CN1233224A - 包含造影剂的容器 - Google Patents

包含造影剂的容器 Download PDF

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CN1233224A
CN1233224A CN97198709A CN97198709A CN1233224A CN 1233224 A CN1233224 A CN 1233224A CN 97198709 A CN97198709 A CN 97198709A CN 97198709 A CN97198709 A CN 97198709A CN 1233224 A CN1233224 A CN 1233224A
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罗伯特·斯诺
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GE Healthcare AS
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Abstract

本发明公开了一种含塑料材质的密闭容器(如,弹性体加塞小瓶),它可用于含有或适于含有挥发物(如,气态卤化烃,如全氟烃)的造影剂和其前体,其中所述塑料材质通过暴露于挥发物中而进行预处理。这种容器可提高造影剂或其前体的储存稳定性。

Description

包含造影剂的容器
本发明涉及用于造影剂、更具体地用于含有或适于含有挥发物的造影剂的储存装置。
人们熟知,例如在血管系统,特别是在心动描记法,以及组织微血管的研究中,超声成像法包括一种可能有价值的诊断工具。现已提出,使用各种造影剂来增强所得声像,其中包括固体颗粒的悬浮液、乳化液滴、气泡和密封气体或液体。一般认为,易压缩的低密度造影剂在其所产生的声能反向散射方面特别有效,因此,制备含气体系和气体生成体系,如含有或适于含有挥发物的造影剂已引起人们的极大关注。
人们非常关注对用于含气超声造影介质的气体的选择,这样可增强各种性能,如其稳定性和回声效应的持续时间。因此,例如,WO-A-9305819提出,使用系数Q大于5的气体的自由微泡,其中
Q=4.0×10-7×ρ/CsD
(ρ为气体密度,公斤/米3;Cs为气体的水溶解度,摩尔/升;D为气体在溶液中的扩散率,厘米3/秒)。现已详细列出了据说能满足这种要求的气体,其中包括各种烃类,如烷烃、烯烃等,和卤化物,如六氟化硫、十氟化二硫、六氟化钨,溴化和/氯化和/或氟化和/或碘化烃类,溴化醛类、氟化酮类、氟化胺类、氟化硫醇类、等。
EP-A-0554213提出,人们可通过向注气微囊中加入至少一种气体而赋予其以耐压破性,对于所述气体来说,除以其分子量平方根的其水溶解度、以标准条件下的气体升数/水升数表示、不超过0.003。据说,优选的这些气体包括,卤化物如六氟化硫、六氟化硒和各种Freons。
WO-A-9416739公开了包含液包液胶态分散液的超声造影剂,其中分散相为其沸点低于成像者体温的液体。因此,在投药给成像者之后,这种试剂可通过相变成为回声气泡。据说,合适的挥发性分散相液体的例子包括:脂族烃类,如丁烷和戊烷,和有机卤化物,特别是氟烃类,如全氟丁烷、全氟戊烷和全氟新戊烷。
WO-A-9503835提出,使用包含其组成基于微泡内外气体分压的气体混合物的微泡,这样需根据微泡尺寸来考虑渗透效应。有代表性的混合物包含,在血液或浆液中具有低气压和有限溶解度的气体(如,氟烃)、以及能够与正常血液或浆液中气体较快交换的另一种气体(如,氮气、氧气、二氧化碳或其混合物)。
WO-A-9516467提出,使用包含气体A和B的混合物的超声造影剂,其中气体B的量为0.5-41%v/v,分子量大于80道尔顿,且其在标准条件下的水溶解度低于0.0283ml/ml。有代表性的气体B包括:卤化气体,如硫氟化硫,和各种溴化和/或氯化和/或氟化烃类。作为混合物剩余部分的气体A,其代表例包括:空气、氧气、氮气、二氧化碳及其混合物。
WO-A-9608234所要求的容器包含脂悬浮水相和完全与脂相分离的气相,比如包含诸如烷烃或烯烃的烃类或,更优选氟化气体如全氟烃。据说,通过振荡这种容器的内容物可产生在,例如超声或磁谐振成像中用作造影剂的注气微脂粒组合物。
