CN102869366A - 过敏性腹泻的预防和治疗 - Google Patents
过敏性腹泻的预防和治疗 Download PDFInfo
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- CN102869366A CN102869366A CN2010800311782A CN201080031178A CN102869366A CN 102869366 A CN102869366 A CN 102869366A CN 2010800311782 A CN2010800311782 A CN 2010800311782A CN 201080031178 A CN201080031178 A CN 201080031178A CN 102869366 A CN102869366 A CN 102869366A
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Abstract
本发明涉及短双歧杆菌CNCM I-3865(NCC2950),涉及包含短双歧杆菌CNCM I-3865(NCC2950)的组合物和涉及短双歧杆菌CNCM I-3865(NCC2950)在预防或治疗过敏性腹泻中的用途。
Description
发明领域
本发明涉及预防和治疗过敏性腹泻。
发明背景
迄今为止,导致腹泻的疾病仍然是主要的全球性健康威胁。腹泻严重的影响世界各地的患者的生活质量,并对缺乏手段来补偿脱水与矿物质严重丢失的婴儿、儿童以及老年人和患者的存活产生特别的威胁。
因此,急性腹泻是发展中国家中常见的死因,也是全世界婴儿死亡的第二常见原因。据估计,它导致了5百万5岁以下儿童的死亡。控制腹泻的成本是日益增加的健康预算负荷的主要流向之一。
腹泻可具有多种不同的病因,例如感染——包括由轮状病毒导致的腹泻、炎症、过敏和导致最常见类型的腹泻的营养失衡,包括例如分泌性腹泻、渗透性腹泻和运动性相关腹泻。如果不能通过因果手段治疗腹泻,例如消除病原体,则腹泻的类型而非潜在的病因提示了对症疗法。
在过去十年内,作为治疗胃肠道疾病的安全和容易获得的形式,益生细菌的使用吸引了广泛的关注。益生菌成功的用于控制由病毒感染(例如,轮状病毒)导致的腹泻。在病毒源性腹泻的情况下,用于干预的细菌属于乳杆菌属(Lactobacillus)和双歧杆菌属(Bifidobacterium)。某些益生细菌抗轮状病毒导致的胃肠炎的治疗能力归因于其稳定和强化粘膜屏障、生产抗菌物质和刺激局部的抗原特异性和非特异性免疫应答的能力。已注意到不同菌株的效率和作用模式之间的显著差异。
例如,在上世纪90年代早期,Saavedra等人观察到在美国医院的慢性护理病房中施用乳酸双歧杆菌(Bifidobacterium lactis)和嗜热链球菌(Streptococcus thermophilus)的组合,在之后的18个月后,降低了29名儿童的腹泻发病和轮状病毒排泄(Saavedra等人,The Lancet 344,1046;1994)。然而,在使用双歧杆菌的其他试验中获得了较不明确的结果(Thibault等人,J Ped Gastro Nutr 39,147;2004)。
更新的发现是,短双歧杆菌(Bifidobacterium breve)CNCM I-3865(NCC2950)可用于治疗或预防由轮状病毒感染导致的腹泻(EP08172263.9)。
除轮状病毒导致的腹泻(其中症状是由病原体导致的)外,患过敏性腹泻的人,特别是特定的食物过敏,可对某些食物反应,所述食物如同泻药。
食物过敏代表了当今社会的严重的健康问题。它影响所有的年龄段,特别是儿童。所有儿童中约6-8%患至少一种食物过敏。对成人的影响略低于儿童,但仍有约4%的成人患食物过敏。
除确诊食物过敏的患者外,有多达35%的大量人群患有对一种或多种食物过敏原的超敏反应(Rona,R.J.等人,2007,J.Allergy Clin.Immunol.120:638-646)。
长期的过敏性腹泻可以消弱患者,导致严重的脱水和矿物质(例如钾)丢失,并可能致使机体难以补充所有的必需营养化合物。
目前,通常通过避免食物过敏原和/或对症的补水和摄入矿物质来治疗过敏性腹泻,对生活质量和健康护理体系的成本都产生了极大的困扰。因此,需要这样的可获得的组合物,所述组合物允许预防过敏性腹泻的发生和/或治疗过敏性腹泻,并且可以安全无副作用的施用,因此可整合到食品中。
由前文可见,仍然需要有效的抗过敏性腹泻活性的组合物,所述组合物适合整合到被例如婴幼儿食用的产品中。
因此,本发明的目标是改善现有技术现状,为本领域提供满足上述需要的组合物。
发明概述
本发明人令人惊讶的发现短双歧杆菌(Bifidobacterium breve)CNCM I-3865(NCC2950)实现了本发明的目的。
越来越清楚的是,益生菌的特定健康益处通常不能根据细菌的种类而预测。
更具体的是,本发明人发现原始分离自人乳的具体短双歧杆菌菌株——短双歧杆菌CNCM I-3865(NCC2950)在预防和治疗过敏性腹泻中是非常有效的。令人感兴趣的是,即使是非复制的形式,它也保留了这一活性。
