CN101678111A - 有色的艾司洛尔浓缩品 - Google Patents
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Abstract
本发明提供了浓缩的艾司洛尔制剂,其可与浓缩艾司洛尔制剂的稀释形式区分开。浓缩艾司洛尔制剂可包含约25到约1000mg/ml的艾司洛尔盐酸盐、缓冲剂和颜色添加剂。许多颜色添加剂可被包含,诸如吲哚花氰绿、酚比啉、血色素、氰钴胺素、专利蓝和靛蓝胭脂红、维生素B2以及天然存在的维生素和矿物质。本发明还提供了医药产品,其包括被容纳在容器中的有色的浓缩艾司洛尔制剂和容纳所述容器和说明书的包装。本发明另外提供了允许容易地鉴别浓缩艾司洛尔制剂的方法。该方法包括提供有色的浓缩艾司洛尔制剂,其具有约25到约1000mg/ml的艾司洛尔和颜色添加剂。
Description
发明背景
本发明涉及包含颜色添加剂的有色的、强化的浓缩艾司洛尔制剂。更具体地说,本发明涉及具有无毒颜色添加剂的浓缩艾司洛尔制剂,所述颜色添加剂优选被批准用于非肠道给药,优选被批准用于静脉内给药。本发明涉及浓缩艾司洛尔制剂,其具有的颜色足以容易地与以至少约一份浓缩品对四份稀释剂(1∶4)的比率的浓缩品稀释物区分开。
施用适当剂量的药物是一个其中可出现差错的领域。大部分药物在适当剂量下是安全和有效的,但是在高剂量下可以具有不利的后果。在一些情况下,给药差错可以有危及生命的后果。
关于以各种强度提供的液体药物而言,可以令人遗憾地发生给药差错。在其中浓缩形式的药物在视觉上与被稀释的形式不能区分开的情况下,诸如都是基本透明和无色的液体,尤其如此。液体药物可以作为即用制剂以及在给药前需要稀释的浓缩形式。通常将浓缩和稀释的制剂区分开的唯一手段是通过装药容器的标签。作为附加的防范措施,容器自身或封闭体可给予有区别的特征,诸如颜色。然而,因为药物经常被转移到第二容器诸如注射器中,仍然会发生差错。
为了协助保健执业医师来鉴定有潜在危险的浓氯化钾制剂,已经试图包含颜色添加剂。一种已知的有色氯化钾浓缩品采用亚甲蓝帮助执业医师将浓缩品与稀释形式鉴别开不幸的是,由于该有色的浓缩氯化钾制剂的缺点,让浓缩医药制剂有色并没有被所有的药物所采用,其中浓缩形式如果直接施用可能是潜在危险的,并且其中浓缩形式的药物与稀释形式基本上不能区分开。
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。同时可以提供有浓缩形式和稀释的即用形式的一种被广泛使用的液体药物是甲基-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)和有关化合物具有β-肾上腺素能阻断活性。β-阻断剂当以适当剂量施用时,是用于治疗和预防心脏病的治疗有效药剂。然而,高剂量可危险地引起低心输出量。艾司洛尔是短效β-阻断剂,通常在紧急救护背景下使用,以控制患者的心率。艾司洛尔盐酸盐和有关化合物的即用等渗和浓缩的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。制备艾司洛尔和有关化合物的方法和使用这类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。
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能区分开。因为艾司洛尔盐酸盐可以提供成浓缩品或即用强度,因而希望具有一些手段,当浓缩品一旦从其一级容器中被取出后,对其进行鉴别浓缩品。
希望提供与有色浓缩品的稀释物容易区分开的浓缩艾司洛尔制剂。
发明概述
在本发明的一个方面,提供了有色的浓缩艾司洛尔制剂。有色的浓缩艾司洛尔制剂包含约25到约1000mg/ml的艾司洛尔(或其药学可接受的盐),约0.005到约2M的缓冲剂,pH被调节到约3.5到约7.0,和颜色添加剂。
在本发明的另一个方面,提供了医药产品。该医药产品包含浓缩的艾司洛尔制剂,该制剂包含约25到约1000mg/ml的艾司洛尔(或其药学可接受的盐)和颜色添加剂,说明书,以及容纳有色的浓缩艾司洛尔制剂和说明书的包装。
