CN101744676B - For adhesion promoting primer coated surface - Google Patents

For adhesion promoting primer coated surface Download PDF

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CN101744676B
CN101744676B CN 200910253495 CN200910253495A CN101744676B CN 101744676 B CN101744676 B CN 101744676B CN 200910253495 CN200910253495 CN 200910253495 CN 200910253495 A CN200910253495 A CN 200910253495A CN 101744676 B CN101744676 B CN 101744676B
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CN 200910253495
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CN101744676A (en )
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V·达夫
R·法洛蒂科
C·李
T·M·阮
T·L·帕克
J·Z·赵
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科迪斯公司
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Abstract

本发明涉及用于带涂层表面的促粘附底漆,具体涉及可扩张的医疗装置,包括多个细长撑条,形成可从第一直径扩张至第二直径的基本圆柱形的装置。 The present invention relates to an adhesion promoting primer coated surface, particularly to an expandable medical device, comprising a plurality of elongated struts, a substantially cylindrical device expandable from a first diameter to a second diameter is formed. 可将多种不同的有益药剂装载进所述撑条内的不同开口中用于递送至组织。 It can be a variety of different beneficial agents loaded into different openings within the support bar for delivery to tissue. 为治疗诸如再狭窄之类的病症,将不同药剂装载进所述装置内的不同开口中以解决再狭窄所涉及的不同生物过程,并且以与所治疗的所述生物过程相匹配的不同释放动力学进行递送。 For the treatment of disorders such as restenosis and the like, the different agents loaded into different openings within the device to address different biological processes involved in restenosis, the biological process and to be treated with different release kinetics matched learn delivered. 还可使用来自相同的所述药物递送装置的所述不同药剂来解决不同的疾病。 The medicament may also be used from the same delivery device of the different agents to address different diseases. 另外,可将抗血栓形成剂固定至所述医疗装置的表面的至少一部分用于防止亚急性血栓形成。 Further, an anti-thrombotic agent affixed to at least a portion of the surface of the medical device for preventing subacute thrombosis. 可利用底漆来确保所述不同药剂保持固定在所述装置上以及彼此固定。 The primer may be utilized to ensure that the different agents remain fixed on the device and fixed to each other.

Description

用于带涂层表面的促粘附底漆 For adhesion promoting primer coated surface

技术领域 FIELD

[0001] 本发明涉及组织支承医疗装置,更具体地讲涉及不可移除的可扩张式装置,该装置被植入活体动物或人的体腔内以支承器官和保持器官不闭合,并且具有用于将多种有益药剂递送至介入位点的开口以及抗血栓形成剂表面涂层。 [0001] The present invention relates to tissue-supporting medical devices, and more particularly relates to a non-expandable removable device, the device is implanted in a body cavity of a living animal or human to support the organ and maintaining the organ is not closed, and has a the delivery of multiple beneficial agents to the intervention site of the opening and forming a surface coating antithrombotic agents. 本发明还涉及在抗血栓形成剂涂层与其他治疗剂/聚合物基质之间使用的底漆涂层。 The present invention also relates to primer coatings for use between the antithrombotic agent coating and other therapeutic agent / polymer matrix.

背景技术 Background technique

[0002] 在过去,已经研发出用于植入体内通道中以保持通道不闭合的永久型或可生物降解型装置。 [0002] In the past, it has been developed permanent or biodegradable for implantation apparatus body passageway to maintain patency of the passageway. 这些装置通常是以经皮的方式引入,并经腔运送直至定位在所需位置。 These devices are typically introduced percutaneously manner, and transported through the chamber until positioned at a desired position. 然后,以机械方式(例如通过扩张设置在装置内的轴柄或气球)扩张装置,或通过在身体激发时即释放所储存的能量来自身扩张。 Then, mechanically (e.g. a balloon or expanded by mandrel disposed within the device) expansion means, or by self-expanding body by the excitation i.e. when the stored energy is released. 一旦在体腔内扩张,装置(称为支架)便被封存在身体组织内并保留下来成为永久性植入物。 Once expanded within the body cavity, means (called a stent) will be sealed within the body tissue and preserved as a permanent implant.

[0003] 已知的支架设计包括:单丝线圈支架(美国专利No. 4,969,458);焊接金属笼(美国专利No. 4,733,665和4,776,337)以及最为著名的在圆周上形成有轴向槽的薄壁金属筒(美国专利No · 4,733,665、No · 4,739,762和No · 4,776,337)。 [0003] Known stent designs include: a monofilament coil stents (U.S. Pat. No. 4,969,458); welded metal cages (U.S. Pat. No. 4,733,665 and 4,776,337) and most famous axial grooves are formed thin-walled metal cylinders (U.S. Patent No · 4,733,665, No · 4,739,762 and No · 4,776,337) in circumference. 用于支架的已知构造材料包括:聚合物、有机纤维及生物相容性材料,例如,不锈钢、金、银、钽、钛以及形状记忆合金(例如,镍钛合金)。 Known construction materials for stents include: polymers, organic fibers and a biocompatible material, e.g., stainless steel, gold, silver, tantalum, titanium, and shape memory alloys (e.g., nitinol).

[0004] 美国专利No. 6,241,762公开了一种非棱形支架设计,其可弥补先前的支架的多个性能缺陷,将该专利以引用的方式全文并入本文。 [0004] U.S. Patent No. 6,241,762 discloses a non-prismatic stent design, which may make up the plurality of performance deficiencies of previous stents, which patent is incorporated by reference in its entirety herein. 另外,该专利中公开的优选实施例提供了具有大的、不变形的撑条和联接元件的支架,该支架可包括孔而不会有损撑条或联接元件或整个装置的机械性质。 Further, this patent disclosed a preferred embodiment provides a large, the stent struts and the coupling element has not deformed, the stent may include holes without compromising the mechanical properties of the strut or the coupling element or the entire apparatus. 此外,这些孔可用作将各种有益药剂递送至装置植入位点的大的、 受保护的贮器而无需在支架上有表面涂层。 Further, these holes may be used as a variety of beneficial agents to the device implantation site delivery of a large, protected reservoirs without surface coating on the stent.

[0005] 通过有益药剂基于支架的局部递送可解决许多的问题,其中一个最为重要的问题是再狭窄。 [0005] By the beneficial agent-based local delivery of the stent can solve many problems, one of the most important issue is restenosis. 再狭窄是在脉管介入(例如,血管成形术和支架植入)之后可能出现的重大并发症。 Restenosis is a major complication that can occur after vascular intervention (eg, angioplasty and stenting). 简单地定义,再狭窄就是由于细胞外基质沉积以及脉管平滑肌细胞增殖而造成脉管腔直径减小的伤口愈合过程,并且其可能最终导致腔的再次变窄或甚至再次闭塞。 Simply defined, restenosis is due to the proliferation and extracellular matrix deposition and vascular smooth muscle cells in the vessel lumen caused by the reduced diameter of the wound healing process, and which may ultimately result in re-narrowing or even closing the chamber again. 尽管引入了改进的外科技术、装置和药剂,但据报告显示,在接受血管成形术后的6至12个月内,植入裸金属支架的再狭窄总发生率仍有约25%至约50%。 Despite the introduction of improved surgical techniques, devices and pharmaceutical, but according to the report, the receiving angioplasty in 6 to 12 months, bare metal stents overall restenosis rate is still about 25% to about 50 %. 为应对这种情况,经常还需要另外的脉管再通手术,从而增大了患者的创伤和风险。 To deal with this situation, often also require additional vascular recanalization surgery, thereby increasing trauma and risk to the patient.

[0006] 带有各种有益药剂表面涂层的常规支架在减少再狭窄方面已经显示出的令人振奋的结果。 [0006] Conventional stents with surface coatings of various beneficial agents in reducing restenosis have shown encouraging results. 例如,美国专利No.5,716,981公开了一种表面涂覆有包含聚合物载体和紫杉醇的组成物的支架。 For example, U.S. Patent No.5,716,981 discloses a surface-coated stent with a composition comprising a polymer carrier and paclitaxel. 该专利提供了关于涂覆支架表面的方法(例如,喷涂和浸涂)以及涂层自身有利特性的详细描述:对支架应"平滑均匀地进行涂覆,并且让抗血管形成因子得到均匀、可预测地并且长效地释放"。 The patent provides a method of coating on the stent surface (e.g., spray coating and dip coating) as well as a detailed description of their advantageous properties of the coating: the stent should be a "smooth evenly coated, so that an anti-angiogenic factor and a homogeneous, be predictable and long-term release. " 然而,表面涂层几乎不能对有益药剂的释放动力学提供任何实际的控制。 However, the surface coating can hardly provide any real control over the release kinetics of beneficial agents. 这些涂层必须是非常薄,通常5-8微米厚。 These coatings must be very thin, typically 5-8 microns thick. 相比较之下,支架的表面积非常大,以致全部量的有益药剂排入周围组织的扩散路径非常地短。 In comparison, the surface area of ​​the stent is very large, so that the total amount of beneficial agent into the tissue surrounding the diffusion path is short. 所得的累积药物释放曲线表征为:开始时大量急促释放,继而快速接近渐近线,而非所需的"均匀、长效释放"或线性释放。 The resulting cumulative drug release profile is characterized as: rapid release of a large amount at the beginning, followed by fast approaching asymptote, rather than the desired "uniform, extended release," or linear release.

[0007] 增加表面涂层的厚度具有改善药物释放动力学的有益效应,包括能更好地控制药物释放并且允许增大药物的装载量。 [0007] The increased thickness of the surface coating has a beneficial effect improving drug release kinetics, including better control drug release and to allow increased drug loading amount. 然而,涂层厚度增加会导致支架壁的总厚度增加。 However, increasing the coating thickness results in an increased overall thickness of the stent wall. 出于以下多种原因,这是不可取的,这些原因包括:在植入期间对脉管腔的潜在创伤增加;植入后腔流量横截面减小;以及在扩张及植入期间,涂层受机械失效或损坏的影响增大。 For several reasons, it is undesirable for these reasons include: increasing the potential trauma to the vessel lumen during implantation; after implantation of reduced cross-sectional flow chamber; and during expansion and implantation, the coating affected mechanical failure or damage is increased. 涂层厚度是影响有益药剂释放动力学的多个因素的其中一个,因此,限制厚度就会限制可实现的释放速率、持续时间长度等的范围。 Effect of coating thickness is one of the beneficial agent release kinetics of a number of factors, thus limiting the thickness of the release rate will be achieved to limit the scope of, the time length and the like.

[0008] 表面涂层还会限制从支架递送多种药物。 [0008] The surface coating can also limit the delivery of multiple drugs from a stent. 例如,假如拟从表面涂层释放出多种药物,则可能不能以容易的方式单独控制释放速率、递送周期及其他释放特性。 For example, if a variety of drugs intended for release from the surface of the coating, it may not be individually controlled in an easy way the rate of release, period of the delivery and other release characteristics. 然而,再狭窄涉及多个生物过程且可通过选择作用于这些不同生物过程的药物组合而得到最有效的治疗。 However, restenosis involves multiple biological processes and may be obtained by selecting the most effective therapeutic effect of the combination of these drugs in various biological processes.

[0009] Chao-Wei Hwang等人标题为"Physiological Transport ForcesGovern Drug Distribution for Stent-Based Delivery(生理转运能力支配着支架式递送的药物分布)"的论文揭示了药物洗脱支架的空间药物分布性质与时间药物分布性质之间的重要相互关系以及细胞药物转运的机制。 [0009] Chao-Wei Hwang et al., Entitled "Physiological Transport ForcesGovern Drug Distribution for Stent-Based Delivery (physiological scaffolding dominated transport capacity delivered drug distribution)" discloses a paper distribution properties of drug eluting stents with drugs space and the important relationship between the intracellular drug distribution mechanism of drug transport properties of time. 为了寻求增强的机械性能和结构性质,支架设计已演变为更为复杂的几何形状,支架撑条的圆周上和纵向上的分布有着内在的不均匀性。 In order to seek enhanced mechanical properties and structural properties, stent designs have evolved to more complex geometries, distributed over the circumference of the stent struts in the longitudinal direction and has an inherent non-uniformity. 典型的市售支架便是这种趋势的例子,这些支架在部署于身体内腔时扩张成大致为菱形或多边形的形状。 Typical commercially available example of this trend is the stent, these stents deployed in a body lumen when expanded into a substantially rhombic shape or polygonal. 这两种形状都一直用于以表面涂层的形式来递送有益药剂。 Both have been used to form the shape of a surface coating of a beneficial agent to be delivered. 据研究显示,紧邻撑条的腔组织部分比稍远的组织部分(例如,位于"菱形"撑条格子中间的组织)需要更高浓度的药物。 Research shows that, stay close tissue portions tissue portion farther than the cavity (e.g., in the "diamond" shaped strut intermediate lattice tissue) requires higher concentrations of the drug. 重要的是,对于疏水性有益药剂(例如,迄今为止证明为最为有效的抗再狭窄药的紫杉醇或雷帕霉素),这种在腔中的药物浓度梯度会随时间推移而增大。 Importantly, for hydrophobic beneficial agents (e.g., so far proven to be the most effective anti-restenosis rapamycin or paclitaxel drug), the drug concentration in the chamber will increase the gradient over time. 由于局部药物浓度及梯度与生物效应密不可分,所以有益药剂源(支架撑条)的初始空间分布就是功效的关键。 Because local drug concentrations and gradients are inseparable and biological effects, it is the key to the efficacy of the initial space of the beneficial agent sources (the stent struts) distribution.

[0010] 除了有益药剂欠佳的空间分布以外,带表面涂层的支架还有潜在的缺点。 [0010] In addition to poor spatial distribution of beneficial agents, there are potential disadvantages with surface coated stents. 装置涂层中经常使用的某些固定的基质聚合物载体通常会在涂层中无限期地保留着相当百分比的有益药剂。 Certain fixed matrix polymer carriers frequently used in the device coatings typically retain a significant percentage indefinitely beneficial agent in the coating. 由于这些有益药剂可能是细胞毒素药剂,例如,紫杉醇,所以可能会发生亚急性和慢性问题(例如,慢性炎症、晚期血栓形成)以及脉管的愈合较迟或不彻底。 Since these beneficial agents may be cytotoxic agents, e.g., taxol, it may subacute and chronic problems (e.g., chronic inflammation, late thrombosis) and later vascular healing or incomplete. 另外,载体聚合物自身常常可引起脉管壁组织发炎。 Additionally, the carrier polymers themselves are often the vessel wall can cause tissue inflammation. 另一方面,在支架表面上使用可生物降解的聚合物载体,可能会在聚合物载体降解后在支架和脉管壁组织之间造成"贴壁不良"或空隙。 On the other hand, use of biodegradable polymer carriers on stent surfaces may result in "poor adherence" or voids between the stent and tissue of the vessel wall after the polymer carrier will degrade. 这些空隙会导致支架与相邻组织之间出现差动运动。 These voids can lead to differential movement occurs between the stent and adjacent tissue. 所造成的问题包括微磨损和发炎、支架滑移和无法使脉管壁再内皮化。 Including problems caused by micro-abrasion and inflammation, stent slippage and can not be re-endothelialization of the vessel walls.

[0011]早期的人体临床试验显示,第一代药物递送装置可能存在着某些缺点。 [0011] Early human clinical trials have shown that first generation drug delivery devices there may be certain disadvantages. 植入带药物涂层的支架后6至18个月,对临床试验患者进行的随访检查表明,在相当多的患者中会发生支架撑条与脉管壁的贴壁不良和边缘效应再狭窄。 After the drug-coated stent with a 6 to 18-month follow-up examination of clinical trial patients showed a considerable number of patients will occur holder stay adherent vessel wall and undesirable edge effect restenosis. 边缘效应再狭窄发生在刚好超出支架近端边缘和远端边缘的地方,进而发展到支架边缘的周围,并且发展进入内部(腔内)空间, 患者常常需要再次进行脉管再通手术。 Edge effect restenosis occurs just beyond the proximal edge and the distal edge of the stent, thereby progressing around the stent edges and into the interior of the development (luminal) space, patients often require reoperation vascular recanalization.

[0012]另一个潜在的缺点是,支架的扩张会对覆盖在上方的聚合物涂层产生应力,从而致使涂层剥落、断裂或破裂,这会影响药物释放动力学或者引起其他不利的结果。 [0012] Another potential disadvantage is that expansion of the stent polymeric coating will cover the top of the stress, causing the coating flaking, cracking or breakage, which may affect the drug release kinetics or cause other adverse consequences. 当第一代支架扩张到较大直径时,这些药物涂层支架中会观察到这样的结果,从而到目前为止妨碍着这种支架在较大直径动脉中的使用。 When the first generation of the stent expand to a larger diameter, these drug-eluting stents will observe such results, so far hampered use of such stents in larger diameter arteries. 此外,这种带涂层的支架在动脉粥样硬化血管中的扩张会对聚合物涂层施加剪切力,从而会致使涂层与下方的支架表面分离。 In addition, the expansion of such a stent coated with polymer coating will atherosclerotic vessels shearing force is applied, which will cause the coating to the lower surface of the stent separation. 这样的分离可能会再次引起包括涂层碎片的栓塞形成(导致脉管阻塞)在内的不利结果。 Such separation can cause embolism include coating fragments formed again (leading to vessel obstruction), including unfavorable results.

[0013] 血栓形成是可通过有益药剂基于支架的局部递送来解决的另一个问题。 [0013] Another problem with thrombosis is based on local delivery of the stent can be solved by the beneficial agent. 可用抗血栓形成剂以及一种或多种治疗剂涂覆支架,用于治疗再狭窄。 Antithrombotic agents and one or more therapeutic agents coated stents for the treatment of restenosis. 然而,取决于支架表面上的涂层,例如抗血栓形成药物涂层,可优选使用额外的层或底漆层来提高其他治疗剂与支架涂层表面的粘附。 However, depending on the stent surface a coating, for example, an antithrombotic drug coating, additional layers can be preferably used to enhance the adhesion primer layer or other therapeutic agent to coat the surface of the stent.

