CN100358533C - 用于药物诱导的神经病的药物组合物 - Google Patents
用于药物诱导的神经病的药物组合物 Download PDFInfo
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- CN100358533C CN100358533C CNB038164485A CN03816448A CN100358533C CN 100358533 C CN100358533 C CN 100358533C CN B038164485 A CNB038164485 A CN B038164485A CN 03816448 A CN03816448 A CN 03816448A CN 100358533 C CN100358533 C CN 100358533C
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- induced neuropathy
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Abstract
本发明涉及用于预防或治疗药物诱导的神经病的药剂，其含有胞苷5’-二磷酸胆碱(CDP-胆碱)作为有效成分。本发明用于预防或治疗药物诱导的神经病的药剂对药物诱导的神经病显示有效的改善作用并且还在安全性方面优越。
Description
技术领域
本发明涉及用于预防或治疗药物诱导的神经病的、含有胞苷5’-二磷酸胆碱(CDP-胆碱)作为有效成分的药剂，包含给药有效量CDP-胆碱的、用于预防或治疗所述病症的方法，CDP-胆碱在生产用于预防或治疗所述病症的药剂中的应用，和用于预防或治疗所述病症的药物组合物，该药物组合物包含有效量的CDP-胆碱和药用载体。
背景技术
目前，已知神经病如外周神经病等是作为各种药品的副作用诱导的。外周神经诱导感觉神经，运动神经和自主神经。如果其紊乱，依据紊乱的区域显示各种症状，显著损害患者的生活质量。因此，已经对药品的使用赋予足够关注。
作为导致外周神经病的主要药品，已知抗抑郁药(丙咪嗪，阿米替林)，抗癫痫药(苯妥英，卡马西平，巴比妥)，抗结核药(异烟肼，乙胺丁醇)，抗生素(氯霉素，甲砜霉素)，抗恶性肿瘤药(顺铂，长春花属生物碱类(长春新碱等)，丙卡巴肼，紫杉醇，阿糖胞苷)，AIDS治疗剂，包括AIDS的高效抗逆转录治疗(HAART)(齐多夫定，拉米夫定，司他夫定，扎西他滨，去羟肌苷，阿巴卡韦)，抗风湿药(硫代苹果酸金钠)，抗心律失常剂(amminodarone)，用于雷亥综合症的皮肤病药(氨苯砜)，针对过量饮酒的抗酒精药(双硫仑)，抗高血压药(肼屈嗪)，辐射敏化剂(米索硝唑)，维生素(吡哆醇)，免疫抑制剂(他克莫司等)，等等。
除了这些药品以外，已经报道有毒物质如丙烯酰胺，烯丙基氯，砷，白喉毒素，hexacarbones，无机铅，镉，三氯乙烯，有机磷酸及其酯，铊(灭鼠剂)等，和乙醇(饮酒等)导致外周神经病。本说明书中的“药物”包含药品，有毒物质和乙醇。
为了处理这种药物诱导的神经病，认为最重要的是尽可能地停止使用、接触或摄入诱导外周神经病的药物。
即使停止药物的使用、接触或摄入，外周神经病长期持续感觉异常的主观症状，如疼痛、麻木等。另外，药品的停止意味着中止患者原发病的治疗和因此期望开发更理想的治疗药物诱导的神经病的方法。
作为处理药物诱导的神经病的方法，例如，已知通过同时使用维生素B6可以预防由抗结核药异烟肼诱导的外周神经病的发作。另外，已经报道三乙酰尿苷对低敏感性有效，低敏感性是由抗癌剂紫杉醇[WO 00/11952]诱导的外周神经病的一个症状。
然而，维生素B6不用于由除了异烟肼以外的药物诱导的神经病，没有对药物诱导的神经病显示全能效果的药物。
另外，以上国际公开未考虑或甚至提示三乙酰尿苷是否对由除了紫杉醇以外的药物诱导的神经病有效。然而，以上国际公开例举性地显示除了三乙酰尿苷以外的核酸相关化合物CDP-胆碱。然而，在其中CDP-胆碱仅显示具有这种可能性，没有任何数据证实CDP-胆碱对外周神经病的效力。
发明内容
鉴于以上情形，本发明人已经深入研究了核酸相关化合物对药物诱导的神经病的功效，发现尽管常规上仅允许通过静脉给药应用于中枢神经系统的病症，如与颅脑损伤和脑手术相关的意识障碍，CDP-胆碱意外地显示，即使通过口服给药，对药物诱导的神经病如感觉过敏等优越的改善作用，其导致本发明的完成。
