CN101674803A - 浓艾司洛尔 - Google Patents
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Abstract
本发明提供浓缩艾司洛尔制剂,其比目前的浓缩(例如250mg/ml)艾司洛尔组合物更安全。浓缩艾司洛尔制剂可以包含约40-60mg/ml的艾司洛尔盐酸盐。浓缩艾司洛尔组合物允许执业医师具有选择用于直接给患者注射的快速体积或者任选使用该组合物来制备定制的稀释的艾司洛尔组合物的灵活性。本发明的方法提供了由不适当给药现有技术的浓缩艾司洛尔组合物所引起的潜在不利健康后果的降低。另外,提供了医药产品,其包括在容器中容纳的浓缩艾司洛尔和容纳所述容器和说明书的包装。
Description
发明背景
本发明涉及改善的浓缩艾司洛尔制剂,其用于降低药物差错的风险,并基本上没有潜在的注射部位疼痛或刺激。更具体地说,本发明涉及优选被批准用于静脉内给药的40-60mg/ml浓缩艾司洛尔制剂,其可作为即用组合物给药或在对患者给药之前稀释到所需浓度。
药物当在其适当的剂量范围内给药时一般是安全和有效的。施用不适当剂量的药物具有不利的后果,并且在有些情况下这种给药差错有危急生命的后果。
常用的安全和有效的液体药物有许多,其在浓缩形式下可具有潜在的危险,并且其中浓缩液体与该液体的稀释形式不能区分开。能够同时提供浓缩液体形式和稀释液体的即用形式的一种广泛使用的药物是甲基-3-[4-(2-羟基-3-异丙基氨基)丙氧基]苯基丙酸酯盐酸盐(艾司洛尔盐酸盐)。
艾司洛尔(及其药学可接受的盐,例如盐酸盐)和相关化合物具有β-肾上腺素能阻断活性。β-阻断剂当以适当剂量给药时,是用于治疗和预防心脏病的治疗有效剂。然而,高剂量可危险地引起低心输出量。艾司洛尔,其是短效β-阻断剂,通常在紧急救护背景下使用,以控制患者的心率。艾司洛尔盐酸盐和相关化合物的即用等渗浓缩制剂公开在美国专利Nos.5,017,609,6,310,094和6,528,540中,所述文献作为参考并入本文。制备艾司洛尔和相关化合物的方法和使用这样的化合物治疗或预防心脏病的方法公开在美国专利4,387,103和4,593,119中,所述文献作为参考并入本文。
目前可获得的市售艾司洛尔浓缩制剂在10毫升溶液中包含约250mg/ml的艾司洛尔盐酸盐、25体积%的乙醇、25体积%的丙二醇、17mg/ml的三水乙酸钠和0.715体积%的冰醋酸。该组合物不计划用于直接给患者注射,而是作为储液源用于加入到更大体积的稀释剂中。可获得的其它上市的艾司洛尔组合物包括10和20mg/ml预混合的即用溶液用于输注,和10mg/ml小瓶用于快速注射。如果执业医师需要与即用组合物所提供的不同的浓度或者使用不同的稀释剂,则执业医师可以使用浓缩组合物并用所需稀释剂稀释到定制浓度。
尽管市售的现有技术浓缩和即用组合物产品包装不同,带有适当的标记和操作说明书,但是任一种产品都是透明的无色溶液,在装入注射器内时,它们是不可区分的。因此,如果浓缩产品未经稀释而被错误地直接给患者注射,其可导致严重的健康后果,包括死亡。
因为执业医师偏好使用艾司洛尔的浓缩或即用组合物的灵活性,因此,两种产品在医院环境中都有备。然而,因为艾司洛尔制剂基本透明和无色,因此浓缩制剂在视觉上与稀释制剂不可区分。另外,10mg/ml的即用组合物和250mg/ml供稀释的浓缩组合物每种均备有相似的10毫升体积。因此,可由于执业医师误操作两种组合物而发生给药差错。因此,希望提供艾司洛尔的浓缩液体制剂,其可减少上述潜在的给药差错,并仍具有提供组合物可用来制备定制艾司洛尔组合物的灵活性。
市售的250mg/ml艾司洛尔浓缩品含有丙二醇和乙醇,是已知引起注射部位疼痛或刺激的介质。因此,希望提供不含任何丙二醇和乙醇的浓缩品。
执业医师使用艾司洛尔注射剂用于快速起效,并且一般要求根据患者的体重进行剂量递增。对于过重患者和对于流体受限患者而言,非常希望提供可以无需稀释或使用最小体积稀释即可被给药的浓缩艾司洛尔形式。
发明概述
在本发明的一个方面,提供了浓缩艾司洛尔制剂。浓缩艾司洛尔制剂包含约40-60mg/ml的艾司洛尔(或其药学可接受的盐)和任选的约0.005到约2摩尔(M)的缓冲剂,和调节到约3.5到约7.0的pH。
在本发明的另一个方面,提供了定量给药和施用液体形式的艾司洛尔的方法。该方法包括以下步骤:提供约40-60mg/ml艾司洛尔(或其药学可接受的盐)的浓缩艾司洛尔制剂,从该液体选择一定体积用于直接注射给患者,或者任选用适当的稀释剂进一步稀释,然后注射给患者。
在本发明的另一个方面,提供了减轻由浓缩艾司洛尔制剂直接给药引起的明显不利的健康后果的方法。所述方法包括以下步骤:提供具有一定浓度的浓缩艾司洛尔制剂,其可直接施用于患者,与如果同样给药相似体积的目前使用的浓缩艾司洛尔组合物相比,不利的健康后果减少或不显著。另外,在本发明的实施方案中,其中形式体积为约50毫升或更高,不可能快速注射全部量。这为错误地快速注射10毫升现有技术的市售浓缩品提供了有帮助的对比。因为药物的普通快速注射一般不超过20毫升,因此,本发明的更大体积的浓缩品实施方案提供了阻止执业医师错误地将这种浓缩品全部快速注射的优点。
