CN1136830C - 维生素d溶液贮器和输液用的容器 - Google Patents
维生素d溶液贮器和输液用的容器 Download PDFInfo
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- CN1136830C CN1136830C CNB998024872A CN99802487A CN1136830C CN 1136830 C CN1136830 C CN 1136830C CN B998024872 A CNB998024872 A CN B998024872A CN 99802487 A CN99802487 A CN 99802487A CN 1136830 C CN1136830 C CN 1136830C
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- vitamin
- solution
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- contain
- polyolefin
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Abstract
一种由聚烯烃制作的用于盛包含维生素D或其衍生物的溶液的贮器,其中,构成该贮器的盛溶液部分的聚烯烃体积是每μmol含于其中的维生素D或衍生物为30cm3或更小;以及输液用的容器,每个容器备有所述贮器。贮器或容器的应用使得有可能将维生素D含量的降低减至最小。
Description
本发明涉及由聚烯烃制作的用于盛维生素D溶液的贮器,它使维生素D含量的降低减至最小;还涉及容纳该贮器的输液容器。
在很多情况下,消化道做了手术的患者不能经口摄食营养物。因此,为了给这样的患者提供营养物,通常进行静脉高营养供给(IVH)。IVH有助于上述患者营养状况的改善和改善的营养状况的维持,所以促进这些患者的康复和治愈。因此,人们认为IVH很有效,并且,目前IVH被广泛用于外科治疗领域。
在IVH中,通常施用作为营养源的碳水化合物和氨基酸,以及电解质。已开发了用于IVH的盛装所有这些营养源的输液制品,通常,可商购的制品是这种类型的,即其中有两个容器,一个盛有葡萄糖,另一个则盛有氨基酸(这里,已知葡萄糖和氨基酸会引起美拉德反应)。
当进行IVH达较长一段时间后,就会出现问题。例如,未含于输液制品中的痕量元素和维生素的缺乏会导致营养不良。特别是葡萄糖代谢中消耗维生素B1,所以往往缺乏,引起严重的酸中毒。因而,当IVH延长而超出一定的短时期(例如大约一周)之后,必须同时施用维生素。由于维生素的不稳定性,应单独配制各种维生素并以维生素混合物或多维生素制品的形式提供,在临床环境(例如医院)中,在应用时再将这样的维生素与IVH制品混合。但是,在医院里进行这种混合操作是麻烦的。此外,IVH制品在混合过程中可能受细菌污染,所以该操作要求有效且小心。这给施用IVH的人员施加了过多的工作量。
为了使上述混合操作更方便,人们试图生产一种掺和维生素的两容器型IVH制品。例如,将脂肪和糖盛于两容器之一中,将氨基酸和电解质盛于另一个中,就可将各种维生素掺入这两个容器的任一个中(日本专利申请公开Nos.6-209979和8-709)。
脂肪(它是一种重要的营养成分)也被掺入IVH制品。但是,对患高脂血症、肝功能障碍、血栓形成或糖尿病性酮病的患者不可以施用脂肪。在患者中可改变合适的脂肪剂量,而在某些情况下,可能优选单独施用脂肪。
然而,在前述IVH制品中,特定的维生素是通过掺入脂肪而稳定的,所以,不用脂肪而保持维生素(例如维生素B2)的稳定性是困难的。
一般地,广泛采用由聚烯烃(例如聚乙烯或聚丙烯)生产的输液容器,因为这样的容器容易成型并被认为是安全的。但是,当包含维生素D和其它维生素的溶液长时间被贮存在前述聚烯烃制作的容器中时,维生素D会被吸收入该容器,溶液中的维生素含量就大为降低。结果,在经历了转输被贮存于这样的容器中的液体后的患者中就会由于维生素D缺乏而引起钙的吸收障碍或骨的脆化。
