用高份额的水(＞90体积％，优选＞95体积％，特别优选≥99体积％)。
每种活性剂的浓度范围根据它们不借助微胞形成剂(例如Cremophor的情况下)在生理耐受的溶剂中的溶解性，以及此活性剂的有效性和耐受性而定。浓度的上限通常通过给药的体积(例如100-200ml，用于多次注射入冠状动脉)和系统最大耐受剂量(例如对于紫杉酚约为100mg/m2体表面积)确定。优选地且因为局部给药和局部作用，足量的有效剂量为最大系统耐受剂量的1/10或更少。
可将其他有效物质例如凝结抑制剂、血小板聚集抑制剂、酶抑制剂、钙离子的络合物形成剂等加入此制剂中。这些物质不必符合所述亲脂性、与组织成分结合或分子量的条件，这是因为其作用也可以是急性血管内的；上面关于浓度和剂量段落中所述的内容适用于此，是因为重点集中在制剂流经的血管区域的局部作用上。
抗增生性活性剂的另一种给药方式是通过用于扩张血管的具有引起血管扩张的可膨胀的气囊导管进行给药。气囊可以用活性剂包被。气囊挤压在血管壁上以扩张血管。这为活性剂转运至血管壁提供了机会。如果将此气囊用于扩张斯滕特固定模，也可以将气囊和斯滕特固定模之间的活性剂释放出来，原因是造成了斯滕特固定模的金属支柱相的移动。与血管扩张或斯滕特固定模植入的原有方法相比，这些活性剂给药的方案对医生来说，不需要附加的步骤。
如果活性剂包被扩张血管的导管部分，则可使用下列的方法：将活性剂溶于不腐蚀导管的溶剂中，将相应的导管部分浸泡在该溶液中，将导管从溶液中取出，并干燥。可以将血管耐受的基质或凝胶形成辅剂加入活性剂溶液中，例如药物学上可用的脂质体或聚合物。可在多个步骤中进行包被，其中含有活性剂和不含活性剂的层可交替包被。选择各层溶剂的方法应当是后面的包被层不会将先前的包被层溶解。
本发明所提供的制剂中还可含有不形成微胞的增溶剂。优选所述抗过度增生的活性剂或携带该活性剂的组分与血管壁具有特异亲和力。
本发明还提供根据本发明的制剂在制备药物中的用途，所述药物用于预防再狭窄、抑制病理性管壁变化和用于局部肿瘤治疗，所述药物在血管造影术操作中或治疗措施中借助在管腔中的导管将所述抗过度增生的活性剂以立即生物供给的形式传送到组织中，而无需额外地中断血流或额外地损伤管壁。
下面的实施例进一步解释本发明：
实施例
实施例1a：一次性直接向动脉给药的溶液
将80mg 7-(2”，3”-二羟丙基氧羰基)-紫杉酚溶于5ml二甲亚砜，并用5ml 5％葡萄糖溶液稀释。将此溶液或其一部分缓慢地注入先前已经扩张的动脉中。
实施例1b：含抑制内膜增生的添加剂的X光造影剂
将一份1a中所述溶液加入99份市售的X光造影剂Visipaque 320中，并立即充分混合。该溶液在血管扩张前和后以惯用的方式用于血管造影术。
实施例2a：用于造影剂添加剂的溶液
将200mg 7-(2”，3”-二羟丙基氧羰基)-紫杉酚溶于10ml纯乙醇(＝溶液A)；可将0.35ml该溶液加入100ml造影剂中。
实施例2b：用于预防再狭窄的X光造影剂
100ml Ultravist 370(Schering AG，柏林；活性剂碘普胺，相当于370mg碘/ml)含有0.35体积％的乙醇和7mg 7-(2”，3”-二羟丙基氧羰基)-紫杉酚。通过将7-(2”，3”-二羟丙基氧羰基)-紫杉酚首先溶于乙醇，然后在不间断搅拌下，将其加入造影剂而制备该溶液。
实施例2c：用于预防再狭窄的X光造影剂
加入10 IU低分子肝素按照实施例2b制备。
实施例2d：抑制再狭窄的灌注溶液
将实施例2a中所述的3.5ml溶液A与46.5ml乙醇混合，并在快速振荡下，加至1000ml温(～50℃)5％葡萄糖溶液或等渗电解质溶液中。就象造影剂那样，通过导管将该溶液注入将要治疗的血管中；但是，灌输的速度与给入造影剂相比，可以减慢。