本发明的优点是提供了可直接输注给患者的无菌的、即用艾司洛尔浓缩形式。这类更高浓度、无菌的艾司洛尔组合物允许以较低体积注射给患者,从而减少具有对输注体积敏感的心脏或其它病患的患者的容量效应,包括那些流体受限的患者。
本发明的另一个优点是,与现有技术的包含丙二醇和乙醇的浓缩艾司洛尔组合物不同,本发明的组合物不含刺激性或有害的赋形剂。
本发明的另一个优点是其提供了即用的更高浓度的艾司洛尔,其是无菌的并且不经历制备差错,这一差错当执业医师使用现有技术浓缩品定制制备类似浓度的艾司洛尔组合物时会发生。
发明详述
本发明的组合物包含艾司洛尔或其药学可接受的盐例如盐酸盐,缓冲剂和任选的渗透压调节剂。本文使用的“艾司洛尔”是指艾司洛尔游离碱及其药学可接受的盐。溶液是无菌的并优选包装在适当的容器中并最终压热灭菌。或者,无菌的艾司洛尔浓缩品可通过无菌灌装过程制备。在浓缩品中艾司洛尔的浓度为约40-60mg/ml,优选为约45-55mg/ml,和最优选为50mg/ml。
尽管更低浓度(例如10mg/ml)的即用艾司洛尔组合物需要额外的缓冲剂以保持pH,但是在本发明组合物中的更高艾司洛尔浓度为组合物提供了自我缓冲能力。因此,在本发明的组合物中只需要较少的缓冲剂。浓缩品包含药学可接受的缓冲剂以帮助保持pH在约3.5到约7.0的范围内。pH优选被保持在约4.5到约5.5之间,更优选4.9到5.1之间。艾司洛尔的降解当pH在4.0到6.0范围以外时发生最快,并且在约5.0的pH时最稳定。
适当的缓冲剂是在所需pH范围提供充分缓冲能力的那些缓冲剂,并且对于患者注射是药学可接受的。可用于本发明的缓冲剂的实例包括但不限于乙酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡糖酸盐、磷酸盐和甘氨酸,及其共轭酸。缓冲剂的浓度为约0.005到约2M。在优选的实施方案中,缓冲剂包括乙酸钠和冰醋酸的组合。缓冲剂的优选组合包括约0.005到约0.3M的乙酸钠和约0.05到约0.3M的冰醋酸。
当不使用稀释剂、特别是经过渗透压调节稀释剂,而对患者直接给药艾司洛尔组合物时,为了避免发生或减轻渗压冲击(例如注射部位疼痛),希望在该直接剂量组合物中包含适当水平的重量摩尔渗透压浓度。与现有技术的即用艾司洛尔制剂(10和20mg/ml艾司洛尔盐酸盐)不同的是,本发明的组合物提供了固有水平的重量摩尔渗透压浓度(约245-400mOsmoles/ml),无需存在另外的渗透压调节剂。这是由于更高浓度的艾司洛尔所导致的,其自身赋予组合物以一定程度的重量摩尔渗透压浓度。因此,本发明的组合物一般不要求另外的渗透压调节剂。或者,如果需要,本发明的组合物中可任选包含其它适当的渗透压调节剂。这样的调节剂对于给患者注射是药学可接受的。适当的调节剂包括但不限于氯化钠,葡萄糖,碳酸氢钠,氯化钙,氯化钾,乳酸钠和林格液。所要包含的渗透压调节剂的量将根据组合物中所需的重量摩尔渗透压强度和其它考虑而异,所述其它考虑包括渗透压剂在给定条件下可能对给定患者的影响,例如钠对充血性心力衰竭患者的影响。渗透压调节剂一般以约0.1到5mg/ml的量包含在本发明的组合物中。优选的渗透压调节剂包括氯化钠和葡萄糖。
用于容纳艾司洛尔浓缩品的适当容器是本领域已知的。它们包括小瓶、注射器、袋、瓶和安瓿形式。容器可由聚合物材料或玻璃制造。优选的聚合物容器不含聚氯乙烯(PVC)。容器优选具有优异的屏障性质。优选的容器保持着确保艾司洛尔浓缩品稳定性的水分,诸如包括屏障层或二级包装的玻璃容器或聚合物容器。铝套袋是优选的水分屏障,用作自身缺乏水分屏障的聚合物容器的二级包装。优选的容器将能经得起最终灭菌,诸如压热灭菌。
本发明的组合物是无菌的。该组合物优选被制备然后在其最终容器中通过压热灭菌。或者,浓缩品可被无菌制备或单独通过压热最终灭菌,然后使用无菌程序置于无菌容器中。在制药工业中被用来实现成品最终灭菌的典型压热周期是121℃历时15分钟。本发明的艾司洛尔浓缩品能够在115到130℃的温度范围内压热约5到40分钟的时段,稳定性合格。压热优选在约119到122℃的温度范围内进行约10到36分钟的时间段。
在一个实施方案中,将浓缩品置于透明玻璃或塑料注射器中并进行最终灭菌。这些预灌装注射器可以提供成各种体积,从而允许通过将预灌装注射器的内容物分配到标准的预灌装静脉流体袋中而快速和容易地制备小体积或大体积的非肠道剂量,或任选对患者直接给药。
在本发明的另一个实施方案中,医药产品包括一起放在单一包装内的容纳艾司洛尔浓缩品的容器和说明书。说明书可告知执业医师,根据所需剂量和患者信息和病况,是否使用组合物作为未经稀释的即用注射剂或进一步用所需稀释剂进行稀释。
