CN108438308B - 向容器中灌装发泡组合物的方法 - Google Patents
向容器中灌装发泡组合物的方法 Download PDFInfo
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- CN108438308B CN108438308B CN201810521647.7A CN201810521647A CN108438308B CN 108438308 B CN108438308 B CN 108438308B CN 201810521647 A CN201810521647 A CN 201810521647A CN 108438308 B CN108438308 B CN 108438308B
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Classifications
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- B65B31/00—Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers
- B65B31/04—Evacuating, pressurising or gasifying filled containers or wrappers by means of nozzles through which air or other gas, e.g. an inert gas, is withdrawn or supplied
- B65B31/041—Evacuating, pressurising or gasifying filled containers or wrappers by means of nozzles through which air or other gas, e.g. an inert gas, is withdrawn or supplied the nozzles acting from above on containers or wrappers open at their top
- B65B31/042—Evacuating, pressurising or gasifying filled containers or wrappers by means of nozzles through which air or other gas, e.g. an inert gas, is withdrawn or supplied the nozzles acting from above on containers or wrappers open at their top the nozzles being arranged for insertion into, and withdrawal from, the container or wrapper
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- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
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- A—HUMAN NECESSITIES
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- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
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- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
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- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
- B65B3/003—Filling medical containers such as ampoules, vials, syringes or the like
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B31/00—Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