人们已进行了有关各种盒式输液容器的研究,其中,单独地制备盛例如维生素这样的物质的贮器,并将该贮器连接到所述容器上。例如,日本专利申请公开(kokai)No.6-54889公开了一种袋组合件(其中连接有注射器)。在这类输液容器中,当盛药物的贮器是由不吸收维生素D的原料(例如玻璃)生产时,就能避免前述问题。但是,该贮器会涉及更高的生产成本,并且在使用后拆除该贮器而单独处理会是费力的。
鉴于上述情况,本发明的一个目的是提供一种由聚烯烃制作的用于盛维生素D溶液的贮器,它使维生素D含量的降低减至最小,以及一种装有该贮器的输液容器。
为了解决前述问题,本发明人进行了广泛研究,发现了即使在贮器中应用了吸收维生素D的聚烯烃的情况下,当构成该贮器的盛溶液部分的聚烯烃体积是预定的量或更小时,也能将维生素D含量的降低限制在可接受的范围内。在该发现的基础上完成了本发明。
因此,本发明提供了一种由聚烯烃制作的用于盛包含维生素D或其衍生物的维生素D溶液的贮器,其中,构成该贮器的盛溶液部分的聚烯烃体积是每μmol维生素D或其衍生物为30cm3或更小。
本发明还提供了一种输液容器,它是柔性的并且容纳维生素D溶液的贮器。
图1是一幅示意图,它示出本发明的盛维生素D溶液的贮器的一个实施方案。
图2是一幅示意图,它示出本发明的输液容器的一个实施方案。
本发明的贮器盛装包含维生素D或其衍生物的溶液。维生素D或其衍生物的实例包括:维生素D1、维生素D2、维生素D3(胆钙化甾醇)、及其活性形式(羟基衍生物)。
本发明的贮器中的溶液,除了含维生素D或其衍生物之外还可能包含:脂溶性维生素,例如维生素A、维生素E和维生素K;水溶性维生素;以及电解质。
当该溶液含有脂溶性维生素时,优选通过应用表面活性剂将该维生素变成可溶性的。可应用的表面活性剂实例包括:聚氧乙烯山梨糖醇酐脂肪酸酯(可商购的产品,例如吐温80和吐温20),聚氧乙烯氢化蓖麻油(可商购的产品,例如HCO60),以及乙二醇·丙二醇嵌段共聚物(可商购的产品,例如Pluronic F68)。这些表面活性剂通常以0.1~100g/l的量被应用于所述溶液中。
此外,当该溶液包含维生素C或者还原剂[包括亚硫酸盐、亚硫酸氢盐或硫醇(例如半胱氨酸)]时,该溶液的稳定性就可得到提高。
本发明的贮器是由聚烯烃生产的。聚烯烃的类别不受特别限制,只要它可被用于常规临床上应用的贮器中即可。这样的聚烯烃实例包括链型烯烃聚合物,例如聚乙烯、聚丙烯、聚(1-丁烯)和聚(4-甲基-1-戊烯)。
在这些聚合物中,聚乙烯可以是乙烯均聚物或者是乙烯和α-烯烃(例如丙烯、1-丁烯或4-甲基-1-戊烯)的共聚物。该共聚物可呈线型或支链的形式。在本发明中,聚乙烯可以是高密度或低密度的,所以可选自各种形式。就柔软度和透明性来说,线型低密度聚乙烯是优选的。
聚丙烯可以是丙烯均聚物,或者是丙烯和少量(一般是10wt%或更少,优选是5wt%或更少)烯烃(例如乙烯和1-丁烯)的共聚物。应用的聚丙烯优选是被广泛用于生产临床贮器的优质聚丙烯。
这些聚烯烃可被单独应用或者作为混合树脂组合应用。
本发明的贮器可通过这样生产:密封上述聚烯烃的膜的周边,再应用常规方法使袋成形。
所述贮器的盛溶液部分(即除密封的周边部分之外的部分,也就是与溶液接触的部分)中树脂的体积是溶液中每μmol的维生素D或其衍生物为30cm3或更小,优选为20cm3或更小,更优选为10cm3或更小。当体积超过30cm3时,维生素D的吸收就不能被抑制。
上述树脂的体积可通过将该贮器盛溶液部分的表面积乘以该部分的厚度而计算。
聚乙烯制作的膜的厚度是100μm或更小,优选是20~50μm。
本发明的贮器可以从如上所述的聚烯烃单层膜生产,或者从多层膜(它包括一层聚烯烃层,其上形成一层基本上不吸收维生素D的树脂层)生产。不吸收维生素D的树脂实例包括:聚对苯二甲酸乙二酯、聚萘二羧酸乙二醇酯、聚丙烯腈、聚酰胺(例如尼龙)、聚碳酸酯、聚氟乙烯,以及环烯烃共聚物。通常,这些树脂的热熔接是困难的,但包括作为最内层的聚烯烃的多层膜容易被加工成形为贮器。
一个这种多层膜的具体实例是三层膜,它包括由聚乙烯构成的内层和外层以及尼龙中间层(图1)。
另一个具体实例优选是三层膜,它包括由聚烯烃(例如聚乙烯或聚丙烯)构成的内层和外层,以及由环烯烃共聚物构成的中间层。一个这种环烯烃共聚物的实例是可商购的乙烯·四环十二碳烯共聚物。这样的共聚物可用作前述膜的原料。