因此，本发明提供以下各项：
[1]一种用于预防或治疗药物诱导的神经病的药剂，其含有胞苷5’-二磷酸胆碱或其药用盐作为活性成分。
[2]上述[1]的药剂，其中所述药物诱导的神经病是外周神经病。
[3]上述[1]的药剂，其是用于口服给药的剂型。
[4]上述[1]的药剂，其中所述药物诱导的神经病是由选自以下各项的药品诱导的：抗抑郁药，抗癫痫药，抗结核药，抗生素，抗恶性肿瘤药，AIDS治疗剂，抗风湿药，抗心律失常剂，用于雷亥综合症的皮肤病药，针对过量饮酒的抗酒精药，抗高血压药，辐射敏化剂，维生素或免疫抑制剂。
[5]上述[1]的药剂，其中所述药物诱导的神经病是由有毒物质或乙醇诱导的。
[6]一种预防或治疗药物诱导的神经病的方法，其包含向患者给药有效量的胞苷5’-二磷酸胆碱或其药用盐。
[7]上述[6]的方法，其中所述药物诱导的神经病是外周神经病。
[8]上述[6]的方法，其中所述给药包含口服给药。
[9]上述[6]的方法，其中所述药物诱导的神经病是由选自以下各项的药品诱导的：抗抑郁药，抗癫痫药，抗结核药，抗生素，抗恶性肿瘤药，AIDS治疗剂，抗风湿药，抗心律失常剂，用于雷亥综合症的皮肤病药，针对过量饮酒的抗酒精药，抗高血压药，辐射敏化剂，维生素或免疫抑制剂。
[10]上述[6]的方法，其中所述药物诱导的神经病是由有毒物质或乙醇诱导的。
[11]胞苷5’-二磷酸胆碱或其药用盐在生产用于预防或治疗药物诱导的神经病的药剂中的应用。
[12]上述[11]的应用，其中所述药物诱导的神经病是外周神经病。
[13]上述[11]的应用，其中所述药剂是用于口服给药的剂型。
[14]上述[11]的应用，其中所述药物诱导的神经病是由选自以下各项的药品诱导的：抗抑郁药，抗癫痫药，抗结核药，抗生素，抗恶性肿瘤药，AIDS治疗剂，抗风湿药，抗心律失常剂，用于雷亥综合症的皮肤病药，针对过量饮酒的抗酒精药，抗高血压药，辐射敏化剂，维生素或免疫抑制剂。
[15]上述[11]的应用，其中所述药物诱导的神经病是由有毒物质或乙醇诱导的。
[16]用于预防或治疗药物诱导的神经病的药物组合物，该药物组合物包含有效量的胞苷5’-二磷酸胆碱或其药用盐，和药用载体。
[17]上述[16]的药物组合物，其中所述药物诱导的神经病是外周神经病。
[18]上述[16]的药物组合物，其是用于口服给药的剂型。
[19]上述[16]的药物组合物，其中所述药物诱导的神经病是由选自以下各项的药品诱导的：抗抑郁药，抗癫痫药，抗结核药，抗生素，抗恶性肿瘤药，AIDS治疗剂，抗风湿药，抗心律失常剂，用于雷亥综合症的皮肤病药，针对过量饮酒的抗酒精药，抗高血压药，辐射敏化剂，维生素或免疫抑制剂。
[20]上述[16]的药物组合物，其中所述药物诱导的神经病是由有毒物质或乙醇诱导的。
[21]一种商业包装物，其包含上述[16]的药物组合物和与之相关的书面材料，该书面材料指明所述药物组合物可以或应当用于预防或治疗药物诱导的神经病。
附图简述
图1显示弹尾试验(Tail Flick Test)的结果(CDP-胆碱关于长春新碱诱导的神经病的效果)，其中纵轴表示反应潜伏期(秒)。
图2显示弹尾试验的结果(CDP-胆碱关于丙烯酰胺诱导的神经病的效果)，其中纵轴表示反应潜伏期(秒)。
发明详述
本发明提供用于预防或治疗药物诱导的神经病的药剂，其包含CDP-碱或其药用盐作为活性成分。
本发明还提供预防或治疗药物诱导的神经病的方法，其包含给药有效量的CDP-胆碱或其药用盐。
本发明另外提供CDP-胆碱或其药用盐在生产用于预防或治疗药物诱导的神经病的药剂中的应用。
本发明还提供用于预防或治疗药物诱导的神经病的药物组合物，该药物组合物包含有效量的CDP-胆碱或其药用盐，和药用载体。
本发明另外提供用于预防或治疗药物诱导的神经病的药物组合物，该药物组合物包含有效量的CDP-胆碱或其药用盐，和药用载体，和商业包装物，其包含所述药物组合物和与药物组合物相关的书面材料，该书面材料指明所述药物组合物可以或应当用于预防或治疗药物诱导的神经病。
作为本发明活性成分的CDP-胆碱可以是游离态或盐形式。盐形式的实例包括但不限于，碱金属盐如锂盐，钠盐，钾盐等；碱土金属盐如镁盐等；等等。之中，特别优选药用盐。
CDP-胆碱或其盐可以是水合物或溶剂化物。在水合物的情形中，例举其中1-20个水分子与1个CDP-胆碱或其盐分子吸附或键合的水合物或盐水合物。
