CN1777428A - 末梢静脉给药用输液制剂及维生素b1的稳定化方法 - Google Patents
末梢静脉给药用输液制剂及维生素b1的稳定化方法 Download PDFInfo
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- CN1777428A CN1777428A CNA2004800105385A CN200480010538A CN1777428A CN 1777428 A CN1777428 A CN 1777428A CN A2004800105385 A CNA2004800105385 A CN A2004800105385A CN 200480010538 A CN200480010538 A CN 200480010538A CN 1777428 A CN1777428 A CN 1777428A
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Abstract
在以可以连通的分隔手段分隔的容器中,分别装有含有80~200g/L浓度的葡萄糖的输液(A)和50~150g/L浓度的氨基酸的输液(B)的末梢静脉给药用输液制剂,输液(A)不含亚硫酸盐,滴定酸度在1或以下,进一步与维生素B1配混,而且调整pH3~5,输液(B)调整pH6.5~8,两种溶液混合后,pH为6~7.5,滴定酸度为5~10。
Description
技术领域
本发明涉及稳定地配混了维生素B1的末梢静脉给药用输液制剂及维生素B1的稳定化方法。
背景技术
以往,为了给难于经口补给营养的患者补给维持生命所必要的全部营养成分,广泛使用通过静脉给予输液的输液疗法。所给予的营养成分除了含有糖,氨基酸,电解质以外,还有维持生命所必需的矿物质、维生素等营养成分。
已知通过静脉给予高热量输液时(TPN,IVH),维生素B1的缺乏引起的需氧糖代谢不进行,产生乳糖,引起重度乳酸酸中毒,维生素B1添加是必须的。因此,研究了预先添加维生素B1的高热量输液制剂(下面的专利文献1~4)。
另外,也有报道通过末梢静脉较短时间内给予中度热量的总合营养输液时(PPN),虽然不会出现高热量输液情况下那样程度的重症,也会引起血液中维生素B1浓度降低的维生素B1缺乏症(下述非专利文献1)。因此,尝试在末梢静脉给药输液中预先添加维生素B1(下面的专利文献5)。
可是,维生素B1溶液在碱性~中性下不稳定,由于存在亚硫酸离子而引起分解,上述输液制剂中,将配混有任何一种维生素溶液的输液调至特定的pH,而且不添加或添加最小限度的亚硫酸盐,使输液制剂中的维生素B1得以稳定。
上述以往的输液制剂中,通过使添加维生素B1的输液的性状处于特定状态,意图稳定维生素B1,虽然如此,还是希望使其更加稳定。
专利文献1:特开平8-143459号公报
专利文献2:特开平9-59150号公报
专利文献3:特开平10-226636号公报
专利文献4:特开平11-35471号公报
专利文献5:特开2003-55195号公报
非专利文献1:中村等“给急救患者施行末梢静脉营养情况下的血液维生素B1浓度”,外科与代谢营养,36(6),307(2002)
发明内容
本发明的课题是提供不影响制剂安全性或效力、使维生素B1具有更高稳定性的末梢静脉给药用输液制剂及维生素B1的稳定化方法。
本发明人等为解决上述课题而锐意研究的结果,发现在输液中配混的具有缓冲性的盐妨碍了维生素B1的稳定性。因此,发现了通过使配混维生素B1的输液中含有的电解质的滴定酸度在1以下,可以不影响安全性或效力,实现了维生素B1具有更好稳定性的制剂这一新的事实,完成了本发明。
即,本发明的末梢静脉给药用输液制剂的特征是以可以连通的分隔手段分隔的容器中,分别装有含有80~200g/L浓度的葡萄糖输液(A)和50~150g/L浓度的氨基酸的输液(B),上述输液(A)不含亚硫酸盐,且滴定酸度在1以下,进一步与维生素B1配混,而且调整pH3~5,上述输液(B)调整pH6.5~8,上述输液(A)和输液(B)混合后,pH为6~7.5,滴定酸度为5~10。