当这种多层膜以与聚烯烃单层膜相同的方式被用于贮器中时,构成该多层膜的最内层的聚烯烃的体积(它相应于盛溶液部分)是该贮器内盛装的溶液中每μmol的维生素D或其衍生物为30cm3或更小,优选为20cm3或更小,更优选为10cm3或更小。
与溶液接触的聚烯烃层(最内层)厚度是100μm或更小,优选是5~50μm。
本发明的用于盛维生素D溶液的贮器可以作为终产品单独生产。也可将该贮器装在柔性输液容器内部。本发明包括这样的输液容器。
为了将该贮器装入输液容器,可以让该贮器浮在容器中的溶液中。优选地,将用于盛维生素D溶液的贮器周边密封部分的边缘夹在所述容器的周边部分之间并密封,于是将该贮器的边缘固定在容器上。在该情况下,为了进行密封,所述容器的材料优选与用来盛维生素D溶液的贮器的材料相同或者与该贮器最外层的材料相同。
优选地,上述用于盛维生素D溶液的贮器包括容易揭开的密封条或者是用厚度为100μm或更小的膜生产的,这样,当包括该贮器的输液容器被安装供施用时,能手工揭开或撕破该贮器。
这种输液容器的一个具体实例包括由隔壁分开的两个隔室,隔壁允许液体通过它连通,其中,在一个隔室中盛有含氨基酸的溶液(B),另一个隔室中盛有含还原糖的溶液(A),电解质和其它维生素则适当地盛于这两个隔室的任一个中。盛维生素D溶液的贮器可被装入任一隔室中(图2)。
上述输液容器优选盛有:含维生素B1的溶液(A),含叶酸的溶液(B),以及含其它脂溶性维生素和维生素C的维生素D溶液;其中,维生素B2被掺入溶液(B)或维生素D溶液中,并将溶液(A)、溶液(B)和维生素D溶液的pH分别调节到3.5~4.5、5.0~7.0和5.0~7.0。
优选地,溶液(A)进一步包含泛酸衍生物,并且维生素D溶液包含维生素B2,更优选地,溶液(B)包含维生素B12。
特别优选地,溶液(A)进一步包含维生素B6,溶液(B)进一步包含烟酸衍生物,并且维生素D溶液进一步包含生物素。
下面将更详细地描述上述输液容器的一个优选实例。
可被掺入溶液(A)中的还原糖的实例包括:葡萄糖、果糖和麦芽糖。考虑到血糖控制,在这些糖中葡萄糖是特别优选的。溶液(A)可包含非还原糖,例如木糖醇、山梨糖醇和甘油。
还原糖可以单独地或者两种或多种组合地掺入溶液(A)中,并且,当掺和时,它们以120~450g/l、优选150~300g/l的量被掺入溶液(A)中。
溶液(A)进一步包含维生素B1。为了稳定维生素B1,将溶液(A)的pH调节到3.5~4.5,优选3.8~4.2。常用的各种有机酸、无机酸、有机碱和无机碱可适当地被用来调节pH。
维生素B1以1~12mg、特别优选1.5~8mg的量被掺入溶液(A)的半天剂量或日剂量中。可被应用的各种维生素B1(硫胺素)的实例包括:盐酸硫胺素、硝酸硫胺素、丙舒硫胺和奥托硫胺。为了防止维生素B1的分解,优选地,含维生素B1的溶液(A)基本上未混有亚硫酸盐或亚硫酸氢盐。
可被掺入溶液(B)中的氨基酸实例包括必需氨基酸和非必需氨基酸,例如:L-异亮氨酸、L-亮氨酸、L-赖氨酸、L-甲硫氨酸、L-苯丙氨酸、L-苏氨酸、L-色氨酸、L-缬氨酸、L-丙氨酸、L-精氨酸、L-天冬氨酸、L-半胱氨酸、L-谷氨酸、L-组氨酸、L-脯氨酸、L-丝氨酸、L-酪氨酸和甘氨酸。这些氨基酸优选是纯晶状氨基酸。这些氨基酸通常呈游离氨基酸的形式,但也可呈其它形式。例如,这些氨基酸可呈药物上可接受的盐、酯、N-酰基衍生物、两种氨基酸的盐和肽的形式。
含于溶液(B)中的这些氨基酸优选的量(基于游离形式)如下。
表1
L-异亮氨酸 3.0-12.0g/l L-色氨酸 0.6-3.6g/l L-谷氨酸 0.3-9.0g/lL-亮氨酸 6.0-21.0g/l L-缬氨酸 2.1-12.6g/l L-组氨酸 2.4-8.1g/lL-赖氨酸 4.5-22.5g/l L-丙氨酸 3.0-12.6g/l L-脯氨酸 1.8-7.8g/lL-甲硫氨酸 1.5-7.5g/l L-精氨酸 4.2-16.5g/l L-丝氨酸 0.9-5.1g/lL-苯丙氨酸 3.0-12.0g/l L-天冬氨酸 0.3-5.1g/l L-酪氨酸 0-1.5g/lL-苏氨酸 2.4-9.0g/l L-半胱氨酸 0.3-2.1g/l 甘氨酸 3.0-13.5g/l |
溶液(B)进一步包含叶酸,并且,将该溶液的pH调节到5.5~7.5,优选6.0~7.0。常用的各种有机酸、无机酸、有机碱和无机碱可适当地被用来调节该pH。叶酸以0.1~1mg、特别优选0.1~0.7mg的量被掺入溶液(B)的半天剂量或日剂量中。