发明内容 SUMMARY

[0014] 本发明的用于带肝素涂层的表面的促粘附底漆克服了上面简单描述的那些困难。 [0014] a heparin coated surface of the adhesion promoting primer of the invention overcomes the difficulties briefly described above.

[0015] 根据一个方面,本发明涉及一种植入式医疗装置。 [0015] According to one aspect, the present invention relates to an implantable medical device. 该植入式医疗装置包括:管腔内支架,其内具有多个开口;第一涂层,其包含固定至该管腔内支架的表面以及该多个开口的表面的至少一部分的具有第一电荷的材料;第二涂层,其包含固定至该第一涂层的至少一部分的具有第二电荷的材料,第二电荷与第一电荷相反;以及至少一种治疗剂,其沉积在该多个开口中的至少一个中;其中第二涂层构造为第一涂层与该至少一种治疗剂之间的中间层。 The implantable medical device comprising: an intraluminal scaffold having a plurality of openings therein; a first coating comprising a surface fixed to the inner surfaces of the intraluminal scaffold and a plurality of openings of at least a portion having a first charge-generating material; a second coating comprising a material having a second electric charge affixed to at least a portion of the first coating, a second charge opposite the first charge; and at least one therapeutic agent deposited in the multi- openings in at least one of; wherein the second coating is configured as an intermediate layer between the first coating and the at least one therapeutic agent.

[0016] 根据另一方面,本发明涉及一种植入式医疗装置。 [0016] According to another aspect, the present invention relates to an implantable medical device. 该植入式医疗装置包括:基本圆柱形的管腔内支架,其能够从用于递送进脉管内的第一直径扩张至用于扩张脉管的第二直径,该管腔内支架具有腔内表面和腔外表面,腔内表面和腔外表面之间的距离限定了该管腔内支架的壁厚度,该管腔内支架还包括从腔内表面延伸至腔外表面的多个开口;第一涂层,其包含固定至腔外表面、腔内表面以及该多个开口的表面的至少一部分的具有第一电荷的材料;第二涂层,其包含固定至第一涂层的至少一部分的具有第二电荷的材料,第二电荷与第一电荷相反;以及至少一种治疗剂,其沉积在该多个开口中的至少一个中;其中第二涂层构造为第一涂层与该至少一种治疗剂之间的中间粘合层。 The implantable medical device comprising: a substantially cylindrical intraluminal stent capable of delivering into the expandable from a first diameter to a second inner diameter of the vessel to the expansion vessel, the intraluminal scaffold having a lumen distance between the surface, luminal surface and an abluminal surface and an outer surface defining a chamber wall thickness of the intraluminal scaffold, the intraluminal scaffold also including a plurality of extending from the luminal surface to the abluminal surface of the opening; first a coating comprising a material having a first electric charge affixed to at least a portion of the abluminal surface, luminal surface and a surface of the plurality of openings; and a second coating layer, which comprises at least a first portion fixed to the coating layer a material having a second charge, a second charge opposite the first charge; and at least one therapeutic agent deposited in at least one of the plurality of openings; and wherein the second coating is configured as a first coating and the at least intermediate between the therapeutic agent of the adhesive layer.

[0017] 根据另一方面,本发明涉及一种用于涂覆其内具有多个开口的管腔内支架的方法。 [0017] According to another aspect, the present invention relates to a method for coating having therein a plurality of openings in the intraluminal scaffold. 该方法包括:将包含具有第一电荷的材料的第一涂层施加至管腔内支架表面和该多个开口的表面的至少一部分;将包含具有第二电荷的材料的第二涂层施加至第一涂层的至少一部分,第二电荷与第一电荷相反;以及将至少一种治疗剂施加至该多个开口中的至少一个内。 The method comprising: a coating comprising a first material having a first electric charge is applied to at least a portion of the inner luminal surface of the stent and a plurality of openings surfaces; and a second coating comprising a material having a second electric charge is applied to the at least a portion, a second charge opposite the first charge and a first coating layer; and at least one at least one therapeutic agent applied to the plurality of openings therein.

[0018] 鉴于现有技术的缺陷,有利的是能提供一种可将相对较大量的有益药剂递送至脉管腔中的创伤点的支架,而同时又可避免与包含有益药剂的表面涂层相关的诸多潜在问题,而又无需增加支架的有效壁厚,而又不会不利影响支架的机械扩张性质。 [0018] In view of the deficiencies of the prior art, it is advantageous to be able to provide a stent may be delivered to the wound site relative to the vessel lumen in a relatively large amount of beneficial agent, and while avoiding the surface of the coating layer comprising the beneficial agent many potential problems associated with, but without increasing the effective wall thickness of the stent, but that does not adversely affect the mechanical properties of the stent expansion.

[0019] 更有利的是能提供一种在不同孔口内设有不同有益药剂的组织支承装置,以实现所需的两种或更多种有益药剂的空间分布。 [0019] More advantageous to be able to provide a different orifice equipped with different beneficial agents tissue supporting device to achieve a desired space of two or more beneficial agents distribution.

[0020] 更有利的是能提供一种在不同孔口内设有不同有益药剂的组织支承装置,以实现所需的两种不同有益药剂从同一装置的不同释放动力学。 [0020] More advantageous to be able to provide a tissue supporting device with a different beneficial agents in different holes equipped to achieve different release kinetics required for two different beneficial agents from the same device.

[0021] 更有利的是能提供一种所有表面都涂覆有抗血栓形成剂的组织支承装置,然后利用该装置内的孔或开口中的底漆来增加填充孔的一种或多种有益药剂的粘附。 [0021] More advantageous to be able to provide an all surfaces are coated with a tissue-supporting device antithrombotic agent, and then utilizing holes or openings in the device to increase a primer for filling holes or more beneficial adhesion agent.

[0022] 本发明涉及用于改善药物递送基质(如治疗剂与聚合物的组合)与医疗装置(例如,具有肝素涂层的支架)开口的粘附的底漆组成物及构造。 [0022] The present invention relates to primer compositions and configurations for improving the drug delivery matrix (e.g., a therapeutic agent in combination with the polymer) and the medical device (e.g., heparin coated stent having a) an opening adhesion. 在肝素涂层共价结合至医疗装置的金属表面或聚合物表面的情况下,本发明尤其有利。 In the case where the heparin coating is covalently bound to the metal surface of the medical device or the polymer surface, the present invention is particularly advantageous. 在本发明中,底漆优选包含高分子量组分或低分子量组分,药物递送基质包含药物和/或其他有益药剂以及赋形剂,优选聚合物赋形剂。 In the present invention, the primer preferably comprises a high molecular weight component or the low molecular weight component, a drug and / or other beneficial agent and an excipient, preferably a drug delivery matrix comprises polymeric excipients. 另外,底漆还可优选包含与下层(例如,肝素层)的电荷相反密度相似的材料。 Further, the primer may also preferably comprise a density similar to the opposite lower layer (e.g., heparin layer) of the charge material.

附图说明 BRIEF DESCRIPTION

[0023] 根据下文附图所示的本发明优选实施例的更为具体的说明,本发明上述及其他特征和优点将显而易见。 [0023] more particular description of a preferred embodiment of the present invention shown in the drawings hereinafter, the present invention is the above-mentioned and other features and advantages will be apparent.

[0024] 图1是根据本发明的端部带有有益药剂的可扩张医疗装置的等轴视图。 [0024] FIG. 1 is an isometric view of an expandable medical device of the present invention with an end portion of the beneficial agent according to.

[0025] 图2是根据本发明的中央部分带有有益药剂而端部没有有益药剂的可扩张医疗装置的等轴视图。 [0025] FIG. 2 is an end portion of the beneficial agent with no beneficial agent may be expandable medical device according to an isometric view of a central portion of the present invention.

[0026] 图3是根据本发明的不同孔内带有不同有益药剂的可扩张医疗装置的等轴视图。 [0026] FIG. 3 is an isometric view with different beneficial agents in different holes of this invention according to an expandable medical device.

[0027] 图4是根据本发明的孔内交替带有不同有益药剂的可扩张医疗装置的等轴视图。 [0027] FIG. 4 is an isometric view of the alternate with different beneficial agents may be expandable medical device according to the present invention the hole.

[0028] 图5是根据本发明的在桥接元件中带有有益药剂开口的可扩张医疗装置的一部分的放大侧视图。 [0028] FIG. 5 is an enlarged side view of a portion of an expandable medical device with beneficial agent openings in the bridging elements in accordance with the present invention.

[0029] 图6是根据本发明的具有分叉开口的可扩张医疗装置的一部分的放大侧视图。 [0029] FIG. 6 is an enlarged side view of part of the bifurcation opening having expandable medical device according to the present invention. [0030]图7是根据本发明的可扩张医疗装置的剖面图,该扩张医疗装置具有位于多个第一孔内的第一药剂(例如抗炎剂)和位于多个第二孔内的第二药剂(抗增殖剂)的组合。 [0030] FIG. 7 is a cross-sectional view of an expandable medical device according to the present invention, the expandable medical device having a first agent (e.g., anti-inflammatory agents) and a plurality of first holes located on a second plurality of holes combination of two agents (an antiproliferative agent).

[0031] 图8是根据本发明的由图7可扩张医疗装置递送的抗炎剂和抗增殖剂的一个实例的释放速率曲线图。 [0031] FIG. 8 is a graph showing the release rate of one example of a medical device delivery antiinflammatory and antiproliferative agent in accordance with the present invention in FIG 7 may be expandable.

[0032] 图9A-9C是根据本发明的可扩张医疗装置的备选示例性实施例的局部图示。 [0032] Figures 9A-9C are partial diagram illustrating an alternate exemplary embodiment of an expandable medical device according to the present invention.

[0033]图10示出了根据本发明的具有羧酸端基的PLGA与低分子量PE I之间的缀合反应。 [0033] FIG. 10 shows a conjugation between the low molecular weight PLGA in accordance with the reaction bonded PE I having carboxylic acid end groups of the present invention. [0034]图11图示了根据本发明的带有羧酸端基的PLGA与高分子量PEI或带支链PEI之间的缀合反应。 [0034] FIG 11 illustrates an engagement between the conjugation reaction according to the PLGA and PEI molecular weight or branched PEI with a carboxylic acid end groups of the present invention.

具体实施方式 detailed description

[0035]图1图示了具有多个孔的可扩张医疗装置,该多个孔包含由该可扩张医疗装置递送至组织的有益药剂。 [0035] FIG 1 illustrates an expandable medical device having a plurality of holes, the plurality of apertures comprises a beneficial agent from the delivery of the expandable medical device to tissue. 图1中所示的可扩张医疗装置10是材料管截取而来以形成圆柱形可扩张装置。 The expandable medical device 1 shown in FIG. 10 is cut from a tube of material to form a cylindrical expandable device. 可扩张医疗装置10包括由多个桥接元件14互连的多个圆柱形区段12。 An expandable medical device 10 includes a plurality of bridging elements interconnecting the plurality 12 of cylindrical section 14. 桥接元件14允许该组织支承装置在穿过脉管系统的曲折路径到达部署点时可以轴向弯曲,并且允许该装置在需要与待支承的腔的曲率相匹配时可以轴向弯曲。 The bridging member may be axially bent to allow the tissue supporting device 14 reaches the point of deployment in the tortuous path through the vasculature, and allow the device when necessary to match the curvature of the cavity can be supported axially bent. 每个圆柱形管12都由细长撑条18构成的网络来形成,细长撑条18由可延展铰链20及环周撑条22互连。 Each cylindrical pipe 12 constituted by an elongated support bar 18 to the network is formed, the elongated struts 18 by the ductile hinges 20 and circumferential struts 22 interconnecting strip. 在医疗装置10扩张期间,可延展铰链20发生变形,而撑条18不发生变形。 During expansion of the medical device 10, the ductile hinges 20 deform while the struts 18 is not deformed. 关于该可扩张医疗装置的一个例子的更多细节在美国专利No.6,241,762中有所描述,将该美国专利以引用的方式全文并入本文。 Further details regarding one example of the expandable medical device are described in U.S. Patent No.6,241,762 in the U.S. patents are incorporated herein by reference in its entirety.

[0036] 如图1中所示,细长撑条18和环周撑条22包括开口30,开口30中的一些包含递送至可扩张医疗装置所植入的腔的有益药剂。 [0036] As shown in FIG. 1, the elongated struts 18 and circumferential struts 22 include openings 30, 30 in some of the beneficial agent delivered to the chamber containing the expandable medical device is implanted in the openings. 另外,如下文关于图5论述的,装置10的其他部分(例如,桥接元件14)也可包括开口。 Additionally, as discussed with respect to Figure 5, other portions of the device (e.g., the bridging element 14) may also include an opening 10. 优选地,开口30设置在装置10的不变形部分(例如,撑条18)中,使得开口不变形且在装置扩张期间递送有益药剂时没有断裂、排出的风险或换句话说没有被损坏的风险。 Preferably, the openings 30 are not deformed portion provided at the device 10 (e.g., struts 18), such that the opening is not deformed, and when the beneficial agent is delivered without fracture during expansion of the device, the risk of not being discharged or otherwise risk of damage . 关于如何可将有益药剂装载在开口30内的方式的一个例子的进一步说明在2001年9月7日提交的美国专利申请系列号09/948,987中有所描述,将该美国专利申请案以引用的方式全文并入本文。 About how beneficial agents can be loaded at further illustrate an example of the way in the opening 30 in the US Patent September 7, 2001 filed application serial number are described in 09 / 948,987, the US patent application by reference in its entirety herein.

[0037]通过使用有限元分析及用于优化有益药剂在开口30内的部署的其他技术,可进一步改良本发明的示例性实施例。 [0037] In other techniques within the deployment opening 30 may be further modified exemplary embodiment of the present invention, by using Finite Element Analysis and Optimization for beneficial agents. 基本上,可改变开口30的形状和位置以使空隙体积最大化, 而同时保持撑条相对于可延展铰链20有相对较高的强度和刚性。 Substantially, the opening 30 may be changed in shape and position to maximize the void volume, while maintaining the struts with respect to the ductile hinge 20 has a relatively high strength and rigidity. 根据本发明的一个优选示例性实施例,开口具有至少5 X 10-6平方英寸的面积,且优选地具有至少7 X 10-6平方英尺的面积。 According to a preferred exemplary embodiment of the present invention, the opening has at least 5 X 10-6 square inches, and preferably at least 7 X 10-6 square feet. 通常,开口填充有约50 %至约95 %的有益药剂。 Typically, the openings are filled about 50% to about 95% of the beneficial agent.

[0038] H [0038] H

[0039] ^文所用,术语"药剂"、"治疗剂"或"有益药剂"旨在具有最广泛的可能的解释意义,且用以包括任何治疗剂或药物以及非活性剂,例如障壁层、载体层、治疗层或保护层。 [0039] ^ As used herein, the term "agent", "therapeutic agent" or "beneficial agent" is intended to have the broadest possible interpretation sense, and is intended to include any therapeutic agent or drug as well as inactive agents such as barrier layers, the carrier layer, therapeutic or protective layers.

[0040] 术语"药物"与"治疗剂"可互换使用,指递送至生物的身体内腔以产生所需的、通常有益的效果的任何治疗活性物质。 [0040] The term "drug" and "therapeutic agent" are used interchangeably to refer to delivery to the organism to produce the desired body lumen, generally any therapeutically active substance beneficial effect. 有益药剂可包括一种或多种药物或治疗剂。 Beneficial agents may include one or more drugs or therapeutic agents.

[0041] 本发明尤其很适用于递送抗肿瘤剂、抗血管形成剂、血管生成因子、抗炎剂、免疫抑制剂(例如雷帕霉素)、抗再狭窄剂、抗血小板剂、血管扩张剂、抗血栓形成剂、抗增殖剂(例如紫杉醇)以及抗凝血酶剂(例如肝素)。 [0041] The present invention is particularly well suited for delivery of anti-tumor agents, anti-angiogenic agents, angiogenic factors, anti-inflammatory agents, immunosuppressive agents (e.g., rapamycin), an anti-restenosis agents, antiplatelet agents, vasodilators , antithrombotic agents, antiproliferative agents (such as paclitaxel) and an anti-thrombin agent (e.g. heparin).

[0042]术语"溶蚀"意指化学过程或物理过程或酶促过程对介质或基质的组分进行生物再吸收和/或降解和/或分解的过程。 [0042] The term "erosion" means a chemical or physical processes or enzymatic processes of the media or matrix component is bioresorbable and / or degrade and / or decomposition process. 例如,对于可生物降解聚合物基质来说,溶蚀可通过裂解或水解聚合物链,由此增加基质和悬浮的有益药剂的可溶性而发生。 For example, a biodegradable polymer matrix, the dissolution can be obtained by cleavage or hydrolysis of the polymer chains, thereby increasing the solubility of the matrix and suspended beneficial agents occurs.

[0043] 术语"溶蚀速率"是溶蚀过程的发生所需要的时间量的度量,通常单位是单位面积/单位时间。 [0043] The term "erosion rate" is a measure of the amount of corrosion occurrence time required for the process, usually the unit is a unit area / unit time.