另外，CDP-胆碱或其盐，或其结晶或非结晶形式的水合物或盐水合物可以用于本发明。
这种CDP-胆碱或其盐(以下简称为“CDP-胆碱”)可作为已知化合物商购，并且可以按照已知方法生产(参见JP-B-6-31306，EP专利号329627，美国专利号6057301等)。
通过混合上述CDP-胆碱和常规药用载体(药物载体)，并将混合物加工成药品，可以制备本发明的药物组合物。CDP-胆碱在组合物中的含量可以适当地选自不小于0.01％(w/w)的范围，优选1-80％(w/w)。
作为用于制备的载体使用不与CDP-胆碱反应的常规用于药物制剂领域的物质。具体的实例包括乳糖，葡萄糖，甘露糖醇，糊精，淀粉，蔗糖，偏硅酸铝镁，合成硅酸铝，结晶纤维素，羧甲基纤维素钠，羟丙基淀粉，羧甲基纤维素钙，离子交换树脂，甲基纤维素，明胶，阿拉伯树胶，羟丙基纤维素，低取代的羟丙基纤维素，羟丙基甲基纤维素，聚乙烯吡咯烷酮，聚乙烯醇，轻质无水硅酸，硬脂酸镁，滑石，羧基乙烯基聚合物，二氧化钛，失水山梨糖醇脂肪酸酯，十二烷基硫酸钠，甘油，脂肪酸甘油酯，纯羊毛脂，甘油胶，聚山梨醇酯，聚乙二醇，植物油，蜡，液体石蜡，白凡士林，非离子型表面活性剂，丙二醇，水等。
剂型例举为片剂，胶囊，颗粒，粉末，糖浆，混悬剂，栓剂，软膏，凝胶，贴片，注射剂，滴眼剂等。这些药品可以按照常规方法使用以上药物载体制备。优选口服给药的剂型。
在液体形式的药物制剂的情形中，当使用时它可以是溶解或悬浮在水或其它适当介质中的形式。还可以通过公知方法将包衣应用于片剂和颗粒。
本发明预防或治疗剂或药物组合物的目标疾病是药物诱导的神经病，即给药、接触或摄入药物诱导的神经病，只要给药CDP-胆碱改善其症状不特别限制该神经病。具体地，可以提及给药一种或多种药品诱导的外周神经病，所述药品如抗抑郁药(丙咪嗪，阿米替林)，抗癫痫药(苯妥英，卡马西平，巴比妥)，抗结核药(异烟肼，乙胺丁醇)，抗生素(氯霉素，甲砜霉素)，抗恶性肿瘤药(顺铂，长春花属生物碱类(长春新碱等)，丙卡巴肼，紫杉醇，阿糖胞苷)，AIDS治疗剂，包括AIDS的高效抗逆转录治疗(HAART)(齐多夫定，拉米夫定，司他夫定，扎西他滨，去羟肌苷，阿巴卡韦)，抗风湿药(硫代苹果酸金钠)，抗心律失常剂(amminodarone)，用于雷亥综合症的皮肤病药(氨苯砜)，针对过量饮酒的抗酒精药(双硫仑)，抗高血压药(肼屈嗪)，辐射敏化剂(米索硝唑)，维生素(吡哆醇)，免疫抑制剂(他克莫司等)，等等，或接触或摄入一种或多种有毒物质(丙烯酰胺，烯丙基氯，砷，白喉毒素，hexacarbones，无机铅，镉，三氯乙烯，有机磷酸及其酯，铊(灭鼠剂)等)或乙醇诱导的外周神经病。外周神经病包括例如由受影响的单一神经导致的单神经病，由不同区域中的两个或多个受影响的神经导致的多种(multiple)单神经病，由许多同时受影响的神经导致的多重神经病(multiple neuropathy)等等。
本发明的预防或治疗剂或药物组合物能够特别地改善外周神经病的症状(烧灼感，急性痛，麻木，感觉过敏，低敏感性，肌力损失，肌肉萎缩，深部腱反射丢失等)，和有效用于预防或治疗药物诱导的外周神经病。
本发明用于预防或治疗药物诱导的神经病的药剂或药物组合物的给药方法可以是任何一种，取决于其剂型，选自口服给药，肠胃外给药，直肠内给药和局部给药。优选口服给药。
尽管本发明活性成分CDP-胆碱的剂量根据给药方法、患者的症状和年龄等而变化，它通常为大约0.1-1000mg/kg/天，优选大约0.5-500mg/kg/天，其可以单剂量或分剂量给药。
本发明中“预防药物诱导的神经病”包括向经历给药、接触或摄入上述能够诱导神经病的药物但还未发展神经症状的患者或预定给药上述药品的患者预先给药CDP-胆碱。例如，与能够诱导神经病的上述药品同时或在给药、接触或摄入上述药物之前给药CDP-胆碱。
含有CDP-胆碱作为有效成分的本发明用于预防或治疗药物诱导的神经病的药剂或药物组合物对药物诱导的神经病显示有效的改善作用，并且在安全性方面优越。因此，它可以用于预防或治疗药物诱导的神经病。此外，因为它通过口服给药显示效果，它还有效用于改善患者的QOL(生活质量)。
实施例
通过参考实施例详细解释本发明，该实施例不应认为是限制性的。
实施例1
试验化合物：腺苷5’-二磷酸胆碱-一钠盐
(CDP-胆碱-Na：由YAMASA CORPORATION制备)