可被掺入维生素D溶液中的脂溶性维生素的实例包括维生素A、维生素D和维生素E。如果必要的话,该溶液可包含维生素K。维生素A(视黄醇)可呈酯的形式,例如棕榈酸酯或乙酸酯。维生素D可以是维生素D1、维生素D2、维生素D3(胆钙化甾醇)、或者这些维生素的活性形式(羟基衍生物)。维生素E(生育酚)可呈酯的形式,例如乙酸酯或琥珀酸酯。维生素K(植物甲萘醌)可以是四烯甲萘醌或2-甲萘醌的衍生物。
这些脂溶性的维生素以下列量被掺入维生素D溶液的半天剂量或日剂量中。维生素A的量是1,250~5,000IU,优选1,400~4,500IU;维生素D的量是10~1,000IU,优选50~500IU;维生素E(生育酚)的量是2~20mg,优选3~15mg;以及维生素K的量是0.2~10mg,优选0.5~5mg。
这些脂溶性维生素优选通过应用表面活性剂而在水中被增溶。可应用的表面活性剂实例包括:聚氧乙烯山梨糖醇酐脂肪酸酯(可商购的产品,例如吐温80和吐温20),聚氧乙烯氢化蓖麻油(可商购的产品,例如HCO60),以及乙二醇·丙二醇嵌段共聚物(可商购的产品,例如Pluronic F68)。这些表面活性剂通常以10~1,000mg/l的量被应用于溶液中。
维生素D溶液进一步包含维生素C,并且,将该溶液的pH调节到5.0~7.0,优选6.0~7.0。常用的各种有机酸、无机酸、有机碱和无机碱可适当地被用来调节该pH。
维生素C(抗坏血酸)可呈钠盐的形式。维生素C以20~250mg、优选30~150mg的量被掺入维生素D溶液的半天剂量或日剂量中。
维生素B2被掺入溶液(B)或维生素D溶液中。
维生素B2(核黄素)可呈其磷酸酯、钠盐的形式,或呈黄素单核苷酸形式。维生素B2以1~10mg、特别优选2~7mg的量被掺入溶液(B)或维生素D溶液的半天剂量或日剂量中。特别地,优选将维生素B2掺入维生素D溶液中。
在本发明的输液容器中,两个隔室中的每一个还可包含其它维生素。
例如,溶液(A)可进一步包含泛酸衍生物。该维生素(即该衍生物)既可被掺入溶液(A),又可被掺入溶液(B)中,但优选只被掺入溶液(A)中,这考虑到稳定性的增强作用。泛酸衍生物可呈游离形式或者呈钙盐或泛醇(它是泛酸的还原产物)的形式。泛酸衍生物以1~30mg、优选5~20mg的量被掺入溶液(A)的半天剂量或日剂量中。
溶液(B)可进一步包含维生素B12。该维生素既可被掺入溶液(A),又可被掺入溶液(B)中,但优选只被掺入溶液(B)中,这考虑到稳定性的增强作用。优选地,维生素B12与维生素C分别被掺和。
维生素B12以1~30μg、优选2~10μg的量被掺入溶液(B)的半天剂量或日剂量中。
溶液(A)、溶液(B)和维生素D溶液可进一步分别包含维生素B6、烟酸衍生物和生物素。这些维生素可被掺入这些溶液的任一种中,但优选如上所述掺入相应的溶液中,这考虑到便于生产。
维生素B6以1~10mg、优选1.5~7mg的量被掺入溶液(A)的半天剂量或日剂量中。维生素B6(吡哆醇)可呈盐的形式,例如盐酸吡哆醇。
烟酸衍生物以5~50mg、优选10~45mg的量被掺入溶液(B)的半天剂量或日剂量中。烟酸衍生物可呈游离形式或者呈酰胺、钠盐或甲酯的形式。
生物素以0.01~0.3mg、优选0.01~0.1mg的量被掺入维生素D溶液的半天剂量或日剂量中。
在本发明的输液容器中,两个隔室中的每一个还可包含电解质,可将电解质掺入溶液(A)、溶液(B)和维生素D溶液的任一种中。对于电解质的类别没有特别的限制,只要它们可被用于常规电解质输液中即可。这样的电解质实例包括:钠、钾、钙、镁、磷、氯和锌。例如,上述溶液中可应用下列化合物的水合物和酐。
钠源的实例包括:氯化钠、乙酸钠、柠檬酸钠、磷酸二氢钠、磷酸氢二钠、硫酸钠和乳酸钠。这样的钠源优选被掺入任何上述溶液中以致混合全部液体之后的溶液中达到25~70mEq/l的量。
钾源的实例包括:氯化钾、乙酸钾、柠檬酸钾、磷酸二氢钾、磷酸氢二钾、硫酸钾和乳酸钾。这样的钾源优选被掺入任何上述溶液中以致混合后达到15~50mEq/l的量。
钙源的实例包括:氯化钙、葡糖酸钙、泛酸钙、乳酸钙和乙酸钙。这样的钙源优选被掺入任何上述溶液中以致混合后达3~15mEq/l的量。
