CN112972828A - 注射器 - Google Patents
注射器 Download PDFInfo
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- CN112972828A CN112972828A CN202110166906.0A CN202110166906A CN112972828A CN 112972828 A CN112972828 A CN 112972828A CN 202110166906 A CN202110166906 A CN 202110166906A CN 112972828 A CN112972828 A CN 112972828A
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Abstract
本发明涉及一种注射器,特别是一种小体积注射器诸如适合眼科注射用的注射器。具体而言,本发明中提供了一种用于玻璃体内注射的预填充注射器,所述注射器包括本体、止挡件及柱塞;以及采用所述注射器给予眼病患者以治疗眼病的抗体VEGF拮抗剂。
Description
技术领域
本发明涉及一种注射器,特别是一种小体积注射器诸如适合眼科注射的注射器。
现有技术
许多药物是由使用者可自其分配药物的注射器递送给患者。若以注射器形式将药物递送给患者,通常使患者或护理者能够注射药物。注射器及注射器的内容物经充分灭菌以避免感染或带给患者其他风险,这对于患者安全及药物完整性而言是重要的。灭菌可借由终端灭菌而实现,其中利用热量或灭菌气体对一般已经呈其相关包装的组装产品灭菌。
对于小体积注射器,例如用于注入眼中的注射器等,其中欲注射约0.1ml或更少的液体,灭菌可造成未必与更大注射器相关的困难。注射器内部或外部的压力变化可导致注射器的部件不可预料地移动,其可改变密封特性及潜在地降低无菌性。不正确地处理注射器也可给产品无菌性造成风险。
而且,某些治疗剂诸如生物分子尤其对灭菌(其为冷气体灭菌、热灭菌或辐射)敏感。因此,要求小心地平衡操作以确保在进行适当程度的灭菌时,注射器保持适宜地密封,从而不损害治疗剂。当然,注射器也必须容易使用,表现在按压柱塞以施用药物所需的力必须不过大。
因此,需要一种新颖注射器结构,其为其内容物提供强密封且保持使用便利。
发明内容
本发明提供一种预填充注射器,该注射器包括本体、止挡件及柱塞,该本体包括位于出口端的出口及该止挡件配置在该本体内使得该止挡件的前表面及该本体界定一流体可透过该出口排出的可变体积室,该柱塞包括位于第一端的柱塞接触表面及在该柱塞接触表面与尾部之间延伸的杆,该柱塞接触表面经配置以与该止挡件接触,使得该柱塞可用于迫使止挡件朝向本体出口端移动,从而减少该可变体积室的体积,其特征在于该流体包括眼科用溶液。在一个实施方案中,该眼科用溶液包括VEGF-拮抗剂。
在一个实施方案中,注射器适合用于眼科注射,更具体而言,适用于玻璃体内注射,及因此具有适宜的小体积。注射器也可不含硅油,或实质上不含硅油,或可包含作为润滑剂的低含量的硅油。在一个实施方案中,尽管存在低含量的硅油,止挡件松脱及滑动力小于20N。
对于眼科注射,含有特低的颗粒内容物对于眼科用溶液尤其重要。在一个实施例中,该注射器符合美国药典标准(US Pharmacopeia standard)789(USP789)。
注射器
注射器的本体可为实质上圆柱形壳,或可包括具有非圆形外部形状的实质上圆柱形孔。本体的出口端包括出口,通过该出口,容纳在可变体积室中的流体随着该室的体积减小而排出。出口可包括自出口端的突出物,通过其延伸具有比可变体积室的直径更小直径的通道。可调整该出口,例如经由鲁尔锁(luer lock)型连接件,以连接至针头或其他附件,诸如能够密封可变体积室但可以操作或移除以对可变体积室去封闭及容许注射器与另一附件(诸如针头)连接的密封装置。可在注射器与附件之间直接或经由密封装置形成该连接。本体沿第一轴从出口端延伸至尾端。