本发明的组合物提供了所提供的组合物可用作即用组合物或作为可用于进一步稀释的组合物的灵活性。作为即用形式,该高浓度组合物可施用于需要快速起效的患者,并还有过重患者。另外,因为该组合物包含较高浓度的艾司洛尔,因此可以将较小的输注体积施用于流体受限的患者。表1显示了根据所用的艾司洛尔注射剂浓度计算的输注速率降低。
表1
剂量 | 重75Kg患者所需的剂量 | 待用的艾司洛尔注射剂浓度 | 输注速率 |
300μg/Kg/min | 22500μg/min | 10mg/mL | 2250μL/min |
20mg/mL | 1125μL/min | ||
50mg/mL | 450μL/min | ||
200μg/kg/min | 15000μg/min | 10mg/mL | 1500μL/min |
20mg/mL | 750μL/min | ||
50mg/mL | 300μL/min |
如果执业医师希望更低浓度的艾司洛尔和/或喜好的稀释剂结合艾司洛尔给药向患者输注,则执业医师可能希望稀释本发明的组合物。适当的稀释剂包括由本领域有经验的执业医师使用的稀释剂。典型实例包括氯化钠,林格液和葡萄糖溶液。当需要时,艾司洛尔的稀释浓度将改变,典型的浓度范围为约1至约25mg/ml,优选10mg/ml。
用于非肠道给药的适当途径包括静脉内、皮下、皮内、肌内、关节内和鞘内。被稀释的浓缩品优选通过静脉输注给药。
以下实施例的组合物和制备方法进一步说明了本发明,但不应解释为限制其范围。
实施例1
以下描述了本发明的艾司洛尔组合物的制备。组合物各成分的浓度提供在下表1和表2中:
表1:制剂1-3
成分 | 制剂1 | 制剂2 | 制剂3 |
艾司洛尔盐酸盐 | 50mg/mL | 50mg/mL | 50mg/mL |
三水乙酸钠,USP | --- | 1.4mg/mL | 0.7mg/mL |
冰醋酸,USP | 0.546mg/mL | 0.546mg/mL | 0.546mg/mL |
氯化钠,USP | 1mg/mL | 1mg/mL | 1mg/mL |
注射用水 | 适量 | 适量 | 适量 |
表2:制剂4-6
成分 | 制剂4 | 制剂5 | 制剂6 |
艾司洛尔盐酸盐 | 50mg/mL | 50mg/mL | 50mg/mL |
三水乙酸钠,USP | 1.4mg/mL | 2.8mg/mL | 2.8mg/mL |
冰醋酸,USP | 0.546mg/mL | 0.546mg/mL | 0.546mg/mL |
氯化钠,USP | --- | 1mg/mL | --- |
葡萄糖,USP | 1mg/mL | --- | --- |
注射用水 | 适量 | 适量 | 适量 |
在上述的制剂1-6中,pH可被调节到4.5-5.5的范围,优选5.0。用于混合、过滤和灌装的设备和玻璃器皿经过彻底洗涤和除热原。将过滤器组件、灌装管组件和其它部件和设备灭菌。
将冷注射用水终容积的百分之八十(80%)集中在混合槽中。然后将冰醋酸和任选的乙酸钠加入到该槽中。将艾司洛尔盐酸盐称重并加入到该槽中。然后,任选称重氯化钠或葡萄糖并加入到该槽中。将溶液搅拌直到所有的赋形剂溶解为止。然后使用1.0N氢氧化钠或盐酸将溶液调节到pH 5.0。将溶液用注射用水补足到最终体积并混合。将艾司洛尔浓缩品转移到容器中并进行压热,从而提供了具有约50mg/ml浓度的艾司洛尔盐酸盐溶液。
尽管本发明已经参考某些优选的实施方案进行了描述,但应理解的是优选的实施方案仅仅用于说明本发明的原理。因此,本领域技术人员可进行改变和/或变化而不脱离所附权利要求所限定的本发明的真实精神和范围。
Claims (34)
1.浓缩艾司洛尔组合物,其包含:
a)约40-60mg/ml的艾司洛尔盐酸盐;和
b)约0.01到约2M的缓冲剂;
其中组合物的pH为约4.0到6.0。
2.权利要求1的组合物,其中缓冲剂包括乙酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡糖酸盐、磷酸盐和甘氨酸中的至少一种及其共轭酸。
3.权利要求2的组合物,其中缓冲剂包括乙酸钠和乙酸。
4.权利要求1的组合物,还包含渗透压调节剂。
5.权利要求4的组合物,其中渗透压调节剂选自:葡萄糖,氯化钠,碳酸氢钠,氯化钙,氯化钾,乳酸钠和林格液。
6.权利要求4的组合物,其中渗透压调节剂的存在量为约0.1约5mg/mL。
7.权利要求4的组合物,包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的冰醋酸;和
c)约1mg/ml的氯化钠。
8.权利要求4的组合物,包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
9.权利要求4的组合物,包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.005M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
10.权利要求4的组合物,包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/mL的葡萄糖。
