CN102058893B - 具有生物活性涂层的医疗装置的电子束灭菌 - Google Patents
具有生物活性涂层的医疗装置的电子束灭菌 Download PDFInfo
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Classifications
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- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
- A61L2/08—Radiation
- A61L2/087—Particle radiation, e.g. electron-beam, alpha or beta radiation
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B31/00—Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B65B55/00—Preserving, protecting or purifying packages or package contents in association with packaging
- B65B55/02—Sterilising, e.g. of complete packages
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B65D81/24—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants
- B65D81/26—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants with provision for draining away, or absorbing, or removing by ventilation, fluids, e.g. exuded by contents; Applications of corrosion inhibitors or desiccators
- B65D81/266—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants with provision for draining away, or absorbing, or removing by ventilation, fluids, e.g. exuded by contents; Applications of corrosion inhibitors or desiccators for absorbing gases, e.g. oxygen absorbers or desiccants
Abstract
本发明提供了一种用于医疗装置,例如导管、组织工程支架或药物递送载体材料中所用的含肝素的材料和生物材料上的生物活性肝素涂层的单步骤最终灭菌处理方法。这可包括可受益于抗血栓形成作用改善且生物相容的肝素表面的任何医疗装置或植入物。其他相关装置的例子可包括涂覆有肝素或肝素衍生物的用于减少凝固和再狭窄的支架、牙科用或眼科用植入物。这些材料可包含另外的聚合物组合物例如聚乙烯亚胺、硫酸葡聚糖或它们的改性形式。可将这些材料与肝素涂层一起施加至诸如金属、陶瓷或生物衍生材料之类的其他医疗装置基材上。
Description
背景技术
1.技术领域
本发明涉及具有生物活性表面涂层的医疗装置,更具体地讲,涉及利用电子束灭菌技术,对处于其包装中的具有生物活性表面涂层的医疗装置进行灭菌的方法。
2.背景技术