本体可由塑料材料(例如环状烯烃聚合物)或玻璃制成,且在其表面上可包括标记以充当注射导引。在一个实施方案中,本体可包括加注(priming)标示。这容许内科医生将止挡件的预定部分(诸如本文随后讨论的前表面的末端或圆周棱之一)或柱塞与标示对准,因此从注射器排出多余的眼科用溶液及任何气泡。加注处理可以确保将精确、预定剂量施用至患者。
止挡件可由橡胶、硅或其他适宜的弹性上不可变形材料制成。止挡件可为实质上圆柱形,且围绕止挡件的外表面可包括一或多个圆周棱,该止挡件与棱经尺寸化,使得棱与注射器本体的内表面形成实质上不透流体的密封。止挡件的前表面可为任何适宜的形状,例如实质上呈平面的、实质上圆锥形或半球形。止挡件的后表面可包括实质上居中的凹陷。该中央凹陷可用于以已知的方式,利用搭扣配合零件或螺纹连接来连接柱塞。止挡件可实质上关于通过止挡件的轴旋转对称。
柱塞包括柱塞接触表面及自其延伸的杆,该杆从该柱塞接触表面延伸至尾部。该尾部可包括经调适以由使用者在注射事件期间接触的使用者接触部分。该使用者接触部分可包括实质上圆盘形部分,该圆盘的半径实质上垂直于杆延伸所沿的轴而延伸。使用者接触部分可为任何适宜的形状。杆延伸所沿的轴可为第一轴,或可实质上与第一轴平行。
注射器可包括配置在本体尾部的后挡块。该后挡块可从注射器移除。若注射器本体在与出口端相对的末端包括终端凸缘,该后挡块可经配置以实质上包夹本体的终端凸缘,这样可以预防后挡块以平行于第一轴的方向移动。
杆可包括至少一个背向出口端的杆肩,且后挡块可包括一个朝向出口端的后挡块肩,从而在后挡块肩及杆肩接触时,后档块肩与杆肩配合以实质上预防杆远离出口端方向移动。杆远离出口端方向的移动的限制可有助于在终端灭菌操作或可变体积室内或室外压力可发生变化的其他操作期间维持无菌性。在这些操作期间,可变体积室内包含的任何气体,或在其中液体中可形成的气泡可改变体积,且因此导致止挡件移动。止挡件远离出口的移动可导致破坏由止挡件创建的无菌区。这对于组件尺寸允许非常低的偏差且止挡件存在更低灵活性的低体积注射器而言尤其重要。文中所用的术语无菌区用于指代由止挡件所密封而无法自注射器任一端进入的注射器内的区域。这可以是离出口最接近的止挡件的密封件(例如圆周棱)与离出口最远的止挡件的密封件(例如圆周棱)之间的区域。由于止挡件在无菌环境中安装于注射器筒内,介于该两个密封件之间的距离界定该止挡件的无菌区。
为进一步有助于在上述操作期间维持无菌性,止挡件可包括前圆周棱及后圆周棱,且该些棱可沿第一轴的方向分隔至少3mm、至少3.5mm、至少3.75mm或4mm或更大。可在该前棱及后棱之间配置一个或多个额外的棱(例如2、3、4或5个额外的棱,或1至10个、2至8个、3至6个或4至5个额外的棱)。在一个实施方案中,一共存在3个圆周棱。
具有该增强无菌区的止挡件也可在终端灭菌处理期间为可注射药物提供保护。止挡件上的更多的棱或介于前棱与后棱之间的更远的距离可减少药物与灭菌剂潜在的接触。然而,增加棱数可增加止挡件与注射器本体之间的摩擦,降低使用的便利性。尽管这可以通过增加注射器的硅化而克服,但是硅油含量的增加对于眼科用注射器尤其是不希望的。
杆肩可配置在杆的外径内或可配置在杆的外径外。通过提供延伸超过杆的外径但仍然适配在本体内的肩,该肩可通过减少杆垂直于第一轴的移动而有助于稳定杆在本体内移动。杆肩可包括杆上的任何适宜的肩形成组件,而在一个实施方案中,杆肩包括位于杆上的实质上圆盘形的部件。
在注射器的一个实施方案中,当以柱塞接触表面与止挡件接触及可变体积室处于其预期的最大体积配置时,在杆肩与后挡块肩之间存在不大于约2mm的空隙。在一些实施方案中,存在小于约1.5mm的空隙及在一些实施方案中,小于约1mm的空隙。选择该距离以实质上限制或预防止挡件朝后(远离出口端的方向)过度移动。
在一个实施方案中,可变体积室具有大于5mm或6mm、或小于3mm或4mm的内径。内径可介于3mm与6mm之间或介于4mm与5mm之间。
在另一实施方案中,注射器经尺寸化以具有介于约0.1ml与约1.5ml之间的标称最大填充体积。在某些实施方案中,标称最大填充体积为介于约0.5ml与约1ml之间。在某些实施方案中,标称最大填充体积为约0.5ml或约1ml、或约1.5ml。
