CN1407857A - 低聚糖混合物 - Google Patents
低聚糖混合物 Download PDFInfo
- Publication number
- CN1407857A CN1407857A CN00816812A CN00816812A CN1407857A CN 1407857 A CN1407857 A CN 1407857A CN 00816812 A CN00816812 A CN 00816812A CN 00816812 A CN00816812 A CN 00816812A CN 1407857 A CN1407857 A CN 1407857A
- Authority
- CN
- China
- Prior art keywords
- oligosaccharide
- milk
- mixture
- kinds
- animal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
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Abstract
本发明涉及一种基于低聚糖的低聚糖混合物，所述的低聚糖得自于一种或多种动物乳，并且由二个或多个单糖单元构成。所述的低聚糖混合物的特征在于其含有至少两种低聚糖部分，所述的低聚糖部分至少由两种不同的低聚糖组成。本发明的进一步的特征在于乳糖不包括在内，以及存在于低聚糖混合物中的低聚糖的总谱与得自从中获取了低聚糖部分的一种或多种动物乳的低聚糖总谱不同，且a)如果所述的低聚糖仅得自于一种动物乳，则中性低聚糖对酸性低聚糖的比例为90－60∶10－40重量％，或者b)如果所述的低聚糖得自至少两种动物乳，则其中得自两种不同动物乳的每种低聚糖将至少占低聚糖混合物中存在的低聚糖总量的10重量％。本发明的低聚糖混合物的积极效果，特别是其抗感染作用与人乳近似。
Description
本发明涉及一低聚糖混合物，该低聚糖得自于一种或多种动物乳，并且是由二种或多种单糖单元构成，该低聚糖混合物可被用于抵御胃肠功能紊乱。
成人乳中的低聚糖含量约为10g/l。在成人乳中至今为止约有80种不同的低聚糖被确认了结构，它们是由3-13个单糖构成；Newburg，D.S.和Neubauer，S.H.(1995)“乳中的碳水化合物：分析，定量和意义”(Carbyhydrates in milk：Analysis，quantities and significance)，《乳组份手册》(Handbook of Milk Composition)：Jensen，R.G.，编辑，学术出版社(Academic Press)，273-349。在这些低聚糖的多种结构中，结构和位置异构起着重要的作用。中性低聚糖或低聚糖结构对唾液酸(酸性)低聚糖或低聚糖结构的比例在成人乳中约为10∶1。
低聚糖在对人体中特定的和非特定的感染抵抗力方面具有下述的重要作用：
1.人乳中的低聚糖构成双歧杆菌的一种基质源。因此其支持肠胃功能所必须的正常的肠内菌丛，并抑制病原菌；Rose，C.S.，Kuhn，R，Zilliken，F.和Gyrgy，P.(1954)双歧因子(Bifidus Factor)V.α-和β-甲基-N-乙酰基-D-氨基葡糖苷的活性，Arch.Biochem.Biophys.49，123-129。
2.低聚糖会阻止病原菌和/或细菌、毒素和真核寄生虫类物质的附着，因为其起着作为特殊的接收器类似物的作用，并由此防止了感染的第一步。不同的体外试验显示低聚糖对于许多不同的致病微生物表现为抗附着作用；Kunz，C.和Rudloff，S.(1993)人乳中低聚糖的生物功能(Biological functions of oligosaccharides in human milk)，ActaPaediatr.82，903-912。