在本发明的另一个方面,提供了区分浓缩艾司洛尔制剂的方法。该方法包括以下步骤:提供有色的浓缩艾司洛尔制剂,其包含约25到约1000mg/ml的艾司洛尔(或其药学可接受的盐)和颜色添加剂。
发明详述
在本发明的一个实施方案中,提供了的浓缩艾司洛尔制剂,其有色从而允许鉴别浓缩品,与有色浓缩品的稀释物区分开并且与其它的即用艾司洛尔制剂区分开。有色的浓缩品当被稀释到适当的浓度时适合非肠道给药。
有色的艾司洛尔浓缩品在含水溶液中包含艾司洛尔或其药学可接受的盐例如盐酸盐,和着色剂。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。溶液优选被包装在适当的容器中并通过压热进行最终灭菌。或者,有色的艾司洛尔浓缩品可通过无菌灌装过程制备。艾司洛尔盐酸盐在有色的艾司洛尔浓缩品中的浓度可为约25到约1000mg/ml。优选,浓缩制剂中艾司洛尔的浓度为约50到500mg/ml,更优选约100到300mg/ml,最优选约250mg/ml。
有色的浓缩品还可包含药学可接受的缓冲剂以保持pH在约3.5到约7.0的范围内。pH优选保持在约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周围最稳定。
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,并且对于注射给患者是药学可接受的。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。缓冲剂的浓度可为约0.005摩尔(M)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。
为了改善有色浓缩品的稳定性,可以包含一种或多种醇。一种或多种醇可根据醇或醇混合物,包含约1到约60体积%的浓度。优选的醇是乙醇,优选包含约5到约60体积%、更优选约10到约45体积%和更优选约20到约30体积%的浓度。另一个优选的醇是苯甲醇,优选包含约1到约20体积%的浓度。
为了增强艾司洛尔的稳定性,有色的艾司洛尔浓缩品还包含生理可接受的液体多羟基化合物,优选浓度为约5到约60体积%,更优选约10到约45体积%,和甚至更优选约20到约30体积%。生理可接受的液体多羟基化合物包括但不限于1到约10个碳原子并具有两个或更多个相邻羟基的链烃基化合物,诸如乙二醇,丙二醇,甘油等等;分子量约200到约600道尔顿的聚乙二醇;和甘油。优选的液体多羟基化合物包括1到约10个碳原子并具有两个或更多个相邻羟基的链烃基化合物,和分子量约200到约600道尔顿的聚乙二醇。优选的液体多羟基化合物是丙二醇。在优选的实施方案中,液体多羟基化合物与乙醇一起可用于稳定浓缩的艾司洛尔溶液。优选的组合包括乙醇和丙二醇。在优选的组合物中,乙醇与丙二醇的体积比可为约1∶1。在另一个优选的实施方案中,乙醇的浓度为约20到约30体积%,优选约26.5体积%,以及丙二醇的浓度为约20到约30体积%,优选约25体积%。
有色的浓缩品包含一种或多种无毒或相对无毒的颜色添加剂。本发明所用的颜色添加剂或试剂优选被批准用于非肠道给药,包括静脉内给药。颜色试剂包括但不限于氰钴胺素,靛蓝胭脂红,专利蓝,吲哚花氰绿,酚比啉(phenopheylene)和血色素。美国食品与药物管理局(The United States Food and Drug Administration)已经在其网址www.cfsan.fda.gov/~dms/opa-col2.html或链接网址上公开和列举了一系列已用于食品、药物和医疗装置中的着色剂,所述网址作为参考并入本文。应注意,不是所有的这些颜色添加剂都在所有的国家被批准用于非肠道应用。可用于本发明的优选着色剂组包括基于维生素的剂,包括但不限于维生素B 12(氰钴胺素-颜色为粉红)。维生素B2(核黄素-颜色为橙色)。其它优选的着色剂可包括天然存在的基于矿物质的着色剂。所列举的和包括在FDA网址中列举的那些着色剂可用于本发明中,只要着色剂相对于透明溶液提供足以区分的颜色,并且对于非肠道给药到主体而言是药学可接受的。