已将许多金属材料和聚合物材料用于制造可植入医疗装置以及可植入医疗装置上的涂层。表面改性和具有相同或不同组成的涂层常常用于进一步改善可植入医疗装置的生物相容性、血液相容性和功能性。这些装置的表面改性或涂层通常需要若处理步骤来完成。通过每种这些处理改性的基材以及表面涂层需要一定方式的最终灭菌以确保产品的无菌性来用于患者。当前所用的对裸金属装置的灭菌处理可能具有潜在的缺点,例如当用于带涂层的装置时,可降低涂层的稳定性和功能,因为涂层材料可能与这些传统的灭菌方法不相容。
已经在文献中评述了为了有利的宿主-材料响应目的的不同表面改性方法。若干美国专利描述了用于涂覆医疗装置(尤其是诸如支架之类的与血液接触的那些)的手段和方法,但没有解决后续灭菌的问题(美国专利No.4,656,083;No.5,034,265;No.5,132,108;No.5,244,654;和No.5,409,696)。Palmaz等人在血管内支架的综述中对支架涂层的使用持怀疑态度(Palmaz,J.,F.Rivera和C.Encamacion.Intravascular Stents,Adv.Vasc.Surg.,1993,1:107-135)。然而,Kocsis等人报道,带肝素涂层的支架可有效降低支架表面的致血栓性(Kocsis,J.,G.Llanos和E.Holmer.Heparin-Coated Stents,J.of Long-TermEffects of Medical Implants,2000,10 19-45)。
典型的表面改性包括心血管植入物(例如支架和起搏器)、留置医疗装置、局部伤口愈合敷用物、接触镜片、眼内镜片等的表面上的亲水性涂层和/或水凝胶涂层,例如聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)或透明质酸(HA)。疏水性或润滑性涂层被用于诸如冠状动脉或神经血管导丝、缝合线、针、导管和套管针之类的医疗装置。生物活性涂层在组织工程应用中被用于定向细胞响应例如细胞粘附分子(CAM,例如RGD(氨基酸序列Arg-Glu-Asp)、层粘连蛋白、胶原等),或防止粘附的涂层被用于诸如腔静脉过滤器或小直径人工血管之类的医疗装置上。涂层材料还包括抗感染剂或抗微生物剂。某些涂层还提供持续的药物释放,例如提供药物从支架的持续释放,或作为疏水性外涂层来延长加载了药物的储库的释放时间。为了提供抗血栓形成性质使用了含有治疗剂(例如肝素、磷酰胆碱(PC)、尿激酶等)的生物活性涂层。
可将涂层用于递送治疗剂和药剂,所述治疗剂和药剂包括:抗增殖/抗有丝分裂剂,包括天然产物例如长春花碱类(即长春花碱、长春新碱和长春瑞滨)、紫杉醇、表鬼臼毒素类(即依托泊苷、替尼泊苷)、抗生素类(更生霉素(放线菌素D)、柔红霉素、阿霉素和去甲柔红霉素)、蒽环类、米托蒽醌、博来霉素类、光辉霉素(光神霉素)和丝裂霉素、酶类(L-天冬酰胺酶,其系统性地代谢L-天冬酰胺并除去不具有合成它们自身天冬酰胺的能力的细胞);抗增殖/抗有丝分裂烷化剂例如氮芥类(双氯乙基甲胺、环磷酰胺及类似物、苯丙氨酸氮芥、苯丁酸氮芥)、乙撑亚胺类和甲基三聚氰胺类(六甲基三聚氰胺和塞替派)、烷基磺酸酯类-白消安、亚硝基脲(双氯乙基亚硝脲(BCNU)及类似物、链脲菌素)、三氮烯类--氮烯咪胺(DTIC);抗增殖/抗有丝分裂抗代谢物例如叶酸类似物(甲氨喋呤)、嘧啶类似物(氟尿嘧啶、氟尿苷和阿糖胞苷)、嘌呤类似物和相关的抑制剂(巯嘌呤、硫鸟嘌呤、喷司他丁和2-氯脱氧腺苷{克拉屈滨});铂配位络合物(顺铂、卡铂)、甲基苄肼、羟脲、邻氯苯对氯苯二氯乙烷、氨鲁米特;激素类(即雌激素);抗凝血剂(肝素、合成的肝素盐以及凝血酶的其他抑制剂);纤维蛋白溶解剂(例如组织纤维蛋白溶酶原激活剂、链激酶和尿激酶)、阿司匹林、双嘧啶氨醇、氯匹啶、氯吡格雷、阿昔单抗;抗迁移剂(antimigratory);抗分泌因子(布