注射器本体的长度可为小于70mm、小于60mm或小于50mm。在一个实施方案中,注射器本体的长度为介于45mm与50mm之间。
在一个实施方案中,注射器填充有介于约0.01ml与约1.5ml之间(例如,介于约0.05ml与约1ml之间、介于约0.1ml与约0.5ml之间、介于约0.15ml与约0.175ml之间)的VEGF拮抗剂溶液。在一个实施方案中,注射器填充有0.165ml的VEGF拮抗剂溶液。当然,考虑到因注射器与针头内的“死角”的浪费,一般以多于待施用至患者要求的剂量来填充注射器。当内科医生加注注射器以准备注射患者时,也可能存在特定量的浪费。
因此,在一个实施方案中,注射器填充有介于约0.01ml与约1.5ml之间(例如介于约0.05ml与约1ml之间、介于约0.1ml与约0.5ml之间)的剂量体积(即欲递送给患者药物的体积)的VEGF拮抗剂溶液。在一个实施方案中,剂量体积为介于约0.03ml与约0.05ml之间。例如,对于诺适得(Lucentis),剂量体积为0.05ml或0.03ml(0.5mg或0.3mg)的10mg/ml可注射药物溶液;对于阿柏西普(Eylea),剂量体积为0.05ml的40mg/ml可注射药物溶液。尽管未经批准用于眼科适应症,但贝伐单抗(bevacizumab)被超适应症(off-label)使用,以25mg/ml的浓度,一般以0.05ml(1.25mg)的剂量体积用于眼科适应症中。在一个实施方案中,从注射器的可提取体积(考虑因注射器与针头的死角引起的损失,其为填充后可从注射器获取的产品的量)为约0.09ml。
在一个实施方案中,注射器本体的长度为介于约45mm与约50mm之间,内径为介于约4mm与约5mm之间,填充体积为介于约0.12与约0.3ml之间及剂量体积为介于约0.03ml与约0.05ml之间。
由于注射器包含药物溶液,可以可逆地密封出口以维持药物的无菌性。可通过使用本领域已知的密封装置来实现该密封。例如,可从Vetter Pharma International GmbH获得的OVSTM系统。
一般可硅化注射器以实现使用的便利,即将硅油应用至筒的内部,其可减少移动止挡件所需的力。然而,对于眼科应用,希望减少将硅油滴注入眼睛的可能性。在多次注射下,硅滴的量可在眼中积聚,导致潜在的不良反应,包括“漂浮物(floaters)”及眼内压的增加。而且,硅油可导致蛋白质聚集。尽管制造商的调查报道预填充注射器中一般使用500至1000μg硅油(Badkar等人,2011,AAPS PharmaSciTech,12(2):564-572),但典型的1ml注射器在筒中包括100至800μg的硅油。因此,在一个实施方案中,根据本发明的注射器在筒中包括小于约800μg(即约小于约500μg、小于约300μg、小于约200μg、小于约100μg、小于约75μg、小于约50μg、小于约25μg、小于约15μg、小于约10μg)的硅油。若注射器包括低含量的硅油,其在筒中可包含多于约1μg、多于约3μg、多于约5μg、多于约7μg或多于约10μg的硅油。因此,在一个实施方案中,注射器在筒中可包括约1μg至约500μg、约3μg至约200μg、约5μg至约100μg或约10μg至约50μg的硅油。测量该注射器筒中的硅油的含量的方法在本领域是已知的,且包括例如差示测重法及借由对稀释于适当溶剂中的油的红外线光谱法的定量法。可获得各种类型的硅油,但DC360(Dow具有1000cP的黏度)或DC365乳液(Dow具有350cP的黏度的DC360油)一般用于注射器硅化。在一个实施方案中,本发明的预填充注射器包括DC365乳液。