颜色添加剂的量高度取决于所选择的特定着色剂。着色剂应当加入的量要足以清楚区分开有色的艾司洛尔浓缩品与包含艾司洛尔的稀释制剂。艾司洛尔溶液即使加入上述浓度的缓冲剂或醇诸如乙醇和丙二醇时也是基本透明和无色的。另外,应当加入的着色剂量要使得有色艾司洛尔浓缩品的至少约1∶4的稀释物产生的稀释艾司洛尔制剂优选在颜色上更类似于未着色的艾司洛尔浓缩品,即基本透明和无色,或稀释剂,而不是类似于起始的有色浓缩品。
在一个实施方案中,氰钴胺素作为着色剂以约0.002到约0.003mg/ml、优选0.0024mg/ml的浓度被包含在有色的艾司洛尔浓缩品中。在该浓度下,本来透明无色的艾司洛尔溶液呈现浅粉色。当用适于非肠道给药的稀释剂诸如林格氏液或适于静脉内给药的稀释剂以至少1∶4的比例稀释时,得到的溶液至少基本无色或者为稀释剂的颜色。
在另一个实施方案中,靛蓝胭脂红作为着色剂以约0.0005到约0.001mg/ml、优选0.0008mg/ml的浓度被包含在有色的艾司洛尔浓缩品中。在该浓度下,本来透明无色的艾司洛尔浓缩溶液呈现浅蓝色。当用适于非肠道给药的稀释剂诸如林格氏液或适于静脉内给药的稀释剂以至少1∶4的比例稀释时,得到的溶液几乎是无色的或为稀释剂的颜色。
在另一个实施方案中,专利蓝作为着色剂以约0.0001到约0.0003mg/ml、优选0.0002mg/ml的浓度被包含在有色的艾司洛尔浓缩品中。在该浓度下,本来透明无色的艾司洛尔浓缩溶液呈现浅蓝色。当用适于非肠道给药的稀释剂诸如林格氏液或适于静脉内给药的稀释剂以至少1∶4的比例稀释时,得到的溶液至少基本无色或者为稀释剂的颜色。
有色的艾司洛尔浓缩品可被等渗溶液诸如林格液或本领域使用的其它稀释剂稀释,或者用注射用水稀释,使得可对患者进行非肠道给药。例如,稀释的组合物可以用快速注射或静脉输注的形式施用。非肠道给药的适当途径包括静脉内、皮下、皮内、肌肉内、关节内和鞘内。稀释的浓缩品优选通过静脉内输注途径施用。
用于容纳有色的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,并且应当是透明的或具有透明部分,允许在视觉上识别颜色。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。优选的容器保留有水分屏障,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。
优选的容器应能经得起最终灭菌诸如压热。或者,有色的浓缩品可无菌制备或单独通过压热进行最终灭菌,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。本发明的有色艾司洛尔浓缩品可以在115到130℃的温度范围内压热5到40分钟的时段,稳定性合格。压热优选在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,将有色的浓缩品置于基于透明玻璃或塑料的注射器中并进行最终灭菌。这些预灌装的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内流体袋中,而快速和容易地制备小体积或大体积的非肠道剂量。这将消除算错适当稀释度的风险。在另一个实施方案中,预灌装注射器容纳艾司洛尔浓度为约25到1000mg/ml的有色艾司洛尔浓缩品。
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。容器是透明和无色的或者至少包括透明和无色的一部分。说明书可以告知执业医师颜色添加剂已被加入以指示浓缩制剂。说明书还提供了未稀释的有色艾司洛尔浓缩品的颜色或在推荐的稀释后有色浓缩品的颜色的说明或描述。
在本发明的又一个实施方案中,提供了可以鉴别浓缩艾司洛尔制剂的方法。该方法可以包括提供有色的浓缩艾司洛尔制剂的步骤。有色的浓缩艾司洛尔制剂可包含约25到约1000mg/ml的艾司洛尔和颜色添加剂。
以下的实施例进一步说明了本发明,然而,不应以任何方式解释为对本发明范围的限制。
实施例1
