CN1244110A - 用于储存液体药物的环状烃聚合物药物容器 - Google Patents
用于储存液体药物的环状烃聚合物药物容器 Download PDFInfo
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Abstract
本发明涉及用于储存液体药物如胰岛素的药物容器,容器具有顶侧的和底侧的端部分和壁,壁的至少两部分为聚合物材料。该聚合物壁部分的厚度为0.3毫米到3毫米,在400纳米处聚合物壁部分的透光率至少为25%。聚合物壁部分包含至少70%重量的由5至7元环的脂环族或脂双环族烃和乙烯或丙烯组成的共聚物材料,该材料的玻璃化转变温度大于50℃,并且密度为0.95g/cm3或更大。容器的聚合物材料对药物大体上为惰性,而且容器为透明的,因此能够通过目测检查容器的内容物,以确定药物没有结晶或聚合。此外,容器的壁分别提供了对间甲苯酚/苯酚/苯甲醇防腐剂和水的很好的屏障作用。本发明还涉及这种药物容器的应用,以及至少部分装有药物的药物容器。
Description
本发明涉及了用于储存液体药物的药物容器,这种药物容器的应用,以及至少装有部分药物的药物容器。
传统上,储存液体药物和制剂的药物容器是由玻璃制成的。对于某些药物,如经口投药的药物,也可使用不透明的聚乙烯或聚酯的容器。在美国专利4,565,851号中介绍了由乙醇酸聚酯和对苯二甲酸聚酯制成的这种聚合物容器。这种容器提供了对氧气和其它气体的很好的屏障作用,但是它对于防腐剂和水不能提供足够的屏障作用。
药物,如胰岛素或生长激素,装在小容器或安瓿中。这种安瓿中通常装有1.5到10毫升的即服药物。这些安瓿储存在医院或药房的药品库中,或由使用者保存。这意味着储藏期限必须足够长。药物,如胰岛素或生长激素的含水溶液或悬浮液中通常含有防腐剂,如苯酚和/或苯甲醇和/或间甲苯酚。由于含有蛋白、肽和/或DNA序列的药物的敏感性,不可能进行终末消毒,必须加入防腐剂。容器中装有多于一个剂量的药物,如在禽畜中使用的药物,有很大的被污染的危险。因此,这些药物,特别是肠胃外投药的药物中,防腐剂为必需的成分。苯酚、苯甲醇和间甲苯酚经允许,可在肠胃外药物,如肌内投药药物中少量使用。含有防腐剂的药物的含水溶液或悬浮液可以在玻璃容器中储存最多2年的时间。
T.J.McCarthy的文章“含水的防腐剂溶液和其塑料容器的相互作用”Pharm.Weekblad 107(1972年)中,介绍了分别在以白珍珠颜料涂色的聚丙烯(PP)容器和聚氯乙烯(PVC)容器中储存某些防腐剂的含水溶液的作用,特别介绍了关于防腐剂从溶液中的流失。文中没有讨论在透明容器中储存防腐剂的含水溶液。此外,这篇文章的结论为,一些类型的防腐剂从储存在PP、PVC容器中的溶液中大量流失,尽管容器似乎对防腐剂提供了很好的屏障。由于PVC中含有氯,因环境污染的原因,PVC是不适于使用的。
Tarr等人的文章“在塑料胰岛素注射器中储存28天的生物合成人胰岛素的稳定性和无菌性”,美国医院药师学会(American Societyof Hospital Pharmacists),第48卷,2631-34页,1991年中,介绍了在聚丙烯-聚乙烯注射器中分别储存苯酚、苯甲醇和间甲苯酚的含水溶液的类似的试验,特别是分别关于苯酚、苯甲醇和间甲苯酚从溶液中的流失。
试验仅进行了28天,但从试验可以得出结论,聚丙烯-聚乙烯注射器不能用于储存含有苯酚和/或苯甲醇和/或间甲苯酚的药物。装有胰岛素或生长激素的安瓿在药品库或医院或药房储存时,通常在5℃的冰箱中储存。当由使用者储存时,这些药品通常在室温下储存长达一个月。尤其由于使用者一般需要把胰岛素一直带在身边,胰岛素是在室温下储存的。在储存期间,胰岛素和防腐剂的浓度必须接近于常数。如果防腐剂的浓度太低,药物就不能得到很好的保存。这使人想到制备有高防腐剂起始浓度的药物。但这对于肠胃外用药是不能接受的。储存期间水的流失也应很低,因为流失大量的水会导致活性药物浓度太高,而且可能导致防腐剂的浓度太高。如果流失太多的水,使用者就会服用过多剂量的活性药物,如胰岛素。
此外,使用者能够目测检查药物,以确定药物没有由于自缔合或变性引起的结晶或聚合,或任何其它的可通过目测发现的药物的变化,如活性药物的氧化,是很重要的。