在测试期间出人意料地发现,对于具有小尺寸的注射器(诸如以讨论的注射器,及尤其是以下结合附图描述的注射器),通过将硅化程度减少至远低于当前标准的本文中讨论的程度,未实质上影响注射器内的止挡件的松脱及滑动力。这与常规思维相反,常规思维建议若降低硅油含量,所需要的力会增加(参见例如Schoenknecht,AAPS NationalBiotechnology Conference 2007–摘要号NBC07-000488,其表明尽管400μg硅油为可接受的,当增加至800μg时可改进使用性能)。移动止挡件所需的力过大对于一些使用者在使用期间可带来问题,例如,若需要明显的强度来移动及/或保持移动止挡件,则可使得精确的剂量设定或顺利的剂量递送更加困难。顺利的施用在敏感组织诸如眼睛中特别重要,其中注射器在施用期间移动会导致局部组织损伤。本领域已知的用于预填充注射器的松脱及滑动力一般为小于20N的范围,但其中预填充注射器包含约100μg至约800μg的硅油。在一个实施方案中,预填充注射器内的止挡件的滑移/滑动力为小于约11N或小于9N、小于7N、小于5N或介于约3N至5N之间。在一个实施方案中,松脱力为小于约11N或小于9N、小于7N、小于5N或介于约2N至5N之间。注意:所述测量值为针对已填充注射器而非空注射器。一般在190mm/min的止挡件移动速度下测量所述力。在一个实施方案中,以连接至注射器的30G x 0.5英寸针头测量力。在一个实施方案中,注射器具有介于约0.5ml与1ml之间的标称最大填充体积,包含小于约100μg的硅油及具有介于约2N至5N之间的松脱力。
在一个实施方案中,注射器筒包括具有平均厚度约450nm或更小(即400nm或更小、350nm或更小、300nm或更小、200nm或更小、100nm或更小、50nm或更小、20nm或更小)的硅油的内部涂层。测量注射器中的硅油厚度的方法在本领域是已知的且包括rap.ID LayerApplication,其也可用于测量注射器筒内硅油的质量。
在一个实施方案中,注射器不含硅油,或实质上不含硅油。可利用未涂布的注射器筒及/或通过避免使用硅油作为产品接触机械部件、注射器组装件中的泵及填充管线的润滑剂而实现该低硅油含量。另一种减少预填充注射器中硅油及无机二氧化硅含量的方法为避免使用填充管线中的硅管,例如在储存罐及泵之间。
根据本发明的注射器也可满足针对颗粒物内容物的某些要求。在一个实施方案中,眼科用溶液每毫升包括不超过2个直径≥50μm的颗粒。在一个实施方案中,眼科用溶液每毫升包括不超过5个直径≥25μm的颗粒。在一个实施方案中,眼科用溶液每毫升包括不超过50个直径≥10μm的颗粒。在一个实施方案中,眼科用溶液每毫升包括不超过2个直径≥50μm的颗粒、每毫升包括不超过5个直径≥25μm的颗粒及每毫升包括不超过50个直径≥10μm的颗粒。在一个实施方案中,根据本发明的注射器符合USP789(美国药典:眼科用溶液中的颗粒物质(United States Pharmacopoeia:Particulate Matter in OphthalmicSolutions))。在一个实施方案中,该注射器具有使注射器足以符合USP789的低含量的硅油。
VEGF拮抗剂
抗体VEGF拮抗剂
非抗体VEGF拮抗剂
在本发明的一个方面中,非抗体VEGF拮抗剂为免疫黏附素。一种该免疫黏附素为阿柏西普(aflibercept)其近期已被批准供人类使用且也称为VEGF捕获剂(Holash等人,(2002)PNAS USA 99:11393-98;Riely&Miller(2007)Clin Cancer Res 13:4623-7s)。阿柏西普是在本发明中使用的优选的非抗体VEGF拮抗剂。阿柏西普为一种重组人类可溶性VEGF受体融合蛋白,其由融合至人类IgG1的Fc部分的人类VEGF受体1及2细胞外结构域组成。其为具有97千道尔顿(kDa)的蛋白质分子量的二聚糖蛋白且包含糖基化,该糖基化构成额外15%的总分子量,产生115kDa的总分子量。其通常借由在重组CHO K1细胞中表达而以糖蛋白形式产生。各单体可具有下列氨氨基酸序列(SEQ ID NO:1):
且在各单体内的残基30-79、124-185、246-306及352-410之间及单体之间的残基211-211及214-214之间可形成二硫键。