11.权利要求4的组合物,包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.02M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
12.权利要求1的组合物,包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.02M的乙酸钠;和
c)约0.01M的冰醋酸。
13.医药产品,包含:
a)容纳在容器中的组合物,其包含约40到约60mg/ml的艾司洛尔盐酸盐和约0.01到约2M的缓冲剂;
b)指导执业医师使用组合物用于直接注射或用于稀释并然后注射的说明书;和
c)容纳容器和说明书的包装。
14.权利要求13的医药产品,其中缓冲剂包括乙酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡糖酸盐、磷酸盐和甘氨酸中的至少一种及其共轭酸。
15.权利要求13的医药产品,其中缓冲剂包括乙酸钠和乙酸。
16.权利要求13的医药产品,其中浓缩艾司洛尔制剂还包含渗透压调节剂。
17.权利要求16的方法,其中组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的冰醋酸;和
c)约1mg/ml的氯化钠。
18.权利要求16的方法,其中组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
19.权利要求16的方法,其中组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.005M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
20.权利要求16的方法,其中组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/mL的葡萄糖。
21.权利要求16的方法,其中组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.02M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
22.权利要求13的方法,其中组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.02M的乙酸钠;和
c)约0.01M的冰醋酸。
23.提供降低由不适当给药艾司洛尔浓缩液体组合物所引起的明显不利的健康后果的可能性的方法,包括以下步骤:
a)提供的无菌的液体组合物,其包含约40-60mg/ml艾司洛尔盐酸盐;和
b)约0.01到约2M的缓冲剂;
其中组合物的pH为约4.0到6.0。
24.权利要求23的方法,其中缓冲剂包括乙酸盐、谷氨酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、乳酸盐、葡糖酸盐、磷酸盐和甘氨酸中的至少一种及其共轭酸。
25.权利要求23的方法,其中缓冲剂包括乙酸钠和乙酸。
26.权利要求23的方法,还包含渗透压调节剂。
27.权利要求23的方法,其中渗透压调节剂选自:葡萄糖,氯化钠,碳酸氢钠,氯化钙,氯化钾,乳酸钠和林格液。
28.权利要求23的方法,其中渗透压调节剂的存在量为约0.1约5mg/mL。
29.权利要求27的方法,其中无菌的液体组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的冰醋酸;和
c)约1mg/ml的氯化钠。
30.权利要求27的方法,其中无菌的液体组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
31.权利要求27的方法,其中无菌的液体组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.005M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
32.权利要求27的方法,其中无菌的液体组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.01M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/mL的葡萄糖。
33.权利要求27的方法,其中无菌的液体组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.02M的乙酸钠;
c)约0.01M的冰醋酸;和
d)约1mg/ml的氯化钠。
34.权利要求23的方法,其中无菌的液体组合物包含:
a)约45到55mg/mL的艾司洛尔盐酸盐;
b)约0.02M的乙酸钠;和