以下描述了在混合、包装和压热灭菌后包含250mg/ml艾司洛尔盐酸盐和着色剂的有色艾司洛尔浓缩品的制备。组合物中各成分的浓度提供在下表1中:
表1
成分 | 浓度 |
艾司洛尔盐酸盐 | 250mg/mL |
三水合乙酸钠 | 17mg/mL |
冰醋酸 | 0.00715mL/mL |
醇,USP | 0.265mL/mL |
丙二醇,USP | 0.25mL/mL |
氰钴胺素 | 0.0024mg/mL |
注射用水,USP | 适量 |
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进行灭菌。
将冷注射用水的最终容积的百分之八十(80%)集中在混合槽中。然后将冰醋酸和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。将丙二醇和乙醇称重并加入到该槽中。将所需量的着色剂称重并加入到该槽中。搅拌溶液直到所有的赋形剂溶解为止。然后用1.0N氢氧化钠或盐酸将溶液调节到pH 5.0。用注射用水将溶液补足到最终体积并混合。将有色的艾司洛尔浓缩品转移到容器中并进行压热,以提供具有约250mg/ml浓度的艾司洛尔盐酸盐溶液。
颜色是浅粉色并且在用水进行1∶4稀释后,得到的50mg/ml的艾司洛尔溶液是透明和无色的并具有约0.00048mg/ml的氰钴胺素浓度。
实施例2
以下描述了在混合、包装和压热灭菌后,包含250mg/ml的艾司洛尔盐酸盐和着色剂的有色艾司洛尔浓缩品的制备。组合物中各成分的浓度提供在下表2中:
表2
成分 | 浓度 |
艾司洛尔盐酸盐 | 250mg/mL |
三水合乙酸钠 | 17mg/mL |
冰醋酸 | 0.00715mL/mL |
醇,USP | 0.265mL/mL |
丙二醇,USP | 0.25mL/mL |
专利蓝 | 0.0002mg/mL |
注射用水,USP | 适量 |
表2制剂的制备与实施例1的制剂类似,不同之处在于着色剂和浓度不同。
颜色是浅蓝色并且在用水进行1∶4稀释后,得到的50mg/ml的艾司洛尔溶液是透明和无色的并具有约0.000004mg/ml的专利蓝浓度。
实施例3
以下描述了在混合、包装和压热灭菌后包含250mg/ml艾司洛尔盐酸盐和着色剂的有色艾司洛尔浓缩品的制备。组合物中各成分的浓度提供在下表3中:
表3
成分 | 浓度 |
艾司洛尔盐酸盐 | 250mg/mL |
三水合乙酸钠 | 17mg/mL |
冰醋酸 | 0.00715mL/mL |
醇,USP | 0.265mL/mL |
丙二醇,USP | 0.25mL/mL |
靛蓝胭脂红 | 0.0008mg/mL |
注射用水,USP | 适量 |
表3制剂的制备与实施例1的制剂类似,不同之处在于着色剂和浓度不同。
实施例4
以下描述了制备含25-1000mg/ml艾司洛尔盐酸盐和苯甲醇的艾司洛尔浓缩品。组合物中各成分的浓度如下所示:
表4
成分 | 浓度 |
艾司洛尔盐酸盐 | 25-1000mg/mL |
三水合乙酸钠 | 17mg/mL |
冰醋酸 | 0.00715mL/mL |
苯甲醇,USP | 1-10% |
注射用水,USP | 适量 |
将用于混合、过滤和灌装的设备和玻璃器皿进行彻底洗涤和除热原。对过滤器组件、灌装管组件和其它部件和设备灭菌。
将冷注射用水的最终容积的百分之八十(80%)集中在混合槽中。然后将冰醋酸和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。将所需量的苯甲醇称重并加入到该槽中。搅拌溶液直到所有的赋形剂溶解为止。然后用1.0N氢氧化钠或盐酸调节溶液到pH 5.0。用注射用水将溶液补足到最终体积并混合。
尽管已经参考某些优选的实施方案对本发明进行了描述,但应理解,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精神和范围。
Claims (19)
1.有色的浓缩艾司洛尔制剂,包含:
a)约25到约1000mg/ml的艾司洛尔;
b)约0.005到约2M的缓冲剂;和