当前在临床前开发中的另一非抗体VEGF拮抗剂为一种类似于VEGF捕获剂的重组人类可溶性VEGF受体融合蛋白质,其包含来自VEGFR2/KDR的细胞外配体结合结构域3及4,及来自VEGFR1/Flt-1的结构域2;这些结构域融合至人类IgG Fc蛋白质片段(Li等人,2011Molecular Vision 17:797-803)。该拮抗剂可结合至亚型VEGF-A、VEGF-B及VEGF-C。利用两种不同的制法制备该分子,在最终蛋白质中产生不同的糖基化模式。两种糖型指KH902(康柏西普(Conbercept))及KH906。融合蛋白可具有下列氨氨基酸序列(SEQ ID NO:2):
及如同VEGF捕获剂,可以二聚体存在。EP1767546中进一步表征该融合蛋白及相关分子。
其他非抗体VEGF拮抗剂包括具有VEGF拮抗剂活性的抗体拟似物(例如分子、泛素(affilin)、阿非廷(affitin)、抗卡林(anticalin)、阿非莫(avimer)、库尼兹(Kunitz)结构域肽及单体(monobodies))。这包括含有结合VEGF-A并预防其结合至VEGFR-2的锚蛋白重复结构域的重组结合蛋白。该分子的一个实例为MP0112。锚蛋白结合结构域可具有下列氨氨基酸序列(SEQ ID NO:3):
包括结合VEGF-A并预防其结合至VEGFR-2的锚蛋白重复结构域的重组结合蛋白更详细地叙述于WO2010/060748及WO2011/135067中。
具有VEGF拮抗剂活性的其他特异性抗体拟似物为40kD聚乙二醇化抗卡林PRS-050及单体安吉赛特(angiocept)(CT-322)。
可修饰前述非抗体VEGF拮抗剂以进一步改进其药代动力学性质或生物可利用度。例如,可化学修饰(例如聚乙二醇化)非抗体VEGF拮抗剂以延长其体内半衰期。或者或另外,其可通过糖基化作用或在VEGF拮抗剂所来源的天然蛋白质的蛋白质序列中增加原本不存在的其他糖基化位点而修饰。
可通过增加或删除氨氨基酸生成具有针对所需应用的改进特性的上述VEGF拮抗剂的变体。这些氨氨基酸序列变体通常包括具有与SEQ ID NO:1、SEQ ID NO:2或SEQ IDNO:3的氨氨基酸序列至少60%氨氨,优选至少80%,更优选至少85%,更优选至少90%及最优选至少95%,包括例如80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%及100%的氨基酸序列一致性的氨基酸序列。与该序列的一致性或同源性在此定义为在比对序列及视需要引入空隙以实现最大百分比的序列一致性,及不考虑任何保守取代作为序列一致性的部分之后,候选序列的氨氨基酸残基与SEQ ID NO:1、SEQ ID NO:2或SEQ ID NO:3一致的百分比。
序列一致性可以通过通常用于比较两个多肽的氨基酸的位置的相似性的标准方法而测定。利用计算器程序诸如BLAST或FASTA,比对两个多肽以最佳地匹配其各自的氨基酸(沿1或2个序列的全部长度或沿1或2个序列的预定部分)。程序提供默认开放罚分及预设空隙罚分,及计分矩阵,诸如PAM 250[一种标准计分矩阵;参见Dayhoff等人于Atlas ofProtein Sequence and Structure,第5卷,supp.3(1978)]可与计算器程序联合使用。例如,百分比一致性可被计算成:一致匹配氨基酸的总数×100,接着除以匹配跨度内更长序列的长度与引入更长序列内以比对两个序列的空隙的数目的总和。
本发明的非抗体VEGF拮抗剂优选地经由一或多个非来源于抗体的抗原结合结构域的蛋白质结构域结合至VEGF。本发明的非抗体VEGF拮抗剂优选地是蛋白质的,但可包括非蛋白质的修饰(例如聚乙二醇化作用、糖基化作用)。
治疗
本发明的注射器可用于治疗眼病,包括但不限于脉络膜血管新生、年龄相关的黄斑变性(湿性及干性形式)、继发于视网膜静脉梗阻(RVO)(包括分支RVO(bRVO)及中央RVO(cRVO))的黄斑水肿、继发于病理性近视(PM)的脉络膜血管新生、糖尿病性黄斑水肿(DME)、糖尿病性视网膜病及增生性视网膜病。