[0044] 术语"基质"或"可生物再吸收基质"可互换使用,指在植入受试者体内后不会引发足以导致基质排异的有害相应的介质或材料。 [0044] The term "matrix" or "bioresorbable matrix" are used interchangeably to refer to the subject after implantation will not lead to sufficient to result in a corresponding detrimental medium or matrix material rejection. 通常,基质本身并不提供任何治疗响应,但基质可含有或包裹如本文中定义的有益药剂。 Typically, the substrate itself does not provide any therapeutic response, but the matrix may contain or wrap beneficial agent as defined herein. 同时,基质也可以是简单地提供支承、结构完整性或结构障壁层的介质。 At the same time, the matrix may simply provide support, structural integrity or structural dielectric barrier layer. 基质可为聚合物基质、非聚合物基质、疏水性基质、亲水性基质、亲脂性基质、两性分子基质等等。 The matrix may be a polymer matrix, non-polymeric matrices, hydrophobic matrices, hydrophilic matrices, the lipophilic matrix, an amphiphilic matrix and the like. 另外,可生物再吸收基质也应理解为意指随时间推移被身体完全吸收的基质。 In addition, bioresorbable matrix shall also be understood to mean transition matrix is ​​completely absorbed by the body over time.

[0045] 术语"开口"既包括贯穿开口也包括凹陷。 [0045] The term "openings" includes both through openings also comprises a recess.

[0046] 术语"可药用的"指对宿主或患者不具有毒性的特性,并且适用于维持有益药剂的稳定性并且允许有益药剂递送至靶细胞或组织。 [0046] The term "pharmaceutically acceptable" refers to a host or patient does not have toxic properties, and is suitable for maintaining the stability of a beneficial agent and allowing the beneficial agent delivered to a target cell or tissue.

[0047] 术语"聚合物"指由两个或多个称为单体的重复单元化合而形成的分子。 [0047] The term "polymer" refers to a repeating unit of two or more compounds known as monomers to form a molecule. 因此,例如,二聚物、三聚物及低聚物可包含在术语"聚合物"的范围。 Thus, for example, dimers, trimers and oligomers may be included in the scope of the term "polymer". 聚合物可以是合成聚合物、天然存在的聚合物或半合成聚合物。 The polymer may be synthetic polymers, naturally occurring polymers or semisynthetic polymers. 就其优选的形式而言,术语"聚合物"指通常斷大于约3000,优选大于约10,000,且Mw小于约10,000,000,优选小于约1,000,000,更优选小于约200,000的分子。 In terms of its preferred form, the term "polymer" refers generally it is greater than about 3000, preferably greater than about 10,000, and Mw less than about 10,000,000, preferably less than about 1,000,000, more preferably less than about 200,000 molecules. 聚合物的例子包括但不限于:聚-α-羟酸酯,例如,聚乳酸(PLLA或DLPLA)、 聚羟基乙酸、聚乳酸-羟基乙酸共聚物(PLGA)、聚乳酸-己内酯共聚物;环氧乙烷/丙交酯-乙交酯共聚物嵌段聚合物(ΡΕ0-嵌段-PLGA和ΡΕ0-嵌段-PLGA-嵌段-PE0);聚乙二醇及聚氧化乙烯、环氧乙烷/环氧丙烷/环氧乙烷嵌段共聚物;聚乙烯基吡咯烷酮;聚原酸酯;多糖和多糖衍生物,例如,聚透明质酸、聚(葡萄糖)、聚海藻酸、几丁质、壳聚糖、壳聚糖衍生物、纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、环糊精及取代的环糊精,例如,β-环糊精磺丁基醚;多肽及蛋白质,例如,聚赖氨酸、聚谷氨酸、白蛋白;聚酸酐;聚羟基烷酸酯,例如,聚羟基戊酸酯、聚羟基丁酸酯等等。 Examples of polymers include but are not limited to: poly -α- thiol ester, e.g., polylactic acid (PLLA or DLPLA), polyglycolic acid, polylactic acid - glycolic acid copolymer (PLGA), polylactic - caprolactone copolymer ; ethylene oxide / lactide - glycolide copolymer block polymer (ΡΕ0- ΡΕ0- block and block -PLGA -PLGA- block -PE0); polyethylene glycol and polyethylene oxide, ring ethylene oxide / propylene oxide / ethylene oxide block copolymers; polyvinyl pyrrolidone; polyorthoesters; polysaccharides and polysaccharide derivatives, e.g., poly hyaluronic acid, poly (glucose), poly alginic acid, several chitin, chitosan, chitosan derivatives, cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, cyclodextrins and substituted cyclodextrins, e.g. , [beta] -cyclodextrin sulfobutyl ether; polypeptide or protein, e.g., polylysine, polyglutamic acid, albumin; polyanhydrides; polyhydroxyalkanoate, e.g., polyhydroxy valerate, polyhydroxybutyrate esters and so on.

[0048] 关于定向递送的术语"主要地"指提供至血管的治疗剂总量的约50%以上的量在该主要方向上提供。 [0048] The term & about targeted delivery, "primarily" refers to an amount to provide about 50% of the total amount of therapeutic agent provided on the vessel main direction.

[0049] 本文描述的本发明多个示例性实施例在可扩张装置中的不同开口中提供不同的有益药剂,或者在某些开口中提供有益药剂而不在其他的开口中提供有益药剂。 [0049] plurality of different openings present invention described herein in the exemplary embodiment of the expandable device in a different beneficial agents provided in, or provide the beneficial agent in some openings and not in others the beneficial agent provided in the openings. 可扩张医疗装置的具体结构可以有所不同而不脱离本发明的精神。 DETAILED expandable medical device configuration can vary without departing from the spirit of the present invention is different. 由于每个开口是独立填充的,所以可给每个开口内的有益药剂赋予单独的化学成分及药物代谢动力学性质。 Since each opening is filled independently, it is possible to beneficial agent in each opening to impart individual chemical constituents and pharmacokinetic properties.

[0050] 在可扩张医疗装置中的不同开口中使用不同有益药剂或在某些开口中使用有益药剂而不在其他开口中使用有益药剂的一个实例是为了解决边缘效应再狭窄。 One example of different openings in the expandable medical device for use in [0050] the use of different beneficial agent or beneficial agents in some openings and not in other beneficial agent openings is in addressing edge effect restenosis. 如上所论述的,当代的带涂层的支架可能在避免在刚好超出支架边缘的地方发生边缘效应且发展到支架周围并进入内部的腔内空间的再狭窄方面有困难。 As discussed above, the present stent may be coated to avoid edge effects occur and progressing around the stent and into the interior luminal space of the stenosis and then just beyond the edges of the stent difficult.

[0051] 第一代药物递送支架的边缘效应再狭窄的起因目前不是很了解。 [0051] The first generation drug delivery stents edge effect restenosis causes of the current is not very understanding. 可能是,血管成形术和/或支架植入所引起的组织损伤区域延伸到当代有益药剂(例如紫杉醇,其在组织中有着强烈的分区趋势)的扩散范围之外。 May be, area of ​​tissue damage angioplasty and / or stent implantation extends due to the contemporary beneficial agents (such as paclitaxel, which have a strong tendency to partition in the tissue) outside the diffusion range. 放射疗法中一直观察到类似的现象,其中在存在损伤的情况下,支架边缘处的低辐射剂量已证明具有刺激性。 Radiation therapy has been observed a similar phenomenon, which in the presence of damage, low radiation dose at the edge of the bracket has proved an irritant. 在该种情况下,在更长长度上照射直至未损伤组织受到照射,就解决了该问题。 In this case, over a longer length until uninjured tissue is irradiated with light, to solve the problem. 在药物递送支架的情况下,沿支架边缘放置较高剂量的或较高浓度的有益药剂、在支架边缘处放置更易于扩散穿过组织的不同药剂或在装置的边缘处放置不同的有益药剂或有益药剂的组合,可帮助弥补边缘效应再狭窄的问题。 In the case of drug delivery stents, placing higher doses of beneficial agents along the stent edges or higher concentrations, placing different agents diffuse more readily through the tissue at the edge of a stent or placing different beneficial agents at the edges of the device or a combination of beneficial agents, can help make up for the edge effect restenosis problem.

[0052]图1示出了具有"热端",或在装置末端处的开口30a内提供有益药剂以便治疗和减小边缘效应再狭窄的可扩张医疗装置10。 [0052] FIG. 1 shows a "hot ends" or beneficial agent provided in the openings 30a at the ends of the device in order to treat and reduce edge effect restenosis may be expandable medical device 10. 该装置中央部分内的其余开口30b可为空的(如所示),或可装有较低浓度的有益药剂。 Remaining openings 30b may be empty in the central portion of the device (as shown), or beneficial agent may contain a lower concentration.

[0053]边缘效应再狭窄的其他机理可能牵涉具体药物或药物组合的细胞毒性。 [0053] Other mechanisms of edge effect restenosis may involve cytotoxicity of particular drugs or combinations of drugs. 这些机理可包括类似于表皮疤痕组织形成中所看到的组织的物理收缩或机械收缩,而支架可在其自身边界内防止该收缩性反应,但不能防止超出其边缘外的收缩性反应。 These mechanisms may include similar epidermal scar tissue seen in a physical or mechanical contraction of tissue contraction, and the stent may prevent the contractile response within its own boundaries, but can not prevent the contractile response beyond the outer edge thereof. 此外,后一种形式的再狭窄的机理可能涉及持续或局部药物递送至动脉壁的后遗症,该递送甚至在该壁内不再存在药物之后仍然明显。 In addition, the mechanism of restenosis may involve latter form of sustained or local drug delivery to the arterial wall sequelae, even after the delivery is still in the wall drug is no longer significant. 即,再狭窄可能是对一种与药物和/或药物障壁层有关的有毒性损伤的反应。 That is, the restenosis may be a response to toxic damage one kind of drug and / or drug-related barrier layer. 在这种情况下,装置的边缘不包含某些药剂可能是有益的。 In this case, the edge device does not include certain agents may be beneficial.

[0054]图2示出了可扩张医疗装置200的备选示例性实施例,其具有多个开口230,其中该装置中央部分中的开口230b填有有益药剂,而装置边缘处的开口230a保持为空。 [0054] FIG. 2 shows an alternative exemplary embodiment of an expandable medical device 200 having a plurality of openings 230, in which the openings 230b in a central portion of the device filled with a beneficial agent and the openings 230a at the edges of the holding device Is empty. 图2的装置称为具有"冷端"。 Apparatus of FIG. 2 is referred to as having "cool ends."

[0055]除了用于减少边缘效应再狭窄以外,当必须为初期支架植入手术补充另外的支架时,图2的可扩张医疗装置200还可与图1的可扩张医疗装置10或另一个药物递送支架结合使用。 [0055] In addition to reducing the edge effect restenosis outside, it must be added when an additional stent initial stent implantation, FIG. 2 of an expandable medical device 200 may be an expandable medical device 10 of FIG. 1 or the other drugs using a delivery scaffold binding. 例如,在一些情况下,图1具有"热端"的装置10或药物均匀分布的装置可能会被不当地植入。 For example, in some cases, the apparatus of FIG 1 having a uniform distribution of the "hot end" of a drug or device 10 may be implanted improperly. 如果内科医生确定该装置并未覆盖腔的足够部分,可在现有装置的一端处添加一个与现有装置稍微重叠的补充装置。 If the physician determines that the device does not cover a sufficient portion of the chamber, means to add a supplement conventional device and slightly overlapping the existing device at one end. 当植入补充装置时,就使用图2的装置200,从而让医疗装置200的"7令端"防止有益药剂在装置10、200的重叠部分处的剂量加倍。 When the supplemental device is implanted, the device 200 on FIG. 2, the medical device 200 so that "end to make 7" to prevent doubling of the dose of the beneficial agent at the overlapping portions 10, 200 of the apparatus.

[0056]图3示出了本发明另一备选的示例性实施例,其中不同的有益药剂设置在可扩张医疗装置300的不同孔口内。 [0056] FIG 3 illustrates an exemplary embodiment of another alternative embodiment of the present invention, wherein the different apertures of different beneficial agents provided in the expandable medical device 300. 第一有益药剂设置在该装置末端处的孔口330a内,而第二有益药剂设置在装置中央部分处的孔330b内。 The first beneficial agent disposed within the aperture 330a at the ends of the apparatus and a second beneficial agent is provided in the hole 330b at a central portion of the device. 有益药剂可包含不同的药物、不同浓度的同种药物或同种药物的不同变型形式。 Beneficial agent may contain different drugs, the same drugs in different concentrations of the same drug or different variations. 图3的示例性实施例可用于提供具有"热端"的"冷端"的可扩张医疗装置300。 FIG 3 is an exemplary embodiment may be used to provide a "hot end" of the "cold end" of an expandable medical device 300.

[0057]优选地,装置300的包括含有第一有益药剂的孔口330a的每个端部都从边缘延伸至少一个孔且最多约15个孔的距离。 [0057] Preferably, each device 300 includes a first end portion comprises an orifice 330a of the beneficial agent extends at least one hole and a distance from the edge up to about 15 holes. 该距离对应于距未扩张装置的边缘约0.005至约0.1英寸。 This distance corresponds to the edge of an unexpanded device from about 0.005 to about 0.1 inches. 距装置300的包含第一有益药剂的边缘的距离优选为约为1个区段,其中区段是在桥接元件之间限定。 Distances beneficial agent comprising a first edge device 300 is preferably about one section, where a section is defined between the bridging elements.

[0058] 可将包含不同药物的不同有益药剂设置在支架中不同的开口内。 Different beneficial agents [0058] may be provided comprising different drugs in different openings in the stent. 这允许以任何所需的递送方式从单个支架递送两种或更多种有益药剂。 This allows any desired delivery means delivery of two or more beneficial agents from a single stent. 作为另一种选择,可将包含不同浓度的同种药物的不同有益药剂设置在不同的开口内。 Different beneficial agents as an alternative, may comprise different concentrations of the same drug disposed in different openings. 这允许药物均匀地分布至具有非均匀装置结构的组织。 This allows a uniform distribution of the drug to the tissue having a non-uniform device structure.

[0059] 设置在本文所述装置内的两种或更多种不同的有益药剂可包括:(1)不同的药物; (2)不同浓度的同种药物;(3)具有不同释放动力学(即,不同基质溶蚀速率)的同种药物;或(4)不同形式的同种药物。 Two or more different beneficial agents [0059] disposed within the devices described herein may include: (1) different drugs; (2) different concentrations of the same drug; (3) with different release kinetics ( i.e., different matrix erosion rates) of the same drug; or (4) different forms of the same drug. 包含具有不同释放动力学的同种药物的不同有益药剂的实例可使用不同的载体来实现不同形状的洗脱曲线。 Examples of different beneficial agents comprising the same drug with different release kinetics may be achieved in the elution profiles of different shapes using different carriers. 不同形式的同种药物的一些例子包括亲水性或亲脂性不同的药物形式。 Some examples of different forms of the same drug include hydrophilic or lipophilic different pharmaceutical forms.

[0060] 在图3的装置300的一个实例中,装置末端处的孔330a装载有包含高亲脂性药物的第一有益药剂,而装置中央部分处的孔330b装载有包含低亲脂性药物的第二有益药剂。 [0060] In one example of the device 300 of Figure 3, the apertures at the ends of the device 330a is loaded comprising a first beneficial agent highly lipophilic drugs, and the holes central device portion at 330b is loaded comprising a first low-lipophilic drug two beneficial agents. "热端"处的第一高亲脂性有益药剂将更容易扩散进入周边组织,从而减少边缘效应再狭窄。 The first high lipophilicity beneficial agent at the "hot ends" will diffuse more readily into the surrounding tissue reducing the edge effect restenosis.

[0061] 装置300可具有有益药剂从第一药剂转变成第二药剂的突变线。 [0061] The device 300 may have the beneficial agent from a first agent to a second agent mutant line. 例如,装置端部〇. 05英寸内的全部开口可包含第一药剂,而其余开口包含第二药剂。 For example, the device end portion billion. All the openings may comprise a first agent within 05 inches, while the remaining openings comprise the second agent. 作为另一种选择,装置可在第一药剂与第二药剂之间具有逐级过渡。 Alternatively, the device may have a gradual transition between the first agent and the second agent. 例如,开口内的药物浓度可朝向装置的端部逐渐地增加(或)降低。 For example, the concentration of the drug toward the opening end portion of the device may be gradually increased (or) decreases. 在另一实例中,在朝装置端部移动时,开口内第一药物的量增大,而开口内第二药物的量减少。 In another example, when the moving means moves the end portion, the opening amount of the first drug increases, the amount of opening of the second medicament is reduced.

[0062] 图4示出了可扩张医疗装置400的另一备选的示例性实施例,其中不同的有益药剂以交替或散布的方式设置在装置中的不同开口430a、430b内。 Different openings embodiment [0062] FIG. 4 illustrates another alternate exemplary embodiment of an expandable medical device 400 in which different beneficial agents provided in an alternating or interspersed in the device 430a, 430b within. 以此方式,可将多种有益药剂递送至装置所支承的整个区域或一部分区域上方的组织。 In this manner, multiple beneficial agents may be delivered to the entire area of ​​the support means or tissue over a partial region. 在由于有益药剂间的相互作用或稳定性问题使得多种药剂组合成装载于装置内的单种组成物不可行的情况下,该示例性实施例可用于递送多种有益药剂。 Due to interactions or stability problems between the beneficial agents such that the combination of multiple agents in the case of the loading apparatus into a single composition infeasible, this exemplary embodiment may be used to deliver a variety of beneficial agents.