雷菲德菌素);抗炎剂:例如肾上腺皮质类固醇(皮质醇、可的松、氟氢可的松、泼尼松、泼尼松龙、6α-甲泼尼龙、曲安西龙、倍他米松和地塞米松)、非甾族试剂(水杨酸衍生物即阿司匹林;对-氨基苯酚衍生物即对乙酰氨基酚;吲哚和茚乙酸类(消炎痛、舒林酸和依托度酸)、杂芳基乙酸类(托美丁、双氯芬酸和酮咯酸)、芳基丙酸类(布洛芬及衍生物)、邻苯氨基甲酸类类(甲灭酸和甲氯芬那酸)、烯醇酸类(吡罗昔康、替诺昔康、保泰松和oxyphenthatrazone)、萘普酮、金化合物(金诺芬、金硫葡糖、硫代苹果酸金钠);免疫抑制剂:(环孢霉素、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:血管内皮生长因子(VEGF)、成纤维细胞生长因子(FGF);一氧化氮供体;反义寡核苷酸以及它们的组合。
可通过将一种或多种治疗剂与聚合物涂层混合物进行混合来配制涂层。治疗剂可以液体、细分固体或任何其他合适的物理形式存在。可任选的,涂层混合物可包括一种或多种添加剂,例如非毒性辅助性物质例如稀释剂、载体、赋形剂、稳定剂等。其他合适的添加剂可用聚合物与药物活性剂或配混物配制。例如,可将亲水性聚合物加至生物相容性疏水涂层以改变释放曲线,或可将疏水性聚合物加至亲水性涂层以改变释放曲线。一个例子是将选自聚环氧乙烷(PEO)、PVP、聚乙二醇(PEG)、羧甲基纤维素和羟甲基纤维素的亲水性聚合物加至疏水性共聚物/聚合物涂层以改变释放曲线。合适的相对量可通过监测治疗剂的体外和/或体内释放性质来确定。
用于表面改性的方法通常包括表面活化步骤,然后偶联所需的分子。表面活化常常通过能量辅助的气相反应(等离子体、脉冲等离子体、流量反应化学(flow discharge reactive chemistry,FDRC)、电晕放电等)和/或用高度反应性离去基团(N--OH琥珀酰亚胺、咪唑等)活化基材;用自组装分子(SAM,官能化硅烷和硫醇)使表面官能化;表面的酯和酰胺(聚对苯二甲酸乙二醇酯(PET)、聚乳酸(PLA)、聚乙醇酸(PGA)、PLGA等)的控制水解。偶联合反应通常通过碳二亚胺化学、还原胺化、马来酰亚胺-硫醇反应等。
光化学表面改性常常是优选的,因为该方法通常不需要前面的活化步骤。芳基酮基化学、叠氮化学、丙烯酸酯化学是关键的例子。
如上所述的,无论涂层的类型如何,终产品的灭菌可引起潜在的问题。常规的灭菌方法(例如热蒸汽、辐射(γ射线和电子束)和环氧乙烷)可对涂层的活性有负面影响。例如,常常通过最终的灭菌处理(例如环氧乙烷(EtO)灭菌、γ射线灭菌或更新近的电子束灭菌)对医疗装置进行灭菌。EtO灭菌对基于金属和聚合物的医用产品(例如导管、裸金属支架以及早期药物洗脱支架)较温和。其为耗时长且通常麻烦的过程,需要精细调节处理方法参数(例如持续时间、温度、湿度、载气和水分之间的比率),以及需要在处理后进行大范围的脱气处理以除去残余的EtO。更重要地是,EtO在存在水分的条件下杀死病原体的确切机制(核酸的断裂)也可能对敏感的化合物以及大多数生物分子有害。蛋白质、肽和基因产品最易于受EtO破坏。γ射线灭菌(其不涉及水分)能量极其强而不能用于对大多数含生物分子的装置和药物装置组合产品的灭菌。电子束灭菌(其为电子产生的γ辐射)也是高能量的,也已知对许多生物制剂有潜在的破坏。
环氧乙烷灭菌(与水蒸汽混合的EtO)已知能降低生物活性表面例如带肝素涂层的表面的活性。此外,在EtO处理中存在水蒸汽也已知对具有肝素表面的无菌医疗装置的储存寿命有负面影响。其他高能量处理方法(例如γ射线束和电子束灭菌处理方法)已显示可引起生物活性涂层的活性降低,参见(例如)美国专利No.6,787,179。
使用带肝素涂层的支架和EtO灭菌的经验已表明,在这种类型的灭菌处理中,其难以控制并且可引起肝素活性的显著降低。EtO还可引起肝素活性在不同制备位点波动。EtO灭菌条件的细微改变可导致肝素活性的宽泛变化并因此导致带肝素涂层的支架的出厂规格(release specification)和储存寿命宽泛变化。