镁源的实例包括:硫酸镁、氯化镁和乙酸镁。这样的镁源优选被掺入任何上述溶液中以致混合后达3~10mEq/l的量。
磷源的实例包括:磷酸二氢钠、磷酸氢二钠和甘油磷酸钠。这样的磷源优选被掺入任何上述溶液中以致混合后达5~20mmol/l的量。
氯源的实例包括:氯化钠、氯化钾、氯化钙和氯化镁。这样的氯源优选被掺入任何上述溶液中以致混合后达25~70mEq/l的量。
锌源的实例包括氯化锌和硫酸锌。这样的锌源优选被掺入任何上述溶液中以致混合后达0~30μmol/l的量。
在这些电解质中,钙盐和镁盐优选与磷化合物分开地被掺入上述溶液中。其它电解质可被掺入任何上述溶液中而没有限制。
溶液(B)可包含作为稳定剂的亚硫酸盐或亚硫酸氢盐。这样的稳定剂以200mg/l或更少、优选100mg/l或更少的量被掺入溶液(B)中。
在很多情况下,本发明的输液容器包含半天剂量或一天剂量的液体,所以,维生素D溶液贮器通常具有1~20ml的体积。
一般说来,将输液容器与脱氧剂一起装入气体屏蔽包装袋内,以便防止氨基酸的氧化分解。如果必要的话,在包装过程中往袋内充入惰性气体。当该容器包含可光分解的维生素时,包装袋优选具有光屏蔽能力。
由各种物质形成的常用薄膜或片材可用作适合包装的气体屏蔽包装袋的材料。这样的材料的实例包括含至少一种选自下列的物质的薄膜或片材:乙烯·乙烯醇共聚物、聚偏1,1-二氯乙烯、聚丙烯腈、聚乙烯醇、聚酰胺和聚酯。当赋予包装袋光屏蔽能力时,可对前述薄膜或片材进行例如铝层压。
可应用的脱氧剂实例包括已知脱氧剂,它们含作为活性组分的铁化合物,例如氢氧化铁、氧化铁和一碳化三铁。可应用例如可商购的化合物,诸如“Ageless”(Mitsubishi Gas Chem.Co.,Inc.的产品)、“Modulan”(Nippon Kayaku Co.,Ltd.的产品)和“Secule”(Nippon Soda Co.,Ltd.的产品)。
如果必要的话,本发明的输液容器在施用时可任选含其它作用剂,例如痕量元素(诸如铁、锰、铜和碘)和抗生素,只要它们不引起转输液体中的任何变化即可。
实施例
下面将通过实施例更详细地描述本发明,但不能认为这些实施例限制本发明。
实施例1
将葡萄糖和电解质溶于注射用蒸馏水,应用乙酸将形成的溶液的pH调节到4,于是配成糖电解质溶液。独立地将维生素B1(盐酸硫胺素)、维生素B6(盐酸吡哆醇)和生物素溶于注射用蒸馏水,再将形成的溶液与前面配制的糖电解质溶液混合。将该混合物进行无菌过滤,从而配成具有表2中所示组成的溶液(A)。
将晶状氨基酸、维生素B12(氰钴胺素)、烟酰胺、泛醇和电解质溶于注射用蒸馏水,应用乙酸将溶液的pH调节到6。往形成的溶液中添加叶酸,将该混合物进行无菌过滤,从而配成具有表2中所示组成的溶液(B)。往溶液(B)中添加作为稳定剂的亚硫酸氢钠以致达到50mg/l的浓度。
独立地用聚山梨酯80(在溶液(C)中的浓度=10g/l)和聚山梨酯20(在溶液(C)中的浓度=2g/l)增溶维生素A(棕榈酸维生素A)、维生素D3(胆钙化甾醇)、维生素E(醋酸维生素E)和维生素K(植物甲萘醌)。然后,将增溶的维生素溶于注射用蒸馏水。另外,将维生素B2(核黄素磷酸酯钠)和维生素C(抗坏血酸)加到形成的溶液中,应用氢氧化钠调节该混合物的pH至6。将形成的混合物进行无菌过滤,从而配成具有表2中所示组成的溶液(C)。
将溶液(C)(4ml)注入由厚度为30μm的聚乙烯膜生产的贮器并熔融密封入口,于是得用于含维生素D3的溶液的贮器。该贮器盛溶液部分的表面积是16cm2,构成盛溶液部分的聚乙烯体积是0.048cm3。
100IU维生素D3相当于2.5μg(即0.0065μmol),所以,聚乙烯的体积是溶液中每μmol的维生素D3为7.4cm3。
在聚乙烯制作的两隔室容器(见图2)中,已预先将上述盛维生素D3溶液的贮器连到其中的一个隔室上。在氮置换的气氛中,独立地将溶液(A)(600ml)和溶液(B)(300ml)注入两个隔室中,并将该容器密封。接着,通过常规方法将该容器进行高压灭菌,从而得一个输液产品。将该输液产品与脱氧剂(商品名:Ageless,Mitsubishi Gas Chem.Co.,Inc.的产品)一起包入光屏蔽尼龙多层袋。
实施例2