因此,本发明提供一种治疗患有选自如下眼病的患者的方法:脉络膜血管新生、湿性年龄相关的黄斑变性、继发于视网膜静脉梗阻(RVO)(包括分支RVO(bRVO)及中央RVO(cRVO))的黄斑水肿、继发于病理性近视(PM)的脉络膜血管新生、糖尿病性黄斑水肿(DME)、糖尿病性视网膜病及增生性视网膜病,其包括利用本发明的预填充注射器施用眼科用溶液至该患者的步骤。该方法优选地进一步包括初期的加注步骤,其中内科医生按压预填充注射器的柱塞以将止挡件的预定部分与加注标示对准。
在一个实施方案中,本发明提供一种治疗选自如下眼病的方法:脉络膜血管新生、湿性年龄相关的黄斑变性、继发于视网膜静脉梗阻(RVO)(包括分支RVO(bRVO)及中央RVO(cRVO))的黄斑水肿、继发于病理性近视(PM)的脉络膜血管新生、糖尿病性黄斑水肿(DME)、糖尿病性视网膜病及增生性视网膜病,其包括利用本发明的预填充注射器施用非抗体VEGF拮抗剂,其中该患者先前已经接受抗体VEGF拮抗剂的治疗。
试剂盒
也提供包括本发明的预填充注射器的试剂盒。在一个实施方案中,该试剂盒包括在泡罩包装中的本发明的预填充注射器。该泡罩包装自身可在内部经过灭菌。在一个实施方案中,根据本发明的注射器可在进行灭菌(例如终端灭菌)之前放置在该泡罩包装内。
该试剂盒可进一步包括用于VEGF拮抗剂给药的针头。若经玻璃体内施用VEGF拮抗剂,则一般使用30号x1/2英寸针头,尽管可使用31号及32号针头。对于玻璃体内施用,也可使用33号或34号针头。该试剂盒可进一步包括使用说明书。在一个实施方案中,本发明提供包含含于泡罩包装内的根据本发明的预填充注射器、针头及任选的给药说明书的纸盒。
灭菌
如上所述,可使用终端灭菌法以对注射器灭菌及该方法可使用已知的方法诸如环氧乙烷(EtO)或过氧化氢(H2O2)灭菌法。与注射器一起使用的针头可通过相同方法灭菌,根据本发明的试剂盒也可如此。
将包装暴露于灭菌气体中直到注射器的外部被灭菌。该处理之后,注射器的外表面可保持灭菌(当在其气泡包装内时)长达6个月、9个月、12个月、15个月、18个月、24个月或更长。因此,在一个实施方案中,根据本发明的注射器(当在其气泡包装内时)可具有长达6个月、9个月、12个月、15个月、18个月、24个月或更长的保质期。在一个实施方案中,小于百万分之一的注射器在18个月的储存之后可检测到注射器的外部存在微生物。在一个实施方案中,利用EtO,以至少10-6的无菌性保证水平给预填充注射器灭菌。在一个实施方案中,利用过氧化氢,以至少10-6的无菌性保证水平给预填充注射器灭菌。当然,要求不应当有显著量的灭菌气体进入注射器的可变体积室。文中所用的术语“显著量”指可导致可变体积室内的眼科用溶液发生不可接受的改变的气体量。在一个实施方案中,灭菌法导致≤10%(优选地≤5%、≤3%、≤1%)的VEGF拮抗剂烷基化。在一个实施方案中,预填充注射器已经利用EtO灭菌,但注射器的外表面具有≤1ppm,优选地≤0.2ppm EtO残留物。在一个实施方案中,预填充注射器已经利用过氧化氢灭菌,但注射器的外表面具有≤1ppm,优选地≤0.2ppm过氧化氢残留物。在另一实施方案中,预填充注射器已经利用EtO灭菌,及在注射器的外表面及泡罩包装的内部发现的总EtO残留物为≤0.1mg。在另一实施方案中,预填充注射器已经利用过氧化氢灭菌,及在注射器的外表面及气泡包装的内部发现的总过氧化氢残留物为≤0.1mg。
综述
术语“包含”意味着“包括”以及“由……组成”,例如一种组合物“包含”X,其可排他性地由X组成或可包括其他,例如X+Y。
与数值x有关的术语“约”意指例如x±10%。