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- B65B31/00—Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers
- B65B31/04—Evacuating, pressurising or gasifying filled containers or wrappers by means of nozzles through which air or other gas, e.g. an inert gas, is withdrawn or supplied
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B7/00—Closing containers or receptacles after filling
- B65B7/16—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons
- B65B7/28—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons by applying separate preformed closures, e.g. lids, covers
Landscapes
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Dispersion Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
本发明涉及包含气态微气泡的组合物的制备方法。更特别地,本发明涉及将此组合物灌装入容器的方法。所制备的组合物优选为可在容器中提供的超声造影剂组合物,其中,容器的顶部空间中包含的气体与微气泡中的气体相同。
Description
本申请是申请日为2013年4月26日,中国国家申请号为201380022644.4,发明名称为“向容器中灌装发泡组合物的方法”的发明申请的分案申请。
技术领域
本发明涉及制备包含气态微气泡的组合物的方法。更特别地,本发明涉及将所述组合物灌装入容器的方法。所制备的组合物优选为可在容器中提供的超声造影剂组合物,其中,容器顶部空间包含的气体与微气泡中的气体相同,并且其中所述气体不同于空气。
背景技术
众所周知,超声波成像包含一种有价值的诊断工具,例如用于血管系统的研究,尤其用于心动描记法,并且用于组织微血管的研究。已经提出了多种超声造影剂,用于增强如此获得的声像,包括:固体颗粒悬浮液、乳化液滴、气泡以及封装气体和液体。通常,最成功的超声造影剂由可静脉注射的小气泡的分散体组成。如果适当稳定的话,微气泡可允许经常以有利的低剂量高效超声可视化例如血管系统和组织微血管。这样的造影剂通常包括使气体分散体稳定的材料,例如,乳化剂、油、稠化剂或糖;或者通过在多种系统中产生或封装气体,以使气体分散体稳定,例如,作为含气体多孔微粒或作为封装的气态微气泡。所述微气泡包括具有如下性质的气体:其对超声造影剂的性能是必需的;并且已发现多种气体增强性质,例如微气泡稳定性和回声生成效果的持续时间。一组超声造影剂在容器中作为成品制剂制备并递送,所述制剂包含气态微气泡的液体组合物。
在这样的含有气态微气泡的液体组合中,通常所述微气泡可包含与空气不同的另一种气体,本文中称作分散气体,如氟化气体。为了补偿或避免所述分散气体在储存过程中从所述微气泡中泄漏,所述容器的顶部空间灌装有顶部空间气体,其通常与所述微气泡中使用的气体相同。若非如此,随着时间推移和微气泡的泄露,所述微气泡中的一定量的气体将包含相当数量的空气而非所需的分散气体。针对认可的液体超声造影剂,通常具有说明书,提供了需要多少百分比的顶部空间气体作为微气泡气体。因此,当制备造影剂时,灌装方法通常包含如下的步骤:灌装造影剂之后,将其为顶部空间气体的吹扫气体送入所述容器,以排出顶部空间的空气,然后加盖。然而,本申请人在如此制备造影剂的过程中面临一个难题。已发现难以确保绝对所有的灌装有造影剂的容器在顶部空间中含有所需数量的顶部空间气体。当发现不符合说明书时,所述容器,并且通常整个批次,不得不被废弃。在现有的制备方法中,所制备的包含微气泡悬浮液的造影剂组合物,从散装容器中泵出并分配到小瓶。在瓶塞和盖放入小瓶口之前,通过将重于空气的顶部空间气体流入所述小瓶并包围所述小瓶,将小瓶的空气排出。然而,本申请人面临的问题是:当将所述造影剂灌装至所述容器时,可能由于文丘里效应,偶尔产生泡沫和含空气的大气体球,并且这样的大空气气泡在将所述顶部空间气体送入所述容器的过程中继续存在。结果,不能总是在所述顶部空间中达到所需数量的顶部空间气体。尝试了多种方法而不能成功移除这些大空气气泡,例如用分散气体替换所述气泡中的空气。因此,在本领域中仍然需要提供灌装有组合物的容器的制备方法,所述组合物在液体载体中含有气态微气泡,其中,对顶部空间的顶部空间气体数量的需求得到满足。