本发明的目的是,提供聚合物材料的药物容器,该材料对药物大体上为惰性,并且该容器为透明的,分别提供了对间甲苯酚/苯酚/苯甲醇和水的很好的屏障作用。
本发明的另一个目的是,提供药物容器,该容器便宜而且易于制造。
本发明的另一个目的是,提供可长期储存含水药物,如胰岛素或人生长激素的含水溶液的药物容器。
本发明的用于储存含有一种或多种活性药物、水和间甲苯酚和/或苯酚和/或苯甲醇的液体药物的药物容器,具有顶侧的和底侧的端部分和壁,壁的至少两部分为聚合物材料。这些聚合物壁部分的厚度为0.3毫米到3毫米,优选地为0.5毫米到1毫米,在400纳米处的透光率为25%或更高。透光率是当容器中充满水时,通过容器相对的两个壁部分,以空气作为参照,用标准分光光度计测定的。聚合物壁部分包含至少70%重量的由5至7元环的脂环族或脂双环族烃和乙烯或丙烯组成的共聚物材料,该材料的玻璃化转变温度大于50℃。玻璃化转变温度是通过从容器壁切下碎片,把碎片在铝盘中从10℃加热到270℃,并在10℃/分的扫描速率下,用差示扫描量热法测定的。玻璃化转变温度为拐折点处温度,并且密度为0.95g/cm3或更大。
材料中可以含有最多5%重量的添加剂,具体地选自于抗氧剂、润滑剂如硬脂酸盐和聚硅氧烷、表面活性剂、成核剂和澄清剂,以及最多30%重量的惰性填料,如折光指数与聚合物材料的折光指数大致相等的玻璃微粒,添加剂和填料的总量最多为30%重量。
如上所述,为控制容器中药物的质量,材料对可见光的散射和吸收必须很低。对于外来微粒、悬浮液的均匀性、晶体的沉积、溶液中的沉淀、肽或蛋白在溶液中的纤维化或聚合,以及药物溶液的吸收光谱的变化,可以由目测检查进行质量控制。
最危险的是影响溶液中的活性药物的浓度的变化,使用者很难注意到这些变化中的聚合或沉淀,特别是当容器的透光率很低时。
对于一些胰岛素配方,如果大于3%的胰岛素聚合,糖尿病患者可以目测观察到是很重要的。聚合的胰岛素可以目测或通过分光光度计观察到透光率的变化。当3%的胰岛素聚合时,胰岛素溶液的透光率的典型的变化相当于1∶400的Ph.Eur标准的透光率变化,当30%的胰岛素聚合时,胰岛素溶液的透光率的典型的变化相当于1∶40的Ph.Eur标准的透光率变化(1997年欧洲药典,2.2部分,物理和物理化学方法,2.2.1液体的澄清度和乳光度)。
在玻璃容器中,0.9毫米壁厚1∶40的Ph.Eur在400纳米处的透光率的典型变化为从约94%到约45%。在非晶形的环状聚烯烃容器中,1∶40的Ph.Eur的透光率的典型变化为从约85%到约41%,变化可以由眼睛目测。在高透明度的聚丙烯容器中,透光率的典型变化为从约40%到约18%。在低透明度的聚丙烯容器中,透光率的典型变化为从约15%到约6%,或甚至为从约4%到约3%,所有的变化都是用1∶40的Ph.Eur测定。
显然,当透光率高、变化大时患者最可能观察到药物容器中的这些问题。实际上,为了能够目测观察大于3%的聚合,壁厚0.9毫米、装有商品胰岛素溶液如Actrapid 100 IU/毫升(Novo Nordisk A/S)的3毫升容器在400纳米处的透光率推荐为大于25%。
已令人惊讶地发现,用于包装用间甲苯酚保存的肠胃外药物的几种适宜的材料,都属于聚烯烃材料。如上所述,任何材料必须满足许多规定,以能够防止间甲苯酚和水从药物配方中流失,并能够允许对产品质量进行目测检查。
本发明的药物容器应优选地满足以下要求:
聚合物壁部分对间甲苯酚的渗透率小于0.0072克/米2/24小时,渗透率是在37℃和12%的相对湿度(RH)下,使聚合物壁与3毫克/毫升的间甲苯酚含水溶液接触,储存三个月后测定的。聚合物壁部分对水的渗透率小于0.4克/米2/24小时,是在37℃和12%的RH下,储存三个月后测定的。更优选地,聚合物壁部分对间甲苯酚的渗透率小于0.0055克/米2/24小时,更优选地,小于0.0020克/米2/24小时,渗透率是在37℃和12%的RH下,使聚合物壁与3毫克/毫升的间甲苯酚含水溶液接触,储存三个月后测定的。优选地,聚合物壁部分对水的渗透率小于0.35克/米2/24小时,更优选地,小于0.30克/米2/24小时,甚至更优选地,小于0.20克/米2/24小时,是在37℃和12%的RH下,储存三个月后测定的。