3.低聚糖通过影响不同的有免疫活性的细胞促进抵御感染的能力。一定低聚糖结构的免疫调节作用在动物试验中表现为至少将白介素的产量提高10倍；Velupillai，P.和Harn，D.A.(1994)得自被血吸虫感染的小鼠的B220+细胞对10倍量白介素的低聚糖特异性指令：CD4+T-细胞亚群的调节机制(Oligosaccharide-specific instruction ofinterleukin 10 production by B 220+cells from schistosome-infected mice：a mechanism for regulation of CD4+T-cell subsets)，Proc.Natl.Acad.Sci.91，1-2。
来自至今已知的大多数哺乳动物的低聚糖的多相性在许多方面与人乳中的低聚糖不同。无论在数量和质量上其低聚糖组成均存在非常大的区别。哺乳动物乳中的低聚糖的种特异性差别表现在单一组分的浓度上，同时在相似特征的结构上，或基本结构上均有不同。与人乳的低聚糖相比其单糖序列及键合均不同。因此在大多数动物乳中大多数单一组分的含量比人类母乳中低很多。
假定该区别是由新生儿胃肠道对乳中的低聚糖组分的需求确定的。那么该需求对不同的种类变化也很大。与需求有关的这类区别不仅新生儿和新生的动物间有，而且在不同新生动物间也有。该区别取决于于新生儿的胃肠道的功能状况、免疫系统的成熟程度、偏好的营养种类以及各种类的极特异的细菌环境。
如果人们试图用人造乳或基于动物乳的婴儿乳粉代替人乳，则会面对一个问题，即按照今天的认识状况就可以看出单一动物种的乳与人乳相比不仅在结构多样性上会有不同，其相关的低聚糖含量也有不同。
本发明的目的是提供一种低聚糖混合物，其中的低聚糖得自一种或多种动物乳，该混合物的积极作用，特别是其抗感染的作用最大程度地与人乳相当。
通过按照权利要求书所述的低聚糖的混合物可以实现这一任务。
非常惊奇地发现，通过将得自一种或多种不同动物乳的低聚糖混合而得的新型混合物，可使动物乳中低聚糖的抗感染和/或生物效应得到加强。因此本发明低聚糖混合物由至少两种低聚糖部分混合而成，每种低聚糖部分至少含有两种不同的低聚糖。该低聚糖部分可以来自一种或多种动物乳。很自然地，在动物乳中不包括人乳。
每一种低聚糖部分至少含有两种不同的低聚糖。这样的低聚糖可认为是，至少有一种特征是不同的。例如两种二糖，其由相同的单糖单元组成，但是键合次序不同，则被视为不同的低聚糖。其不同之处可为结构上的，也可为组成上的。
本发明的一个最重要方面是，将来自一种或多种不同种的动物乳的低聚糖部分以一种新的方式重新组合，以实现增强的生物效应。当然在此重新组合，或称为重新混合时应保证，不会得到在一种动物乳或多种动物乳中已存在的原始混合物。鉴于此，在低聚糖混合物中存在的低聚糖的总谱与从中获取了低聚糖部分的某种动物乳或多种动物乳的低聚糖的总谱必须不同。例如按照本发明的低聚糖混合物仅来自于一种动物乳时，则该混合物应由后面的有关总谱的特征表达，即从所述单一动物乳获得的低聚糖部分的新的组合物或新的混合物不再导致产生原始的动物乳。如果该低聚糖混合物来自多种动物乳，则新的组合或新的混合过程不会使所得的低聚糖混合物与原始使用的动物乳的一种低聚糖组合物相应。
如果按照本发明的低聚糖混合物的低聚糖仅来自一种动物乳，则此时中性低聚糖对酸性低聚糖的比例关系是90-60∶10-40重量％。换句话说，除了酸性的低聚糖部分外，还存在中性的低聚糖部分。这两种部分均含有至少两种不同的低聚糖。相对于在动物乳中的中性低聚糖对酸性低聚糖的原始比例，通过改变酸性低聚糖对中性低聚糖的比例，生理作用的效果上升明显。