c)颜色添加剂,选自:吲哚花氰绿,酚比啉,血色素,氰钴胺素,专利蓝,靛蓝胭脂红,维生素B2以及天然存在的维生素和矿物质;
其中制剂的pH为约3.5到约7.0。
2.权利要求1的制剂,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的制剂,其中缓冲剂包括乙酸钠和乙酸。
4.权利要求3的制剂,还包含约1到约60体积%的乙醇和约5到约60体积%的丙二醇。
5.权利要求4的制剂,包含约26.5体积%的乙醇和25体积%的丙二醇。
6.权利要求1的制剂,其中着色剂是氰钴胺素。
7.权利要求1的制剂,其中着色剂选自约0.002到约0.003mg/ml的氰钴胺素,约0.0005到约0.001mg/ml的靛蓝胭脂红和约0.0001到约0.0003mg/ml的专利蓝。
8.权利要求1的制剂,包含:
a)约250mg/ml的艾司洛尔盐酸盐;
b)约17mg/ml的三水合乙酸钠;
c)约0.00715ml/ml的冰醋酸;
d)约0.265ml/ml的乙醇;
e)约0.25ml/ml的丙二醇;和
f)约0.0024mg/ml的氰钴胺素。
9.权利要求1的制剂,包含:
a)约250mg/ml的艾司洛尔盐酸盐;
b)约17mg/ml的三水合乙酸钠;
c)约0.00715ml/ml的冰醋酸;
d)约0.265ml/ml的乙醇;
e)约0.25ml/ml的丙二醇;和
f)约0.0002mg/ml的专利蓝。
10.权利要求1的制剂,包含:
a)约250mg/ml的艾司洛尔盐酸盐;
b)约17mg/ml的三水合乙酸钠;
c)约0.00715ml/ml的冰醋酸;
d)约0.265ml/ml的乙醇;
e)约0.25ml/ml的丙二醇;和
f)约0.0008mg/ml的靛蓝胭脂红。
11.医药产品,包含:
a)被容纳在容器中的浓艾司洛尔制剂,其包含约25到约1000mg/ml的艾司洛尔盐酸盐、约0.005到约2M的缓冲剂和选自以下的颜色添加剂:吲哚花氰绿,酚比啉,血色素,氰钴胺素,专利蓝,靛蓝胭脂红,维生素B2以及天然存在的维生素和矿物质。
b)说明书;和
c)容纳容器和说明书的包装。
12.权利要求11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、磷酸盐和甘氨酸中以下的至少一种及其共轭酸。
13.权利要求12的医药产品,其中缓冲剂包含乙酸钠和乙酸。
14.权利要求13的医药产品,还包含约5到约60体积%的乙醇和约5到约60体积%的丙二醇。
15.权利要求14的医药产品,包含约26.5体积%的乙醇和25体积%的丙二醇。
16.权利要求11的医药产品,其中颜色添加剂选自约0.002到约0.003mg/ml的氰钴胺素,约0.0005到约0.001mg/ml的靛蓝胭脂红和约0.0001到约0.0003mg/ml的专利蓝。
17.权利要求11的医药产品,其中制剂包含:
a)约250mg/ml的艾司洛尔盐酸盐;
b)约17mg/ml的三水合乙酸钠;
c)约0.00715ml/ml的冰醋酸;
d)约0.265ml/ml的乙醇;
e)约0.25ml/ml的丙二醇;和
f)选自以下的颜色添加剂:约0.0008mg/ml的靛蓝胭脂红、约0.0002mg/ml的专利蓝、约0.0024mg/ml的氰钴胺素。
18.权利要求11的医药产品,其中说明书告知颜色添加剂已被加入到浓缩艾司洛尔制剂中。
19.允许容易地鉴别浓缩艾司洛尔制剂的方法,包括以下步骤:
a)提供有色的浓艾司洛尔制剂,其包含约25到约1000mg/ml的艾司洛尔和选自以下的颜色添加剂:吲哚花氰绿,酚比啉,血色素,氰钴胺素,专利蓝,靛蓝胭脂红,维生素B2以及天然存在的维生素和矿物质。
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US11/752,086 US8426467B2 (en) | 2007-05-22 | 2007-05-22 | Colored esmolol concentrate |