按与实施例1相同的方法,配制了具有图2中所示组成的溶液(A)、溶液(B)和溶液(C),再将这些溶液注入实施例1中所述贮器和输液容器的两个隔室。接着,将该容器进行高压灭菌,从而得一个输液产品。将该输液产品与脱氧剂(商品名:Ageless,Mitsubishi GasChem.Co.,Inc.的产品)一起包入光屏蔽尼龙多层袋。
在聚乙烯制作的盛溶液(C)的维生素D3溶液贮器中,盛溶液部分的表面积是16cm2,该部分的厚度是150μm。构成盛溶液部分的聚乙烯体积是0.24cm3,所以,聚乙烯的体积是溶液中每μmol的维生素D3为18.5cm3。
在实施例1和2中,即使贮存四个月后,维生素D3的吸收也受抑制,维生素D3的含量降低在可接受的范围内(≥80%)。其它维生素的含量也降低在可接受的范围内。
表2
实施例3
组分 | 实施例1 | 实施例2 | |
溶液(A) | 葡萄糖氯化钠硫酸镁氯化钙硫酸锌盐酸硫胺素(B1)盐酸吡哆醇(B6)生物素 | 292 g/l2.83 g/l1.23 g/l0.73 g/l9.6 mg/l3.25 mg/l4.08 mg/l0.05 mg/l | 292 g/l2.83 g/l1.23 g/l0.73 g/l9.6 mg/l6.5 mg/l8.16 mg/l0.1 mg/l |
溶液(B) | 氰钴胺素(B12)烟酰胺泛醇叶酸L-异亮氨酸L-亮氨酸L-赖氨酸乙酸盐L-甲硫氨酸L-苯丙氨酸L-苏氨酸L-色氨酸L-缬氨酸L-丙氨酸L-精氨酸L-天冬氨酸L-半胱氨酸L-谷氨酸L-组氨酸L-脯氨酸L-丝氨酸L-酪氨酸甘氨酸柠檬酸钠乙酸钾磷酸钾 | 0.0084 mg/l66 mg/l23.4 mg/l0.667 mg/l8.0 g/l14.0 g/l14.8 g/l3.9 g/l7.0 g/l5.7 g/l2.0 g/l8.0 g/l8.0 g/l10.5 g/l1.0 g/l1.0 g/l1.0 g/l5.0 g/l5.0 g/l3.0 g/l0.5 g/l5.9 g/l0.97 g/l1.15 g/l2.61 g/l | 0.0166 mg/l132 mg/l46.7 mg/l1.334 mg/l8.0 g/l14.0 g/l14.8 g/l3.9 g/l7.0 g/l5.7 g/l2.0 g/l8.0 g/l8.0 g/l10.5 g/l1.0 g/l1.0 g/l1.0 g/l5.0 g/l5.0 g/l3.0 g/l0.5 g/l5.9 g/l0.97 g/l1.15 g/l2.61 g/l |
溶液(C) | 棕榈酸维生素A(A)胆钙化甾醇(D3)醋酸维生素E(E)植物甲萘醌(K)核黄素磷酸酯钠(B2)抗坏血酸(C) | 412500 IU/l25000 IU/l1.25 g/l0.25 g/l0.575 g/l12.5 g/l | 825000 IU/l50000 IU/l2.5 g/l0.5 g/l1.150 g/l25.0 g/l |
将实施例l中配制的溶液(C)注入每个表3所示原料制作的贮器中,从而得盛有维生素D3溶液的贮器。将盛有维生素D3溶液的这些贮器中的每个进行高压灭菌,与脱氧剂(商品名:Ageless,MitsubishiGas Chem.Co.,Inc.的产品)一起包入尼龙多层膜袋中。将这样包装的贮器在40℃下放置四个月。然后,通过HPLC测定每个贮器中各种维生素的含量。结果示于表3中。各种维生素的含量以初始掺入的量的百分数(%)表示。
表3
1号 | 2号 | 3号 | 4号 | 5号 | |||
贮器 | 原料 | 聚乙烯 | 聚乙烯 | 聚丙烯 | 聚乙烯 | 聚丙烯 | |
厚度(μm) | 30 | 100 | 30 | 250 | 250 | ||
盛溶液部分的面积(cm2) | 16 | 16 | 16 | 32 | 32 | ||
树脂的体积(cm3) | 0.048 | 0.12 | 0.048 | 0.8 | 0.8 | ||
树脂的体积(cm3)/维生素D(1μmol) | 7.4 | 18.5 | 7.4 | 123.2 | 123.2 | ||
维生素含量(%) | 维生素A | 灭菌后 | 91.1 | 90.9 | 90.7 | 89.1 | 88.9 |
40℃,4个月 | 80.7 | 81.3 | 81.2 | 78.3 | 77.8 | ||
维生素E | 灭菌后 | 98.7 | 99.4 | 97.6 | 98.2 | 97.6 | |