c)约0.01M的冰醋酸。
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2007
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- 2007-07-25 WO PCT/US2007/074325 patent/WO2008153582A1/en active Application Filing
- 2007-07-25 EP EP07840511A patent/EP2164463A1/en not_active Withdrawn
- 2007-07-25 MX MX2009012616A patent/MX344131B/es active IP Right Grant
- 2007-07-25 RU RU2009147458/15A patent/RU2493824C2/ru not_active IP Right Cessation
- 2007-07-25 KR KR1020097026610A patent/KR20100022068A/ko not_active Application Discontinuation
- 2007-07-25 CN CN200780053072A patent/CN101674803A/zh active Pending
- 2007-07-25 AU AU2007354870A patent/AU2007354870A1/en not_active Abandoned
- 2007-07-25 JP JP2010509320A patent/JP5759720B2/ja not_active Expired - Fee Related
- 2007-07-25 BR BRPI0721680-7A patent/BRPI0721680A2/pt not_active IP Right Cessation
- 2007-07-25 CA CA002686548A patent/CA2686548A1/en not_active Abandoned
-
2008
- 2008-05-21 AR ARP080102161A patent/AR066670A1/es not_active Application Discontinuation
-
2009
- 2009-11-08 IL IL201985A patent/IL201985A0/en unknown
- 2009-12-09 ZA ZA200908756A patent/ZA200908756B/xx unknown
-
2014
- 2014-09-12 US US14/485,632 patent/US20150005376A1/en not_active Abandoned
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103347513A (zh) * | 2011-01-27 | 2013-10-09 | 巴克斯特国际公司 | (s)-艾司洛尔用于控制与心脏病治疗相关的静脉刺激的应用 |
CN104379134A (zh) * | 2012-05-10 | 2015-02-25 | Aop孤儿药品股份公司 | 肠外艾司洛尔剂型 |
Also Published As
Publication number | Publication date |
---|---|
WO2008153582A1 (en) | 2008-12-18 |
ZA200908756B (en) | 2010-08-25 |
CA2686548A1 (en) | 2008-12-18 |
MX2009012616A (es) | 2009-12-11 |
BRPI0721680A2 (pt) | 2014-02-25 |
JP2010528000A (ja) | 2010-08-19 |
RU2009147458A (ru) | 2011-06-27 |
AR066670A1 (es) | 2009-09-02 |
AU2007354870A1 (en) | 2008-12-18 |
JP5759720B2 (ja) | 2015-08-05 |
MX344131B (es) | 2016-12-06 |
EP2164463A1 (en) | 2010-03-24 |
US20150005376A1 (en) | 2015-01-01 |
US20080293814A1 (en) | 2008-11-27 |
KR20100022068A (ko) | 2010-02-26 |
RU2493824C2 (ru) | 2013-09-27 |
IL201985A0 (en) | 2010-06-16 |
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