实验：使用长春新碱诱导的感觉神经病小鼠的弹尾试验(体内)
(1)制备患有长春新碱诱导的感觉神经病的小鼠
将溶解在注射生理盐水中的长春新碱(第一次0.05mg/kg，第二次和接下来0.125mg/kg)腹膜内给药于雄性ICR品系小鼠(7-周-大，每组10只)，一周两次，共10周，诱导感觉神经病。
(2)给药CDP-胆碱
将CDP-胆碱·Na溶解在蒸馏水中并在与长春新碱的同一天开始将其给药(每剂量500mg/kg)，一天一次，共10周。
(3)弹尾试验
给予小鼠尾巴光热刺激，测量在感觉热以后直至尾巴运动的反应潜伏期。
对照组，长春新碱给药组和给药CDP-胆碱(500mg/kg)的长春新碱给药组的反应潜伏期的测量结果在图1中显示。在该图中，测量值显示10只小鼠的反应潜伏期的平均值±S.E.，其中*表示与对照组的显著性差异(P＜0.05)。
如图1中明显的，与对照组相比，长春新碱给药组显示显著缩短的反应潜伏期，因此显示类似于感觉过敏的症状。
当给药500mg/kg的CDP-胆碱来处理在该长春新碱给药组中观察到的感觉神经病时，上述神经病几乎完全被抑制，反应潜伏期与对照组水平相同。
从该结果，已经阐明通过口服给药，CDP-胆碱对药物诱导的神经病显示优越效果。
实施例2
试验化合物：腺苷5’-二磷酸胆碱-一钠盐
(CDP-胆碱-Na：由YAMASA CORPORATION制备)
实验：使用丙烯酰胺诱导的感觉神经病小鼠的弹尾试验(体内)
(1)制备患有丙烯酰胺诱导的感觉神经病的小鼠
将溶解在注射生理盐水中的丙烯酰胺(2.5mg/只小鼠)腹膜内给药于雄性ICR品系小鼠(7-周-大，每组10只)，1周5次，共1周，诱导感觉神经病。
(2)给药CDP-胆碱
将CDP-胆碱·Na溶解在蒸馏水中并在与丙烯酰胺的同一天开始将其给药(每剂量100mg/kg)，一天一次，共10周。
(3)弹尾试验
给予小鼠尾巴光热刺激，测量在感觉热以后直至尾巴运动的反应潜伏期。
对照组，丙烯酰胺给药组和给药CDP-胆碱(100mg/kg)的丙烯酰胺给药组的反应潜伏期的测量结果在图2中显示。在该图中，测量值显示10只小鼠的反应潜伏期的平均值±S.E.，其中*表示与对照组的显著性差异(P＜0.05)。
如图2中明显的，与对照组相比，丙烯酰胺给药组显示显著缩短的反应潜伏期，因此显示类似于感觉过敏的症状。
当给药100mg/kg的CDP-胆碱来处理在该丙烯酰胺给药组中观察到的感觉神经病时，上述神经病几乎完全被抑制，反应潜伏期与对照组水平相同。
从该结果，已经阐明通过口服给药，CDP-胆碱对药物诱导的神经病显示优越效果。
制剂实施例1 片剂
CDP-胆碱 30.0mg
微晶纤维素 25.0mg
乳糖 39.5mg
淀粉 40.0mg
滑石 5.0mg
硬脂酸镁 0.5mg
通过常规方法由以上组合物制备片剂。
制剂实施例2 胶囊
CDP-胆碱 30.0mg
乳糖 40.0mg
淀粉 15.0mg
滑石 5.0mg
通过常规方法由以上组合物制备胶囊。
制剂实施例3 注射剂
CDP-胆碱 30.0mg
葡萄糖 100.0mg
将以上组合物溶解在纯化的注射用水中制备注射剂。
工业适用性
含有CDP-胆碱作为有效成分的本发明用于预防或治疗药物诱导的神经病的药剂或药物组合物对药物诱导的神经病显示有效的改善作用，并且在安全性方面优越。因此，它可以用于预防或治疗药物诱导的神经病。此外，因为它通过口服给药显示效果，它还有效用于改善患者的QOL(生活质量)。
本申请是基于在日本提出的专利申请号2002-202715，其内容通过参考结合于此。
Claims (4)
1.胞苷5’-二磷酸胆碱或其药用盐在生产用于预防或治疗药物诱导的外周神经病的药剂中的应用。
2.权利要求1的应用，其中所述药剂是用于口服给药的剂型。
3.权利要求1的应用，其中所述药物诱导的神经病是由选自以下各项的药品诱导的：抗抑郁药，抗癫痫药，抗结核药，抗生素，抗恶性肿瘤药，AIDS治疗剂，抗风湿药，抗心律失常剂，用于雷亥综合症的皮肤病药，针对过量饮酒的抗酒精药，抗高血压药，辐射敏化剂，维生素或免疫抑制剂。
4.权利要求1的应用，其中所述药物诱导的神经病是由有毒物质或乙醇诱导的。
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| Application Number | Priority Date | Filing Date | Title |