[0063] 除了在不同开口内使用不同的有益药剂以在组织的不同限定区域实现不同的药物浓度之外,还可在不同开口内装载不同的有益药剂,用于在可扩张医疗装置处于扩张构造时具有非均匀开口分布的情况下,使有益药剂的空间分布更为均匀。 [0063] In addition to the different defined areas of tissue to achieve different drug concentrations in the use of different beneficial agents in different openings, they can also loading of different beneficial agents in different openings may be configured for expanding the expandable medical device is a case where an opening having a non-uniform distribution of the spatial distribution of the beneficial agent more uniform. 在不同开口内以散布或交替方式使用不同的药物可允许递送如果在同种聚合物/药物基质组成物内组合则无法递送的两种不同药物。 In different openings in an interspersed or alternating manner allows the use of different drugs may deliver two different drugs within the composition if the composition in the same polymer / drug matrix composition can not be delivered. 例如,药物自身可能会以不期望的方式相互作用。 For example, the drugs themselves may interact in an undesirable manner. 或者,两种药物可能与形成基质的同种聚合物不相容或与递送聚合物/药物基质进入开口的同种溶剂不相容。 Alternatively, the two drugs may not be compatible with the delivery solvent or isotype polymer / drug matrix into the openings formed in the same polymer incompatible with the matrix.

[0064] 此外,图4的以散布的布置方式在不同开口内具有不同药物的示例性实施例使得能够从同个医疗装置或支架递送具有十分不同的所需释放动力学的不同药物,并能能够根据单独药剂的作用机理和性质来优化释放动力学。 [0064] Further, the exemplary embodiment in a spread arrangement having different drugs in different openings in FIG. 4 embodiment enables delivery has a very different desired release kinetics from the same drugs in different medical device or stent, and can the release kinetics can be optimized action mechanism and properties of the individual agents. 例如,药剂的水溶性可极大地影响药剂从聚合物基质或其他基质的释放。 For example, the water-soluble agent greatly affects the release of the agent from the polymer matrix or other matrix. 一般来讲,高水溶性化合物将会很快从聚合物基质递送出来,而亲脂性药剂从相同基质递送出来的时间周期较长。 Generally, highly water soluble compound will be delivered very quickly from a polymer matrix, and the lipophilic agent will be delivered over a longer time period from the same matrix. 因此,如果亲水性药剂和亲脂性药剂要作为双种药物组合从医疗装置递送,则难以针对从相同聚合物基质递送的这两种药剂实现所希望的释放曲线。 Thus, if a hydrophilic agent and a lipophilic agent are to be delivered as a dual drug combination from a medical device, it is difficult to achieve for these two agents delivered from the same polymer matrix the desired release profile.

[0065] 图4的系统允许容易地从同一支架递送亲水性和亲脂性药物。 [0065] The system of Figure 4 allows the delivery of a hydrophilic and a lipophilic drug from the same stent. 此外,图4的系统允许以两种不同的释放动力学和/或给药周期来递送两种药剂。 Further, the system of Figure 4 allows two different release kinetics and / or administration periods to deliver both agents. 可对该两种药物在开始的24 小时内的初始释放、开始的24小时后的释放速率、总给药周期以及任何其他释放特性中的每一者进行独立控制。 Each of the initial release of the two drugs in the first 24 hours, the release rate after the first 24 hours, the total administration period and any other characteristics of the release is controlled independently. 例如,可将第一有益药剂的释放速率设计为:在开始的24小时内递送药物的至少40% (优选至少50%),而可将第二有益药剂设计为:在开始的24小时内递送药物的至少20% (优选少于10% )。 For example, the release rate of the first beneficial agent can be designed to: deliver the drug at least 40% within the first 24 hours (preferably at least 50%), while the second beneficial agent may be designed to: deliver in the first 24 hours at least 20% of the drug (preferably less than 10%). 第一有益药剂的给药周期可为约三个星期或更少(优选两个星期或更少),而第二有益药剂的给药周期可为约四个星期或更长。 The administration period of the first beneficial agent may be about three weeks or less (preferably two weeks or less), and the administration period of the second beneficial agent may be about four weeks or longer.

[0066] 介入后的再狭窄或阻塞复发涉及生物过程的组合或一系列生物过程。 [0066] The recurrence of stenosis or occlusion of a combination of biological processes involving re-intervention or after a series of biological processes. 这些过程包括血小板和巨噬细胞的激活。 These processes include the activation of platelets and macrophages. 细胞因子和生长因子有助于平滑肌细胞增生,基因和金属蛋白酶的上调导致细胞生长、细胞外基质重塑以及平滑肌细胞迀移。 Cytokines and growth factors contribute to smooth muscle cell proliferation, gene regulation, and metalloproteinases lead to cell growth, remodeling of extracellular matrix, and smooth muscle cell shift Gan. 最为成功的抗再狭窄疗法可能是通过药物组合来解决多个这些过程的药物疗法。 The most successful anti-restenosis therapy, drug therapy may be used to solve more of these processes by drug combinations. 本发明提供一种实现这样一种成功的组合药物疗法的装置。 The present invention provides an apparatus for such a successful combination drug therapy is achieved.

[0067] 下文论述的实例示出了可得益于在不同孔或开口中释放不同药物的能力的一些组合药物系统。 Examples [0067] discussed below illustrate some systems may benefit from combination drug release different drugs in different holes or openings in capacity. 用于从散布的或交替的孔递送两种药物的有益系统的一个实例是递送抗炎剂或免疫抑制药剂与抗增殖剂或抗迀移药剂的组合。 One example of a beneficial system for delivering two drugs from interspersed or alternating holes is the delivery of anti-inflammatory or immunosuppressive agent or antiproliferative agent, an anti-shift Gan combination of agents. 还可使用这些药剂的其他组合来靶向涉及再狭窄的多个生物过程。 Other combinations of these agents may also be used to target restenosis involves multiple biological processes. 抗炎剂缓和了脉管对血管成形术及支架植入的初始炎症应答,并且在约两周的时间周期内先是以高速率递送,继而较慢地递送,以匹配刺激炎症应答的巨噬细胞发育高峰。 Anti-inflammatory agents to ease the vascular angioplasty and stenting of the initial inflammatory response, first at a high rate and delivery time period of about two weeks, and then slowly delivered, to match the inflammatory response stimulate macrophages development of peak. 抗增殖剂在更长的时间周期内以相对平稳的速率递送,以减少平滑肌细胞的迀移和增生。 Antiproliferative agent delivered at a relatively steady rate over a longer time period to reduce smooth muscle cell migration and Gan proliferation.

[0068] 除了下文给出的实例外,下表还示出了一些可用的两种药物组合疗法,可通过将药物置于医疗装置中的不同开口来实现这些疗法。 [0068] In addition to the examples given below, the following table also shows some of the available two drugs in combination therapy, by placing the drugs into different openings in the medical device to implement these therapies.

[0069] [0069]

Figure CN101744676BD00121

[0070] 无论药物是亲水性药物还是亲脂性药物,将药物放入不同开口都允许针对具体药剂来定制释放动力学。 [0070] Whether the drug is a hydrophilic drug or a lipophilic drug, drugs into different openings are allowed to be customized for a particular drug release kinetics. 以基本恒定或线性释放速率递送亲脂性药物的一些设计的例子在2004年12月23日公布的W0 04/110302中有所描述,将该文献以引用的方式全文并入本文。 Some examples of design at a substantially constant or linear release rate of delivery of lipophilic drugs are described in W0 04/110302 in December 23, 2004 published the document in its entirety by reference herein. 递送亲水性药物的一些设计的例子在2004年5月27日公布的W0 04/043510中有所描述,将该文献以引用的方式全文并入本文。 Examples of some of the delivery of hydrophilic drug are described in W0 04/043510 in May 27, 2004 published the documents by reference are incorporated herein. 上面列出的亲水性药物包括:CdA、格列卫、VIP、胰岛素和ApoA-lmilano。 Hydrophilic drugs listed above include: CdA, Gleevec, VIP, insulin, and ApoA-lmilano. 上面列出的亲脂性药物包括:紫杉醇、埃博霉素D、雷帕霉素、吡美莫司、 PKC-412和地塞米松。 The lipophilic drugs listed above include: paclitaxel, Epothilone D, rapamycin, pimecrolimus, PKC-412 and dexamethasone. 法格立他扎为部分亲脂性的而部分亲水性的。 Method Farglitazar partially lipophilic pro partially hydrophilic.

[0071] 除了递送多种药物来解决再狭窄中牵涉的不同生物过程,本发明还可从同一支架递送两种不同的药物来治疗不同的疾病。 [0071] In addition to the delivery of multiple drugs to address different biological processes involved in restenosis, the present invention may also be used to treat different diseases delivery of two different drugs from the same stent. 例如,支架可从一组开口递送抗增殖剂(例如紫杉醇或1 imus药物)来治疗再狭窄,而同时从其他开口递送心肌保护药物(例如胰岛素)来治疗急性心肌梗塞。 For example, the stent may be treated restenosis delivery openings from the group antiproliferative agents (e.g. paclitaxel or 1 imus drug), while from the other opening of the delivery cardioprotective medicament (e.g. insulin) for the treatment of acute myocardial infarction.

[0072] 在许多已知的可扩张装置中,并且对于图5所示的装置而言,装置500在圆柱形管状部分512处的覆盖度大于在桥接元件514处的覆盖度。 [0072] In many known expandable devices and for the device shown in FIG 5, means 500 coverage coverage cylindrical tubular portion 512 is greater than in the bridging element 514. 覆盖度被定义为装置表面积与装置所部署在其内的腔的面积之比。 It means the specific surface area coverage of the device is deployed in the area of ​​the inner cavity defined. 当使用覆盖度不均匀的装置来递送装置开口中所包含的有益药剂时,递送至邻近圆柱管状部分512的组织的有益药剂浓度大于递送至邻近桥接元件514的组织的有益药剂浓度。 When using a device with varying coverage is used to deliver a beneficial agent contained in openings in the device, the beneficial agent concentration delivered to the tissue adjacent the cylindrical tubular portion 512 is greater than the beneficial agent concentration delivered to the tissue adjacent the bridging elements 514. 为了解决在装置结构纵向上的差异以及装置覆盖度方面的其他差异,这些差异会导致有益药剂递送浓度不均匀,可改变装置多个部分处的开口中的有益药剂的浓度,以实现有益药剂在整个组织分布更均匀。 In order to solve differences and other differences coverage means the longitudinal direction of the device in terms of structure, these differences will lead to uneven beneficial agent delivery concentrations, the concentration of beneficial agent in the openings at portions of the plurality of apparatus may be varied to achieve the beneficial agent more evenly distributed throughout the organization. 就图5中所示的示例性实施例而言,管状部分512中的开口530a包含的有益药剂的药物浓度低于桥接元件514中的开口530b 的药物浓度。 To the exemplary embodiment illustrated in FIG. 5, the drug concentration in the opening 530a of the tubular portion 512 of the beneficial agent contained in the drug concentration is lower than the opening 530b in the bridging elements 514. 可以采用多种方式来实现药剂递送的均匀性,包括改变药物浓度、改变开口直径或形状、改变开口内的药剂量(即,开口的填充百分比)、改变基质材料或改变药物的形式。 It may be implemented uniformity of agent delivery, including changing the drug concentration, the opening diameter or shape change, dose (i.e., the percentage of the opening filled) within the opening to change, alter or change the form of the drug matrix material using a variety of ways.

[0073] 在不同开口中使用不同有益药剂的另一应用实例是图6中所示的构造成用于在脉管分叉处使用的可扩张医疗装置600。 Another application example [0073] The use of different beneficial agents in different openings is in the configuration shown in FIG. 6 as an expandable medical device 600 for use in a vessel bifurcation. 分叉装置包括定位成允许血流流过侧枝脉管的侧孔610。 It comprises a bifurcated device positioned to allow blood to flow through the side hole 610 of the side branch vessel. 分叉装置的一个例子在美国专利No.6,293,967中有所描述,将该专利以引用的方式全文并入本文。 One example of a bifurcation device is described in U.S. Patent No.6,293,967 in the patent is herein incorporated by reference in its entirety. 分叉装置600包括侧孔结构610,侧孔结构610中断了形成装置其余部分的横条的规则图案。 Bifurcation device 600 includes the side hole feature 610, side hole feature 610 interrupting the regular pattern of the rest of the bar forming apparatus. 由于分叉周围的区域是再狭窄特别严重的区域,所以可增加装置600的侧孔610周围区域处开口830a中的抗增殖药物的浓度,以在需要的地方递送增高浓度的药物。 Since the crotch region particularly around restenosis serious region, the apparatus can be increased in the anti-830a at a region around the opening of the side hole 610,600 proliferation concentration of the drug to deliver increased concentrations of the drug where needed. 剩余的远离侧面开口的区域中的开口630b装有的有益药剂具有较低的抗增殖浓度。 Beneficial agent openings 630b away from the remaining area of ​​the side opening equipped with a lower concentration of the antiproliferative. 可通过含有不同药物的不同有益药剂或者通过含有较高浓度的同一药物的不同有益药剂来提供递送至分叉孔周围区域的增加的抗增殖剂。 It may be provided or delivered to the area around the hole of the bifurcation increased antiproliferative different beneficial agents comprising the same drug in different concentrations higher beneficial agents comprising different drugs.

[0074] 除了将不同有益药剂递送至可扩张医疗装置的腔壁侧或腔外侧来治疗脉管壁以外,还可将有益药剂递送至可扩张医疗装置的腔内侧以防止或减少血栓。 [0074] In addition to the delivery of different beneficial agents to the mural or abluminal side of the expandable medical device for treating vessel wall other than the beneficial agent may also be delivered to the luminal side of the expandable medical device to prevent or reduce thrombosis. 从装置的腔内侧送入血流的药物可位于装置近端或装置远端。 It means proximal or distal blood flow from the cavity means into a pharmaceutical may be located inside the device.

[0075] 用于将不同有益药剂装载到可扩张医疗装置中不同开口内的方法可包括诸如浸渍和涂覆之类的已知技术以及已知的压电微喷射技术。 [0075] means for loading different beneficial agents to an expandable medical device in different openings in the method may include known techniques such as dipping and coating and the like known piezoelectric micro-jetting technique. 可以已知的方式,通过计算机来控制微喷射装置来将精确量的两种或更多种液体有益药剂递送至可扩张医疗装置上的精确位置。 A known manner, controlled by computer means microprojection precise amounts of two or more liquid beneficial agents may be delivered to a precise location on the expandable medical device. 例如,双药剂喷射装置可将两种药剂同时或依次递送进开口内。 For example, a dual agent jetting device may deliver two agents simultaneously or sequentially into the openings. 当将有益药剂装载到可扩张医疗装置内的通孔中时,可在装载期间通过弹性芯棒来阻挡通孔的腔内侧,从而允许以液体的形式来递送有益药剂(例如,与溶剂一同递送)。 When the beneficial agents may be loaded into the through hole when the expandable medical device, a luminal side of the barrier may be a through hole during loading by a resilient mandrel allowing the liquid form to deliver beneficial agents (e.g., together with a solvent delivery ). 也可通过人工注射装置来装载有益药剂。 Beneficial agents may also be loaded by manual injection devices.

[0076] 实例1 [0076] Example 1

[0077] 图7图示了双药物支架700,其具有从支架的不同孔口递送的抗炎剂和抗增殖剂, 以使该两种药物具有特定设计成与再狭窄生物过程相匹配的独立的释放动力学。 [0077] FIG 7 illustrates a dual drug stent 700 having delivered from different holes in the stent an anti-inflammatory agent and an antiproliferative agent, to separate the two drugs which are specifically programmed to have the biological processes of restenosis match the release kinetics. 根据该实例,双药物支架包含第一组开口710中的抗炎剂吡美莫司和第二组开口720中的抗增殖剂紫杉醇的组合。 According to this example, the dual drug stent comprising a combination of a first group of anti-inflammatory agents 710. US-pyrazol limus second set of openings and the antiproliferative agent paclitaxel in the opening 720. 每种药剂以特定的布置方式设置在支架孔内的基质材料中,该布置方式设计成可实现图8所示的释放动力学。 Each agent is provided in a specific arrangement of support holes in the matrix material, the arrangement designed to achieve the release kinetics shown in Figure 8. 每种药物都主要沿腔壁递送壁,以治疗再狭窄。 Each drug delivery cavity wall along the main wall, to treat restenosis.

[0078] 如图7所示,通过在孔的腔内侧使用障壁层712,将吡美莫司设置在支架中用于定向递送至支架的腔壁侧。 [0078] As shown in FIG 7, a barrier layer by using the side of the hole in the cavity 712, the pimecrolimus is provided for targeted delivery to the mural side of the stent in the stent. 障壁层712由可生物降解聚合物形成。 Barrier layer 712 is formed by a bio-degradable polymer. 吡美莫司以可产生具有两个阶段的释放动力学的方式装载在孔口内。 Pimecrolimus manner to produce two phases can release kinetics is loaded within the holes. 吡美莫司的第一释放阶段由基质位于腔壁侧的区域716来提供,该阶段具有包括吡美莫司和可生物降解聚合物(PLGA)的快速释放制剂,该制剂具有高的药物百分比,例如,约90%的药物:约10 %的聚合物。 The first phase of the pimecrolimus release of the cavity wall located by the side areas of the substrate 716 is provided, which has a fast release formulation phase comprising pimecrolimus and biodegradable polymer (PLGA), which pharmaceutical formulation has a high percentage of , e.g., about 90% of the drug: about 10% polymer. 第二释放阶段由基质的中央区域714来提供,其中吡美莫司与可生物降解聚合物(PLGA)之比为约50%的药物:50%的聚合物。 The second release stage is provided by a central region of the substrate 714, wherein pimecrolimus and biodegradable polymer (PLGA) ratio of about 50% of the drug: 50% polymer. 如图8曲线上所见,吡美莫司的第一释放阶段在约开始的24小时内递送约50%的装载药物。 Curve seen in FIG. 8, the first phase of the pimecrolimus release delivers about 50% of the loaded drug in about the first 24 hours. 第二释放阶段是在约两周内递送其余的50%。 The second stage is released in about two weeks to deliver the remaining 50%. 这种释放被特定地设计成与血管成形术和支架植入后炎性过程的进展相匹配。 This release is specifically programmed with the progress of the inflammatory process following angioplasty and stenting match. 除了改变两个区域间的药物浓度来实现两阶段式释放外或作为该方法的另一种选择,可在两种药物的不同区域中使用不同的聚合物或共聚单体比例不同的相同聚合物来实现两种不同的释放速率。 In addition to changing the drug concentration between the two regions to achieve the two phase release, or as an alternative to an outer of the method, different polymers or different comonomer ratio in different regions of the same polymer in both drugs to achieve the two different release rates.