如果低聚糖得自不同来源且至少两种动物乳，必须以这样的一种方式实现新的组合或新的混合，即得自两种不同动物乳的每种低聚糖将至少占低聚糖混合物中存在的低聚糖总量的10重量％。如果该低聚糖得自两种动物乳，则得自一种动物乳的低聚糖应至少占10重量％，而得自另一动物乳的低聚糖同样至少应占10重量％且最多90重量％，反之亦然。但如果低聚糖得自三种或更多种的动物乳，则其中两种动物乳的低聚糖必须至少占10重量％，而得自于其他动物乳的低聚糖所占份额可低于10重量％。
作为制备本发明的低聚糖混合物的来源，可使用所有的动物乳，这里优选牛、山羊、绵羊、马、骆驼和水牛的乳的低聚糖部分。
低聚糖部分的分离可通过已知的分离方法来进行。通过使用分离机借助密度离心法脱脂。蛋白质的分离可借助超滤或借助溶剂(例如乙醇、丙酮)的沉淀来进行。乳糖可通过下述的一种或多种方法分离：结晶法、过滤法以及色谱法(配位体交换色谱法、凝胶过滤法、洗脱色谱法、循环色谱法和模拟逆流色谱法(SMB))。矿物质可通过电透析、超微过滤、离子交换和/或反渗透来分离。在中性和酸性低聚糖中的低聚糖部分的分离可通过一种上述提及的色谱法和/或阴离子交换色谱法，以及也可借助传统的过滤法来进行。
按照优选的方式，本发明的来自至少两种动物乳的低聚糖混合物为重新组合而成，此时中性低聚糖对酸性低聚糖的比例为90-60∶10-40重量％。
上述给出的比例90-60∶10-40重量％包括了至少全部整数中间值的比例关系，如89∶11，88∶12，87∶13，......85∶15，......80∶20，79∶21，......75∶25，74∶26，73∶27，72∶28，......68∶32，67∶33，66∶34，65∶35，64∶36，63∶37，62∶38，61∶39。
本发明的低聚糖混合物中的低聚糖主要是由一个或多个下述的单糖单元构成：D-葡萄糖、D-半乳糖、D-N-乙酰基葡糖胺、D-N-乙酰基基半乳糖胺、L-海藻糖、D-甘露糖、D-形式的唾液酸(例如D-N-乙酰基神经氨酸和D-N-羟乙酰基神经氨酸)，及其O-乙酰化的、硫酸化的和磷酸化的衍生物。
在动物乳中大量存在的游离乳糖通常不计入得自动物乳的、本发明应用的低聚糖部分内。当然在本发明的低聚糖混合物中除本发明应用的低聚糖部分外，也可以有游离的乳糖存在。
换言之，按照本发明的低聚糖混合物也可仅用含低聚糖的低聚糖部分构成，该部分得自于一种或多种动物乳，由两个或多个单糖单元构成，在此不计入游离的乳糖。但如上所述，该低聚糖混合物可含有来源于或非来源于动物乳的游离的乳糖。此外低聚糖混合物可含有非来自于动物乳的一种或多种低聚糖。因此按照本发明的低聚糖混合物可与通常用于食品，特别是婴儿食品的糖类一同使用、混合。此外，在本发明的低聚糖混合物中也可存在这样的低聚糖，其是通过化学、酶和/或技术转化来获得本发明使用的低聚糖或低聚糖部分时，从糖脂和/或糖蛋白中释放出来的。
按照本文上述所给出的低聚糖范围，术语低聚糖特别涉及来自于动物乳的低聚糖。除此之外也可存在其它的如上所述的低聚糖，此时该情况是上面提及的或者是与下文有关联的。
乳制品是用于低聚糖分离的一个优选的来源，其中部分或完全除去了蛋白质以及脂肪。由诸如生产奶油时的乳糖-矿物质部分、酪蛋白部分和其他成分这样的产品制取，可使加工和分离大大简化。在药用乳糖的制备中出现的上清液同样也是一种合适的不同低聚糖制备的来源。对此可在实际分离该部分之前，将一种动物或不同动物种的乳或乳清在分离低聚糖之前按所希望的比例混合，使其满足具有单一结构或结构组的活性低聚糖组成的需要。
按照本发明的低聚糖混合物也可以高度浓缩或以纯品形式在胃肠功能紊乱时使用，此时肠内菌丛中的细菌种类的失衡(即肠胃菌丛的失衡，例如由在服用抗生素或其他因造成营养吸收障碍等而影响肠内菌丛的药物后引起)或病毒感染对胃肠功能紊乱起着主要作用。本发明的低聚糖混合物也可在预防这类肠胃感染中应用。因此按照本发明的低聚糖混合物也可加入婴儿食品、保健食品或药品之中。