本发明中,上述输液(A)含有的羧酸及其盐的浓度优选0~5mEq/L。
本发明中,上述输液(A)含有的电解质优选全部是强电解质。本发明中,输液(A)的电解质组成为K+:10~20mEq/L,Ca2+:2~10mEq/L,Mg2+:2~10mEq/L,Cl-:12~30mEq/L,Zn:2~10mmol/L,输液(B)的电解质组成为Na+:80~150mEq/L,K+:20~40mEq/L,P:10~20mmol/L,输液(A)和输液(B)的体积比(A∶B)可以是1~4∶1。
特别是本发明中,作为上述强电解质,将钙和钾分别以氯化物形式配混,而且输液(A),(B)的任何一个优选不使用氯化钠作为其钠供给源。
而且,对于上述容器,优选是具有用易剥离隔板(seal)分隔的至少2个室的柔软性塑料制输液袋。
另外,本发明的维生素B1的稳定化方法的特征是在以可以连通的分隔手段分隔的容器中,分别装有含有维生素B1和80~200g/L浓度的葡萄糖的输液(A)和含有50~150g/L浓度的氨基酸、pH调整至6.5~8的输液(B),在上述输液(A)和输液(B)混合后使pH为6~7.5,滴定酸度达到5~10的末梢静脉给药用输液制剂中,上述输液(A)不含亚硫酸盐,输液(A)的滴定酸度在1以下,而且调整pH至3~5。
这一稳定方法中,上述输液(A)含有的羧酸及其盐的浓度可以是0~5mEq/L,而且上述输液(A)含有的电解质可以全部是强电解质。
本发明的末梢静脉给药用输液制剂具有不影响安全性或效力,使维生素B1的稳定性进一步提高的效果。
具体实施方式
以下,详细说明本发明的末梢静脉给药用输液制剂(以下简称输液制剂)。本发明的输液制剂,在可以连通的分隔手段分隔的容器中,分别装有含有葡萄糖的输液(A)和含有氨基酸的输液(B),使用时使两种输液(A),(B)混合进行使用。
输液(A)
本发明中,输液(A)以葡萄糖,强电解质及维生素B1为基本组成,为了使维生素B1稳定而不含有亚硫酸盐。使用的葡萄糖的浓度为80~200g/L,优选80~150g/L。控制这一葡萄糖溶液中羧酸及其盐的浓度在0~5mEq/L,有利于维生素B1的稳定,从而优选。另外,为了使葡萄糖液尽量不具有缓冲性,优选用盐酸等矿酸调整pH,或进而使含有的电解质全部为强电解质。输液(A)的pH范围为3~5,优选3.5~4.5。pH不到3时,维生素B1自身的稳定性虽然好,但葡萄糖变的不稳定。另外,如果pH超过5,维生素B1的稳定性受损。
另外,葡萄糖溶液的液量可以是200~1000mL。作为葡萄糖溶液的溶剂,一般使用注射用蒸馏水。需说明的是为了使维生素B1的稳定性进一步提高,或使后面所述混合溶液的pH易于调整至6~7.5,葡萄糖溶液的滴定酸度在1或以下,优选0.5或以下,特别优选0.1或以下。
另外除葡萄糖外根据需要可以添加果糖,麦芽糖等还原糖的1种或2种以上,或适量配混山梨糖醇,甘油等非还原糖。
输液(B)
本发明中,输液(B)为氨基酸溶液,由至少含有必须氨基酸的氨基酸组合物配混而成。所含氨基酸的浓度换算为游离氨基酸为50~150g/L,优选80~120g/L。所用的各种氨基酸与一般的氨基酸输液相同,优选纯粹结晶状的氨基酸。通常这些都以游离氨基酸形态使用,也可以不是游离状态,可以以药理学允许的盐,酯,N-酰基衍生物,2种氨基酸盐或多肽的形态使用。特别是L-半胱氨酸,以N-乙酰体的形式配混有利于稳定性。另外,输液容器中含有的输液(B)的液量可以是100~500mL。作为输液(B)的溶剂,通常使用注射用蒸馏水。
作为优选氨基酸组成,换算为游离氨基酸可以表示为L-亮氨酸:10~20(g/L),L-异亮氨酸:5~15(g/L),L-缬氨酸:5~15(g/L),L-赖氨酸:5~15(g/L),L-苏氨酸:2~10(g/L),L-色氨酸:0.5~5(g/L),L-蛋氨酸:1~8(g/L),L-苯丙氨酸:3~15(g/L),L-半胱氨酸:0.1~3(g/L),L-酪氨酸:0.1~2(g/L),L-精氨酸:5~15(g/L),L-组氨酸:2~10(g/L),L-丙氨酸:5~15(g/L),L-脯氨酸:2~10(g/L),L-丝氨酸:1~7(g/L),甘氨酸:2~10(g/L),L-天门冬氨酸:0.2~3(g/L),L-谷氨酸:0.2~3(g/L)的范围。