[0079] 如图8中所示,紫杉醇以可产生这样的释放动力学的方式装载在开口720内:在大约开始的24小时后具有基本线性的释放。 [0079] As shown in FIG. 8, paclitaxel can be produced in a manner such release kinetics of 720 loaded in the opening: a substantially linear release after 24 hours is about to start. 紫杉醇开口720是以如下三个区域进行装载:底部区域722,其中主要是聚合物并在孔的腔内侧带有最少量的药物;中间区域724,其中紫杉醇和聚合物(PLGA)以浓度梯度提供;以及顶盖区域726,其中主要是控制紫杉醇释放的聚合物。 Paclitaxel openings 720 are loaded with three regions as follows: a bottom region 722 of primarily polymer and with a minimum amount of drug at a luminal side of the hole; intermediate region 724, wherein paclitaxel and polymer (PLGA) provided in a concentration gradient ; region 726 and a top cover, wherein the polymer is mainly controlled release of the paclitaxel. 紫杉醇是这样释放:第一日的初始释放为总药物装载量的约5%至约15%,继而基本线性地释放约20日至90日。 Paclitaxel is released: the first day of the initial release of about 5% to about 15% of the total drug load, in turn, substantially linear release of about 20 to 90 days. 关于紫杉醇在孔内以浓度梯度方式布置的另外的例子在上述W0 04/110302中有所描述。 About paclitaxel in the above described in W0 04/110302 Additional examples of aperture arranged in a concentration gradient.

[0080] 为便于说明,图7将药物区域、障壁区域和顶盖区域图示成在开口内层次分明的区域。 [0080] For convenience of explanation, FIG. 7 the drug, barrier, and cap regions as illustrated as an opening in the region structured. 应理解,这些区域并非层次分明而是不同区域混合而成。 It should be understood that these regions indistinct and mixing of the different areas. 因此,尽管障壁层主要是不带药物的聚合物,但取决于所采用的制造工艺,后续区域的一些少量药物可能会掺入该障壁区域中。 Thus, although the barrier layers are primarily polymer without drug, but some small amount of drug manufacture process, dependent on the subsequent region can be incorporation into the barrier region.

[0081] 取决于支架尺寸,所递送的药物的量会有所不同。 [0081] depends on the size of the stent, the amount of drug delivered will vary. 对于3mmX6mm的支架来说,吡美莫司的量为约50微克至约300微克,优选约100微克至约250微克。 For 3mmX6mm stent, the amount of pimecrolimus is about 50 micrograms to about 300 micrograms, preferably from about 100 micrograms to about 250 micrograms. 从该支架递送的紫杉醇的量为约5微克至约50微克,优选约10微克至约30微克。 The amount of paclitaxel delivered from this stent is about 5 micrograms to about 50 micrograms, preferably from about 10 micrograms to about 30 micrograms. 在一个实例中,递送约200微克的吡美莫司和约20微克的紫杉醇。 In one instance, delivering about 200 micrograms of pimecrolimus and about 20 micrograms of paclitaxel. 可使这些药物位于支架交替的孔内。 Drugs may be located in alternating holes in the stent. 然而,鉴于这两种药物之间待递送剂量的巨大差距,可能有利的是在支架中每三个或四个孔中放入紫杉醇。 However, given the large gap between the dose to be delivered two drugs, it may be advantageous to place the paclitaxel in every three or four holder bore. 作为另一种选择,可将用于递送低剂量药物(紫杉醇)的孔制成小于高剂量的孔。 Alternatively, the hole may be used to deliver low doses (paclitaxel) is made smaller than the high dose of the hole.

[0082] 嵌入的聚合物/药物是通过于2004年4月1日公布的W0 04/026182中所描述的计算机控制压电注射技术来形成,将该文献以引用的方式全文并入本文。 [0082] The embedded polymer / drug is formed by computer controlled piezoelectric injection techniques as described in W0 04/026182, 2004 published on April 1, which is hereby incorporated by reference herein. 可使用压电注射器首先形成嵌入的第一药剂,继而形成嵌入的第二药剂。 It may be formed using the piezoelectric injector is first embedded in the first agent, second agent and then forming an embedded. 作为另一种选择,可为W0 04/02182的系统配备双压电分配器,以便同时分配两种药剂。 Alternatively, the dispenser may be equipped with dual piezoelectric system as W0 04/02182, for dispensing the two agents at the same time.

[0083]实例2 [0083] Example 2

[0084]根据该实例,双药物支架包含第一组开口710中的格列卫与第二组开口720中的抗增殖剂紫杉醇的组合。 [0084] According to this example, the dual drug stent comprising a first set of openings 710 in combination with Gleevec second set of openings in the antiproliferative agent paclitaxel 720. 每种药剂都以特定的嵌入布置方式设置在支架孔口内的基质材料中,该布置方式设计成可实现图8所示的释放动力学。 Each agent is embedded in a particular arrangement is provided in a matrix material within the holes of the stent, the arrangement designed to achieve the release kinetics shown in Figure 8.

[0085]以具有两个阶段的释放来递送格列卫,包括在第一日初始高速释放和随后缓慢释放1周至2周。 [0085] In a two phase release with Gleevec is delivered, including slow release and subsequent release of a high-speed one to two weeks in a first initial day. 格列卫释放的第一阶段是在约开始的24小时内递送约50%的装载药物。 The first phase of the Gleevec release delivers about 50% of the loaded drug in about the first 24 hours. 释放的第二阶段是在约1-2周内递送其余的50%。 The second stage of release is delivered in about 1-2 weeks, the remaining 50%. 如图8中所示并且如以上实例1中所述的,将紫杉醇装载在开口720内,装载的方式使得产生的释放动力学在大约开始的24小时后为基本线性释放。 As shown in Figure 8 and described in Example 1 above, the paclitaxel is loaded within the openings 720, the load generated in a manner such that the release kinetics of release is substantially linear at about 24 hours after the start.

[0086] 取决于支架尺寸,所递送的药物的量会有所不同。 [0086] depends on the size of the stent, the amount of drug delivered will vary. 对于3mmX6mm的支架来说,格列卫的量为约200微克至约500微克,优选约300微克至约400微克。 For 3mmX6mm stent, the amount of Gleevec is about 200 micrograms to about 500 micrograms, preferably from about 300 micrograms to about 400 micrograms. 从该支架递送的紫杉醇的量为约5微克至约50微克,优选约10微克至约30微克。 The amount of paclitaxel delivered from this stent is about 5 micrograms to about 50 micrograms, preferably from about 10 micrograms to about 30 micrograms. 如在实例1中,可使这些药物位于支架中交替的孔内,或以非交替的方式散布。 As in Example 1, the drugs may be located in alternating holes in the stent or interspersed in a non-alternating manner. 嵌入的聚合物/药物以实例1中所述的方式形成。 Embedded polymer / drug is formed in the manner described in Example 1.

[0087] 实例3 [0087] Example 3

[0088]根据该实例,双药物支架包含第一组开口中的PKC_412(细胞生长调节剂)和第二组开口中的抗增殖剂紫杉醇的组合。 [0088] According to this example, the dual drug stent comprising a combination of a first set of openings PKC_412 (cell growth regulator) and the antiproliferative agent paclitaxel in the second set of openings. 每种药剂都以特定的嵌入布置方式设置在支架孔口内的基质材料中,该布置方式被设计成可实现如下所述的释放动力学。 Each agent is embedded in a particular arrangement is provided in a matrix material within the holes of the stent, which arrangement is designed to achieve the release kinetics discussed below.

[0089] PKC-412在约开始的24小时之后以基本恒定的释放速率递送,释放周期为约4周至16周,优选6周至12周。 [0089] PKC-412 at a substantially constant release rate after delivery of about 24 hours, with the release period of about 4-16 weeks, preferably 6-12 weeks. 将紫杉醇装载在开口内,装载的方式使得产生的释放动力学在大约开始的24小时之后具有基本线性的释放,释放周期为约4周至16周,优选约6周至12周。 The paclitaxel is loaded within the openings, in such a way that the loading creates a release kinetic having a substantially linear release after about 24 hours, with the release period of about four to sixteen weeks, preferably about six to twelve weeks.

[0090] 取决于支架尺寸,所递送的药物的量会有所不同。 [0090] depends on the size of the stent, the amount of drug delivered will vary. 对于3mmX6mm的支架来说,PKC-412的量为约100微克至约400微克,优选约150微克至约250微克。 For 3mmX6mm stent, the amount of PKC-412 is about 100 micrograms to about 400 micrograms, preferably from about 150 micrograms to about 250 micrograms. 从该支架递送的紫杉醇的量为约5微克至约50微克,优选约10微克至约30微克。 The amount of paclitaxel delivered from this stent is about 5 micrograms to about 50 micrograms, preferably from about 10 micrograms to about 30 micrograms. 如在实例1中,可使这些药物位于支架中交替的孔内,或以非交替的方式散布。 As in Example 1, the drugs may be located in alternating holes in the stent or interspersed in a non-alternating manner. 嵌入的聚合物/药物以实例1中所述的方式形成。 Embedded polymer / drug is formed in the manner described in Example 1.

[0091] 治疗剂 [0091] The therapeutic agent

[0092] 本发明涉及抗再狭窄药剂的递送,抗再狭窄剂包括:紫杉醇、雷帕霉素、克拉屈滨(CdA)和它们的衍生物,以及其它细胞毒素剂或细胞抑制剂和微管稳定剂。 [0092] The present invention relates to the delivery of anti-restenotic agents, anti-restenosis agents include: paclitaxel, rapamycin, cladribine (CdA), and their derivatives, as well as other cytotoxic or cytostatic agents and microtubule stabilizer. 尽管本文主要阐述抗再狭窄药剂,但本发明也可用于单独递送其它药剂或递送其它药剂与抗再狭窄药剂的组合。 Although this paper describes anti-restenosis agents, but the present invention may also be used to deliver other agents alone or delivery of other agents with anti-restenotic agents in combination. 可通过主要经腔内、主要经腔壁或主要经这两种方式传递且可单独或组合递送的用于本发明的一些治疗药剂包括(但不限于):抗增殖药、抗凝血酶、免疫抑制剂(包括西罗莫司)、抗脂剂、抗炎剂、抗肿瘤药、抗血小板药、血管生成剂、抗血管生成剂、维生素、抗有丝分裂剂、金属蛋白酶抑制剂、N0供体、雌二醇、抗硬化剂和血管活性剂、内皮生长因子、雌激素、 β-阻滞剂、AZ阻滞剂、激素、他汀类药物、胰岛素生长因子、抗氧化剂、膜稳定剂、钙拮抗剂、 类视黄醇、比伐卢定、苯妥帝尔(phenoxodiol)、依托泊苷、噻氯匹啶、双啼达莫和曲匹地尔, 这些药剂单独使用或与本文所提及的任何治疗剂组合使用。 May be primarily luminally, primarily murally, or by both methods and may be transmitted alone or in combination for the delivery of certain therapeutic agents of the present invention include (but are not limited to): antiproliferative agents, anti-thrombin, immunosuppressive agents (including sirolimus), anti-lipid agents, anti-inflammatory agents, antineoplastics, antiplatelets, angiogenic agents, anti-angiogenic agents, vitamins, anti-mitotic agents, metalloproteinase inhibitors, N0 donor , estradiol, anti-sclerosing agents, and vasoactive agents, endothelial growth factors, estrogen, [beta] blockers, AZ blockers, hormones, statins, insulin growth factors, antioxidants, membrane stabilizing agents, calcium antagonists agents, retinoids, bivalirudin, phenytoin Royal Seoul (phenoxodiol), etoposide, ticlopidine, dipyridamole and bis cry trapidil, these agents alone or mentioned herein and in any combination of therapeutic agents. 治疗药剂还包括:肽、脂蛋白、 多肽、编码多肽的聚核苷酸、脂质、蛋白质-药物、蛋白质缀合物药物、酶、寡核苷酸及其衍生物、核糖酶、其它遗传物质、细胞、反义引物、寡核苷酸、单克隆抗体、血小板、阮病毒、病毒、 细菌和真核细胞(例如,内皮细胞、干细胞)、ACE抑制剂、单核细胞/巨细胞或脉管平滑肌细胞,这些仅仅是其中的一些例子。 Therapeutic agent further comprises: a polynucleotide peptides, lipoproteins, polypeptides, encoding the polypeptide, a lipid, a protein - drugs, protein conjugate drugs, enzymes, oligonucleotides and their derivatives, ribozymes, other genetic material , cells, antisense primer, oligonucleotides, monoclonal antibodies, platelets, prions, viruses, bacteria and eukaryotic cells (e.g., endothelial cells, stem cells), the ACE inhibitors, monocyte / macrophages or vascular cells smooth muscle cells, these are only a few examples. 所述治疗剂还可以是在施用给宿主时可代谢成所需药物的前药。 The therapeutic agent may also be administered to the host at the time of prodrugs may be metabolized into the desired medicament. 此外,治疗药剂还可在掺入治疗层之前预先配制成微胶囊、微球、微泡、脂质体、 类脂质体、乳液、分散体等等。 In addition, therapeutic agents may also be incorporated prior to pre-treatment layer is formulated as microcapsules, microspheres, microbubbles, liposomes, niosomes, emulsions, dispersions and the like. 治疗药剂还可以是可通过某些其他形式的能量(例如,光或超声能量)或通过其他可系统给药的其它循环分子来激活的放射性同位素或试剂。 Therapeutic agent may also be through some other form of energy (e.g., light or ultrasonic energy) activated by other circulating molecules or other systemic administration of agents or radioisotopes. 治疗剂可行使多种功能,包括调节血管生成、再狭窄、细胞增殖、血栓形成、血小板凝聚、凝块及血管舒张。 Therapeutic agents may perform multiple functions including modulating angiogenesis, restenosis, cell proliferation, thrombosis, platelet aggregation, clotting, and vasodilation.

[0093]抗炎剂包括(但不限于):非甾体抗炎剂(NSAID),例如,芳基乙酸衍生物,如双氯芬酸;芳基丙酸衍生物,如萘普生;和水杨酸衍生物,如二氟尼柳。 [0093] Anti-inflammatory agents include (but are not limited to): non-steroidal antiinflammatory agent (NSAID), e.g., an aryl acetic acid derivatives, such as diclofenac; aryl propionic acid derivatives such as Naproxen; and salicylic derivatives, such as diflunisal. 抗炎剂还包括糖皮质激素(类固醇),例如地塞米松、阿司匹林、泼尼松龙和曲安西龙、吡非尼酮、甲氯芬那酸、曲尼司特以及非留体抗炎剂。 Further anti-inflammatory agents include glucocorticoids (steroids) such as dexamethasone, aspirin, prednisolone, and triamcinolone, pirfenidone, meclofenamic acid, tranilast, and non-steroidal anti-inflammatory agents . 抗炎剂可与抗增殖剂联合使用以减缓组织与抗增殖剂的反应。 Anti-inflammatory agents may be used in combination with an antiproliferative agent to slow down the reaction with tissue antiproliferative agents.