优选地,聚合物壁部分对水的渗透率小于0.025克/米2/24小时,是在8℃和13%的RH下,储存36个月后测定的,更优选地,小于0.021克/米2/24小时。
间甲苯酚、苯甲醇和苯酚都是有机溶剂,在水中的溶解度很低。间甲苯酚比苯酚和苯甲醇的极性小,因而在高度疏水环境中比苯酚和苯甲醇扩散得快。此外,间甲苯酚在疏水环境如环状聚合物中的溶解度比较高。尽管苯酚和苯甲醇为比间甲苯酚小的分子,而且尺寸对于扩散速率为重要的因素,已经发现,苯酚或苯甲醇的流失比间甲苯酚的流失要小,因而足以确定间甲苯酚的流失。
根据本发明,甚至更为优选的是药物容器,尤其对于肠胃外药物的应用,满足以下的要求:
水的流失在37℃和12%的RH下、储存3个月后应小于1.5%,在8℃和13%的RH下、储存36个月后应小于1%。对于内径9.25毫米的3毫升的容器,这相当于37℃下的渗透率为约0.35克/米2/24小时,8℃下的渗透率为约0.021克/米2/24小时。
在37℃和12%的RH下、储存3个月后,间甲苯酚对于整个容器的流失应小于10%,优选地对于容器的聚合物壁部分的流失为7.5%。对于内径9.25毫米、壁厚0.9毫米的3毫升的容器,这相当于渗透率为约0.0053克/米2/24小时。
根据本发明,已经发现有一组聚合物容器满足规定,即含有无定形聚合物的容器,该无定形聚合物是由5至7元环的脂环族或脂双环族烃和乙烯或丙烯组成的共聚物材料,该材料的玻璃化转变温度大于50℃。该玻璃化转变温度是通过从容器壁切下碎片,把碎片在铝盘中从10℃加热到270℃,并在10℃/分的扫描速率下,用差示扫描量热法测定的。玻璃化转变温度为拐折点处温度,并且密度为0.95g/cm3或更大。
无定形共聚物材料优选由具有一个或多个5至7元环的脂环族烃和乙烯组成,优选共聚物材料完全是无定形的,即它的结晶度低于1%重量。最优选地,无定形共聚物材料是由Schott和Hoechst公司出售的商标为“Topas”的材料(见表1)。
而且,本发明容器的无定形聚合物壁部分优选在400纳米处的透光率为60%或更高,更优选为75%或更高,测量方法如上所述。
本发明容器的无定形聚合物壁部分的密度优选为0.95g/cm3至1.05g/cm3,更优选约1.02g/cm3。
用上述方法测得的玻璃化转变温度(Tg)优选至少75℃,更优选至少100℃。对于具有上述温度范围的Tg的容器可以进行水蒸汽消毒。对于Tg更低的聚合物的容器,可以采用γ-消毒法。
通常,在共聚物中环状组分与线型组分的比越高,聚合物的Tg就越高。水屏障性能与聚合物中环状组分的含量相关,因为通过降低环状组分相对于线型组分的量至一定程度,可以增加对水的屏障性。优选地,聚合物材料包含至少20%线型烯烃,优选至少50%线型烯烃,如乙烯。
相应地,玻璃化转变温度优选至多200℃,如至多170℃,更优选至多150℃。
无定形聚合物优选包含至少75%,更优选大于95%,和最优选98%重量或更多的聚烯烃材料。
材料的其余部分优选地含有最多5%重量的添加剂,尤其是选自于抗氧剂、润滑剂如硬脂酸盐和聚硅氧烷、表面活性剂、成核剂和澄清剂,以及惰性填料,如折光率与聚合物材料的折光率大致相等的玻璃微粒,添加剂和填料的总量最多为30%重量。
本发明的聚合物壁部分含有元定形聚合物材料的容器可以有任何适当的形状。优选的容器壁的内表面,同样优选地容器壁的外表面大体上为圆柱形,因为只有至少容器的内表面大体上为圆柱形时,如果软橡胶活塞在容器中转过一些角度后,仍能保持其紧密性。
容器优选地为药筒,顶侧端部分有可穿透的熔封,底侧端部分有活塞。这种药筒在本领域是熟知的。
聚合物壁部分优选地为整个壁面积的至少30%,优选地为大于50%,更优选地为大于80%。
容器可以有更厚和更薄的壁部分。通过减小容器壁的一部分或多个部分的厚度,可以得到更好的透光率。这会显著影响这些部分的屏障性能。通过增大容器壁的一部分或多个部分的厚度,可以得到容器的更好的屏障性能。
本发明的优选的实施方案中,容器为药筒,药筒具有聚合物壁和圆柱形内表面,顶侧端部分有可穿透的熔封,底侧端部分有活塞,壁有不同的厚度,以提供非常透明的窗口。
容器的壁优选地通过注射成型制造,尤其是当容器壁的主要部分或所有的壁都是由聚合物材料制成时。