另外,输液(B)根据需要可以添加少量的pH调整剂,调整pH6.5~8.0,优选调整pH6.5~7.5。pH不到6.5,混合后的pH不易维持在后面所述的最适范围,而如果超过8.0,L-半胱氨酸等易氧化的氨基酸变的更不稳定,都不优选。
维生素B1
维生素B1作为输液(A)中的硫胺素可以以浓度1~10mg/L进行配混,优选以浓度2~5mg/L进行配混,以绝对量0.5~8mg进行配混是适合的。作为维生素B1(硫胺素),可以使用盐酸硫胺素,硝酸硫胺素,丙硫硫胺,奥托硫胺等。
电解质
(a)钾
优选将钾分别配混到输液(A)和输液(B)中。各部分钾的配混浓度分别为输液(A)优选10~20mEq/L,输液(B)优选20~40mEq/L。输液(A)及输液(B)中钾的合计浓度可以是5~30mEq/L。
输液(A)中配混的钾供给源优选强电解质氯化钾,硫酸钾等,特别是氯化钾被广泛使用,更优选。另一方面,作为输液(B)中配混的钾供给源,可以使用与一般的电解质输液中使用的化合物相同的物质,例如可以举出氯化钾,醋酸钾,柠檬酸钾,磷酸二氢钾,磷酸氢二钾,甘油磷酸钾,硫酸钾,乳酸钾等。其中,磷酸二氢钾,磷酸氢二钾,甘油磷酸钾等磷酸盐,也可以成为磷供给源,是合适的选择。这些钾供给源也可以是水和物的形态。
(b)钙
优选只在输液(A)中配混钙。这是因为如果在输液(B)中配混钙,会与磷酸盐反应生成沉淀,为了防止其发生而区分开。作为钙的供给源,优选强电解质的氯化钙。另外,钙在输液(A)中的浓度优选2~10mEq/L。
(c)钠
钠可以在输液(A)及(B)中的一个或两个中配混,钾或钙优选使用其氯化物,但作为钠的供给源不使用氯化钠,是为了防止高氯性酸中毒的发生。
另外,使用醋酸钠,柠檬酸钠,磷酸二氢钠,磷酸氢二钠,乳酸钠等具有缓冲性的钠盐时,为了满足上述输液(A)的滴定酸度的条件,优选添加到输液(B)中。另外,输液(B)中的配混浓度优选80~150mEq/L。
还有,为了防止混合后磷和钙或镁产生沉淀,钠供给源的一部分使用柠檬酸钠是适当的。
(d)其他电解质
(i)作为镁供给源,可以列举出硫酸镁,氯化镁,醋酸镁等。其中,硫酸镁及氯化镁作为强电解质可以配混到输液(A)中。
(ii)作为磷供给源,可以列举出磷酸二氢钾,磷酸氢二钾,甘油磷酸钾,磷酸二氢钠,磷酸氢二钠,甘油磷酸钠等。这些磷化合物配混到输液(B)中。
(iii)作为锌供给源,可以列举出硫酸锌,氯化锌等。这些锌化合物可以配混到输液(A)中。
(i)~(iii)的各电解质供给源中,也可以使用水和物,具有缓冲性的电解质必须添加到输液(B)中。另外,各电解质的配混浓度优选输液(A)中镁2~10mEq/L,锌2~10mmol/L左右。输液(B)中磷10~20mmol/L左右。
添加剂,配混剂
本发明的输液制剂根据需要可以添加稳定剂等添加剂,作为稳定剂有代表性的亚硫酸氢钠等亚硫酸盐,最好添加到输液(B)中。另外,本发明的输液制剂中为了需要也可以任意添加其他配混药物,如各种维生素,微量元素(矿物质)等。
混合液
本发明的输液制剂使用时将上述输液(A)和输液(B)混合。为了该混合液不引起患者血管痛以提高安全性,优选使pH在6~7.5,滴定酸度范围在5~10。另外,输液(A)和输液(B)的体积比优选1~4∶1。
输液容器
作为保有本发明输液制剂的容器,只要是具有可以连通的两个室就可以,没有特别的限定,例如,可以列举出通过易剥离隔板形成隔壁的容器(特开平2-4671号公报,实开平5-5138号公报等),各室间以夹子夹住而形成隔壁的容器(特开昭63-309263号公报等),隔壁上设计有可开封的各种连通手段的容器(特公昭63-20550号公报等)等以可以连通的隔壁分割为两个室的容器(输液袋)。其中,用易剥离隔板形成隔壁的输液袋,适于大量生产,也容易进行连通操作,所以优选。