WO-A-9618420涉及包含气泡的产品,所述气泡固定在包含合适稳定助剂等的生理上可接受的冻结含水载体介质内;这种产品可融化生成可注射的超声造影剂。据说,有代表性的气体包括:含卤气体,如六氟化硫、全氟甲烷、全氟乙烷、全氟乙烯、全氟丙烷、全氟丙烯、全氟丁烷、全氟丁-2烯、全氟丁二烯、全氟环丁烷、全氟戊烷、全氟环戊烷及其混合物。
在具有给定气体含量的气氛下,通过包含合适的表面活性剂、助剂、稳定剂等,如上述EP-A-0554213、WO-A-9503835和WO-A-9516467中所公开的造影剂通常可用作干配方。通过在,例如静脉注射投药前含有加入载液,如无菌无热原水或盐水,可重新配制这种干配方。
WO-A-9416739和WO-A-9608234中所公开的造影剂可用作液体配方。WO-A-9608234中的那些造影剂特别要求,在脂水相上的液上空间存在气体。按照WO-A-9416739,造影剂储存态上的任何液上空间都可能包含某些蒸汽态的分散相物质,这归因于这种物质所固有的挥发性。
一般来说,造影剂及其前体,如干配方通常装在密闭容器,如用各种密闭装置如塞子或隔膜密封的小瓶或其它容器,或预注注射器中。有利的是,这种容器的内容物可构成或生成合适的单位剂量的造影剂。容器如小瓶通常可包含玻璃和/或塑料材质,且用包含塑料的密封装置,如弹性体进行密封。容器如注射器也可包含玻璃和/或塑料材质,且通常可包括塑料柱塞。
本发明部分基于以下发现,当包含挥发物的造影剂储存在密闭塑料容器中时,通过用所述挥发物预处理该塑料,该试剂的储存稳定性可显著增强,这种储存稳定性可例如由在标准条件下的储存时间长短来度量,其间该产品能够连续产生可再生回声性。还有,现已发现,这种预处理塑料材质也可用作挥发物,加入密闭容器中并由此加入其中所含的造影剂或其前体。
因此,按照本发明,提供了一种包含其中含有或适于含有挥发物的造影剂或其前体的密闭容器,所述容器至少部分包含一种塑料,其特征在于,在密封该容器之前,将其暴露于所述挥发物的样品中而预处理所述塑料。
可用于本发明的密闭容器的例子包括:小瓶,如玻璃瓶、塑料瓶或至少部分衬有塑料的玻璃瓶,这些小瓶例如通过可含有塑料和/或含有密封衬垫和/或该材质衬里的塞子、隔膜或螺帽进行密封;注射器,例如可以是单腔的、双腔的、多腔的,而且例如可包含玻璃、塑料或至少部分衬有塑料的玻璃,这种注射器例如包括含有和/或涂覆有塑料材质的柱塞;以及袋、盒和箱,例如包含和/或涂覆有基本上不可渗透的物质如金属箔,而且也可包括塑料,这些袋、盒和箱通常包含多个含造影剂的小瓶。如果需要,如上所述的容器可另外或可选地包括塑料材质衬垫,例如可以是杆、管、球、盘、片、海绵、泡沫、气凝胶、蜂窝格子、薄膜、等形状。在诸如注射器的容器中,柱塞可有效地构成一种密封装置;其上也可有其它密封装置,如预镶嵌针或针镶嵌配置。
受欢迎的是,按照本发明的容器只要含有一种以上塑料材质和/或塑料组分,就可用挥发物预处理任何或所有这些材质和/或组分。
可用于本发明的塑料材质包括范围广泛的各种天然和合成聚合物。特别是,当这些物质用作密闭或密封装置,如塞子、隔膜、螺帽、帽衬垫或注射器柱塞时,采用弹性聚合物可能是有利的,其例子包括,但不限于,聚乙烯、聚丙烯、聚异丁烯、聚苯乙烯、聚氯乙烯、聚丙烯腈、全氟化聚合物如Teflon、天然橡胶、丁基橡胶、合成橡胶如Hycars或氯丁橡胶、硅氧烷聚合物、Teflon-硅氧烷层压件、Teflon-橡胶层压件、和本领域已知用于密封小瓶如药物、诊断试剂等的容器的其它弹性体。
如果需要,用于本发明的塑料材质可含有吸收剂,如无机物如沸石或分子筛,这样可提高在预处理时对挥发物的吸收。
还有,比如,当塑料材质用作加入密闭容器的挥发物源时,根据例如,在预处理时挥发物的用量水平以及以后挥发物的释放速率,可以选择塑料材质如塞子和衬垫的尺寸和形状以产生合适的性能。为了提高所吸收和吸附的挥发物量,可增加这些尺寸如厚度。通过使用具有较高的表面积:体积比率的塑料材质,如多孔、纤维状(如,在纤维束中)或杆状材质或具有折边、凸纹、沟槽或糙化表面的材质,可提高预处理吸收速率以及以后的挥发物释放速率。