在药物洗脱支架时代,肝素和其他生物活性涂层或表面与药物(例如西罗莫司)和药物载体(例如PLGA聚合物)非常接近。除了肝素对EtO敏感外,西罗莫司和可生物降解聚合物两者在处理后均已知可保留相当量的EtO。另外,PLGA通过EtO处理方法所需的水分进行的水解来降解。因此有利的是采用替代方法,例如电子束来最终对带肝素涂层的药物洗脱装置进行灭菌。在文献中,通常不建议采用高能量处理方法(例如电子束)来对含有生物制剂的医药和/或药物装置组合产品进行灭菌。相反,通过将昂贵的无菌生产、过滤/冻干工艺用于确保最终包装产品的无菌性。
鉴于常规灭菌法(包括环氧乙烷、电子束和γ辐射处理方法)的上述局限性,常规上已不将它们用于对含有生物活性组分例如肝素涂层的医疗装置进行灭菌。因此,存在对可确保医疗装置的无菌性和其生物涂层的活性两者的便利的最终灭菌处理方法的需要。
发明内容
本发明克服了上面简单描述的与当前采用的灭菌技术相关的局限性。
本发明涉及对医疗装置进行灭菌的方法和处理条件,所述灭菌包括如下步骤:在真空下以及使用干燥剂的条件下对具有生物活性肝素涂层的医疗装置进行包装和密封,以及用合适剂量的电子束处理对包装的医疗装置及其生物活性涂层进行灭菌。
本发明涉及电子束处理,电子束处理是通常用于对具有生物组分或不具生物组分的医用产品进行灭菌的高能量方法,可将其用于保持表面肝素涂层的生物活性。在最佳的范围内,电子束能量出乎意料地保持和恢复肝素涂层的生物学功能。该处理方法还可用作延长固定形式以及可能的游离形式的肝素的储存寿命。本发明在对带肝素涂层的医疗装置以及其他基于肝素的医药产品进行灭菌方面具有广泛的应用。
本发明还表明,电子束处理方法在进行正确控制时不仅可保持肝素涂层的生物活性,其还可逆转在涉及溶剂暴露和长时间在高温下干燥的药物洗脱支架制造处理过程中肝素活性的损失。在一控制实验中,还发现25KGy剂量的电子束处理恢复了肝素在长时间存储期间和/或在长时间存储后损失的生物活性。本发明因而可具有维持肝素处于其他形式的潜力,并且可成为通过用电子处理方法进行再次处理来延长产品储存寿命的简单方法。
附图说明
下文是附图所示的本发明优选实施例的更为具体的说明,通过这些说明,本发明的上述及其他特征和优点将显而易见。
图1是根据本发明的可扩张医疗装置的等轴视图。
图2是根据本发明的通过抗凝血酶剂III吸收测定法测量的电子束辐射对肝素活性的影响的图示。
图3是根据本发明的通过抗因子Xa测定法测量的电子束辐射对肝素活性的影响的图示。
图4是根据本发明的电子束辐射对肝素表面密度的影响的图示。
具体实施方式
本发明涉及通过电子束灭菌处理方法来解决破坏或降低与医疗装置相关的生物分子(例如肝素)的活性的长期存在的关键问题。其还远优于已知能严重降低肝素涂层的活性的更常规的灭菌技术(例如环氧乙烷灭菌)。
本发明的一个出人意料的发现是,利用该方法,医疗装置表面上的或医疗装置贮器中的肝素涂层不会如文献预测和其他人所报道的发生降低。通过改进的FXa结合测定法和抗凝血酶结合测定法二者测定的肝素活性在电子束处理后已始终显示出令人意外的与所用电子束剂量成比例的增加,随后将进行详细解释。
通常,本发明的处理方法包括将含有生物活性肝素表面的医疗装置与氮气和干燥剂在真空条件下进行包装,通过采用合适辐射剂量的电子束处理方法对该医疗装置进行灭菌。更具体地讲,要将待灭菌的装置包装于导管圈中以防止运送和搬运过程中的损坏。将每个导管圈单独密封于小袋中。当装置设置于小袋中时,抽吸真空并用非反应性气体例如氮气吹扫。再次抽取真空并密封该小袋。尽管该处理方法可用于任何数量的基材,但为了便于解释,所述处理的示例性实施例将就支架进行描述。