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| JP202715/2002 | 2002-07-11 | ||
| JP2002202715 | 2002-07-11 |
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| CN (1) | CN100358533C (zh) |
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| WO2010025316A1 (en) * | 2008-08-29 | 2010-03-04 | Jeffrey Comanor | Composition and methods for relief of neuropathological pain |
| JP2023002772A (ja) * | 2011-09-23 | 2023-01-10 | レジニアス リミテッド | 脂肪細胞および細胞分泌物を使用する治療 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999026633A1 (en) * | 1997-11-26 | 1999-06-03 | Interneuron Pharmaceuticals, Inc. | Citicoline to treat motor neuron diseases and demyelinating diseases |
| WO2000006174A1 (en) * | 1998-07-31 | 2000-02-10 | Massachusetts Institute Of Technology | Methods for increasing cytidine levels in vivo and treating cytidine-dependent human diseases |
| WO2001072288A2 (en) * | 2000-03-29 | 2001-10-04 | Ferrer Internacional, S.A. | Use of cdp-choline for the treatment of alcohol withdrawal syndrome |
| CN1328417A (zh) * | 1998-08-31 | 2001-12-26 | 普罗神经细胞有限公司 | 治疗线粒体性疾病的组合物和方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1188178B (it) * | 1985-07-05 | 1988-01-07 | Bioresearch Spa | Sali della citidin-difospocolina particolarmente idonei per uso orale |
| US4634443A (en) * | 1985-07-05 | 1987-01-06 | Habley Medical Technology Corporation | Single circuit elastofluidic sphincter |
| US5604202A (en) * | 1990-11-13 | 1997-02-18 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Use of NGF growth factors to treat drug-induced neuropathy |
| KR100740079B1 (ko) * | 2001-09-05 | 2007-07-18 | 야마사 쇼유 가부시키가이샤 | 당뇨병성 신경 장해용 의약 조성물 |
-
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- 2003-07-09 JP JP2004521163A patent/JPWO2004006940A1/ja active Pending
- 2003-07-09 WO PCT/JP2003/008708 patent/WO2004006940A1/ja active Application Filing