本发明还涉及了容器用于储存含有一种或多种防腐剂的药物的应用。药物优选地为人生长激素的含水溶液或悬浮液,或胰岛素的含水溶液或胰岛素的悬浮液,优选地每毫升药物中含有25到600IU的胰岛素、0.1到5毫克的苯酚或苯甲醇、以及0.5到5毫克的间甲苯酚。
实施例中用到了以下的测定材料性能的方法:渗透率
把材料制成外径为11.05毫米,内径为9.25毫米,因而壁厚为0.90毫米的3毫升的容器。容器一端用溴丁橡胶塞子,另一端用溴丁橡胶/天然橡胶层压材料密封。
间甲苯酚的渗透率是在37℃、13%的RH下容器储存胰岛素(Actrapid,100U/ml,Novo Nordisk A/S)3个月后测定的。
水的渗透率是在37℃、13%的RH下容器储存胰岛素配方(Actrapid,100IU/ml,Novo Nordisk A/S)3个月后,以及在8℃、13%的RH下储存6、12及18个月后测定的。间甲苯酚的渗透率
间甲苯酚的流失是在37℃下储存3个月后,用高效液相色谱筛析法测定的,测定中使用Waters Protein-Pak I-125柱,用流动相做等度洗脱,流动相的组成为:600克的冰醋酸、600克的乙腈、2.8克的L-精氨酸以及水总共4000克。用冻结标准(Frozen standard)校正高效液相色谱中的漂移。用与塑料容器尺寸相同的玻璃容器校正经过橡胶塞和橡胶密封的流失。计算可得渗透率。水的渗透率
水的渗透率是在3、6和18个月的试验后,测定的重量流失。在试验期间,流失与时间成线性,因而结果可外推到8℃下储存36个月的情况。用尺寸相同的玻璃容器用作参照。透光率
透光率是以空气作为参照,用标准分光光度计测定的。适当放置容器,使光束垂直地通过塑料表面,以使光束通过容器壁,通过其中的水溶液或水,并从相对的容器壁穿出,进入检测器。在此装置中,光通过了两层壁厚。与容器的直径相比,保持光束的直径很小,以避免光在容器表面的反射。密度
通过把已知重量的塑料放入含有清洁剂的含水溶液中,测量液体体积的变化,确定塑料材料的密度。乙烯的含量
采用质子NMR测定乙烯含量。玻璃化转变温度
用差示扫描量热仪DSC测定环状聚烯烃材料的玻璃化转变温度。从容器上切下样品并置于铝盘中。随后以10℃/min的扫描速率从10℃至270℃加热样品。玻璃化转变温度测定为在与材料玻璃化转变相关的热流曲线中阶梯的拐折点。材料
实施例中使用了表1中的材料。表1
所用的材料环状烯烃 经销商 开发试样 实施例编号
(是/否)Schott Hoechst,Denmark 否 1Topas8007Schott Schott,Denmark 否 1Topas5013Schott Schott,Denmark 是 1Topas6013Schott Hoechst,Denmark 否 1Topas6015Schott Hoechst,Denmark 否 1Topas6017Daikyo Daikyo 是 1CZ-树脂
来自于公司的开发的材料为:不是从市场买到的透明材料,正在开发中有待于以后引入。因此,开发的材料不是可从市场上买到的,但是可通过要求从经销商那里得到。实施例1
用注射成型制造4种不同的环状聚烯烃材料的容器,参见表1。3毫升的容器外径都是11.05毫米,内径为9.25毫米,因而壁厚为0.90毫米。容器一端用溴丁橡胶塞子,另一端用溴丁橡胶/天然橡胶层压材料密封。Hoechst公司生产的Topas材料由双环状单体成分与乙烯成分结合而构成。Daikyo公司的CZ-树脂由单环状单体成分构成。
材料的水渗透性在三种不同的条件下测定。间甲苯酚的渗透性在37℃下测定。大概的乙烯含量来源于生产厂家。玻璃化转变温度用DSC测定。Topas 6015和6017在25℃下的渗透性数据从生产厂家的数据估算,并标以“*”。表2
材料 | Tg | 乙烯含量% | 在37℃、13%RH下的水渗透性g/m2/24hr(0.9mm厚) | 在25℃、13%RH下的水渗透性g/m2/24hr(0.9mm厚) | 在8℃、13%RH下的水渗透性g/m2/24hr(0.9mm厚) | 在37℃、13%RH下的间甲苯酚渗透性g/m2/24hr(0.9mm厚) |
Topas 8007 | 76 | 65 | 0.10 | 0.40 | 0.011 | <0.1 |