挥发物一般可包含一种或多种气体(该术语包括,基本上或完全为气态的包括混合物在内的任何物质,其中包括在常人体温37℃下形成的蒸汽)、挥发性液体(如,其沸点不超过60℃的)、固体(如,通过升华作用或由分解气体而产生明显蒸汽压的固体)、以及前述物质的任何混合物。挥发物的代表例包括,如含有最多10个碳原子的低分子量烃类,比如丁烷、戊烷、己烷、庚烷和相应的环烷烃、烯烃等。但挥发物更优选为含卤物质,如包含选自溴、氯、氟和碘中,优选自氯和/或氟中的至少一个卤原子的含卤物质;使用氟化,更尤其全氟化合物是特别有利的。因此,含卤化合物的代表例包括,卤化硫,如六卤化硫或十氟化二硫,有机卤化物,如包含多至20个碳原子的脂族(可以是直链或支链、饱和或不饱和的)、环脂族、芳脂族或芳族卤化物,比如:含氯烃,如氯仿、二氯甲烷或三氯甲烷;Freons,如三氯氟甲烷、二氯二氟甲烷、氯三氟甲烷、二氯四氟乙烷或氯五氟乙烷;氟溴烃,如溴十七氟辛烷;含碘烃,如1,3,5-三碘苯或1,3,5-三(三氟甲基)-2,4,6-三碘苯;卤化醚麻醉剂,如血清氟烃(seroflurane)或脱氟烃(desflurane);以及,包含多至8个碳原子的饱和或不饱和、脂族或环脂族氟烃,如烷烃如甲烷、乙烷、丙烷、丁烷、戊烷、己烷、庚烷或辛烷的氟化(优选全氟化)衍生物;烯烃,如乙烯、丙烯、丁烯、丁二烯或戊烯;炔烃,如乙炔、丙炔或丁炔;环烷烃,如环丙烷、甲基环丙烷、环丁烷、环戊烷或环己烷;以及芳烃,如苯。
优选使用气态含卤化合物,如全氟化气体如六氟化硫、全氟丙烷、全氟丁烷或全氟戊烷。如果需要,这些气体可与气体非卤化气体混合,比如空气、氧气、氮气、二氧化碳或其混合物。
存在于本发明容器中的造影剂可采用合适的形式,例如包括,适于盛装并稳定气体微泡的含水组合物,如美国专利4466442或WO-A-9115244中所描述的;气体微泡在合适载液中的分散液,它可选地密封在注气微气球中(如,其中气体包含在包络物质如聚合物、蛋白质或成膜表面活性剂中,比如在磷脂囊等中),挥发性液体或固体微颗粒;以及固体造影剂前体配方,它可与载液如无菌水或盐水重新配制用于注射。这些固体配方可以例如通过冻干进行制备,通常包含一种或多种表面活性剂,比如,成膜脂如磷脂、助剂如低温防护剂和/或毒性添加剂、稳定剂等。
对用在或用作本发明密闭容器的塑料材质来说,可在室温或高温和压力下,通过暴露于密封反应器如Parr弹状储气瓶(Parr bomb)中的物质来进行预处理;较为有利的条件应使得,该物质被所吸收或吸附的挥发物饱和。只要必要或需要,也可在密封前将挥发物气氛注入容器中。另外,可让挥发物由预处理塑料材质渗透到容器中,然后与造影剂或其前体相互作用。考虑到工艺成本,后一技术可能有利。因此,包括将挥发物加入容器如小瓶中的步骤的方法,可能会浪费容器腔中的残余挥发物,其中挥发物是这样加入的:在作为冻干法一部分的低压冻干器的腔中,抽空一个或多个小瓶成真空腔,然后向腔中加入挥发物。另一方面,对塑料材质的压力处理可更有效地利用剩余挥发物,因为它在处理完成时易回到挥发物源。
在用密封装置如塞子、隔膜、螺帽等密闭容器如小瓶之后,进一步密封该密封装置的外表面可能是有利的,例如,使用金属箔或金属卷帽,或使用基本上不渗透挥发物的一层物质,如合适的天然和合成蜡或硅氧烷密封剂、或作为挥发物非溶剂的亲水物质如甘油或低分子量聚乙二醇。另外,可以采用例如,在其外表面或表面上含有这种不渗透物质作为涂层或固有组件的预成形密闭装置。
以下非限定性实施例用于说明本发明。
实施例1
将瓶塞置于保持在0℃的无菌Parr弹状储气瓶中。加入全氟丁烷,然后密封该弹状储气瓶,然后加热至50℃ 24小时。冷却弹状储气瓶至20℃,然后透气,释放出气态全氟丁烷。去除塞子,用其密封小瓶,其中含有冻干磷脂微脂粒造影剂配方和在液上空间中的空气与全氟丁烷的混合物;然后用铝卷帽包覆塞子。相对其中塞子未经过全氟丁烷预处理的对比小瓶来说,全氟丁烷在该小瓶中的浓度和造影剂组合物的适用期都得到了提高。
实施例2
如实施例1所述,用全氟丁烷处理瓶塞,然后用其密封小瓶,其中含有冻干磷脂微脂粒造影剂配方和在液上空间中的空气;然后用铝卷帽包覆塞子。在用水重新配制以进行注射时,该组合物可不断产生含全氟丁烷的微泡分散液。
实施例3
洗涤瓶塞,高压灭菌,然后热处理(121℃,15小时)以去除在高压灭菌时所吸收的水分。将热瓶塞暴露于气态全氟丁烷中,然后在该气体下冷却至室温。
实施例4
在配有手套箱的冻干腔中,冻干包含造影剂前体的未加塞小瓶。冻干之后,向装置中加入全氟丁烷。通过使用手套箱,手工将实施例3中制备的预处理瓶塞应用到小瓶中。
实施例5
用实施例3中制备并在冻干腔中冻干的预处理塞子,轻轻地塞住包含造影剂前体的小瓶,然后将塞子压到密封部位上。向腔中加入氮气以解除真空,然后打开密封小瓶。结果发现,全氟丁烷逐渐由塞子释放到小瓶的液上空间。