发明内容
基于本领域的需求,本发明提供了一种方法,包括将含有气态微气泡的组合物灌装到容器中,确保针对每一个灌装的容器,关于容器顶部空间内的顶部空间气体数量的规格得到满足。本申请人惊奇地发现:与其在将造影剂灌装入容器之后用顶部空间气体从灌装容器的顶部空间中替换空气,不如首先将顶部空间气体有利地送入空容器内,由此用顶部空间气体替换整个容器中的空气,之后将组合物灌装到容器内。
在第一方面,本发明由此提供了一种灌装有组合物的容器的制备方法,所述组合物在液体载体中含有气态微气泡,所述方法包含以下序贯步骤:
a)利用顶部空间气体,将空气从容器中排出,并且然后
b)将所述组合物灌装入所述容器。
通过使用这样的灌装方法,包括利用顶部空间气体预吹扫冲洗空容器,不产生空气气泡,并且发现,所有灌装有组合物的容器满足对顶部空间中的气体的规格要求。
所述方法进一步包括以下的任选步骤:在步骤b)之后封闭所述容器,如通过在所灌装的容器口内塞入瓶塞,和/或加盖,和/或安装在瓶塞和/或盖上压接的覆盖封闭。本发明的方法中使用的容器为小瓶、瓶或袋。所述容器可以由玻璃或塑料制成,如透明或不透明塑料,并且可以为刚性或柔性塑料容器。所述容器的尺寸为,例如,3ml~50,000ml,并优选为3~500ml的小瓶或瓶。最优选,所述容器包含一个或至少一个剂量。
当被灌装入所述容器时,所述组合物为成品制剂,即所述组合物优选为在生理可接受的水性载体(例如注射用水)中的气态微气泡的分散体。所述组合物可随时对人类或动物患者进行注射,但在注射前可能需要轻轻摇动,以提供均匀的悬浮液。所述组合物可用于治疗或诊断目的,或组合;并且优选作为超声造影剂用于诊断用途。由于如果适当稳定的话,依靠微气泡的低密度和易压缩性,微气泡分散体是超声的特别有效的反散射体,因此含有气态微气泡的造影剂是优选的。其中所述微气泡包含对生物靶标具有亲和性的载体的超声造影剂亦包括在内。
用于本发明的方法的气态微气泡,通过稳定剂稳定,所述稳定剂可围绕所述气态微气泡,阻碍所述气体向周围液体中扩散并另外阻止微气泡之间的融合。包括多种组合物,例如,包括使用明胶或白蛋白微气泡的那些,所述微气泡最初在液体悬浮液中形成,并且在凝固过程中包裹气体。或者,可以制备厚壳体,例如糖或其他粘性材料,或者固体颗粒或者乳化液滴。另一种类型的稳定剂将气体包裹在磷脂层所产生的脂质体中,例如US 5,334,381。
这样的稳定剂可为表面活性剂或较坚固的外壳材料,并且例如选自聚合物,如多糖、脂质和基于蛋白质的材料。所述稳定材料最优选包含磷脂或基于蛋白质的材料,更优选为热变性生物相容性蛋白质,最优选为人血清蛋白。
生物相容性气体可用于所述组合物的微气泡中,并用于本发明的第一步。本发明的第一步所使用的顶部空间气体优选与所述微气泡中的分散气体相同,应理解,术语“气体”、“分散气体”和“顶部空间气体”包括在人体正常体温37℃下基本或完全为气体(包括蒸气)形式的任何物质(包括混合物)。因此所述气体可以包含,例如氮气、氧气、二氧化碳、氢气、一氧化二氮;惰性气体,如氦气、氩气、氙气或氪气;
氟化硫,如六氟化硫、十氟化二硫或三氟甲基五氟化硫;
六氟化硒;
任选卤代的硅烷,如四甲基硅烷;
低分子量烃(例如,含有最多7个碳原子),例如,烷烃,如甲烷、乙烷、丙烷、丁烷或戊烷;环烷烃,如环丁烷或换环戊烷;烯烃,如丙烯或丁烯;或者炔烃,如乙炔;
醚;酮;酯;
卤代低分子量烃,例如,含有最多7个碳原子;或上述任何物质的混合物。
包含卤代低分子量烃的组合物为优选的。有利地,卤化气体中至少一些卤素原子为氟原子。因此,生物相容性卤代烃气体可以选自,例如:溴氯二氟甲烷、氯二氟甲烷、二氯二氟甲烷、溴三氟甲烷、氯三氟甲烷、氯五氟乙烷、二氯四氟乙烷以及全氟化碳,例如,全氟烷烃,如全氟甲烷、全氟乙烷、全氟丙烷、全氟丁烷(例如,全氟正丁烷,任选与其他异构体如全氟异丁烷混合)、全氟戊烷、全氟己烷和全氟庚烷;全氟烯烃,如全氟丙烯、全氟丁烯(例如全氟丁-2-烯)和全氟丁二烯;全氟炔烃,如全氟丁-2-炔;以及全氟环烷烃,如,全氟环丁烷、全氟甲基环丁烷、全氟二甲基环丁烷、全氟三甲基环丁烷、全氟环戊烷、全氟甲基环戊烷、全氟二甲基环戊烷、全氟环己烷、全氟甲基环己烷和全氟环庚烷。其他卤化气体包括氟化的(例如全氟化的)酮,如全氟丙酮以及氟化的(例如全氟化的)醚,如全氟乙醚。针对含有氟化气体如氟化硫或碳氟化合物(例如全氟化碳)的组合物使用本发明的方法可为进一步有利的,所述气体已知形成特别稳定的微气泡悬浮液,其中,优选为SF6、全氟丙烷和全氟丁烷,并且特别优选为全氟丙烷。