实施例3a：用于抑制内膜增生的X光造影剂
将100ml Ultravist 370(参见实施例2b)与0.4体积％乙醇和14.4mg 7-(2”，3”-二羟丙基氧羰基)-紫杉酚混合。按照实施例2b所述制备此制剂。
实施例4a：用于抑制细胞生长的X光造影剂
100ml Solutrast 370(Byk-Gulden，Konstanz；活性剂碘普胺，相当于370mg碘/ml)，含有1.0体积％的乙醇和8.2mg紫杉酚/ml。制备该制剂，首先在稍微加热下将紫杉酚溶于纯乙醇，溶解后快速加入造影剂，并用力搅拌。
实施例4b：用于抑制内膜增生的X光造影剂
实施例4a的制剂，添加5 IU肝素和5mmol/l柠檬酸缓冲液(pH7.0)。
实施例5a：作为造影剂或灌注溶液的添加剂的溶液
将20mg(±)-反-1，2-二氨基环己烷{7，12-双[1-(1，4，7，10，13，16-六氧十七烷基)-乙基]-3，8，13，17-四甲基卟啉-2，18-二丙酸}铂(II)溶于10ml二甲亚砜(＝溶液B)。
实施例5b：含抑制细胞生长添加剂的X光造影剂
在快速搅拌下，将1ml溶液B加入100ml Ultravist 370(参见实施例2b)。该溶液适于注入动脉或注射入活或死的组织中或体腔中。它可以产生最初分布的良好控制，并引起长期持续的细胞抑制作用。
实施例5c：含抑制细胞生长添加剂的磁共振断层照像术的造影剂
将1ml溶液B加入10ml 50毫摩尔马根维显(＝Gadopentetat)溶液。通过10倍稀释Magnevist[一种市售制剂(Schering AG，Berlin)]制备50毫摩尔马根维显溶液。该溶液可以例如渗入致命的肿瘤或经过乙醇、加热或冷冻处理后的肿瘤。在磁共振断层照相术中该溶液的分布得到很好的显现。溶液本身支持在直接浸润区域及其邻近区域毫无遗漏地消灭肿瘤。
实施例6：实施例2b中所述制剂的体内效力
在麻醉下，将8头猪中每头猪的两条冠状动脉扩张，并植入斯滕特固定模(精细穿孔的金属管)。动脉的反应是壁增厚，它导致动脉原始管腔的狭窄。四头猪给予常规X光造影剂(Ultravist 370)，以使动脉显影和检查斯滕特固定模的植入，四头猪给予实施例2b的制剂。处理后两个试验组的血管具有相同的宽度(内径3.4±0.2mm和3.5±0.2mm)。处理四周后，接受常规照影剂的动物的动脉内径狭窄了1.9±0.8mm，而接受了实施例2b溶液处理的动物的动脉直径仅仅减少了0.9±0.6mm。此差异具有统计学意义(p＝0.01)。尽管在冠状动脉注射后以及ECG和血压测定的同时，加入高浓度的具有相当毒性的细胞抑制剂，实施例2b未稀释的溶液仍是可耐受的，而且没有副作用。
实施例7a：包被导管
在无菌的条件下，将为血管扩张而设计的气囊导管带有气囊的远端区域浸入实施例2a的乙醇溶液(＝溶液A)中约5分钟，然后取出并在室温下干燥2小时。然后可以扩张血管常规的方法使用该气囊导管。或者，在干燥后，将斯滕特固定模装置在气囊区域。
实施例7b：
步骤类似实施例7a，不同的是将100mg药用蓖麻油加入溶液A中。
实施例8a：在造影剂或生理NaCl溶液中的溶解性
将7.6mg紫杉酚溶于0.5mg乙醇，并在室温下，将其加入50mlUltravist-370(含有768mg碘普胺/ml，比重约1.4g/ml)中。混合后获得没有任何浑浊的澄清溶液，该溶液在几天内保持稳定。在显微镜下确定该溶液中没有任何颗粒。
将4.2mg紫杉酚溶于0.5ml乙醇中，并在室温下，将其加入50ml0.9％NaCl溶液中。混合后制剂立刻变得混浊；2小时后溶液表面出现大多数颗粒。使用显微镜可以发现有大量的细颗粒聚集。