在本发明的一个示例性实施例中,基材材料可包括金属、非金属、聚合物或金属和聚合物两者的组合。在一个优选的示例性实施例中,基材材料选自不锈钢、铝、镍钛诺、钴铬和钛以及类似合金。在一个替代实施例中,所述材料选自玻璃、二氧化硅和陶瓷。一个优选的实施例包括还在撑条中具有储器的CoCr合金(L605)冠状动脉支架。
图1示出了具有多个孔的示例性可扩张医用装置或支架,所述多个孔容纳有由该可扩张医用装置递送至组织的有益剂。图1中所示的可扩张医疗装置100是从材料管截取而来以形成圆柱形可扩张装置。可扩张医疗装置100包括由多个桥接件104互连的多个圆柱形区段102。桥接件104使该组织支承装置在穿过脉管系统的曲折路径到达展开位点时能轴向弯曲,并且使该装置在需要与待支承的管腔的曲率相匹配时能轴向弯曲。每个圆柱区段102都由细长撑条108构成的网络来形成,所述细长撑条由可延展铰链110及环周撑条112互连。在医疗装置100扩张期间,可延展铰链110发生形变,而撑条108不会发生形变。
如图1所示,细长撑条108和环周撑条112包括开口114,开口中的一些容纳有用于递送至可扩张医疗装置所植入的管腔的有益剂。另外,装置100的其他部分(例如,桥接件104)也可包括开口。优选地,开口114设置在装置100的非形变部分(例如,撑条108)中,使得开口是非形变性的且在装置扩张期间能递送有益药剂而没有破碎、排出的风险或换句话说没有被损坏的风险。
通过使用有限元分析及用以优化有益药剂在开口114内的配置的其他技术,可进一步改进本发明所示的示例性实施例。基本上,可改变开口114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110有相对较高的强度和刚性。根据本发明的一个优选的示例性实施例,开口具有至少5×10-6平方英寸的面积,且优选具有至少7×10-6平方英寸的面积。通常,开口填充有约50%至约95%的有益剂。
本文描述的本发明的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剂,或者在某些开口中提供有益剂而不在其他的开口中提供有益剂。在其他实施例中,可在单个开口中利用有益剂或治疗剂的组合。可扩张医疗装置的具体结构可在不脱离本发明精神的情况下有所变化。由于每个开口是独立填充的,所以可给每个开口内的有益剂赋予单独的化学组成及药代动力学性质。
在本发明的另一个示例性实施例中,基材材料还可含有额外的聚合物材料,其用作用于控制医疗装置中或其上的药剂的释放的基质。聚合物可以是非降解性的,例如包括聚缩醛、聚氨酯、聚酯、聚四氟乙烯、聚乙烯、聚甲基丙烯酸甲酯、聚甲基丙烯酸羟乙酯、聚乙烯醇、聚丙烯、聚甲基戊烯、聚醚酮、聚苯醚、聚氯乙烯、聚碳酸酯、聚砜、丙烯腈丁二烯苯乙烯、聚醚酰亚胺、聚偏二氟乙烯和它们的共聚物及组合在内的聚合物。在本发明的另一个示例性实施例中,材料选自聚硅氧烷、氟化聚硅氧烷、乙丙橡胶、含氟弹性体以及它们的组合物。聚合物材料可以是生物降解性的或生物吸收性的,例如聚乳酸、聚乙醇酸、聚己内酯、聚对二氧环己酮(polyparadioxanone)、聚碳酸亚丙基酯(polytrimethylene carbonate)以及它们的共聚物、胶原、弹性蛋白、几丁质、珊瑚、透明质酸、骨、聚(己内酯)、乳酸-己内酯共聚物;聚(嵌段-环氧乙烷-嵌段-丙交酯-co-乙交酯)聚合物(PEO-b-PLGA和PEO-b-PLGA-b-PEO);泊洛沙姆聚(b-环氧乙烷-b-环氧丙烷-b-环氧乙烷);聚(原酸酯);多糖和多糖衍生物、聚(葡萄糖)、聚(藻酸)、壳聚糖、壳聚糖衍生物;多肽和蛋白质例如白蛋白、聚(赖氨酸)、聚(谷氨酸);聚(酸酐);聚(羟基链烷酸酯)例如聚(羟基戊酸酯)、聚(羟基丁酸酯)以及它们的组合。
在本发明的另一个示例性实施例中,医用装置还可含有额外的用于所述装置的抗感染抗性、抗微生物性和增加润滑性的生物活性材料。