[0094]药剂还包括:抗淋巴细胞剂;抗巨噬细胞物质;免疫调节剂;环氧合酶抑制剂;抗氧化剂;降胆固醇药;他汀类药物和血管紧张素转化酶(ACE);纤溶剂;内源性凝血连锁的抑制剂;抗高脂蛋白血药;及抗血小板剂;抗代谢药,例如,2-氯脱氧腺苷(2-CdA或克拉屈滨);免疫抑制剂,包括,西罗莫司、依维莫司、他克莫司、依托泊苷和米托蒽醌;抗白细胞剂,例如, 2-CdA、IL-l抑制剂、抗CD116/CD18单克隆抗体、针对VCAM或ICAM的单克隆抗体、锌原卟啉; 抗巨噬细胞物质,例如,可升高N0的药物;针对胰岛素的细胞敏化剂,包括格列酮;高密度脂蛋白(HDL)及衍生物;以及HDL的合成复制物,例如,立普妥、洛维他汀、普拉那他汀、阿托伐他汀、辛伐他汀以及他汀衍生物;血管扩张剂,例如,腺苷和双嘧达莫;一氧化氮供体;前列腺素以及它们的衍生物;抗TNF化合物;高血压药物,包括β- [0094] agent further comprises: an anti-lymphocyte agents; anti-macrophage substances; immunomodulatory agent; a cyclooxygenase inhibitor; antioxidants; cholesterol-lowering agents; statins and angiotensin converting enzyme (the ACE); Fiber the solvent; endogenous coagulation cascade inhibitors; anti-hyperlipoproteinemia agent; and antiplatelet agents; antimetabolites, e.g., 2-chloro-deoxyadenosine (2-CdA or cladribine); immunosuppressive agents, comprising , sirolimus, everolimus, tacrolimus, etoposide, and mitoxantrone; anti-leukocyte agents, e.g., 2-CdA, IL-l inhibitors, anti-CD116 / CD18 monoclonal antibodies, against monoclonal antibodies VCAM or ICAM, zinc protoporphyrin; anti-macrophage substances, for example, a drug that raises N0; for the insulin sensitizer cells, including glitazones; high density lipoprotein (HDL) and derivatives thereof; and a synthetic replica of HDL, e.g., Lipitor, Lowe statins, Paulaner statins, atorvastatin, simvastatin, and statin derivatives; vasodilator, e.g., adenosine and dipyridamole ; nitric oxide donors; prostaglandins and their derivatives; anti-TNF compounds; antihypertensives, comprising β- 阻滞剂、ACE抑制剂和钙通道阻滞剂;血管活性物质,包括血管活性肠多肽(VIP);胰岛素;针对胰岛素的细胞敏化剂,包括格列酮、Ppar激动剂和二甲双胍;蛋白激酶;反义寡核苷酸,包括reste正NG;抗血小板剂,包括替罗非班)、依非巴肽和阿昔单抗;心脏保护剂,包括VIP、垂体腺苷酸环化酶激活肽(PACAP)、apoA-I milano、氨氯地平、尼可地尔、西洛他松和噻吩并啦啶;环氧合酶抑制剂, 包括C0X-1和C0X-2抑制剂;以及增加糖分解代谢的抑制剂,包括奥帕曲拉。 Blockers, ACE inhibitors and calcium channel blockers; vasoactive substances including vasoactive intestinal polypeptide (the VIP); insulin; insulin sensitizer for the cell, including glitazones, PPAR agonists, and metformin; protein kinase ; antisense oligonucleotides, including reste positive NG; antiplatelet agents, including tirofiban), eptifibatide and abciximab; cardioprotective agents, including VIP, pituitary adenylate cyclase activating peptide (PACAP), apoA-I milano, amlodipine, nicorandil, pine and cilostazol it thieno pyridine; cyclooxygenase inhibitors, including C0X-1 and C0X-2 inhibitors; and increased saccharolytic metabolic inhibitors include omapatrilat. 可用于治疗炎症的其它药物包括降脂剂、雌激素和孕激素、内皮素受体激动剂以及白介素-6拮抗剂和脂联素。 May be used to treat inflammation include other drugs lipid lowering agents, estrogen and progestin, endothelin receptor agonists and interleukin-6 antagonists and adiponectin. 治疗剂还可包括磷酸二酯酶抑制剂(PDEi),例如,西洛他唑和腺苷受体激动剂,优选A 2A 受体激动剂,例如,热加腺苷(regadenoson) 〇 Therapeutic agents may also include phosphodiesterase inhibitors (PDEi), for example, cilostazol and adenosine receptor agonists, preferably A 2A receptor agonist, e.g., heat plus adenosine (of regadenoson) square

[0095] 还可使用基于基因疗法的方法与可扩张医疗装置结合来递送药剂。 [0095] may also be used to deliver an agent-based methods of gene therapy in combination with an expandable medical device. 基因疗法指将外源基因递送至细胞或组织,由此致使靶细胞表达外源基因产物。 Gene therapy refers to the delivery of exogenous genes to a cell or tissue, thereby causing target cells to express foreign gene products. 基因通常通过机械方法或载体介导方法来递送。 Genes are generally delivered by a mechanical or vector-mediated methods.

[0096] 可将本文所述的一些药剂与保持药剂活性的添加剂组合。 [0096] described herein can be maintained with some pharmaceutical agents active additive composition. 例如,可使用包括表面活性剂、抗酸剂、抗氧化剂和去垢剂在内的添加剂来将蛋白质药物的变性和聚集作用降到最低。 For example, additives may include surfactants, antacids, antioxidants, and detergents may be used to denaturation and aggregation of a protein drug to a minimum. 可使用阴离子表面活性剂、阳离子表面活性剂或非离子表面活性剂。 May be used anionic surfactants, cationic surfactants or nonionic surfactants. 非离子赋形剂的例子包括(但不限于):糖类,包括山梨醇、蔗糖、海藻糖;葡聚糖类,包括葡聚糖、羧甲基(CM) 葡聚糖、二乙基氨基乙基(DEAE)葡聚糖;糖衍生物,包括D-葡萄糖胺酸和D-葡萄糖二乙基缩硫醛;合成的聚醚,包括聚乙二醇(ΡΕ0)和聚乙烯基吡咯烷酮(PVP);羧酸类,包括D-乳酸、羟基乙酸和丙酸;对疏水性介面具有亲和性的表面活性剂,包括正十二烷基-β-D-麦芽糖苷、 正辛基-β-D-糖苷、ΡΕ0-脂肪酸酯(例如,硬脂酸酯(myrj 59)或油酸酯)、PE〇-脱水山梨糖醇脂肪酸酯(例如,Tween 80,PE0-20脱水山梨糖醇单油酸酯)、脱水山梨糖醇脂肪酸酯(例如, SPAN 60,脱水山梨糖醇单硬脂酸酯)、PE〇-甘油基-脂肪酸酯;甘油基脂肪酸酯(例如,甘油基单硬脂酸酯)、PE〇-烃-醚(例如,PE0-10油基醚;triton X-100;及芦布若尔。离子型除垢剂的例子包括(但不限于):脂肪酸盐,包 Examples of nonionic excipients include (but are not limited to): carbohydrates, including sorbitol, sucrose, trehalose; dextrans including dextran, carboxy methyl (CM) dextran, diethylamino ethyl (DEAE) dextran; sugar derivative, including glucose, D- alanine and D- glucose diethyl Thioacetal; synthetic polyethers including polyethylene glycol (ΡΕ0) and polyvinyl pyrrolidone (PVP ); carboxylic acids, including D- lactic acid, glycolic acid and propionic acid; a surfactant having an affinity for hydrophobic interfaces including n-dodecyl -β-D- maltoside, n-octyl -β- D- glucosidic, ΡΕ0- fatty acid esters (e.g. stearate (myrj 59) or oleate), PE〇- sorbitan fatty acid esters (e.g., Tween 80, PE0-20 sorbitan mono alcohol monooleate), sorbitan fatty acid esters (e.g., SPAN 60, sorbitan monostearate alcohol), glyceryl PE〇- - fatty acid esters; fatty acid glyceryl esters (e.g., glyceryl mono stearate), a hydrocarbon PE〇- - ethers (for example, PE0-10 oleyl ether; triton X-100; and Lo cloth if Seoul examples of ionic detergents include (but are not limited to): fatty acid salts ,package 硬脂酸钙、硬脂酸镁和硬脂酸锌;磷脂,包括卵磷脂和磷脂酰胆碱;(PC)CM-PEG;胆酸;十二烷基硫酸钠(SDS);多库酯(A0T);和牛黄胆酸。 Calcium stearate, magnesium stearate and zinc stearate; phospholipids including lecithin and phosphatidyl choline; (PC) CM-PEG; cholic acid; sodium dodecyl sulfate (SDS); docusate ( A0T); and bezoar acid.

[0097] 根据另一个示例性实施例,除了沉积在孔或开口内的一种或多种治疗剂外,本文所述的支架或管腔内支架还可涂覆有抗血栓形成剂。 [0097] According to another exemplary embodiment, in addition to one or more therapeutic agents deposited in the holes or openings of the stent may be coated with an antithrombotic agent as described herein within the lumen or the stent. 在一个示例性实施例中,可将支架制成其内带有开口,且在添加或沉积其他治疗剂进入开口之前,可将带有或不带有载体媒介物(聚合物或聚合物基质)的抗血栓形成剂固定至支架或其一部分。 In one exemplary embodiment, the stent may be formed with an opening therein, and the addition or deposition of other therapeutic agents into the openings before, may be with or without a carrier vehicle (polymer or polymeric matrix) anti-thrombotic agent to the stent or a portion thereof. 在该示例性实施例中, 支架的腔内表面和腔外表面以及开口壁的表面可涂覆有抗血栓形成剂或涂层。 In the exemplary embodiment, the luminal surface and the abluminal surface of the stent and the wall surface of the opening may be coated with a coating agent or an antithrombotic. 在一个备选的示例性实施例中,可首先用抗血栓形成剂或涂层涂覆支架,然后再制造开口。 In an alternative exemplary embodiment, the first may be coated with an antithrombotic agent or coating and the stent, and then producing the opening. 在该示例性实施例中,仅腔内表面和腔外表面具有抗血栓形成剂或涂层,而开口壁并不具有抗血栓形成剂或涂层。 In the exemplary embodiment, only the outer surface of the cavity and the cavity is formed having a surface coating agent or an antithrombotic walls of the openings does not have a coating agent or an antithrombotic. 在每个这些实施例中,可将任意数目的抗血栓形成剂固定至整个支架或其部分。 In each of these embodiments any number of anti-thrombotic agents may be affixed to the entire stent or portions thereof. 另外,还可利用任意数目的已知技术来将抗血栓形成剂固定至支架,例如,与得自Cordis Corporation的BxVeloci ty®冠状动脉支架上的HEPAC0AT™配合使用的支架。 Further, also use any number of known techniques will antithrombotic agent to the stent, for example, from the use of stents with HEPAC0AT ™ BxVeloci ty® on the coronary stent Cordis Corporation. 作为另一种选择,可将支架制造为带有粗糙表面纹理或具有微纹理,以独立于抗血栓涂层增强细胞贴附及内皮化作用,或与抗血栓形成涂层一起增强细胞贴附及内皮化作用。 Alternatively, the stent may be manufactured with a rough surface texture or have a micro-textured to enhance coating antithrombotic independent cell attachment and endothelialization, or the formation of a coating with enhanced antithrombotic and cell attachment endothelialization. 另外,可将任意数目的治疗剂沉积在开口内,且可在支架的不同区域内使用不同的药剂。 Further, any number of therapeutic agents may be deposited into the openings and different agents may be used in different regions of the stent.

[0098] 如上所述,重要的是应注意,可根据本发明使用任意数目的药物和/或药剂,包括: 抗增殖/抗有丝分裂剂,包括天然产物例如,长春花生物碱(即,长春碱、长春新碱和长春瑞滨)、紫杉醇、表鬼白毒素(即,依托泊苷、替尼泊苷、抗生素(更生霉素(放线菌素D)、柔红霉素、多柔比星和伊达比星)、蒽环类抗生素、米托蒽醌、博来霉素、普卡霉素(光辉霉素)和丝裂霉素、酶α-天冬酰胺酶,其可系统地代谢l-天冬酰胺并剥夺自身不能合成天冬酰胺的细胞);抗血小板剂,例如,G(GP)IMI 13抑制剂和玻璃粘附蛋白受体拮抗剂;抗增殖/抗有丝分裂烷基化剂,例如,氮芥(双氯乙基甲胺、环磷酰胺及类似物、美法仑、苯丁酸氮芥)、乙撑亚胺和甲基蜜胺(六甲基蜜胺和噻替哌)、烷基磺酸酯-白消安、亚硝基脲(卡莫司汀(BCNU)及类似物、链脲霉素)、三氮稀(triazen [0098] As described above, it is important to note that any number of drugs may be used and / or pharmaceutical agent according to the present invention, including: antiproliferative / antimitotic agents including natural products such as vinca alkaloids (i.e. vinblastine , vincristine, and vinorelbine), paclitaxel, white ghost table toxin (i.e., etoposide, teniposide, antibiotics (dactinomycin (actinomycin D), daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin) and mitomycin, enzymes α- asparaginase which systemically metabolisable l- asparagine and deprived cells own synthesis of asparagine); antiplatelet agents, e.g., G (GP) IMI 13 glass adhesion inhibitors and receptor antagonists; antiproliferative / antimitotic alkylating agents , e.g., nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimine and methyl melamine (hexamethylmelamine and thiotepa ), alkyl sulfonate - busulfan, nitrosoureas (carmustine (BCNU) and analogs, streptozocin), tris dilute nitrogen (triazen e)-达卡巴嗪(dacarbazinine) (DTIC);抗增殖/抗有丝分裂抗代谢物,例如,叶酸类似物(甲氨蝶呤)、嘧啶类似物(氟尿嘧啶、氟尿苷和阿糖胞苷)、 嘌呤类似物及相关抑制剂(巯嘌呤、硫鸟嘌呤、喷司他丁和2-氯脱氧腺苷{:克拉屈滨&cbr); 铂配位络合物(顺铂、卡铂)、丙卡巴肼、羟基脲、米托坦、氨鲁米特;激素(即雌激素);抗凝剂(肝素、合成肝素盐及其它凝血酶抑制剂);纤维蛋白溶解剂(例如,组织纤溶酶原激活物、链激酶和尿激酶)、阿司匹林、双嘧达莫、噻氯匹啶、氯吡格雷、阿昔单抗;抗迀移剂(antimigratory);抗分泌剂(布雷菲德菌素(brefeldin));抗炎剂:例如,肾上腺皮质类固醇(氢化可的松、可的松、氟氢可的松、泼尼松、泼尼松龙、6α_甲基泼尼松龙、曲安西龙、倍他米松和地塞米松)、非留体药剂(水杨酸衍生物,即阿司匹林;对-氨基酚衍生物,即对乙 e) - dacarbazine (dacarbazinine) (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine {: CBR & cladribine); platinum coordination complexes (cisplatin, carboplatin), procarbazine hydrazine, hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agent (e.g., tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; anti Gan shift agent (antimigratory); antisecretory agents (brefeldin (brefeldin )); anti-inflammatory agents: e.g., adrenocortical steroids (Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6α_ methylprednisolone, triamcinolone, betamethasone and dexamethasone), non-steroidal agents (salicylic acid derivatives i.e. aspirin; - amino phenol derivative, namely ethyl 氨基酚;吲哚和茚乙酸(吲哚美辛、舒林酸和依托度酸)、杂芳基乙酸(托美丁、双氯芬酸和酮咯酸)、芳基丙酸(布洛芬及衍生物)、邻氨基苯甲酸(甲芬那酸和甲氯芬那酸)、烯醇酸(吡罗昔康、替诺昔康、保泰松和oxyphenthatrazone)、萘丁美酮、金化合物(金诺芬、硫代葡萄糖金、 硫代苹果酸金钠);免疫抑制剂:(环胞素、他克莫司(FK-506)、西罗莫司(雷帕霉素)、硫唑嘌呤、麦考酚酸莫酯);血管生成剂:脉管内皮细胞生长因子(VEGF)、成纤维细胞生长因子(FGF)、血小板衍生生长因子(PDGF)、促红细胞生成素;血管紧张素受体阻滞剂;一氧化氮供体;反义寡核苷酸以及它们的组合;细胞周期抑制剂、mTOR抑制剂以及生长因子信号转导激酶抑制剂。 Acetaminophen; indole and indene acetic acid (indomethacin, sulindac, and etodolac), heteroaryl acetic acid (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives ), anthranilic acid (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, gold thioglucose, gold sodium thiomalate); immunosuppressive :( cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate acid mofetil); angiogenic agents: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), erythropoietin; angiotensin receptor blocker; nitric oxide donors; antisense oligonucleotides, and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor signal transduction kinase inhibitors.

[00"] 现在参照图9A、9B及9C,示出了支架一部分的示意图。 [00 '] Referring now to FIGS. 9A, 9B and 9C, a portion of the stent is shown a schematic diagram.

[0100] 如图9A中所示,支架900包括多个基本圆形的开口902。 [0100] As shown in FIG. 9A, the stent 900 comprises a plurality of substantially circular openings 902. 在该示例性实施例中,多个基本圆形的开口902延伸穿过支架900的壁。 In the exemplary embodiment, a plurality of substantially circular openings 902 extend through the wall 900 of the bracket. 换句话说,多个基本圆形的开口902从支架904 的腔外表面延伸至支架906的腔外表面,其中壁厚被限定为腔内表面与腔外表面之间的距离。 In other words, the plurality of substantially circular openings 902 extend from the abluminal surface of the stent 904 to the abluminal surface of the stent 906, wherein the wall thickness is defined as the distance between the luminal surface and the abluminal surface. 然而,在其他实施例中,开口无需延伸穿过支架900的壁。 However, in other embodiments, the openings need not extend through the wall of the stent 900. 例如,开口或贮器可从腔内表面或腔外表面或从这两者部分地延伸出来。 For example, the openings or reservoirs may extend from the abluminal surface or the luminal surface or partially from both. 图9A中的支架900具有未处理过的表面904和906以及空开口902。 Figure 9A the stent 900 has untreated surfaces 904 and 906 and empty openings 902.

[0101]在图9B中,至少一个表面涂覆有治疗剂908。 [0101] In Figure 9B, at least one surface is coated with a therapeutic agent 908. 治疗剂优选包括抗血栓形成剂,例如肝素;然而,可利用任何的抗血栓形成治疗剂。 Preferred therapeutic agents include anti-thrombotic agents such as heparin; however, using any antithrombotic therapeutic agents. 可将抗血栓形成剂用如上简单描述的任何技术固定。 Any technique may be fixed antithrombotic agent as above briefly described. 在该示例性实施例中,腔外表面和腔内表面都具有固定至其上的抗血栓形成剂。 In the exemplary embodiment, the luminal surface and the abluminal surface having secured thereto to form antithrombotic agent. 另外,由于该结合处的多个基本圆形的开口902是空的,所以开口902的壁也可能有一些抗血栓形成剂固定在其上。 Further, since a plurality of substantially circular openings 902 at the binding it is empty, the walls of the opening 902 may also have some anti-thrombotic agent affixed thereto. 固定至开口910的壁的抗血栓形成剂的量取决于药剂固定的方式。 The amount of anti-thrombotic agent affixed to the walls of the openings 910 depends on the mode fixing agent. 例如,如果药剂通过浸涂法来固定,则开口壁上所固定的药剂将多于利用喷涂法所固定的药剂。 For example, if the agent is fixed by dip coating, the walls of the openings will be fixed more agents using the spray coating method the immobilized agent. 如本文所述,在该示例性实施例中,所有暴露表面都固定有大量的抗血栓形成剂。 As described herein, in this exemplary embodiment, all exposed surfaces have a large number of fixed antithrombotic agent. 然而, 在备选的示例性实施例中,仅特定表面可固定有抗血栓形成剂。 However, in alternate exemplary embodiments, only specific surfaces may have an antithrombotic agent is fixed. 例如,在一个示例性实施例中,仅将与血液接触的表面用抗血栓形成剂处理。 Surface of example, in one exemplary embodiment, only the contact with blood treated with an anti-thrombotic agent. 在又一个备选的示例性实施例中,一个表面或两个表面都可涂覆有抗血栓形成剂,而开口壁不涂覆抗血栓形成剂。 In yet another alternative exemplary embodiment, one or both surfaces may be coated with an antithrombotic agent, and the opening wall is not coated with an antithrombotic agent. 这可以多种方式来实现,包括在涂覆之前塞住开口或在固定抗血栓形成剂后再形成开口。 This can be accomplished in various ways, including closing the opening formed in the fixed or antithrombotic agent after the opening prior to coating.