Topas 5013 | 137 | 55 | 0.14 | 0.62 | 0.019 | <0.1 |
Topas 6013 | 143 | 55 | 0.14 | 0.60 | 0.018 | <0.1 |
Topas 6015 | 162 | 45 | 未测 | 0.70* | 未测 | 未测 |
Topas 6017 | 182 | 40 | 未测 | 0.90* | 未测 | 未测 |
CZ-树脂 | 140 | 0 | 0.25 | 0.91 | 0.027 | 0.34 |
从表2可以看到,Topas8007、Topas5013和6013的容器同时具有优良的透光率和屏障性能。
玻璃化转变温度为76℃的Topas8007样品的渗透性比玻璃化转变温度分别为137℃和143℃的Topas5013和6013样品的渗透性稍低。
CZ-树脂作为对比例,CZ-树脂的乙烯含量为0,从而环状组分构成了聚合物的100%。环状组分的高含量在所有测试温度下,尤其是8℃下损害了水渗透性。而且,与本发明的聚合物相比,间甲苯酚的屏障性能也降低了。
Claims (22)
1.用于储存液体药物的药物容器,其中装有一种或多种药物、水和间甲苯酚和/或苯酚和/或苯甲醇,容器具有顶侧的和底侧的端部分和壁,壁中至少两个相对的部分为聚合物材料,该聚合物壁部分的厚度为0.3毫米到3毫米,在400纳米处的透光率为25%或更高,透光率是当容器中充满水时,通过容器相对的两个壁部分,以空气作为参照,用标准分光光度计测定的,聚合物壁部分包含至少70%重量的由5至7元环的脂环族或脂双环族烃和乙烯或丙烯组成的共聚物材料,该材料的玻璃化转变温度大于50℃,玻璃化转变温度是通过从容器壁切下碎片,把碎片在铝盘中从10℃加热到270℃,并在10℃/分的扫描速率下,用差示扫描量热法测定的,玻璃化转变温度为拐折点处温度,并且密度为0.95g/cm3或更大。
2.根据权利要求1的容器,其中聚合物壁材料含有至少75%,优选地大于95%,最优选地大于98%重量的共聚物材料。
3.根据权利要求1或2的容器,其中聚合物壁材料含有最多5%重量的添加剂,优选地选自于抗氧剂、润滑剂、表面活性剂、成核剂和澄清剂,以及最多30%重量的惰性填料,优选地为折光率与聚合物材料的折光率大致相等的玻璃微粒,添加剂和填料的总量最多为30%重量。
4.根据权利要求1、2或3的容器,其中共聚物材料由5至7元环,优选双环状物质和乙烯组成。
5.根据权利要求1至4中任一项的容器,其中聚合物材料包含至少20%乙烯,优选至少50%乙烯。
6.根据权利要求1至5中任一项的容器,其中共聚物材料为完全无定形的。
7.根据权利要求1至6中任一项的容器,其中聚合物壁部分在400纳米的透光率为60%或更高,优选75%或更高,该值用权利要求1中定义的方法测定。
8.根据权利要求1至7中任一项的容器,其中聚合物壁材料的密度为0.95至1.05g/cm3,优选约1.02g/cm3。
9.根据权利要求1至8中任一项的容器,其中聚合物壁材料的玻璃化转变温度为至少75℃,优选至少100℃。
10.根据权利要求1至9中任一项的容器,其中聚合物壁材料的玻璃化温度至多200℃,优选至多170℃,最优选至多150℃。
11.根据权利要求1到10中任何权利要求的容器,其中容器壁有内表面和外表面,内表面大体上为圆柱形。
12.根据权利要求1到11中任何权利要求的容器,其中容器壁有内表面和外表面,壁的外表面大体上为圆柱形。
13.根据权利要求1到12中任何权利要求的容器,其中容器为药筒,顶侧端部分有可穿透的熔封,底侧端部分有活塞。
14.根据权利要求1到13中任何权利要求的容器,其中聚合物壁部分占整个壁面积的至少30%,优选地为大于50%,更优选地为大于80%。
15.根据权利要求1到14中任何权利要求的容器,其中聚合物壁部分对间甲苯酚的渗透率为小于0.0072克/米2/24小时,渗透率是在37℃和12%的RH下,使聚合物壁与3毫克/毫升的间甲苯酚含水溶液接触,储存三个月后测定的,聚合物壁部分对水的渗透率小于0.4克/米2/24小时,是在37℃和12%的RH下,储存三个月后测定的。
16.根据权利要求15的容器,其中聚合物壁部分对间甲苯酚的渗透率小于0.0070克/米2/24小时,优选地小于0.0055克/米2/24小时,更优选地小于0.0020克/米2/24小时,渗透率是在37℃和12%的RH下,使聚合物壁与3毫克/毫升的间甲苯酚含水溶液接触,储存三个月后测定的。