评价：紫杉酚在造影剂中的溶解性令人惊奇的高。造影剂溶液含有0.7ml水/ml的溶液混合物，即与在NaCl溶液中的相比，在造影剂中对于紫杉酚有较少的溶剂可应用。尽管如此，紫杉酚在造影剂中溶解得好于在NaCl溶液中。
实施例8b：磁铁矿作为抗增生剂的载体
将75mg紫杉酚溶于5ml乙醇。将紫杉酚溶液加入50ml降解葡聚糖包被的胶态磁铁矿的含水制剂(浓度为Fe2+/3+0.5摩尔，例如SH U555C，柏林Schering AG的测试制剂)并快速相互混合。磁铁颗粒吸附紫杉酚，并在静脉内或动脉内注射后，将其转运至具有动脉硬化和脑肿瘤的动脉壁中。剂量随磁铁矿的使用而变化，大约50μmol Fe/kg体重。

Claims (19)

1.包含至少一种抗增生剂的制剂的用途，所述抗增生剂在丁醇和水之间的分配比为≥0.5，所述制剂施用于制造阻止或减轻由于在血管扩张和可能的斯滕特固定模的植入后的血管损伤所致的初期反应性增生的产品，其中所述活性剂仅在血管扩张过程中有可能渗透血管壁。
2.根据权利要求1的用途，其用于局部治疗。
3.根据权利要求1或2的用途，其特征在于，所述制剂包含所述抗增生剂连同用于增强动脉/静脉显影的技术。
4.根据权利要求1至3的用途，其特征在于，所述制剂应用于导管。
5.根据权利要求1至4的用途，其特征在于，所述抗增生剂为细胞生长抑制剂、类皮质激素、前列腺环素、抗氧化剂、抗生素、细胞增殖抑制剂或免疫抑制剂。
6.根据权利要求1至5的用途，其特征在于，所述抗增生剂为类紫杉。
7.根据权利要求1至6的用途，其特征在于，所述抗增生剂为紫杉醇、多西他塞、普罗布考、卟啉衍生物、秋水仙碱或大环内酯类抗肿瘤药。
8.根据权利要求4至7的用途，其特征在于，所述活性剂用于增强动脉/静脉显影，由血管可耐受并且适用于X光照相、超声波检测、光成像或磁共振成像用以增强血管或血流显像的溶液、悬浮液或乳液组成。
9.根据权利要求4至8的用途，其特征在于，所述用于增强动脉/静脉显影的活性剂为X光造影剂。
10.根据权利要求4至9的用途，其特征在于，所述用于增强动脉/静脉显影的活性剂为碘克沙醇(Visipaque)、钆-DTPA(马根维显)、轧布醇(Gadovist)、碘普胺(Ultravist)、碘海醇(Omnipaque)或碘帕醇(Solutrast)。
11.根据权利要求4至10的用途，其特征在于，所述抗增生剂为紫杉醇和所述用于增强动脉/静脉显影的活性剂为碘普胺(Ultravist)。
12.根据权利要求1至11的用途，其特征在于，所述制剂还包含凝结抑制剂和/或血小板聚集抑制剂和/或酶抑制剂和/或钙螯合剂。
13.根据权利要求1至12的用途，其特征在于，至少10％的所述活性剂可逆或不可逆地与组织结合。
14.根据权利要求1至13的用途，其特征在于，所述活性剂或携带该活性剂的组分与血管壁具有特异亲和力。
15.根据权利要求1至14的用途，其特征在于，所述溶液包含不形成微胞的增溶剂。
16.根据权利要求1至15的用途，其特征在于，所述活性剂的使用不包含形成基质或凝胶的佐剂。
17.根据权利要求1至16的用途，其用于防止再狭窄。
18.包含至少一种抗增生剂的制剂，所述抗增生剂在丁醇和水之间的分配比为≥0.5，所述制剂应用于导管，特别地用于阻止或减轻由于在血管扩张和可能的斯滕特固定模的植入后的血管损伤所致的初期反应性增生，其中所述活性剂仅在血管扩张过程中有可能渗透血管壁。
19.根据权利要求18的制剂，其特征在于，所述制剂包含所述抗增生剂连同用于增强动脉/静脉显影的活性剂。
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