- 2003-07-09 EA EA200500187A patent/EA008179B1/ru not_active IP Right Cessation
- 2003-07-09 CA CA002492725A patent/CA2492725A1/en not_active Abandoned
- 2003-07-09 CN CNB038164485A patent/CN100358533C/zh not_active Expired - Fee Related
- 2003-07-09 US US10/520,772 patent/US20060094685A1/en not_active Abandoned
- 2003-07-09 MX MXPA05000451A patent/MXPA05000451A/es unknown
- 2003-07-09 KR KR1020057000444A patent/KR20050044890A/ko not_active Application Discontinuation
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999026633A1 (en) * | 1997-11-26 | 1999-06-03 | Interneuron Pharmaceuticals, Inc. | Citicoline to treat motor neuron diseases and demyelinating diseases |
| WO2000006174A1 (en) * | 1998-07-31 | 2000-02-10 | Massachusetts Institute Of Technology | Methods for increasing cytidine levels in vivo and treating cytidine-dependent human diseases |
| CN1328417A (zh) * | 1998-08-31 | 2001-12-26 | 普罗神经细胞有限公司 | 治疗线粒体性疾病的组合物和方法 |
| WO2001072288A2 (en) * | 2000-03-29 | 2001-10-04 | Ferrer Internacional, S.A. | Use of cdp-choline for the treatment of alcohol withdrawal syndrome |
Non-Patent Citations (1)
| Title |
|---|
| Treatment of chronic dyskinesia with CDP choline. ARRANZ J. ET.ALARZNEIMITTEL FORSCHOUNG,Vol.33 No.7A. 1983 * |
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| Publication number | Publication date |
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| JPWO2004006940A1 (ja) | 2005-11-10 |
| CN1668313A (zh) | 2005-09-14 |
| CA2492725A1 (en) | 2004-01-22 |
| EA008179B1 (ru) | 2007-04-27 |
| AU2003252488A1 (en) | 2004-02-02 |
| EP1541154A1 (en) | 2005-06-15 |
| WO2004006940A1 (ja) | 2004-01-22 |
| US20060094685A1 (en) | 2006-05-04 |
| MXPA05000451A (es) | 2005-03-23 |
| KR20050044890A (ko) | 2005-05-13 |
| EA200500187A1 (ru) | 2005-08-25 |
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