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PCT/US2007/075069 WO2008143682A1 (en) | 2007-05-22 | 2007-08-02 | Colored esmolol concentrate |
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2007
- 2007-05-22 US US11/752,086 patent/US8426467B2/en active Active
- 2007-08-02 KR KR1020097026609A patent/KR20100022991A/ko not_active Application Discontinuation
- 2007-08-02 AU AU2007353795A patent/AU2007353795B2/en not_active Ceased
- 2007-08-02 WO PCT/US2007/075069 patent/WO2008143682A1/en active Application Filing
- 2007-08-02 CA CA002686488A patent/CA2686488A1/en not_active Abandoned
- 2007-08-02 JP JP2010509321A patent/JP5825785B2/ja not_active Expired - Fee Related
- 2007-08-02 MX MX2009012620A patent/MX2009012620A/es active IP Right Grant
- 2007-08-02 AT AT07813699T patent/ATE512673T1/de active
- 2007-08-02 CN CN2007800530913A patent/CN101678111B/zh not_active Expired - Fee Related
- 2007-08-02 BR BRPI0721681-5A patent/BRPI0721681A2/pt not_active IP Right Cessation
- 2007-08-02 EP EP07813699A patent/EP2162154B1/en not_active Not-in-force
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105263809A (zh) * | 2013-03-15 | 2016-01-20 | Hq专业制药公司 | 在改进的柔性塑料容器中的随时可以使用的助溶剂药物组合物 |
Also Published As
Publication number | Publication date |
---|---|
AU2007353795B2 (en) | 2012-09-13 |
JP5825785B2 (ja) | 2015-12-02 |
KR20100022991A (ko) | 2010-03-03 |
WO2008143682A1 (en) | 2008-11-27 |
BRPI0721681A2 (pt) | 2014-02-25 |
EP2162154B1 (en) | 2011-06-15 |
US8426467B2 (en) | 2013-04-23 |
ATE512673T1 (de) | 2011-07-15 |
US20080292558A1 (en) | 2008-11-27 |
MX2009012620A (es) | 2009-12-11 |
EP2162154A1 (en) | 2010-03-17 |
CN101678111B (zh) | 2013-01-02 |
JP2010528001A (ja) | 2010-08-19 |
CA2686488A1 (en) | 2008-11-27 |
AU2007353795A1 (en) | 2008-11-27 |
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