另外,作为上述输液袋的材料,可以列举出医疗用容器等惯用的各种玻璃透过性塑料,例如聚乙烯,聚丙烯,聚氯乙烯,交联乙烯·醋酸乙烯酯共聚物,乙烯·α-烯烃共聚物,这些聚合物的混合物或叠层体等柔软性塑料。
向输液袋中充填,装入本发明的输液制剂,可以按常法进行,例如,可以列举出将各输液在惰性气体环境下充填到各室中后,封好,加热灭菌的方法。这里可以采用加热灭菌,高压蒸汽灭菌,热水淋浴灭菌等已知的方法,根据需要可以在二氧化碳,氮气等惰性气体环境下进行。
进而,为了确实防止上述输液袋中装入的输液制剂发生变质,氧化等,优选该输液袋与脱氧剂一起用氧气阻隔性外包装袋进行包装。特别是作为2室容器,采用以易剥离板形成隔壁的输液袋时,优选利用外压使该输液袋的隔壁不连通地易剥离隔板部分折叠状态,例如以易剥离隔板部分折叠成两部分的状态进行包装。另外,根据需要也可以进行惰性气体充填包装等。
作为适用于上述包装的气体非透过性外装容器的材质,可以使用一般广泛使用的各种材质的膜,板等。作为其具体例子,可以列举出例如乙烯·乙烯基醇共聚物,聚偏氯乙烯,聚丙烯腈,聚乙烯基醇,聚酰胺,聚酯等,另外,可列举出含有至少其中的一种材质制成的膜,板等。
另外,作为脱氧剂,可以使用已知的各种产品,例如氢氧化铁,氧化铁,碳化铁等以铁化合物为有效成分的产品,或使用低分子酚和活性炭的产品。作为其代表的市售商品名,可列举出“ェ-ジレス”(三菱瓦斯化学社制),“モジュラン”(日本化药社制),“セキュ-ル”(日本曹达社制),“タモツ”(王子化工社制)等。
以下,列举实施例及比较例进一步详细说明本发明,但不仅限于以下实施例。
实施例1
输液(A)
葡萄糖及各种强电解质按以下浓度溶于注射用蒸馏水,调制成如下组成的输液(A)。该输液(A)中添加微量的盐酸调整pH至4.5。
另外,输液(A)的滴定酸度为0.08。
葡萄糖 107.14g/L
氯化钾 0.92g/L
氯化钙(2H2O) 0.53g/L
硫酸镁(7H2O) 0.88g/L
硫酸锌 2.00mg/L
盐酸硫胺素 2.71mg/L
输液(B)
下述结晶氨基酸及各种强电解质溶于注射用蒸馏水,调制成如下组成的输液(B)。用醋酸作为pH调整剂调整该输液(B)pH至6.8。
L-亮氨酸 14.0g/L
L-异亮氨酸 8.0g/L
L-缬氨酸 8.0g/L
盐酸L-赖氨酸 13.1g/L
L-苏氨酸 5.7g/L
L-色氨酸 2.0g/L
L-蛋氨酸 3.9g/L
L-苯丙氨酸 7.0g/L
N-乙酰基L-半胱氨酸 1.3g/L
L-酪氨酸 0.5g/L
L-精氨酸 10.5g/L
L-组氨酸 5.0g/L
L-丙氨酸 8.0g/L
L-脯氨酸 5.0g/L
L-丝氨酸 3.0g/L
甘氨酸 5.9g/L
L-天门冬氨酸 1.0g/L
L-谷氨酸 1.0g/L
磷酸氢二钾 3.31g/L
磷酸氢二钠 5.13g/L
乳酸钠 7.63g/L
柠檬酸钠 1.77g/L
亚硫酸氢钠 0.05g/L
输液制剂
上面得到的两种溶液在无菌条件下过滤,输液(A)700mL及输液(B)300mL分别充填到各室用易剥离隔板分隔的聚乙烯制2室容器中的各室,输液(B)进行氮气置换,密封后按常法进行高压灭菌。
然后,将容器在易剥离隔板部分折叠,与脱氧剂(商品名“ェ-ジレス”;三菱瓦斯化学社制)一起,封入多层阻隔性膜(商品名“ボブロン”;NSR社制)的外包装袋中(氧气体阻隔性外装袋),得到本发明的输液制剂。
另外,该输液制剂2种溶液混合后的混合液pH为6.7,滴定酸度为7。
实施例2
除实施例1的输液(A)中,用醋酸代替盐酸,调整pH至4.5以外,其他与实施例1相同,得到输液制剂。而且,输液(A)的滴定酸度为0.1,醋酸浓度为0.2mEq/L。另外,2种溶液混合后的混合溶液pH为6.7,滴定酸度为7。
实施例3
除实施例1的输液(A)中,用磷酸二氢钾1.68g/L代替氯化钾添加以外,其他与实施例1相同,得到输液制剂。而且,输液(A)的滴定酸度为1。另外,2种溶液混合后的混合溶液pH为6.7,滴定酸度为7。