按照本发明的低聚糖混合物本身还可作为一种添加剂在其他全营养食品(food complete)中应用。这样的食品例如有婴儿食品和肠胃临床营养制剂。此外它还可作为一般食品的添加剂，用以保持正常的肠胃功能(一种预防作用)以及肠胃功能紊乱的恢复，此时在肠胃中不正常的细菌集群或病毒对肠胃功能紊乱起着重要的作用。
按照本发明的低聚糖混合物也可以被制成胶囊或粉末，也可以稀液的形式作为添加剂添加到其它全营养食品中。
优选以每天至少10mg/kg至4g/kg体重的量应用本发明的低聚糖混合物，这里的毫克值是指本发明低聚糖混合物中的得自动物乳的那些低聚糖的毫克值。其它可能存在的低聚糖如乳糖，及不是出自动物乳的低聚糖在此不作考虑。优选按每天约100mg/kg体重的量服用。
该发明将按下述优选的实施例作进一步的详细说明。
实施例1
按照下述的方法进行加工100升的牛奶：
脂肪的分离是在45℃下借助密度离心法进行的。所得的脱脂牛奶通过乙醇沉淀脱去蛋白质(最终浓度：66％的乙醇)。借助分离机分离沉淀物。借助降流式蒸发器蒸去乙醇和部分水，至体积为40升为止。其中约含有4kg乳糖、1kg矿物质和其它可溶性的成分如水溶性维生素、尿素或柠檬酸盐。低聚糖部分的量约为10克。低聚糖部分的组成约为同等量的中性和酸性结构物。通过AG1×2阴离子交换色谱法可将其分为中性部分(洗脱剂：脱矿物质的水)和酸性部分(洗脱剂：300mM乙酸铵)。可借助结晶技术将该中性部分的乳糖含量降至60％。借助Toyopearl HW40(S)凝胶色谱可获得5g中性低聚糖部分，其中残留的乳糖含量为约10％。酸性的低聚糖部分将通过电渗析，从阴离子交换洗脱缓冲液(乙酸铵)中释放出来，并同中性低聚糖部分一样进行冷冻干燥。按此法可获得4.5g酸性低聚糖部分。组合1g酸性部分和5g中性部分，得到一种具有比天然组成的混合物更高活性的混合物。
实施例2
在加工奶酪生产中沉淀的山羊乳、绵羊乳和牛奶的乳清之前将其以3∶1∶1的比例混合，以获得源自三种不同动物的混合乳清4000升备用。借助一种聚砜膜(截止点20kDa)超滤，将残余的脂肪、溶液中存在的糖巨肽和乳清蛋白分离。通过反渗透将渗透液浓缩至900升。进一步采取的步骤与上述相同，首先结晶乳糖，然后进行阴离子交换层析以离出肽。经用去矿物质的水和300mM的乙酸铵洗出的部分被合并、浓缩、电渗析和冷冻干燥。可获得一种来自三种不同动物的低聚糖混合物约570g。在进行进一步的凝胶色谱分离和电渗析脱盐后，可通过冷冻干燥获得最终产品。用凝胶过滤、HPAEC-PAD和MALDI-MS的分析表明，按所使用的乳和混合比例，酸性低聚糖对中性低聚糖的比例为1∶5。由于原料中山羊乳清份额较高，半乳糖基乳糖的份额达到120g。在绵羊乳中，与酸性低聚糖的重要成分N-乙酰基神经氨酸相比占主导地位的是N-羟乙酰基神经氨酸。因此与山羊乳或牛乳相比，绵羊乳的羟乙酰基神经氨酸低聚糖(glycolyl neuraminyloligosaccharide)的含量上升。
实施例3
将马和山羊的乳分别加工。每种准备50升。借助离心、乙醇蛋白沉淀和分离，每种均得到碳水化合物-矿物质部分。通过使用旋转蒸发器将每种溶液浓缩至8升。借助在AG 501×8(Ca2+型)上进行的配位体交换层析，并用脱矿物质的水洗脱，一方面使得乳糖和单糖发生了色谱分离，另一方面还成功对低聚糖进行了细级分离。对马乳而言收集在排斥体积和四糖的洗脱范围之间的部分，并将其用作以后的低聚糖的新成分。用同样的方法分离来自山羊乳的碳水化合物-矿物质部分，可得到降解了乳糖和降解了单糖单元的的全部低聚糖部分。在此之后对各部分进行脱盐和通过超微过滤进行同步浓缩，然后冷冻干燥。将这两个部分以2∶5(马乳低聚糖部分：山羊乳低聚糖部分)的比例混合。
实施例4