[0102] 图9C示出了根据该示例性实施例的完整支架。 [0102] Figure 9C shows a completed stent in accordance with this embodiment of the exemplary embodiment. 如该图所示,多个基本圆形的开口902填充有用于治疗一种或多种脉管疾病(例如,再狭窄和炎症)或本文所述的任何其他疾病的治疗剂。 As shown in Fig, a plurality of substantially circular openings 902 are filled with one or more useful for treating vascular diseases (e.g., restenosis and inflammation) or any therapeutic agent described herein, other diseases. 每个开口902都可填充如上详细描述的同种治疗剂或不同药剂。 As each of the openings 902 can be filled with different therapeutic agents or pharmaceutical agent described in detail. 如图中所示, 这些不同药剂912、914和916以特定的图案来使用;然而,如上详细描述的,任何组合都是可行的以及利用不同浓度的单种药剂也是可行的。 As shown, these different agents 912, 914 and 916 used in a particular pattern; however, as detailed above, any combination is possible as well as a single agent with different concentrations are possible. 可以任何适合的方式将这些药物(例如雷帕霉素)沉积在开口902中。 May be in any suitable manner such drug (e.g. rapamycin) is deposited in the opening 902. 用于沉积药剂的技术包括微量移液和/或喷墨填充方法。 Techniques for depositing the agent include micro-pipetting and / or ink-jet filling methods. 在一个示例性实施例中,可填充药物使得开口内的药物和/或药物/聚合物基质低于支架表面水平,从而不与周围组织发生接触。 In one exemplary embodiment, the drug may be filled in the opening so that the drug and / or drug / polymer matrix below the surface of the horizontal bracket so as not to contact with the surrounding tissue. 作为另一种选择,也可填充开口使得药物和/或药物/聚合物基质可接触周围的组织。 Alternatively, openings may be filled so that the drug and / or tissue drug / polymer matrix may contact the surrounding. 另外,如果利用多种药物,可以最大程度灵活性来设计每种药物的总剂量。 In addition, if the use of multiple drugs can be designed to maximize flexibility in the total dose of each drug. 另外,可单独地控制每种药物的释放速率。 Further, the release rate may be controlled independently of each drug. 例如,两端附近的开口可含有较多的药物,以便治疗边缘再狭窄。 For example, the openings near the ends may contain more drugs to treat edge restenosis.

[0103] 根据该示例性实施例中,孔口或开口不仅可构造成用于实现最为有效的药物疗法,还可构造成用于在不同药物之间形成物理隔离。 [0103] Not only may be configured for the most efficacious drug therapy according to this exemplary embodiment, apertures or openings, may also be configured to form a physical separation between different drugs. 该物理隔离可有助于防止药物发生相互作用。 This physical isolation can help to prevent the occurrence of drug interactions.

[0104] 本文所使用的雷帕霉素包括:雷帕霉素以及所有类似物、衍生物和与FKBP12结合的缀合物以及与雷帕霉素具有相同药理学性质(包括抑制TOR)的其他亲免疫因子。 [0104] As used herein, rapamycin includes: rapamycin and all analogs, derivatives and conjugates bound to FKBP12 and rapamycin having the same pharmacological properties (including inhibition of TOR) Other immunophilins. 另外,本文所述的所有药物和药剂还包括其类似物、衍生物和缀合物。 Furthermore, all drugs described herein further comprises a pharmaceutical agent and its analogs, derivatives and conjugates.

[0105] 如本文所述,可将其内带有通孔、孔、储器或开口的支架涂覆诸如本文所述的那些的抗血栓形成剂和/药物或药物组合,且开口可只填充一种或多种治疗剂,或可填充一种或多种治疗剂与一种或多种聚合物的组合。 [0105] As described herein, may be within the holes, reservoirs or openings of the stent is coated with those antithrombotic agents such as described herein and / or pharmaceutical pharmaceutical compositions with through holes, and the opening may be filled only One or more therapeutic agents, or a combination may be filled with one or more therapeutic agents with one or more polymers. 本质上,可将支架制成其内具有开口,且在将单独的治疗剂或治疗剂与一种或多种聚合物的组合添加或沉积进开口之前,可将带有或不带有载体媒介物的抗血栓形成剂固定至支架或支架的一部分。 Essentially, the stent may be formed having an opening therein, and prior to adding the individual therapeutic agent or agents in combination with one or more polymers or deposited into the opening, can be with or without a carrier medium antithrombotic agent was fixed to a portion of the stent or stent. 在本文所述的示例性实施例中, 可用抗血栓形成剂涂覆支架的腔内表面和腔外表面以及开口壁表面。 In the exemplary embodiment described herein, the available antithrombotic luminal surface and an abluminal surface coating agent is formed and the opening wall surface of the stent. 在该示例性实施例中,抗血栓形成剂包含肝素或其多种衍生物,例如低分子量肝素(LMWH),但也可利用任意数目的适合抗血栓形成剂。 In the exemplary embodiment, the antithrombotic agent comprises heparin or its various derivatives such as low molecular weight heparin (of LMWH), but may utilize any suitable number of an antithrombotic agent. 肝素和/或LMWH具有非常高的负电荷。 Heparin and / or LMWH have very high negative charges.

[0106] 先让本文所述支架的整个表面具有共价结合的肝素涂层,所述整个表面包括成为治疗剂和/或聚合物和治疗剂组合的储器的通孔或开口的内表面。 [0106] Let the entire surface of the stent described herein has a covalently bonded heparin coating, the entire surface including the through-hole becomes therapeutic agent and / or a polymer and a reservoir of therapeutic agents or the inner surface of the opening. 肝素涂层通过其自有的底漆自身结合至支架的金属表面,该底漆由聚(乙烯亚胺)(强阳离子聚合物,简称PEI)和硫酸葡聚糖(聚合物型阴离子)的交替层构成。 Heparin coating bonded by its own self-primer to the metal surface of the stent, the primer from (ethyleneimine) (strong cationic polymer, referred to as PEI), and dextran sulfate (polymer anion) alternating poly layer. 该类底漆的应用是本领域已知的,并且在多个专利中有所描述,包括美国专利如.5,213,898川〇.5,049,403、如.6,461,665和吣.6,767, 405。 Such primer application are known in the art, and are described in a number of patents, including U.S. Patent No. .5,213,898 as Sichuan 〇.5,049,403, such .6,461,665 and Qin .6,767, 405. 更具体地讲,肝素共价结合至底漆(包括PEI-硫酸葡聚糖层),而底漆继而又结合至金属表面。 More specifically, the heparin is covalently bound to the primer (layer comprises PEI- dextran sulfate), and in turn the primer bound to the metal surface. 一旦全部表面都涂覆有肝素混合物,就利用本所述的其中一种工艺来填充每个孔或储器。 Once all surfaces are coated with the heparin mixture, on the use of the present process to fill each one of the holes or reservoirs.

[0107] 根据另一个示例性实施例,本发明涉及用于改善药物递送基质(如治疗剂与聚合物的组合)与医疗装置(例如,支架)带肝素涂层的表面的粘附的底漆组成物和构造。 [0107] According to another exemplary embodiment, the present invention relates to a primer for improving the adhesion of a drug delivery matrix (e.g., a therapeutic agent in combination with the polymer) and the medical device (e.g., stent) heparin coated surface composition and structure. 在肝素涂层共价结合至医疗装置的金属表面或聚合物表面的情况下,本发明尤其有利。 In the case where the heparin coating is covalently bound to the metal surface of the medical device or the polymer surface, the present invention is particularly advantageous. 在本发明中,底漆优选包含高分子量组分或低分子量组分,药物递送基质包含药物和/或其他有益药剂以及赋形剂,优选聚合物赋形剂。 In the present invention, the primer preferably comprises a high molecular weight component or the low molecular weight component, a drug and / or other beneficial agent and an excipient, preferably a drug delivery matrix comprises polymeric excipients. 另外,该底漆还可优选包含与下层(例如,肝素层)电荷相反且电荷密度相似的材料。 Further, the primer may also preferably comprise opposite to the lower layer (e.g., heparin layer) and a charge similar to the charge density material.

[0108] 鉴于通常肝素表面是用来赋予抗血栓性质并因而在实际使用时是不被覆盖的,因此肝素层或肝素涂层顶部上的底漆增加带肝素涂层的表面与任何其他基质或涂层的结合是个独特的概念。 [0108] In view of the heparin surface is generally used to impart anti-thrombotic properties and hence in actual use is not covered, thus increasing the primer layer or heparin heparin coated surface of the tape on top of the heparin coating and the substrate or any other bond coat is a unique concept. 在本发明中,将覆盖有本发明底漆的药物-聚合物储器仅由支架内的孔或开口的内壁表面来保持,因此增加了这两个层之间的粘附并限制了药物-聚合物基质的潜在损失,而不会对储器外的肝素表面有大的影响。 In the present invention, covered with the primer of the present invention is a pharmaceutical - a polymer reservoir is only held by the inner wall surfaces of the holes or openings in the stent, thereby increasing the adhesion between the two layers and limiting drug - potential loss of the polymer matrix, without having a large effect of heparin surface outside the reservoirs. 重要的是应注意,根据本发明的肝素阻断底漆在其初始的预期用途方面具有生物相容性。 It is important to note that the heparin blocking primers in accordance with the present invention are biocompatible in their original intended use aspect.

[0109] 本发明的打底层可与任何类型的支架一同使用。 [0109] The primer layer of the present invention may be used with any type of stent. 在本文所述的示例性实施例中, 底漆与图1、图2、图3和图4中所不的一个或多个支架一同使用。 In the exemplary embodiment described herein, the primer of FIG. 1, FIG. 2, FIG. 3, and one or more brackets in FIG. 4 are not used together.

[0110] 根据一个示例性实施例,该底漆包含聚合物-聚(乙烯亚胺)缀合物(例如,聚乳酸-羟基乙酸共聚物(PLGA))和聚(乙烯亚胺)PEI和/或PLGA-鱼精蛋白。 [0110] According to an exemplary embodiment, the primer comprises polymer - poly (ethyleneimine) conjugates (e.g., polylactic acid - glycolic acid copolymer (of PLGA)) and poly (ethyleneimine) and the PEI / or PLGA- protamine. 聚(乙烯亚胺)是结合至某些带负电荷的蛋白质或多糖的强阳离子聚合物。 Poly (ethyleneimine) is bound to certain negatively charged proteins or polysaccharides strong cationic polymers. 除了PEI之外,该缀合物中另一有用物质是鱼精蛋白。 In addition to PEI, the conjugate Another useful substance is protamine. 鱼精蛋白是一种批准了的用作肝素解毒药的低分子量蛋白质药物。 Protamine is an approved antidote of heparin as low molecular weight protein drugs. 其在水中为稀疏溶液。 Which is sparse in the water solution. 以此方式,该底漆可与肝素涂层和含药物的基质同时发生强烈的相互作用,因而改善了这两种物质之间的粘附。 In this manner, the primer may heparin coating and the drug-containing matrix occurs simultaneously interact strongly, thus improving the adhesion between two substances. 由于肝素是聚(阴离子)物种,所以可以预料,聚(阳离子) 物种(例如鱼精蛋白)可与肝素良好地结合,而在其结构的其他区段中具有充分的疏水性, 从而允许药物聚合物基质的PLGA组分良好地结合在储器内。 Since heparin is a poly (anionic) species, it is anticipated that a poly (cationic) species (e.g., protamine) can be well combined with heparin, have sufficient hydrophobicity in the other sections of its structure, thereby permitting the drug to the polymerization PLGA matrix component was well incorporated within the reservoir. PLGA与PEI以及PEI与肝素之间的结合反应可以是离子键合反应或可以是共价键合反应。 Binding reaction between PLGA and PEI and PEI and heparin may be ionic bonding reaction or may be covalently bonded reaction. 图10示出了PLGA与PEI之间的共价键合的例子。 FIG 10 shows an example of covalent bonding between PLGA and PEI. 更具体地讲,图10示出了带羧酸端基的PLGA与低分子量PEI之间的缀合反应。 More specifically, FIG. 10 shows a PLGA with a carboxylic acid end group and low molecular weight PEI conjugated engagement between the reaction. 作为另一种选择,底漆可包含高分子量PEI或支链PEI。 Alternatively, the primer may comprise a high molecular weight PEI or a branched PEI. 参见图11,示出了带羧酸端基团的PLGA与高分子量或支链PEI之间的缀合反应。 Referring to Figure 11, shows the conjugation between PLGA with high molecular weight or branched PEI with a carboxylic acid end group bonded reaction. 如图中所示,所述反应的PLGA与PEI之间的比率可设置为1:1或2:1(PLGA-PEI-PLGA缀合物)。 The ratio between PLGA and PEI said reaction may be provided as shown in FIG. 1: 1 or 2: 1 (PLGA-PEI-PLGA conjugate).

[0112]下表示出了PEI作为底漆来增加药物/聚合物复合物与带肝素涂层的表面的粘附的效力。 [0112] The table below shows the effectiveness of PEI as a primer to increase the adhesion of the drug / polymer complex to the heparin coated surface. 将测试支架浸没在模拟生理溶液条件的磷酸盐缓冲液和牛血清白蛋白的测试介质中。 The test rack was immersed in simulated physiological solution conditions of the test medium phosphate buffer and bovine serum albumin. 药物/聚合物复合物包含雷帕霉素和PLGA。 The drug / polymer complex comprises a rapamycin and PLGA.

[0113] [0113]

Figure CN101744676BD00201

[0114] [0114]

[0115] 在备选的示例性实施例中,底漆可包含与肝素络合的低分子量络合阳离子,包括烷基苄基二甲基氯化铵和/或低聚精氨酸肽,或高分子量络合阳离子,包括聚赖氨酸、聚(精氨酸)、鱼精蛋白、聚(二甲基氨乙基)甲基丙烯酸酯或聚(二甲基氨乙基)丙烯酸酯。 [0115] In an alternative exemplary embodiment, the primer may comprise low molecular weight complexing cations to heparin, including alkyl dimethyl benzyl ammonium chloride and / or oligomeric arginine peptides, or high molecular weight complexing cations, including polylysine, poly (arginine), protamine, poly (dimethylaminoethyl) methacrylate or poly (dimethylaminoethyl) acrylate.

[0116]根据本发明,用于增加药物复合物与肝素间的粘附的方法可包括:涂敷促粘附底漆,然后涂敷聚合物/药物填充溶液,或者涂敷促粘附底漆,然后涂敷末端为羧基的PLGA或末端为羧基的规则PLGA与PLGA/药物填充溶液的共混物。 [0116] According to the present invention, a method for increasing the adhesion between the drug and the complex of heparin comprising: applying the adhesion promoting primer followed by polymer / drug fill solution or adhesion promoting primer coating and then applied to the end PLGA or terminal carboxyl group and a carboxyl group of rules PLGA PLGA / drug-filled solution of a blend.

[0117]在给开口填充局部药物递送基质之前,将本发明的底漆施加至支架中的孔或开口的带肝素涂层的内壁。 [0117] Prior to filling the opening local drug delivery matrix, the primer of the invention is applied to an opening or hole in the bracket with the inner wall of heparin coated. 换句话讲,在成品药物洗脱支架中,底漆将占据肝素涂层表面与药物递送基质本体之间的空间,且将增大肝素涂层与药物递送基质之间的粘附力。 In other words, in the finished pharmaceutical eluting stent, the primer will occupy a space between the coating surface heparin body and the drug delivery matrix and will increase the heparin coating and the adhesion between the drug delivery matrix. 粘附力增强是通过多个因素实现的,包括:在由阳离子底漆进行电荷中和后的使用中,肝素涂层的同渗容摩/透水率降低;与单独的肝素表面来相比,肝素/阳离子底漆复合物的水溶解性降低;由于表面张力等引起的底漆与聚合物/药物基质之间的离子键合、共价键合以及更佳的物理粘附。 Adhesion promotion is achieved by a number of factors, including: the use of the charge neutralization by a cationic primer, the osmolarity / water permeability decreased heparin coating; compared to the heparin surface alone, aqueous solubility of heparin / cationic primer complex is reduced; as ionic bonding between the primer and the polymer / drug matrix due to surface tension, covalent bonding and better physical adhesion.