在本发明的一个优选示例性实施例中,医疗装置包括肝素涂层并且其可具有额外的嵌入该装置中的或在其表面上的或在该装置结构中的储器和/或盲孔中的药物活性剂,所述额外的药物活性剂单独存在或与诸如聚合物之类的基质赋形剂相混合。所述药物活性剂可选自抗炎药物例如雷帕霉素(如西罗莫司)以及它们的各种衍生物和类似物;抗增殖药物例如紫杉醇以及它们的衍生物和类似物。
在一个优选的实施例中,生物活性涂层剂是未改性的肝素、部分降解的肝素、低分子量肝素(LMWH)或肝素的多种改性形式。可通过共价键合、缀合、末端连接、离子络合、与带正电荷盐的盐复合以及本领域技术人员已知的其他方法将肝素永久地连接至医用装置的表面。
在制备期间可使施加至材料的涂层共聚化并共价结合至材料表面。涂层的性质可以是亲水的或疏水的。这种聚合并接枝的涂层能抵抗水性移除(水性环境中的浸泡和冲洗和/或植入)并且可在使用前进行灭菌。然而,许多施加的在处理/制造期间未共价结合(以范德华相互作用、静电相互作用、表面张力结合)至材料表面的涂层不能抵抗水移除。
可聚合的涂层可通过进一步处理而共价结合至基材表面,而不可聚合的涂层将不会聚合或接枝到表面上。一进一步的处理步骤(发现可诱导涂层聚合/接枝到材料表面以及在一个步骤进行灭菌)是使用低温过氧化氢气体等离子体的灭菌处理。已与涂层聚合和接枝的材料应该也是使用过氧化氢气体等离子灭菌系统进行进一步灭菌处理的良好候选。
材料还可以是金属或非金属或弹性体。金属材料可由多种金属(包括但不限于不锈钢、铝、镍钛诺、钴、铬或钛构成。材料还可以是弹性体,包括但不限于聚硅氧烷、氟化聚硅氧烷、乙丙橡胶或含氟弹性体。基材还可以是无机物,包括但不限于玻璃、二氧化硅和陶瓷。材料还可以是生物衍生材料,包括但不限于胶原、弹性蛋白、透明质酸、骨、珊瑚或几丁质。
本发明的实用性和功效可通过多个实例进行阐述。
实例1
将具有图1所示设计的电抛光钴铬支架涂覆有与表面结合的肝素。该肝素涂层通过一系列中间层例如粘结层共价结合至支架表面。最终的肝素涂层用水进行重复洗涤,并且具有约13ug/cm2的恒定最终肝素表面密度。该肝素表面的活性通过竞争性抗凝血酶剂III结合测定法测定为约65pmol/cm2,通过改进的USP FXa抑制测定法测定为0.9个肝素单位/支架。
将这些带肝素涂层的支架的撑条中的储器通过喷墨(或“液态纳米沉积(liquid nano-deposition)”)工艺填充丙交酯-乙交酯共聚物(poly(lactide-co-glycolide),PLGA)和西罗莫司基质。在高温下干燥以从贮器中的PLGA/西罗莫司基质除去过量溶剂后,用气动式卷曲机将支架卷曲于匹配的导管球囊上并置于塑料托盘中。然后将该塑料支架托盘置于配备有干燥剂袋的铝袋中。然后用氮气吹扫该塑料托盘,并抽真空以除去任何剩余的气体和水分。重复该处理三次,通过热压密封机密封该袋。
然后通过电子束灭菌器以多种剂量:10KGy、25KGy和40KGy对该真空密封的装有干燥剂的袋进行灭菌。在该处理中使用了三个支架,用于在每个处理点和电子束剂量测定肝素密度和活性。将真空包装塑料袋中的具有肝素表面的支架取出用于肝素密度和活性测定。结果在图2(AT吸收法)和图3(FXa抑制测定法)示出。
图2中的数据清楚地表明,肝素活性有暂时降低,从约65降至约43pmol/cm2。该降低可能是由暴露于处理溶剂例如DMSO和用于驱除过量溶剂的高温而引起的。然而,一旦将支架与另外的干燥剂一起真空包装并通过电子束辐射进行灭菌,该肝素表面恢复其初始的活性。而且,还看起来与灭菌处理中所用的电子束剂量存在正相关性,较高的电子束剂量导致较高的肝素比活性。由于所有文献报道在进行高能量灭菌处理(例如γ射线和电子束灭菌)后会破坏或降低生物活性涂层的活性,这些发现是令人相当惊讶和出乎意料的。如图2所示,与在室温下存储的对照样品相比,精细控制条件下的电子束灭菌甚至实现了更高的AT吸收。