将山羊乳如实施例1所述进行加工。借助在AG 1×2上的阴离子交换色谱处理可获得一种酸性部分，其主要成分为2，3’-和2，6’-唾液酸乳糖，以及2，3’-和2，6’-N-羟乙酰基神经氨酸乳糖。借助反相色谱可将该部分进一步分离，获得由2，3’-和2，6’-羟乙酰基神经氨酸乳糖组成的部分。将该部分通过电渗析脱盐，喷雾干燥，并为以后的混合备用。
对牛乳清可借助凝胶过滤分离出一种具有六种中性三糖的部分：这六种中性三糖体是三种异构的半乳糖基乳糖，一种岩藻糖基化的乳糖胺及分别被N-乙酰基半乳糖胺和N-乙酰基葡糖胺扩展的两种乳糖单元。
将酸性的山羊乳部分，其主要结构为2，3-异构体，按照1∶7的比例与牛乳清的三糖的中性部分在干燥状态下混合，为给食试验备用。
实施例5
采用已述及的方法可从马乳中分离出乳-N-新-四糖以及乳-N-新-己糖结构。在人乳中也存在这些低聚糖。
采用述及的方法，用色谱法从牛奶中分离出二唾液酸乳糖，并冷冻干燥。
来自山羊乳的岩藻糖基化的四糖的两种位置异构体可采用已知的确定方法加以分离。
将低聚糖以2∶1∶2(马乳低聚糖∶牛奶低聚糖∶山羊乳低聚糖)的混合比例进行混合。
实施例6
从山羊乳乳清中可分离出一种中性的低聚糖部分，它是由已叙述过的四糖和其他带有至今为止还未知的单糖组分的戊糖或己糖(2种己糖胺和4种己糖或2种己糖胺和4种己糖以及3种己糖胺和3种己糖)组成。
由同样的加工方法可得到一种酸性部分，其可用阴离子交换色谱加以分离，得到一种由两种不同的唾液酸乳糖和两种不同的羟乙酰基神经氨酸乳糖组成的混合物。在新的低聚糖混合物的新组成中，既不使用长链的酸性低聚糖，也不使用中性的半乳糖基乳糖。分离出的酸性和中性部分以2∶1的比例混合。
实施例7
在奶酪生产中沉淀的乳清除含有游离低聚糖外，通常还含有大量的以N-和O-聚糖形式结合的低聚糖。因此该糖巨肽被O-糖基化，乳铁蛋白被N-糖基化。相应的聚糖结构大部分被唾液酸化。原始的酸性对中性聚糖或低聚糖的比例为约1∶1。为使这一比例向有利于中性低聚糖的方向转化，可让其通过阴离子交换色谱。所有唾液酸化的和结合的酸性低聚糖(部分2)与凝胶母体结合，而中性低聚糖(部分1)可用脱矿物质的水洗脱。所有结合的组分可用较高离子强度(例如1MNaCl)的液体洗脱，并进行进一步的加工。通过在pH2.0和45℃的弱水解条件下几个小时，唾液酸被分离出来。在用NaOH溶液中和后，将部分2和中性低聚糖(部分1)合并。则中性对酸性低聚糖的比例向有利于中性低聚糖的方向转化。
Claims (9)
1.基于低聚糖的低聚糖混合物，所述低聚糖得自一种或多种动物乳，并且由两个或多个单糖单元组成，所述的低聚糖混合物的特征是
所述的低聚糖混合物含有至少两种低聚糖部分，该低聚糖部分由不包括游离的乳糖在内的至少两种不同的低聚糖组成；
在低聚糖混合物中存在的低聚糖的总谱与得自一种或各种动物乳的低聚糖部分的低聚糖总谱不同，且
a)如果该低聚糖仅得自于一种动物乳，则中性低聚糖对酸性低聚糖的比例为90-60∶10-40重量％，或者
b)如果低聚糖得自至少两种动物乳，则其中得自两种不同动物乳的每种低聚糖将至少占低聚糖混合物中存在的低聚糖总量的10重量％。
2.按照权利要求1所述的低聚糖混合物，其特征是
如果低聚糖得自至少两种动物乳，则中性低聚糖对酸性低聚糖的比例为90-60∶10-40重量％。
3.按照权利要求1或2所述的低聚糖混合物，其特征是
低聚糖主要是由下述的一种或多种单糖单元构成：D-葡萄糖、D-半乳糖、D-N-乙酰基葡糖胺、D-N-乙酰基半乳糖胺、L-海藻糖、D-甘露糖、D-形式的唾液酸(例如D-N-乙酰基神经氨酸和D-N-羟乙酰基神经氨酸)，及其O-乙酰化的、硫酸化的和磷酸化的衍生物。
4.按照上述权利要求任一项所述的低聚糖混合物，其特征是
低聚糖得自下述的一种或多种动物的乳：牛、山羊、绵羊、马、骆驼和水牛乳。
5.按照上述权利要求任一项所述的低聚糖混合物，其特征是
低聚糖得自一种或多种动物的未脱脂或脱脂的乳或乳清或未脱脂或脱脂的乳制品。