[0118] 在本发明另一个示例性实施例中,优选的是,本发明底漆的一部分分子结构带正电以便结合至带负电的肝素涂层,且该底漆的一部分为疏水性部分、亲水性部分或均衡部分以结合至药物递送基质的聚合物组分。 [0118] In another exemplary embodiment of the present invention, it is preferable that the part of the molecular structure of the present invention, the primer is positively charged so as to bind to the negatively charged heparin coating, and a portion of the primer is a hydrophobic moiety, equalizing section or hydrophilic moiety to bind to the drug delivery polymer component of the matrix. 取决于药物递送基质的性质,底漆的所述部分可有所不同。 Depending on the nature of the drug delivery matrix, the portion of the primer may vary. 更具体地讲,打底层设计成可改善药物递送基质与支架带肝素涂层的开口的粘附,使得当支架接触水基流体(例如,盐水、血液和/或细胞间液)时,没有或者基本上没有开口或储器丢失其内容物。 More specifically, the primer layer may be designed to improve the adhesion of the opening of the drug delivery matrix and the heparin coated stent, such that when the stent is in contact with water-based fluids (e.g., saline, blood and / or intercellular fluid), there is no, or substantially no openings or reservoirs lose their contents.

[0119] 尽管本文将本发明底漆具体地描述为用于增大支架储器带肝素涂层的内壁与填充该储器的药物/聚合物混合物之间的粘附,但是本发明底漆可用于将任何基底附连或结合至带肝素涂层的表面的一部分。 [0119] Although the primer of the invention herein specifically described adhesion between the inner wall of the reservoir for increasing the heparin coated stent of filling the reservoir with a drug / polymer mixture, but the present invention can primer attached to any substrate or to the surface bound heparin coated part. 例如,接触血液的塑料医疗装置常常涂覆有肝素以使得装置上血栓形成最少,但可能希望将后者结合至该表面。 For example, blood contacting plastic medical devices are often coated with heparin to a minimum so that the apparatus thrombosis, but it may be desirable to bind the latter to the surface. 可将本发明的底漆在溶剂中的混合物施加至装置的选择区域,蒸发溶剂以在肝素表面上形成带底漆涂层的区域,然后接着可将新的子系统结合至该带底漆涂层的区域。 The primer mixtures of the present invention in a solvent may be applied to the selected area of ​​the device, the solvent was evaporated to form a primer coating with a region on the heparin surface, then subsequently a new subsystem may be incorporated into the coating with a primer regions of the layer.

[0120]有利的是,将底漆材料作为聚合物底漆在溶剂(例如,二甲亚砜(DMSO)、N_甲基吡咯烷酮或它们的水混合物)中的溶液进行涂敷,且可使用本申请案中所述的任何填充技术引入储器中。 [0120] Advantageously, the primer material is coated as a primer in a solvent, a polymer (e.g., dimethyl sulfoxide (DMSO), N_-methylpyrrolidone, or water mixtures thereof) solution, and may be used this application of any of the filling techniques introduced into the reservoir. 然后,可使该种底漆溶液干燥从而在带肝素涂层的表面上形成底漆层涂层。 Then, make this type of primer layer solution was dried to form a primer coating on the surface coated with heparin. 优选的是,底漆层的涂敷在支架填充工艺中仅需要一个沉积步骤。 Preferably, the primer layer coating the stent filling process requires only one deposition step. 适用于沉积阳离子底漆的溶剂的选择主要由其溶解底漆的能力以及其与本文所述的填充器具和工艺的相容性。 The choice of solvent adapted to deposit a cationic primer mainly by the ability to dissolve a primer and its compatibility with the filling equipment and process described herein.

[0121] 本发明可简单地表征为一种植入式医疗装置。 [0121] The present invention may simply be characterized as an implantable medical device. 该医疗装置包括:管腔内支架,其内具有多个开口;第一涂层,其包含固定至该管腔内支架的表面和该多个开口的表面的至少一部分的具有第一电荷的材料;第二涂层,其包含固定至第一涂层的至少一部分的具有第二电荷的材料,第二电荷与第一电荷相反;以及至少一种治疗剂,其沉积在该多个开口中的至少一个中;其中第二涂层构造为第一涂层与该至少一种治疗剂之间的中间层。 The medical device comprising: an intraluminal scaffold having a plurality of openings therein; a first coating layer, comprising the surface fixed to a surface and a plurality of openings in the intraluminal scaffold having a first material at least a portion of the charge ; a second coating material having a second charge comprising at least a portion fixed to the first coating layer, a second charge opposite the first charge; and at least one therapeutic agent deposited in the plurality of openings at least one of; wherein the second coating is configured as an intermediate layer between the first coating and the at least one therapeutic agent.

[0122] 第一涂层可包含本文所述的任何适合的抗血栓形成剂。 Any suitable anti-thrombotic agent [0122] The first coating may comprise the herein. 例如,可利用多糖,例如肝素。 For example, polysaccharides can be utilized, such as heparin. 第二涂层可包含本文所述的聚合物型阳离子或带有阳离子片段的聚合物缀合物。 The second coating may comprise a polymeric cation herein or polymer conjugate having cationic segments. 聚合物型阳离子的例子包括:低聚精氨酸肽、聚(赖氨酸)、聚(精氨酸)、鱼精蛋白、聚(二甲基氨乙基)、聚(乙烯亚胺)。 Examples of polymeric cations include: oligomeric arginine peptides, poly (lysine), poly (arginine), protamine, poly (dimethylaminoethyl) poly (ethyleneimine). 聚合物型阳离子缀合物的例子包括诸如乳酸-羟基乙酸共聚物之类的第一组分和包含上面示出的任何阳离子的第二组分。 Examples of polymeric cationic conjugates include such as lactic acid - glycolic acid copolymer of the first component or the like and a second component comprising any cationic shown above. 治疗剂可包含抗再狭窄剂、抗炎剂、 抗血栓形成剂、抗增殖剂、用于使对梗塞组织损害最小的药剂或它们的任何组合。 The therapeutic agent may comprise an anti-restenosis agents, anti-inflammatory agents, anti-thrombotic agents, antiproliferative agents, agents used to minimize damage to infarcted tissue or any combination thereof.

[0123] 在更为广泛的意义上,本发明的概念可扩展至包括增加亲水性表面与疏水性表面之间的粘合强度的底漆。 [0123] In the broader sense, the inventive concept is extended to include a primer to increase the bonding strength between the hydrophilic surface and a hydrophobic surface. 例如,所关注的其他亲水性表面是所谓的"光滑"表面,例如,与导管结合使用的那些表面。 For example, other hydrophilic surfaces of interest are the so-called "smooth" surface, e.g., those surfaces used in conjunction with the catheter. 这些亲水性表面还常常为共价键结合的表面,然而其可仅仅是适形涂层。 These hydrophilic surfaces also often covalently bonded surface, but it may just conformal coatings. 光滑涂层中存在的化学结构的例子是基于聚乙烯基吡咯烷酮、甲基丙烯酸羟乙酯、 聚(环氧乙烷)或聚(乙二醇)的结构。 Examples of the chemical structure of the present lubricious coating is based on polyvinylpyrrolidone, hydroxyethyl methacrylate, poly (ethylene oxide) or poly (ethylene glycol) structure.

[0124] 尽管所示出并描述的据信是最为实用和优选的实施例,但显然,对所述和所示的具体设计和方法的变更对本领域中的技术人员来说不言自明,并且可使用这些变更形式而不脱离本发明的精神和范围。 [0124] It is believed that although shown and described is the most practical and preferred embodiments, it will be apparent, to change the specific designs and methods described and shown will suggest themselves to those skilled in the art, the use and these alternative forms without departing from the spirit and scope of the invention. 本发明并非局限于所述和所示的具体构造,而是应该理解为与落入所附权利要求书的范围内的全部修改形式相符。 The present invention is not limited to the particular constructions described and illustrated, but should be constructed to cohere with all modifications that falls within the scope of the appended claims of.

Claims (12)

  1. 1. 植入式医疗装置,包括: 基本圆柱形的管腔内支架,其能够从用于递送进脉管内的第一直径扩张至用于扩张所述脉管的第二直径,所述管腔内支架具有腔内表面和腔外表面,所述腔内表面和所述腔外表面之间的距离限定了所述管腔内支架的壁厚度,所述管腔内支架还包括从所述腔内表面延伸至所述腔外表面的多个开口; 包括多个层的底漆层,所述底漆层覆盖所述腔内表面、所述腔外表面和所述多个开口的表面; 包含具有第一电荷的材料的第一涂层,其固定至所述底漆层; 包含具有第二电荷的材料的第二涂层,其仅在所述多个开口内固定至所述第一涂层, 所述第二电荷与所述第一电荷相反;以及至少一种治疗剂,其沉积在所述多个开口中的至少一个中,其中所述第二涂层构造为所述第一涂层与所述至少一种治疗剂之间的中间层, 所述第二涂层 1. The implantable medical device, comprising: a substantially cylindrical intraluminal stent capable of delivering into the expandable from a first diameter to a second inner diameter of the vessel to the expansion vessel, the lumen stent having a distance between the luminal surface and an abluminal outer surface, the luminal surface and said cavity surface defining a wall thickness of the intraluminal scaffold, the intraluminal stent from the chamber further comprises a plurality of inner surfaces of said cavity extends to the outer surface of the opening; a plurality of layers including a primer layer, the primer layer to cover the luminal surface, an outer surface and said cavity surface of said plurality of openings; comprising a first coating material having a first charge, which is fixed to the primer layer; a second coating layer comprising a material having a second electric charge, said plurality of openings in which only fixed to the first coating layer, and the second charge opposite the first charge; and at least one therapeutic agent deposited in at least one of the plurality of openings, wherein the second coating is configured as the first coating layer and the intermediate layer between the at least one therapeutic agent, said second coating 含聚合物缀合物,其中所述聚合物缀合物包含第一组分和第二组分, 所述第一组分包含可生物吸收的聚合物,所述第二组分选自由如下物质组成的组:低聚精氨酸肽、聚赖氨酸、聚(精氨酸)、鱼精蛋白、聚(二甲基氨基乙基)甲基丙烯酸酯、聚(二甲基氨基乙基丙烯酸酯)和聚(乙烯亚胺)。 The conjugate-containing polymer, wherein the polymer conjugate comprises a first component and a second component, said first component comprising a bioabsorbable polymer, a second component selected from the group consisting of the following materials the group consisting of: oligomeric arginine peptides, polylysine, poly (arginine), protamine, poly (dimethylaminoethyl) methacrylate, poly (dimethylaminoethyl methacrylate ester) and poly (ethyleneimine).
  2. 2. 根据权利要求1所述的植入式医疗装置,其中所述第一涂层包含抗血栓形成剂。 2. The implantable medical device according to claim 1, wherein the first coating comprises an anti-thrombotic agent.
  3. 3. 根据权利要求2所述的植入式医疗装置,其中所述抗血栓形成剂包含多糖。 3. The implantable medical device according to claim 2, wherein the anti-thrombotic agent comprises a polysaccharide.
  4. 4. 根据权利要求3所述的植入式医疗装置,其中所述多糖包括硫酸化多糖。 4. The implantable medical device of claim 3, wherein the polysaccharide comprises sulphated polysaccharides.
  5. 5. 根据权利要求3所述的植入式医疗装置,其中所述多糖包括肝素。 The implantable medical device according to claim 3, wherein said polysaccharide comprises heparin.
  6. 6. 根据权利要求1所述的植入式医疗装置,其中所述第二涂层包含聚合物型阳离子。 6. The implantable medical device according to claim 1, wherein the second coating comprises a polymeric cation.
  7. 7. 根据权利要求6所述的植入式医疗装置,其中所述聚合物型阳离子选自由如下物质组成的组:低聚精氨酸肽、聚赖氨酸、聚(精氨酸)、鱼精蛋白、聚(二甲基氨基乙基)甲基丙烯酸酯、聚(二甲基氨基乙基丙烯酸酯)和聚(乙烯亚胺)。 7. The implantable medical device according to claim 6, wherein said polymeric cation is selected from the group consisting of: oligomeric arginine peptides, polylysine, poly (arginine), fish protamine, poly (dimethylaminoethyl) methacrylate, poly (dimethylaminoethyl methacrylate) and poly (ethyleneimine).
  8. 8. 根据权利要求1所述的植入式医疗装置,其中所述可生物吸收的聚合物包括乳酸-羟基乙酸共聚物。 8. The implantable medical device according to claim 1, wherein the bioabsorbable polymer comprises a lactic acid - glycolic acid copolymer.
  9. 9. 根据权利要求8所述的植入式医疗装置,其中所述至少一种治疗剂选自由如下物质组成的组:抗再狭窄剂、抗炎剂、抗血栓形成剂、抗增殖剂和保心剂,用于使对梗塞组织的损害最小。 9. The implantable medical device according to claim 8, wherein the at least one therapeutic agent selected from the group consisting of: an anti-restenosis agents, anti-inflammatory agents, anti-thrombotic agents, antiproliferative agents and Paul heart agent for the damage to infarct tissue is minimized.
  10. 10. 根据权利要求1所述的植入式医疗装置,其中所述第二涂层包含聚合物型聚阳离子。 10. The implantable medical device according to claim 1, wherein the second coating comprises a polymeric polycation.
  11. 11. 植入式医疗装置,包括: 基本圆柱形的管腔内支架,其能够从用于递送进脉管内的第一直径扩张至用于扩张所述脉管的第二直径,所述管腔内支架具有腔内表面和腔外表面,所述腔内表面和所述腔外表面之间的距离限定了所述管腔内支架的壁厚度,所述管腔内支架还包括从所述腔内表面延伸至所述腔外表面的多个开口; 包含具有第一电荷的材料的第一涂层,其固定至所述腔外表面、所述腔内表面以及所述多个开口的表面的至少一部分上; 第二涂层,其包含固定至所述第一涂层的至少一部分的具有第二电荷的材料,所述第二电荷与所述第一电荷相反;以及至少一种治疗剂,其沉积在所述多个开口中的至少一个中;其中所述第二涂层构造为所述第一涂层与所述至少一种治疗剂之间的中间粘合层, 所述第二涂层包含聚合物缀合物,其中所述聚合物 11. The implantable medical device, comprising: a substantially cylindrical intraluminal stent capable of delivering into the expandable from a first diameter to a second inner diameter of the vessel to the expansion vessel, the lumen stent having a distance between the luminal surface and an abluminal outer surface, the luminal surface and said cavity surface defining a wall thickness of the intraluminal scaffold, the intraluminal stent from the chamber further comprises a plurality of inner surface extends to an outer surface of the cavity opening; coating layer comprising a first material having a first electric charge, which is fixed to the outer surface of the cavity, the cavity surface and a surface of the plurality of openings at least a portion; a second coating comprising a material having affixed to at least a portion of the second charge of the first coating, the second charge opposite the first charge; and at least one therapeutic agent, deposited on at least one of the plurality of openings; and wherein the second coating is configured as the first coating and said intermediate adhesive layer between the at least one therapeutic agent, said second coating layer comprises a polymer conjugate, wherein said polymer 合物包含第一组分和第二组分, 所述第一组分包含可生物吸收的聚合物,所述第二组分选自由如下物质组成的组:低聚精氨酸肽、聚赖氨酸、聚(精氨酸)、鱼精蛋白、聚(二甲基氨基乙基)甲基丙烯酸酯、聚(二甲基氨基乙基丙烯酸酯)和聚(乙烯亚胺)。 Composition comprising a first component and a second component, said first component comprising a bioabsorbable polymer, said second component is selected from the group consisting of: oligomeric arginine peptides, poly Lai acid, poly (arginine), protamine, poly (dimethylaminoethyl) methacrylate, poly (dimethylaminoethyl methacrylate) and poly (ethyleneimine).
  12. 12.涂覆其内具有多个开口的管腔内支架的方法,所述方法包括: 将包含具有第一电荷的材料的第一涂层施加至所述管腔内支架的表面和所述多个开口的表面的至少一部分; 将包含具有第二电荷的材料的第二粘合涂层施加至所述第一涂层的至少一部分,所述第二电荷与所述第一电荷相反;以及将至少一种治疗剂施加至所述多个开口中的至少一个内, 所述第二粘合涂层包含聚合物缀合物,其中所述聚合物缀合物包含第一组分和第二组分,所述第一组分包含可生物吸收的聚合物,所述第二组分选自由如下物质组成的组:低聚精氨酸肽、聚赖氨酸、聚(精氨酸)、鱼精蛋白、聚(二甲基氨基乙基)甲基丙烯酸酯、聚(二甲基氨基乙基丙烯酸酯)和聚(乙烯亚胺)。 12. The method of coating the inner intraluminal scaffold having a plurality of openings, said method comprising: a coating comprising a first material having a first electric charge applied to the surface of the inner lumen of the stent and the plurality at least a portion of the surface of the openings; adhesive coating layer comprising a second material having a second electric charge is applied to at least a portion of said first coating, said second charge opposite the first charge; and the at least one therapeutic agent applied to the plurality of openings within at least one, the second adhesive coating comprising a polymer conjugate, wherein the polymer conjugate comprises a first component and a second set of points, the first component comprising a bioabsorbable polymer, said second component is selected from the group consisting of: oligomeric arginine peptides, polylysine, poly (arginine), fish protamine, poly (dimethylaminoethyl) methacrylate, poly (dimethylaminoethyl methacrylate) and poly (ethyleneimine).
CN 200910253495 2008-12-16 2009-12-16 For adhesion promoting primer coated surface CN101744676B (en)

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US12335741 US7819914B2 (en) 2008-12-16 2008-12-16 Adhesion promoting primer for coated surfaces

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101273926A (en) * 2007-03-28 2008-10-01 科迪斯公司 Short term sustained drug-delivery system for implantable medical devices and method of making the same
CN201143321Y (en) * 2007-12-29 2008-11-05 上海交通大学医学院附属仁济医院 Vascular undercoat stent

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101273926A (en) * 2007-03-28 2008-10-01 科迪斯公司 Short term sustained drug-delivery system for implantable medical devices and method of making the same
CN201143321Y (en) * 2007-12-29 2008-11-05 上海交通大学医学院附属仁济医院 Vascular undercoat stent

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