该发现看起来表明,存在处理条件的组合,其中包装参数例如真空干燥的精细控制以及插入袋中额外的干燥剂将会防止肝素表面和类似生物活性表面在最终灭菌处理后损失其活性。随电子束剂量增加而增加的肝素活性有可能是由高能量灭菌期间肝素的构象变化引起的。后面的实验间接支持了这些假设,在这些实验中即使肝素表面不暴露于溶剂(DMSO、IPA等)和高温(55C),肝素涂层在电子束灭菌后也显示出较高的AT吸收活性。因而,存在一系列处理条件来确保医疗装置的无菌性和在常规灭菌处理(例如蒸汽、环氧乙烷或γ射线)的条件下易于降解的生物活性表面的活性。
用于肝素表面的改进的USP抗因子X测定法直接测量了肝素表面和从表面释放进测试溶液中的游离形式的肝素的组合能力。图3示出的数据表明,在当前的精细控制条件下的电子束处理可有效保持肝素活性甚至可逆转药物填装处理期间的肝素活性损失。该曲线在如下方面不同于图2中的趋势:与稍后制备阶段的产品相比,对照具有相对较低的抗FXa活性。该趋势指出了使用精细控制的包装和电子束处理来在最终的无菌产品中确保良好肝素活性的重要性。
图2和3中的数据指出了本发明的关键方面,在所述关键方面中肝素活性的剂量响应曲线可在最佳的包装和电子束灭菌处理后得以维持。可根据需要将较高剂量的电子束用于在最终的无菌包装中实现较高的肝素活性水平。由于对包装进行无菌密封,在各时长的存储后将电子束处理用于延长肝素表面的储存寿命是可行的。
图4中示出的结果显示,在电子束处理后肝素表面密度有逐步的降低,其中较高电子束剂量导致肝素密度损失较大。该发现是意料之内的,因为高能量电子束处理有可能引起表面的肝素发生一定的链烧灼,较高剂量导致肝素从支架表面脱离量较高。因而接下来本发明应该调节至最佳的范围,在该范围内可确保肝素活性同时使肝素含量损失程度最小。在所测试的范围中,肝素含量的损失没有影响剩下的肝素表面的肝素活性。25KGy的传统电子束剂量看起来处于可确保无菌性同时又维持高水平肝素活性的最佳范围之内。
实例2
在该研究中,让带肝素涂层的支架接受九个循环的DMSO暴露,其模拟制备药物洗脱支架中所用的药物填充处理的真实处理条件。在每次暴露后用例如如下条件的组合除去与支架表面上的肝素涂层混合的溶剂DMSO:在室温下或在55C下保持一小时,然后在室温下或在55C下进行二十四小时的退火。在这些长时间溶剂处理和移除步骤后,将带肝素涂层的支架与干燥剂一起真空包装并通过25KGy剂量的电子束处理进行灭菌。通过标准的AT III吸收测定法测定经历各种条件的支架的肝素活性。
表1.DMSO、温度和电子束组合对肝素活性的影响
测试组 | 处理 | 测试 |
表1中的数据说明,与对照肝素表面51pmol/cm2的基线AT吸收值相比,在高温(55C)下长时间干燥可降低肝素活性至约39pmol/cm2。该数据还表明,仅暴露于DMSO在随后将其完全除去后看似不会影响肝素活性。数据证实,电子束灭菌处理可有效用于在室温(B组对E组)以及较高温度(C组对F组)二者下干燥后维持肝素活性。数据还证实,电子束灭菌甚至恢复了在将涂层在室温下存储长时间后损失的肝素活性(A组(对照)对电子束处理对照(D组))。根据这些发现,我们有理由提出本发明可用于在各存储期后恢复包装的医疗装置上的肝素活性。
尽管所示和所述的据信是最为可行和优选的实施例,但显然,对所述和所示的具体设计和方法的改变对本领域技术人员来说是显而易见的,并且可在不脱离本发明精神和范围的情况下使用这些变更形式。本发明不局限于所述和所示的具体构造,而是应该理解为与可能落入所附权利要求书的范围内的全部修改形式一致。
Claims (9)
1.一种对具有肝素涂层的医疗装置进行灭菌的方法,其中用药物填充过程将所述肝素涂层施加至医疗装置,所述方法包括如下步骤:
将所述医疗装置置于具有干燥剂的包装中;
用非反应性气体吹扫所述包装至少一次;