本发明的方法更优选用于制备含微气泡的组合物,所述微气泡包含蛋白质,最优选包含白蛋白,其封装有全氟化碳气体,最优选全氟丙烷,又称为八氟丙烷(OFP)或全氟丙烷。
其中顶部空间气体重于空气的本发明的方法是优选的。所述顶部空间气体优选为与所述分散气体相同,因此,如果或当所述分散气体在储存过程中从所述微气泡中泄漏时,所述容器的顶部空间气体对此进行补偿。如果所述顶部空间气体与所述分散气体不同,那么随着时间推移,一定数量的微气泡将包含所述顶部空间气体而非所需的分散气体。在本发明的某些实施例中,备选地,所述顶部空间气体与所述分散气体不同。例如,顶部空间中的气体可包含沸点低于所述分散气体的气体。这是为了避免顶部空间气体在冷却时凝结,如将所述容器置于冷藏器中。在本实施方案中,所述两种气体应相似,如,两种具有不同沸点的不同全氟代烃。在另一实施方案中,所述分散气体为空气,而所述顶部空间气体为另一气体,优选为更重的气体,如氟化气体。在储存过程中,一定数量的微气泡则有利地包含所述顶部空间气体而非原来的空气。
本发明的方法尤其有用于微气泡的水性组合物的制备,其中所述微气泡包含不同于空气的气体。出于示例而非进行限制的目的,可根据本发明制备的具体所述超声造影剂的实例为BR14、MP1950、OptisonTM和PESDA,其中特别优选为OptisonTM。
本发明的方法中所使用的组合物可通过不同方法制备,以产生气态微气泡分散体,如通过超声处理、喷雾干燥或通过机械能混合,如利用胶体磨(转子定子)。在本发明的一个实施方案中,所述方法包括在步骤a)之前的处理步骤,其中所述组合物通过以下方法制备,其中将所述稳定材料的溶液(优选人血清蛋白的水溶液)与待分散的气体输送至胶体磨内,在其中它们完全混合。当气态微气泡的均匀分散体完成制备时,其被送至散装容器。所述散装容器为,例如,容积为例如10~100L的柔性大袋。在本发明的方法的步骤b)中,将所述组合物从所述散装容器分配至所述容器,在步骤a)中已将在所述容器内的空气替换为顶部空间气体。
针对不同的含气造影剂,对所述容器的顶部空间内需要的气体量(即百分比)可存在不同要求,其取决于,例如,微气泡中所包含的气体类型,所使用的稳定材料以及所述气体从气泡中扩散的容易程度。利用本发明的方法,针对每个所灌装的容器,所述容器的顶部空间内的分散气体的量的规格得到满足。所灌装的容器的顶部空间内的气体含量通常通过气相色谱法测量,例如,通过测量统计数量的所制备的容器内的气体的浓度。在本发明的一个实施方案中,通过本发明的方法,得到顶部空间体积的40~100%,如至少50%,或优选至少60%,如至少70%的气体含量。针对制备超声造影剂OptisonTM(其为优选的实施方案),当使用本发明的方法时,顶部空间内至少60%的全氟丙烷的规格要求得到满足。在根据本发明的方法所灌装的容器中,通常,顶部空间为所述容器总体积的约20~50%。当灌装有组合物时,优选容器总体积的约40%为顶部空间。例如,在5mL小瓶中,存在约3mL的所述组合物和约2mL的顶部空间。并且,如上所述,当所述容器灌装有所述组合物时,此顶部空间的40%~100%包含所述顶部空间气体。
在本发明的方法中,将与含有所述顶部空间气体的气罐连接的吹扫针放置在所述容器内,并且所述空容器利用所述顶部空间气体预吹扫。当排出空气时,所述针的方向优选朝向所述容器底部。当从所述容器中抽出所述针时,优选继续吹扫以防止在所述吹扫针移出时空气进入所述容器。所述空容器例如以200~800cc/分钟的速度用所述顶部空间气体吹扫,如400~600cc/分钟,并优选约500cc/分钟。所需的气流速度还取决于所用的小瓶尺寸。由于所述顶部空间气体优选为重于空气,所述气体将在灌装所述组合物的过程中停留在所述容器内。在灌装所述组合物的过程中,不产生泡沫或大气泡,并且在灌装结束时,所述顶部空间气体将纯净地位于所述组合物顶部。如果在灌装过程中产生了气泡,那么其只包含所使用的吹扫气体而不减少所述顶部空间气体含量。将所述组合物灌装至所述容器内的步骤,优选在将空气从所述容器中排出的步骤之后完成,并且例如在排出空气结束后10秒之内、例如5秒之内完成。优选地,随后封闭所述容器。当使用本发明的方法时,灌装可以快速完成而且没有任何产生泡沫的问题,并且每天可制备大量包括具有所述组合物的容器的包装。使用本发明的方法,每小时可灌装约2000~3000个容器,其取决于几个因素,例如,所述容器的尺寸。如果制备灌装有所述组合物的5mL小瓶,那么每天可灌装例如约20~50000个小瓶,从而提供经济上可行的方法。