实施例4
除实施例2的输液(A)中,代替硫酸镁(7H2O)0.88g/L,添加硫酸镁(7H2O)0.44g/L及醋酸镁(4H2O)0.38g/L以外,其他与实施例2相同,得到输液制剂。而且,输液(A)的滴定酸度为0.5,醋酸浓度为4.4mEq/L。另外,2种溶液混合后的混合溶液pH为6.6,滴定酸度为7.5。
比较例1
实施例1的输液(B)中,不添加乳酸钠7.63g/L,而向输液(A)中添加乳酸钠3.27g/L以外,其他与实施例1相同,得到输液制剂。而且,输液(A)的滴定酸度为4.2。
比较例2
实施例1的输液(A)中,不添加氯化钙(2H2O)0.53g/L,添加葡萄糖醛酸钙1.6g/L,而且不向输液(B)中添加乳酸钠7.63g/L,而向输液(A)中添加乳酸钠3.27g/L以外,其他与实施例1相同,得到输液制剂。而且,输液(A)的滴定酸度为4.9。
比较例3
实施例2的输液(A)中,除代替硫酸镁(7H2O)添加醋酸镁(4H2O)0.77g/L以外,其他与实施例2相同,得到输液制剂。而且,输液(A)的滴定酸度为1.6,醋酸浓度为8.5mEq/L。另外,2种溶液混合后的混合溶液pH为6.6,滴定酸度为8。
上述所得实施例1~4及比较例1~3的输液制剂,在60℃,75%RH条件下保存14天以后,由外包装袋取出输液袋,用注射器仅吸取输液(A),用高效液相色谱进行维生素B1的残存量测定,求得相对于初期加入量的维生素B1的残存率。
表1
实施例1 | 实施例2 | 实施例3 | 实施例4 | 比较例1 | 比较例2 | 比较例3 | |
维生素B1残存率(%) | 91.3 | 91 | 88.5 | 88 | 80.3 | 75.5 | 82.5 |
根据表1的结果,与比较例1~3的输液制剂相比,实施例1~4的输液制剂的输液(A)中配混的维生素B1更加稳定。
Claims (14)
1.一种末梢静脉给药用输液制剂,其特征是在以可以连通的分隔手段分隔的容器中,分别装有含有80~200g/L浓度的葡萄糖的输液(A)和含50~150g/L浓度的氨基酸的输液(B);上述输液(A)不含亚硫酸盐,滴定酸度在1或以下,进一步与维生素B1配混,而且调整pH3~5;上述输液(B)调整pH6.5~8;上述轮流(A)和输液(B)混合后的pH为6~7.5,滴定酸度为5~10。
2.权利要求1中记载的末梢静脉给药用输液制剂,其中,上述输液(A)中含有的羧酸及其盐的浓度为0~5mEq/L。
3.权利要求1中记载的末梢静脉给药用输液制剂,其中,上述输液(A)中含有的电解质全部为强电解质。
4.权利要求3中记载的末梢静脉给药用输液制剂,其中,上述输液(A)中电解质的组成为K+:10~20mEq/L,Ca2+:2~10mEq/L,Mg2+:2~10mEq/L,Cl-:12~30mEq/L,Zn:2~10mmol/L,上述输液(B)的电解质组成为Na+:80~150mEq/L,K+:20~40mEq/L,P:10~20mmol/L,上述输液(A)和上述输液(B)的体积比(A∶B)是1~4∶1。
5.权利要求4中记载的末梢静脉给药用输液制剂,其中,作为上述强电解质,将钙和钾分别以氯化物形式配混,而且输液(A),(B)的任何一个均不使用氯化钠作为钠供给源。
6.权利要求1中记载的末梢静脉给药用输液制剂,其中,上述输液(B)的氨基酸组成换算为游离氨基酸为L-亮氨酸:10~20(g/L),L-异亮氨酸:5~15(g/L),L-缬氨酸:5~15(g/L),L-赖氨酸:5~15(g/L),L-苏氨酸:2~10(g/L),L-色氨酸:0.5~5(g/L),L-蛋氨酸:1~8(g/L),L-苯丙氨酸:3~15(g/L),L-半胱氨酸:0.1~3(g/L),L-酪氨酸:0.1~2(g/L),L-精氨酸:5~15(g/L),L-组氨酸:2~10(g/L),L-丙氨酸:5~15(g/L),L-脯氨酸:2~10(g/L),L-丝氨酸:1~7(g/L),甘氨酸:2~10(g/L),L-天门冬氨酸:0.2~3(g/L),L-谷氨酸:0.2~3(g/L)。