40℃,4个月 | 98.3 | 99.7 | 97.3 | 95.6 | 95.3 | ||
维生素K | 灭菌后 | 95.4 | 94.7 | 96.1 | 94.3 | 93.9 | |
40℃,4个月 | 91.3 | 90.8 | 91.3 | 89.1 | 88.7 | ||
维生素B2 | 灭菌后 | 94.8 | 96.3 | 95.4 | 94.6 | 95.3 | |
40℃,4个月 | 90.7 | 91.2 | 91.0 | 90.9 | 91.2 | ||
维生素C | 灭菌后 | 96.2 | 97.1 | 97.3 | 97.5 | 96.8 | |
40℃,4个月 | 94.3 | 95.4 | 94.2 | 94.8 | 93.1 | ||
维生素D3 | 灭菌后 | 95.4 | 94.6 | 96.2 | 89.8 | 87.5 | |
40℃,4个月 | 86.2 | 81.3 | 85.8 | 66.3 | 69.1 |
表3中示出的结果表明,即使放置4个月后,1号~3号贮器(处于本发明的范围内)中各种维生素的含量降低在可接受的范围内。
反之,4号和5号贮器中,维生素D3的含量降到可接受的范围之外。
实施例4和5
按与实施例1相同的方法,配制了具有表4中所示组成的溶液(A)、溶液(B)和溶液(C)。将溶液(C)(4ml)注入由三层膜(每层的厚度:10μm)生产的贮器中并熔融密封入口,所述三层膜中外层和内层是用聚乙烯制作的,中间层是用乙烯·四环十二碳烯共聚物(商品名:Apel,Mitsui Chemicals,Inc.的产品)制作的。在两隔室容器中,将制作的贮器连到其中的一个隔室上。独立地将溶液(A)(600ml)和溶液(B)(300ml)注入两个隔室中,并且按与实施例1中相同的方法将该容器密封,高压灭菌,再包装。
表4
组分 | 实施例4 | 实施例5 | |
溶液(A) | 葡萄糖氯化钠硫酸镁氯化钙硫酸锌盐酸硫胺素(B1)盐酸吡哆醇(B6)泛醇 | 292 g/l2.83 g/l1.23 g/l0.73 g/l9.6 mg/l3.25 mg/l4.08 mg/l11.7 mg/l | 292 g/l2.83 g/l1.23 g/l0.73 g/l9.6 mg/l13.0 mg/l12.3 mg/l25 mg/l |
溶液(B) | L-异亮氨酸L-亮氨酸L-赖氨酸乙酸盐L-甲硫氨酸L-苯丙氨酸L-苏氨酸L-色氨酸L-缬氨酸L-丙氨酸L-精氨酸L-天冬氨酸L-半胱氨酸L-谷氨酸L-组氨酸L-脯氨酸L-丝氨酸L-酪氨酸甘氨酸柠檬酸钠乙酸钾磷酸钾叶酸氰钴胺素(B12)烟酰胺 | 8.0 g/l14.0 g/l14.8 g/l3.9 g/l7.0 g/l5.7 g/l2.0 g/l8.0 g/l8.0 g/l10.5 g/l1.0 g/l1.0 g/l1.0 g/l5.0 g/l5.0 g/l3.0 g/l0.5 g/l5.9 g/l0.97 g/l1.15 g/l2.61 g/l0.667 mg/l0.0084 mg/l66 mg/l | 8.0 g/l14.0 g/l14.8 g/l3.9 g/l7.0 g/l5.7 g/l2.0 g/l8.0 g/l8.0 g/l10.5 g/l1.0 g/l1.0 g/l1.0 g/l5.0 g/l5.0 g/l3.0 g/l0.5 g/l5.9 g/l0.97 g/l1.15 g/l2.61 g/l0.667 mg/l0.0168 mg/l200 mg/l |
溶液(C) | 棕榈酸维生素A(A)胆钙化甾醇(D3)醋酸维生素E(E)植物甲萘醌(K)核黄素磷酸酯钠(B2)抗坏血酸(C)生物素 | 412500 IU/l25000 IU/l1.25 g/l0.25 g/l0.575 g/l12.5 g/l7.5 mg/l | 825000 IU/l50000 IU/l2.5 g/l0.5 g/l1.15 g/l50 g/l15 mg/l |
高压灭菌后将上述实施例4和5中的输液容器在40℃下放置四个月。然后,通过日本药典的生物测定法(对于维生素B12和生物素)或者通过HPLC(对于其它维生素)测定容器中的维生素含量。结果如表5中所示。各种维生素的含量以初始掺入量的百分数(%)表示。