对两个氨基酸序列之间的序列百分比一致性的引用意味着,当比对时,在比较两个序列时相同氨基酸的百分比。该比对及同源性百分比或序列一致性可利用本领域已知的软件程序测定,例如描述于Current Protocols in Molecular Biology(F.M.Ausubel等人编辑,1987)增刊30的章节7.7.18中的软件程序等。一种优选的比对为通过Smith-Waterman同源性检索算法,利用具有12的空隙开放罚分和2的空隙延伸罚分、62的BLOSUM矩阵的仿射空隙检索而测定。Smith&Waterman(1981)Adv.Appl.Math.2:482-489中披露了Smith-Waterman同源性检索算法。
附图简要说明
图1显示注射器的侧视图。
图2显示注射器的俯视图的截面。
图3显示柱塞图。
图4显示柱塞的截面。
图5显示止挡件。
具体实施方式
现将通过举例的方式,参考附图进一步描述本发明。
图1显示注射器1的侧视图,该注射器包括本体2、柱塞4、后挡块6及密封装置8。
图2显示上图1注射器1的截面。注射器1适合用于眼科用注射中。注射器1包括本体2、止挡件10及柱塞4。注射器1沿第一轴A延伸。本体2包括位于出口端14的出口12,且止挡件10配置在本体2内,由此止挡件10的前表面16及本体2界定可变体积室18。可变体积室18包括可注射药物20,其包括含有VEGF拮抗剂诸如雷珠单抗的眼科用溶液。可通过将止挡件10朝出口端14移动由此减少可变体积室18的体积,来通过出口12排出可注射流体20。柱塞4包括位于第一端24的柱塞接触表面22及在柱塞接触表面22与尾部25之间延伸的杆26。柱塞接触表面22经配置以与止挡件10接触,使得柱塞4可用于将止挡件10朝本体2的出口端14方向移动。该移动减少可变体积室18的体积及导致其中的流体通过出口排出。
后挡块6通过偶合至本体2的终端凸缘28而连接至本体2。后挡块6包括经调适以实质上包夹本体2的至少一部分终端凸缘28的包夹部分30。后挡块6经调适,以通过留下后挡块6的一侧开口而从侧面偶合至本体2以使后挡块6可适配于注射器2。
本体2界定具有孔半径的实质上圆柱形孔36。杆26包括远离出口端14方向的杆肩32。杆肩32从第一轴A延伸至杆肩半径,其为使得其略小于孔半径从而该肩可以安装在孔36内者。后挡块6包括朝出口端14方向的后挡块肩34。肩32、34经构建以在后挡块肩34及杆肩32接触时配合以实质上预防杆26远离出口端14方向移动。后挡块肩34由孔半径的外部延伸至小于杆肩半径的半径,使得杆肩32无法通过沿第一轴A移动而越过后挡块肩34。在该情形下,杆肩32实质上为圆盘或环形,且后挡块肩34包括围绕本体2的尾端38的弧形件。
后挡块6也包括两个指状突出物40,其以远离本体2相反方向、与第一轴A实质上垂直地延伸以利于在使用期间对注射器1的手工操作。
在该实例中,注射器包括0.5ml本体2,其填充有介于约0.1与0.3ml之间的可注射药物20,该药物包括10mg/ml的含有雷珠单抗的可注射溶液。注射器本体2具有介于约4.5mm与4.8mm之间的内径、介于约45mm与50mm之间的长度。
将参考后面的附图更详细地描述柱塞4及止挡件10。
图3显示图1柱塞4的透视图,其显示位于柱塞4的第一端24的柱塞接触表面22。杆26从第一端24延伸至尾部25。尾部25包括圆盘形凸缘42以利于用户操作装置。凸缘42提供比杆26的裸端更大的供使用者接触的表面积。
图4显示通过注射器本体2及杆26的横截面。杆26包括四个纵向棱44,且棱之间的角度为90°。
图5显示止挡件10的详细视图,其显示圆锥形前表面16及围绕实质上圆柱形本体58的三个圆周棱52、54、56。介于第一棱52与最后棱56之间的轴向空隙为约3mm。止挡件10的后表面60包括实质上居中的凹陷62。中央凹陷62包括具有第一直径的初始孔64。初始孔64由后表面60深入止挡件10至具有第二直径的内部凹陷66,该第二直径大于第一直径。
止挡件移动力
对利用<100μg硅油进行硅化、经诺适得(Lucentis)填充及包括两种不同止挡件设计中之一的0.5ml注射器测试最大及平均松脱及滑动力。测试之前,将30G x0.5"针头连接至注射器。在190mm/min的止挡件速度下,移动10.9mm长度而进行测试。止挡件设计2在前圆周棱及后圆周棱之间的距离增加45%。