17.根据权利要求15或16的容器,其中聚合物壁部分对水的渗透率小于0.35克/米2/24小时,优选地小于0.30克/米2/24小时,更优选地小于0.20克/米2/24小时,是在37℃和12%的RH下,储存三个月后测定的。
18.根据任何权利要求15、16或17的容器,其中聚合物壁部分对水的渗透率小于0.025克/米2/24小时,优选地,小于0.021克/米2/24小时,是在8℃和13%的RH下,储存3个月后测定的。
19.根据权利要求1到18中任何权利要求的药物容器的应用,用于储存含有一种或多种防腐剂的药物。
20.根据权利要求19的应用,其中药物为胰岛素的含水溶液或胰岛素的悬浮液,优选地每毫升药物中含有25到600U的胰岛素、0.1到5毫克的苯酚或苯甲醇、以及0.5到5毫克的间甲苯酚。
21.根据权利要求19的应用,其中药物为人生长激素的含水溶液或悬浮液。
22.根据权利要求1到18中任何权利要求的药物容器,至少部分装有液体药物溶液,溶液中含有一种或多种活性药物、水和间甲苯酚和/或苯酚和/或苯甲醇。
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CN97181309A Pending CN1244110A (zh) | 1996-12-23 | 1997-12-16 | 用于储存液体药物的环状烃聚合物药物容器 |
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- 1997-12-16 EP EP97949989A patent/EP0954273A1/en not_active Withdrawn
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- 1997-12-16 CA CA002275894A patent/CA2275894A1/en not_active Abandoned
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- 1997-12-16 CN CN97181308A patent/CN1244109A/zh active Pending
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- 1997-12-16 JP JP52825498A patent/JP4672818B2/ja not_active Expired - Fee Related
- 1997-12-16 DK DK97949988T patent/DK0954272T3/da active
- 1997-12-16 KR KR1019997005728A patent/KR20000069681A/ko not_active Application Discontinuation
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- 1997-12-16 CA CA002275903A patent/CA2275903A1/en not_active Abandoned
- 1997-12-16 IL IL13043397A patent/IL130433A0/xx unknown
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1999
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103458849A (zh) * | 2011-04-06 | 2013-12-18 | 株式会社大塚制药工厂 | 塑料安瓿 |
CN103417371A (zh) * | 2012-05-03 | 2013-12-04 | 贝克顿·迪金森公司 | 用于贮存药剂的容器和方法 |
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