7.权利要求6中记载的末梢静脉给药用输液制剂,其中,L-半胱氨酸以N-乙酰基体进行配混。
8.权利要求7中记载的末梢静脉给药用输液制剂,其中,上述输液(A)中维生素B1的配混浓度换算为硫胺素为1~10mg/L。
9.权利要求1中记载的末梢静脉给药用输液制剂,其中,上述容器为通过易剥离隔板分隔出至少具有2室的柔软性塑料制输液袋。
10.权利要求9中记载的末梢静脉给药用输液制剂,其中,上述输液袋以在上述易剥离隔板部分折叠的状态与脱氧剂一起封入氧气阻隔性外包装袋中。
11.权利要求1中记载的末梢静脉给药用输液制剂,其中,进行加热灭菌。
12.一种维生素B1的稳定化方法,其特征是在以可以连通的分隔手段分隔的容器中,分别装有含有维生素B1和80~200g/L浓度的葡萄糖的输液(A)和50~150g/L浓度的氨基酸、调整pH至6.5~8的输液(B),在上述输液(A)和输液(B)混合后使pH为6~7.5,滴定酸度5~10形成的末梢静脉给药用输液制剂中,上述输液(A)不含亚硫酸盐,输液(A)的滴定酸度在1以下,而且pH调整至3~5。
13.权利要求12中记载的维生素B1的稳定化方法,上述输液(A)中含有的羧酸及其盐的浓度为0~5mEq/L。
14.权利要求12中记载的维生素B1的稳定化方法,上述输液(A)中含有的电解质全部为强电解质。
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JP2006001945A (ja) * | 2005-09-01 | 2006-01-05 | Terumo Corp | ビタミンb1配合末梢静脈投与用総合輸液剤 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102883603A (zh) * | 2010-01-04 | 2013-01-16 | 潘泰克健康公司 | 营养组合物及其使用方法 |
CN107095847A (zh) * | 2010-05-07 | 2017-08-29 | Ea制药株式会社 | 混合有维生素的外周静脉给药用营养输液 |
CN105412896A (zh) * | 2016-01-06 | 2016-03-23 | 鲁南制药集团股份有限公司 | 一种避免安神补脑液中维生素b1含量下降的方法 |
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EP1632233A1 (en) | 2006-03-08 |
EP1632233A4 (en) | 2006-05-31 |
CA2526208C (en) | 2011-11-08 |
TWI331043B (en) | 2010-10-01 |
AU2004241840B2 (en) | 2010-02-25 |
WO2004103375A1 (ja) | 2004-12-02 |
CA2526208A1 (en) | 2004-12-02 |
JPWO2004103375A1 (ja) | 2006-07-20 |
EP1632233B1 (en) | 2008-07-02 |
CN100486579C (zh) | 2009-05-13 |
KR101039224B1 (ko) | 2011-06-03 |
KR20060015584A (ko) | 2006-02-17 |
TW200501931A (en) | 2005-01-16 |
JP4594232B2 (ja) | 2010-12-08 |
AU2004241840A1 (en) | 2004-12-02 |
US20060211631A1 (en) | 2006-09-21 |
ATE399556T1 (de) | 2008-07-15 |
DE602004014760D1 (de) | 2008-08-14 |
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