6.按照上述权利要求任一项所述的低聚糖混合物，其特征是
除了得自动物乳的低聚糖或低聚糖部分外，还存在乳糖，所述乳糖得自于从中获取了低聚糖的动物乳，以及一种或多种非动物来源的低聚糖和/或通过化学、酶和/或技术转换提取低聚糖时从由糖脂和/或糖蛋白中释放出来的低聚糖。
7.按照上述权利要求任一项所述的低聚糖混合物，其特征是
该低聚糖可加入婴儿食品、保健食品或药品之中，或此外可作为全营养食品的添加剂。
8.按照权利要求1-5任一项所述的低聚糖混合物的应用是，可用来抵御由于细菌或病毒在胃肠道中的集群而导致的胃肠功能紊乱，或用来保持正常的胃肠功能。
9.按照权利要求8所述的应用，
其中以每天至少10mg/kg至4g/kg体重的量应用低聚糖混合物。
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| CN101330838B (zh) * | 2005-10-21 | 2013-01-23 | 荷兰纽迪希亚公司 | 预防剖腹产分娩的婴儿疾病的方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| HUP0203707A3 (en) | 2004-12-28 |
| US20030129278A1 (en) | 2003-07-10 |
| NO330050B1 (no) | 2011-02-07 |
| NO20022688L (no) | 2002-06-06 |
| HUP0203707A2 (hu) | 2003-03-28 |
| PL356238A1 (en) | 2004-06-28 |
| CZ304817B6 (cs) | 2014-11-12 |
| DK1242436T3 (da) | 2005-03-14 |
| NO20022688D0 (no) | 2002-06-06 |
| ATE282626T1 (de) | 2004-12-15 |
| MXPA02005491A (es) | 2002-09-02 |
| CN1198624C (zh) | 2005-04-27 |
| EP1242436A2 (de) | 2002-09-25 |
| US7939118B2 (en) | 2011-05-10 |
| CZ20021876A3 (cs) | 2003-05-14 |
| JP2003516412A (ja) | 2003-05-13 |
| NZ519706A (en) | 2004-03-26 |
| AU2006201A (en) | 2001-06-18 |
| DE19958985A1 (de) | 2001-06-13 |
| EP1242436B1 (de) | 2004-11-17 |
| ES2233485T3 (es) | 2005-06-16 |
| AU782623B2 (en) | 2005-08-18 |
| WO2001042263A3 (de) | 2001-11-01 |
| WO2001042263A2 (de) | 2001-06-14 |
| HK1052438B (zh) | 2005-07-08 |
| PT1242436E (pt) | 2005-04-29 |
| DE50008706D1 (en) | 2004-12-23 |
| CA2394090C (en) | 2010-09-28 |
| CA2394090A1 (en) | 2001-06-14 |
| BR0016161A (pt) | 2002-10-29 |
| HK1052438A1 (en) | 2003-09-19 |
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