Claims (17)

1.一种包含其中含有或适于含有挥发物的造影剂或其前体的密闭容器,所述容器至少部分包含一种塑料材质,其特征在于,在密封所述容器之前,将其暴露于所述挥发物的样品中而预处理所述塑料材质。
2.根据权利要求1所述的密闭容器,其形式为小瓶、柱塞、袋、盒和箱。
3.根据权利要求1或2所述的密闭容器,其中所述塑料材质是一种密闭/密封装置、衬里材料或衬垫。
4.根据权利要求3所述的密闭容器,其中所述密闭/密封装置包括塞子、隔膜、螺帽、帽衬垫或注射器柱塞。
5.根据前述权利要求中任何一项所述的密闭容器,其中所述塑料材质包括弹性聚合物。
6.根据权利要求1所述的密闭容器,包括用弹性聚合物塞子密封的一种玻璃瓶。
7.根据权利要求6所述的密闭容器,其中所述塞子还含有基本上不渗透挥发物的一种物质作为涂层或作为整体组件。
8.根据前述权利要求中任何一项所整体的密闭容器,其中所述挥发物包括卤化硫或包含多至20个碳原子的脂族、环脂族、芳脂族或芳族卤化物。
9.根据权利要求8所述的密闭容器,其中所述挥发物包括六氟化硫或包含多至8个碳原子的全氟烃。
10.根据权利要求9所述的密闭容器,其中所述全氟烃选自全氟丙烷、全氟丁烷和全氟戊烷。
11.根据前述权利要求中任何一项所述的密闭容器,包含:一种适于盛装并稳定气体微泡的含水组合物,可选密封的气体微泡在载液中的一种分散液,或适于与载液重新配制的固体造影剂前体配方。
12.根据权利要求11所述的密闭容器,其中所述固体造影剂前体配方包含冻干磷脂。
13.根据前述权利要求中任何一项所述的密闭容器,其中所述塑料材质是一种密闭装置,其外表面具有其它密封装置。
14.根据权利要求13所述的密闭容器,其中所述其它密封装置包括金属箔或金属卷帽。
15.一种制造根据权利要求1所述的密闭容器的方法,其中包括:通过暴露于所述挥发物的样品来处理所述塑料材质,然后密闭所述容器。
16.根据权利要求15所述的方法,其中所述塑料材质是在高压和/或高温下暴露于所述挥发物的。
17.根据权利要求15或16所述的方法,其中所述塑料材质被所述挥发物所饱和。
CN97198709A 1996-08-27 1997-08-27 包含造影剂的容器 Pending CN1233224A (zh)

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