表5
实施例4 | 实施例5 | |||
恰在灭菌后 | 40℃,4个月 | 恰在灭菌后 | 40℃,4个月 | |
盐酸硫胺素(B1)盐酸吡哆醇(B6)氰钴胺素(B12)烟酰胺泛醇生物素叶酸棕榈酸维生素A(A)胆钙化甾醇(D3)醋酸维生素E(E)植物甲萘醌(K)核黄素磷酸酯钠(B2)抗坏血酸(C) | 93.8100.591.398.697.4100.497.887.289.894.996.286.598.7 | 87.4100.189.297.896.999.897.584.588.795.195.383.298.3 | 93.599.796.598.298.598.798.386.590.195.395.885.997.8 | 86.699.890.598.597.6100.399.183.989.694.895.484.397.5 |
表5中示出的结果表明,在本发明的输液容器中,即使放置四个月后,13种维生素的维生素含量都降低在可接受的范围内(≥80%)
本发明的维生素D溶液贮器能将贮器对维生素D的吸收减至最少,因而,能保持维生素D的含量降低在可接受的范围内。
Claims (16)
1.一种由聚烯烃制作的用于盛包含维生素D或其衍生物的维生素D溶液的贮器,其中,构成该贮器盛溶液部分的聚烯烃体积是每μmol维生素D或其衍生物为30cm3或更小。
2.权利要求1的用于盛维生素D溶液的贮器,其中,构成该贮器盛溶液部分的聚烯烃体积是每μmol维生素D或其衍生物为20cm3或更小。
3.权利要求1的用于盛维生素D溶液的贮器,其中,构成该贮器盛溶液部分的聚烯烃体积是每μmol维生素D或其衍生物为10cm3或更小。
4.权利要求1~3任一项的用于盛维生素D溶液的贮器,它在聚烯烃层的外面有一层基本上不吸收维生素D的树脂层。
5.权利要求4的用于盛维生素D溶液的贮器,其中,该贮器盛溶液部分的聚烯烃层的厚度是100μm或更小,该层接触液体。
6.权利要求4的用于盛维生素D溶液的贮器,它从最内层到最外层具有聚烯烃、环烯烃共聚物和聚烯烃的层状结构。
7.权利要求5的用于盛维生素D溶液的贮器,它从最内层到最外层具有聚烯烃、环烯烃共聚物和聚烯烃的层状结构。
8.一种输液容器,它是柔性的并容纳权利要求1~7任一项所述的用于盛维生素D溶液的贮器。
9.权利要求8的输液容器,它是由和用于维生素D溶液贮器的材料相同的材料或者由和用于该贮器最外层的材料相同的材料制成的;并且,用于盛维生素D溶液的贮器周边密封部分的一个边缘被夹在该容器的周边部分之间。
10.权利要求8或9的输液容器,它包括由隔壁分开的两个隔室,隔壁允许液体通过它连通,其中,在一个隔室中盛有含氨基酸的溶液(B),另一个隔室中盛有含还原糖的溶液(A),并且用于盛维生素D溶液的贮器被容纳在任一个隔室中。
11.权利要求10的输液容器,其中,含还原糖的溶液(A)进一步含维生素B1,含氨基酸的溶液(B)进一步含叶酸,并且,维生素D溶液进一步含其它脂溶性维生素和维生素C,其中,维生素B2被掺入含氨基酸的溶液(B)或维生素D溶液中,并且含还原糖的溶液(A)、含氨基酸的溶液(B)和维生素D溶液的pH分别被调节到3.5~4.5、5.0~7.0和5.0~7.0。
12.权利要求11的输液容器,其中,含还原糖的溶液(A)进一步含泛酸衍生物,并且,维生素B2被掺入维生素D溶液中。
13.权利要求11的输液容器,其中,含氨基酸的溶液(B)进一步含维生素B12。
14.权利要求11的输液容器,其中,含还原糖的溶液(A)进一步含维生素B6,含氨基酸的溶液(B)进一步含烟酸衍生物,并且,维生素D溶液进一步含生物素。
15.权利要求11的输液容器,其中,含于维生素D溶液中的脂溶性维生素是通过表面活性剂增溶的。
16.权利要求11的输液容器,其中,一种电解质被掺入含还原糖的溶液(A)和/或含氨基酸的溶液(B)和/或维生素D溶液中。
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JP4713706B2 (ja) * | 2000-03-14 | 2011-06-29 | テルモ株式会社 | 脂溶性ビタミン可溶化液入り容器 |
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