在所述包装内产生真空至少一次以除去任何剩余的气体和水分;
密封所述包装;以及
使所述包装和所述医疗装置暴露于一个或多个剂量的电子束辐射,持续预定的一段时间并且处于预定的剂量水平和温度下,所述一个或多个剂量的电子束辐射逆转该肝素涂层的药物填充过程期间的肝素活性损失。
2.根据权利要求1所述的方法,其中所述装置选自心血管、血管内和神经血管支架;心血管、血管内和神经血管药物洗脱支架;血管内移植物;血管和静脉支架移植物;血管成形术球囊;动静脉分流、氧合器、人造心脏膜及辅助装置;腹主动脉瘤装置。
3.根据权利要求1所述的方法,其中所述医疗装置包含选自如下的材料:不锈钢、铝、镍钛诺、钴铬和钛以及它们的合金。
4.根据权利要求1所述的方法,其中所述医疗装置另外还包含选自如下的材料:聚缩醛、聚氨酯、聚酯、聚四氟乙烯、聚乙烯、聚甲基丙烯酸甲酯、聚甲基丙烯酸羟乙酯、聚乙烯醇、聚丙烯、聚甲基戊烯、聚醚酮、聚苯醚、聚氯乙烯、聚碳酸酯、聚砜、丙烯腈-丁二烯-苯乙烯、聚醚酰亚胺、聚偏二氟乙烯,以及它们的共聚物和组合。
5.根据权利要求1所述的方法,其中所述医疗装置另外还包含选自如下的材料:聚乳酸、聚乙醇酸、丙交酯-乙交酯共聚物、聚己内酯、聚对二氧环己酮、聚碳酸亚丙基酯以及它们的共聚物、胶原、弹性蛋白、几丁质、珊瑚、透明质酸、骨以及它们的组合。
6.根据权利要求1所述的方法,其中所述肝素选自未分级肝素、部分解聚的肝素、低分子量肝素(LMWH),和其他化学或生物改性的肝素。
7.根据权利要求1所述的方法,其中所述电子束剂量在10KGy至40KGy之间。
8.根据权利要求1所述的方法,其中所述医疗装置另外还含有药物活性组分。
9.根据权利要求8所述的方法,其中所述药物选自由雷帕霉素、紫杉醇及衍生物组成的抗增殖剂。
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- 2010-10-12 EP EP10187304.0A patent/EP2322230B1/en not_active Not-in-force
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CN102058893A (zh) | 2011-05-18 |
JP2011104369A (ja) | 2011-06-02 |
EP2322230B1 (en) | 2013-05-01 |
BRPI1012815A2 (pt) | 2013-05-14 |
RU2010146515A (ru) | 2012-05-20 |
US8887477B2 (en) | 2014-11-18 |
AU2010226993A1 (en) | 2011-06-02 |
ES2413655T3 (es) | 2013-07-17 |
CA2718605C (en) | 2017-07-04 |
JP5901876B2 (ja) | 2016-04-13 |
MX2010012497A (es) | 2011-05-25 |
KR101726199B1 (ko) | 2017-04-12 |
RU2591829C2 (ru) | 2016-07-20 |
CA2718605A1 (en) | 2011-05-16 |
KR20110053909A (ko) | 2011-05-24 |
US20110113728A1 (en) | 2011-05-19 |
BRPI1012815B1 (pt) | 2019-02-12 |
IL208542A (en) | 2014-05-28 |
AU2010226993B2 (en) | 2015-08-13 |
EP2322230A1 (en) | 2011-05-18 |
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