当使用本发明的方法时,满足对顶部空间内一定数量的顶部空间气体的要求,而无因泡沫产生的任何中断灌装,且没有任何容器需要被废弃。所述顶部空间中的气体和所述微气泡中的气体之间存在平衡,且所述微气泡在储存过程中保持稳定。在灌装和封盖之后,所述微气泡可以漂浮,在表面产生一层。在为患者注射之前,可需要通过轻轻摇动重新悬浮,以提供均匀的悬浮液。
在第二方面,本发明提供了含有根据第一方面的方法所制备的组合物的容器。所述组合物可用于治疗或诊断目的,或组合,并优选作为超声造影剂用于诊断用途。多种成像技术可以在超声波应用中使用,例如,包括基波和谐波B模式成像以及基波和谐波多普勒成像;如有需要,可使用三维成像技术。所述造影剂也可用于基于相关技术的超声波成像方法。
在另一方面,本发明提供了一种在灌装有组合物的容器的制备方法中使用的装置,所述组合物在液体载体中含有微气泡,所述装置包含:
i)预吹扫冲洗装置;
ii)分配机构,用于将所述组合物分配到所述容器中。
所述冲洗装置优选包含至少一个吹扫针,其连接于含有所述顶部空间气体的气罐,用于将所述顶部空间气体送入所述容器。例如,所述分配机构包括连接于散装容器的导管,其中,泵将所述组合物经所述导管从所述散装容器中泵出,并分配至所述容器中。所述导管可进一步与针连接以灌装所述容器。所述装置优选进一步包含管道,其包含通过顶部保持在一起的两壁,其中所述顶部包含一个或多个开口,并优选为至少两个开口。已经发现所述管道的用途是减少文丘里效应。所述吹扫针设计为插入到所述顶部的一个开口中并插入到所述容器口中。在本发明的方法的步骤a)之前,所述空容器置于传送带上,其将这些容器运送至该仪器的管道中,其中首先所述吹扫针插入所述管道的开口并插入所述容器口中,将所述针朝向所述容器的底部放置并利用所述顶部空间气体将空气从所述容器中排出。之后,抽出所述吹扫针,并持续吹扫,并随后和优选在吹扫结束后数秒内,利用所述装置的分配机构将所述组合物灌装到所述容器中。将所述分配机构的导管,或替代地,连接于所述导管的灌装针,置入并穿过所述管道的另一开口,并插入已预排出空气的所述容器口中。当一批容器完成预排出空气时,所述容器被灌装,同时将新一批容器进行吹扫。其后,将所述容器加塞和加盖。在考虑对气体和稳定材料的选择时,此方面包括与第一方面相同的特点。
现在,本发明参考下列非限制性实施例进行说明。
具体实施方式
实施例
实施例1:对照实施例——利用后排出空气,将OptisonTM灌装到容器中使用Groninger灌装机对灌装有OptisonTM的小瓶进行无菌分配、加塞、加盖并压封。
所述Optison溶液通过蠕动泵的方式从散装容器中泵出,并被分配到500个3mL小瓶中。泵速设置为140rpm且泵加速度为100%。其后,在管道内和管道下,通过将全氟丙烷气体(OFP)以300cc/分钟的流速流动将小瓶排出空气。之后,所述Groninger灌装机加塞、加盖并在盖上压封。
在对一产品批次的全氟丙烷顶部空间进行测试的过程中,测试90个样品,并且其中3个不符合至少60%顶部空间的顶部空间标准。对于3个不合格样品,带至运行结束。为了验证所述测试结果,进行重复和额外的实验测试。这些测试包括重新测试3个不合格顶部空间样品以及数个合格样品。基于测试结果,合格和不合格样品两者与原始测试相同。使用此方法,获得的全氟丙烷顶部空间的平均含量为65%。
在将所述Optison组合物灌装至所述小瓶的过程中,在所述小瓶中观察到大气泡。在后吹扫的过程中,大气泡中的气体没有被全氟丙烷替换。在储存过程中,所述大气泡破裂并且其中的气体与所述顶部空间气体混合。由于所述大气泡内的气体为空气,因此所述顶部空间内的总全氟丙烷气体含量减少。在气泡破裂后,测量含有大气泡的小瓶的全氟丙烷顶部空间含量。所有含有大空气气泡的小瓶均不满足全氟丙烷顶部空间规格,并且顶部空间内的全氟丙烷的数值低至40%。
实施例2:利用所要求保护的方法使用预排出空气将OptisonTM灌装到容器中使用Groninger灌装机对灌装有OptisonTM的小瓶进行无菌分配、加塞、加盖并压封。
参照实施例1,调查研究表明,使用灌装后吹扫未将全氟丙烷顶部空间含量最优化。然而确定的是,在灌装之前,在500cc/分钟的吹扫速率下,空小瓶的灌装前全氟丙烷吹扫显著改善了全氟丙烷顶部空间含量。
在500cc/分钟的流速下,通过将全氟丙烷气体流入并包围空小瓶,将500个3mL小瓶预排出空气。然后Optison溶液通过蠕动泵的方式从散装容器中泵出并分配至小瓶中。泵速设置为100rpm且泵加速度为50%。之后,所述Groninger灌装机加塞、加盖并在盖上压封。
在所述过程中,抽取500个小瓶中的90个小瓶进行顶部空间分析,并检查任何生成的大气泡。