对于两种止挡件设计,平均及最大松脱力保持在3N以下。对于两种止挡件设计,平均及最大滑动力保持在5N以下。
应理解,本发明已经仅通过举例的方式加以描述,可进行改变而不超出本发明的范围及精神。
序列表
<110> 诺华股份有限公司(NOVARTIS AG)
<120> 注射器
<130> PAT055157-CN-PCTD03
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<170> PatentIn 3.5版
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<213> 人工序列
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<223> 阿柏西普
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His Leu Glu Ile Val Glu Val Leu Leu Lys Tyr Gly Ala Asp Val Asn
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Claims (13)
1.一种用于玻璃体内注射的预填充注射器,所述注射器包括本体、止挡件及柱塞,其中:
所述本体包括位于出口端的出口,及所述止挡件经配置在所述本体内使得所述止挡件的前表面及所述本体界定流体可通过所述出口排出的可变体积室,所述柱塞包括位于第一端的柱塞接触表面及在所述柱塞接触表面与尾部之间延伸的杆,所述柱塞接触表面经配置以与所述止挡件接触,使得所述柱塞可被用于迫使所述止挡件向所述本体的所述出口端方向移动,从而减少所述可变体积室的体积;
所述流体包括眼科用溶液,所述眼科用溶液包括VEGF拮抗剂:
所述眼科用溶液包含每毫升不超过2个直径>50μm的颗粒;
所述注射器填充的剂量体积介于0.03ml与0.05ml之间;以及
其中,所述止挡件为圆柱形,且围绕止挡件的外表面包括一或多个圆周棱,该止挡件与棱经尺寸化,使得棱与注射器本体的内表面形成实质上不透流体的密封。
2.如权利要求1所述的注射器,其中所述注射器的筒中具有少于25μg的硅油。
3.如权利要求2所述的注射器,其中所述注射器的筒中具有少于15μg的硅油或少于10μg的硅油。
4.如前述权利要求中任一所述的注射器,其中(a)所述注射器的筒未涂布硅油,或者(b)所述注射器不含SO。
5.如前述权利要求中任一所述的注射器,其中所述注射器的本体由(a)或(b)制成:(a)塑料材料,例如环状烯烃聚合物;或(b)玻璃。
6.如前述权利要求中任一所述的注射器,其中所述预填充注射器内止挡件的滑动力小于11N。
7.如权利要求1所述的注射器,其中所述止挡件包括前圆周棱及后圆周棱,且该些棱从沿出口端到尾端的轴的方向分隔至少3mm;可任选地,在前圆周棱及后圆周棱之间配置一个或多个额外的棱。
8.如前述权利要求中任一所述的注射器,所述注射器经尺寸化以具有介于0.1ml与1.5ml之间的标称最大填充体积。
9.如前述权利要求中任一所述的注射器,所述注射器填充有介于0.1ml与0.5ml之间的VEGF拮抗剂溶液。
10.如前述权利要求中任一所述的注射器,所述注射器的本体的长度小于70mm。
11.如前述权利要求中任一所述的注射器,所述VEGF拮抗剂为雷珠单抗。
12.如前述权利要求中任一所述的注射器,所述止挡件的后表面包括实质上居中的凹陷。
13.一种抗体VEGF拮抗剂,其用于治疗患有眼病的患者,其中:(a)所述VEGF拮抗剂采用权利要求1-12中任一项所述的注射器给予所述患者;且(b)所述眼病选自:脉络膜血管新生、湿性年龄相关的黄斑变性、继发于视网膜静脉梗阻(RVO,包括分支RVO(bRVO)和中央RVO(cRVO))的黄斑水肿、继发于病理性近视的脉络膜血管新生(PM)、糖尿病性黄斑水肿(DME)、糖尿病性视网膜病及增生性视网膜病。
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