为了提供灌装前吹扫过程,将产品灌装针向下移动至先前灌装后全氟丙烷吹扫针所在的位置。在吹扫过程中,所述吹扫针降低至所述小瓶的底部。所述灌装前吹扫针和产品灌装针的这种定位,进一步优化了全氟丙烷顶部空间。
使用该预吹扫方法,获得的全氟丙烷顶部空间的平均含量为75%。因此,通过利用500cc/分钟的全氟丙烷气体预吹扫空小瓶代替在300cc/分钟下灌装后吹扫已分配的小瓶,证实从平均65%到75%的改善。所有小瓶满足至少60%顶部空间的顶部空间标准。此外,发现全氟丙烷顶部空间具有更少的偏差且标准偏差从7.4减少至1.9。
重要的是,在吹扫过程中,所述吹扫针降低至所述小瓶底部,从而能够吹洗出空气。如果所述针仅降低至所述小瓶的瓶颈顶部,则全氟丙烷将与小瓶中的气体混合而不吹洗出空气。使用本方法,任何在灌装过程中产生的大气泡将包含全氟丙烷而非空气,并且将不减少全氟丙烷顶部空间含量。
依据得自灌装小瓶的数据,使用6σ极限进行方法能力计算,并且得出结论,所述灌装方法稳定,并且使用推荐的预吹扫参数,没有小瓶将不合格。
Claims (11)
1.一种灌装有超声造影剂组合物的容器的制备方法,其中顶部空间体积的40~100%包含顶部空间气体,所述组合物在液体载体中含有气态微气泡,所述组合物可随时对患者进行注射,其中所述微气泡包含选自脂质或基于蛋白质的材料的稳定材料,所述方法按顺序包括下列步骤:
a)利用顶部空间气体,将空气从容器中排出,并且之后
b)将所述组合物灌装入所述容器,随后封闭所述容器,
其中所述顶部空间气体为重于空气的生物相容性卤代烃气体,并且在步骤a)中,空容器利用所述顶部空间气体以400~600 cc/分钟的速度进行吹扫,并且其中步骤a)中使用的所述顶部空间气体与所述微气泡中的气体相同。
2.根据权利要求1所述的方法,其中所述基于蛋白质的材料是热变性生物相容性蛋白质。
3.根据权利要求1所述的方法,其中所述基于蛋白质的材料是人血清蛋白。
4.根据权利要求1-3中任一项所述的方法,其中所述顶部空间气体是氟化气体。
5.根据权利要求1-3中任一项所述的方法,其中所述顶部空间气体是氟化硫或碳氟化合物。
6.根据权利要求1-3中任一项所述的方法,其中所述顶部空间气体是全氟化碳。
7.根据权利要求1-3中任一项所述的方法,其中所述顶部空间气体是SF6、全氟丙烷和全氟丁烷。
8.根据权利要求1-3中任一项所述的方法,其中所述顶部空间气体是全氟丙烷。
9.根据权利要求1-3中任一项所述的方法,其中所述基于蛋白质的材料是白蛋白和所述顶部空间气体是全氟丙烷。
10.根据权利要求1-3中任一项所述的方法,其中将与含有所述顶部空间气体的气罐连接的吹扫针放置在所述容器内,并且利用所述顶部空间气体预吹扫所述空容器。
11.根据权利要求10所述的方法,其中当排出空气时所述吹扫针的方向朝向所述容器底部。
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EP2844362B1 (en) | 2020-02-26 |
BR112014026783A2 (pt) | 2017-06-27 |
IN2014DN09192A (zh) | 2015-07-10 |
RU2631800C2 (ru) | 2017-09-26 |
EP2844362A1 (en) | 2015-03-11 |
CA2871684C (en) | 2021-01-05 |
JP6594772B2 (ja) | 2019-10-23 |
AU2013255952A1 (en) | 2014-11-06 |
AU2013255952B2 (en) | 2018-04-12 |
KR20150003221A (ko) | 2015-01-08 |
KR102157909B1 (ko) | 2020-09-18 |
US11045748B2 (en) | 2021-06-29 |
RU2014142309A (ru) | 2016-06-20 |
BR112014026783B1 (pt) | 2020-12-15 |
JP2015518407A (ja) | 2015-07-02 |
CA2871684A1 (en) | 2013-11-07 |
HK1207026A1 (zh) | 2016-01-22 |
CN104349827A (zh) | 2015-02-11 |
US20150068157A1 (en) | 2015-03-12 |
MX2014013218A (es) | 2014-12-08 |
CN108438308A (zh) | 2018-08-24 |
WO2013164269A1 (en) | 2013-11-07 |
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