根据布达佩斯条约,短双歧杆菌CNCM I-3865(NCC2950)保藏在法国巴斯德研究所国立微生物保藏中心(COLLECTION NATIONALEDE CULTURES DE MICROORGANISMES,INSTITUT PASTEUR,25rue du Docteur Roux,F-75724 PARIS Cedex 15)。
引人注意的是,短双歧杆菌CNCM I-3865(NCC2950)还表现出抗轮状病毒感染导致的腹泻的活性。
因此,短双歧杆菌CNCM I-3865(NCC2950)是预料之外的化合物,它在治疗或预防不同病因的腹泻中有活性,即过敏性和轮状病毒性腹泻。
因此,在第一个方面,本发明提供了包含短双歧杆菌CNCM I-3865(NCC2950)的组合物,用于治疗或预防过敏性腹泻。
在第二个方面,本发明提供了短双歧杆菌CNCM I-3865(NCC2950)在生产用于预防或治疗过敏性腹泻的组合物中的用途。
在第三个方面,本发明提供了预防或治疗过敏性腹泻的方法,包括向需要的对象施用治疗量的短双歧杆菌CNCM I-3865(NCC2950)。
为了测试短双歧杆菌CNCM I-3865(NCC2950)在预防过敏性腹泻中的体内疗效,使用了过敏性腹泻的小鼠模型(Brandt E.B等人,JCI2003;112(11):1666-1667)。在敏化(以14天的间隔2次腹膜内注射卵清蛋白(OVA)和硫酸铝钾;第0和14天)后,雄性Balb/c小鼠用OVA口服刺激6次(第27、29、32、34、36、39天),导致暂时的临床症状(腹泻)和免疫参数改变(总IgE、OVA特异性IgE、小鼠肥大细胞蛋白酶1的血浆浓度)。在OVA敏化前4天(第-3、-2、-1、0天和第11、12、13和14天)和刺激阶段的过程中(第23至39天),管饲短双歧杆菌CNCM I-3865(NCC2950)。使用日常细菌剂量为约109集落形成单位(cfu)/小鼠。
附图概述
图1显示了在用生理盐水或OVA刺激的OVA敏化小鼠中,或在用活的短双歧杆菌CNCM I-3865(NCC2950)处理后再用OVA刺激的OVA敏化小鼠中观察到的中位腹泻分数。(中位值±RobustSD;第3次刺激:生理盐水=0±0,OVA=1±1.19;活的NCC2950=1±0;第4次刺激:生理盐水=0±0,OVA=3±1.19;活的NCC2950=1±1.19;第5次刺激:生理盐水=0±0,OVA=3±1.19;活的NCC2950=3±1.19;第6次刺激:生理盐水=0±0,OVA=5±0.6;活的NCC2950=3±0)。
发明详述
由于儿童或婴儿特别受食物过敏的影响,本发明的组合物可计划用于儿童和/或婴儿。根据2006年12月22日的欧盟委员会2006/141/EC指令第2章出现的关于婴儿配方和高段配方(follow-on formula)的定义,“婴儿”是年龄小于12个月的儿童,幼儿是年龄为1至3岁的儿童。
术语“儿童”包括1至14岁的年龄段。
当然,本发明的组合物还可用于青少年(15-17岁)或成人(18岁或以上)。
“益生菌”意指对宿主的健康状态具有有益效应的微生物细胞制品或微生物细胞组分(Salminen S,Ouwehand A.Benno Y.等人,“Probiotics:how should they be defined”Trends Food Sci.Technol.1999:10 107-10)。
除非另外陈述,所有的百分比都是按重量计。
本发明的组合物可以施用给需要的任何对象。
所述对象可以是人或者可以是动物,特别是宠物。对象可属于任何年龄段,例如婴儿、幼儿、儿童、青少年或成人。
本发明的组合物,包括足以至少部分治疗过敏性腹泻的量的短双歧杆菌CNCM I-3865(NCC2950)。足以实现上述的量被定义为“治疗有效量”。对该目的有效的量取决于本领域技术人员已知的多个因子,例如疾病的严重程度、消费者的体重和健康状态,以及组合物基质的效应。
在预防性应用中,向易感或者有风险患过敏性腹泻的消费者施用的短双歧杆菌CNCM I-3865(NCC2950)的量足以至少部分的降低出现过敏性腹泻的风险。所述量定义为“预防有效量”。再次的,所述精确的量取决于多个患者具体因素,例如患者的健康状态和体重、以及组合物基质的效应。
本领域技术人员能够恰当的调节治疗有效量和/或预防有效量。
一般而言,本发明的组合物含有治疗有效量和/或预防有效量的短双歧杆菌CNCM I-3865(NCC2950)。
益生菌短双歧杆菌CNCM I-3865(NCC2950)可以作为组合物向对象施用,例如等价于108cfu的日常剂量。它可以方便的在婴儿喂养配方、高段配方或成长奶中向婴儿施用。
典型的,短双歧杆菌CNCM I-3865(NCC2950)施用的量等价于103至1012cfu/g(干重基础)之间,更优选的在107至1011cfu/g之间。
表达方式“等价于……的量”包括细菌是可复制性的、非复制性的或死亡的可能性。换言之。细菌的量以所述量的细菌的集落形成能力来表述,如同所述细菌都是可复制性的,而不论它们是否实际上是可复制性的、非复制性的或死亡的,或者任意或所有这些状态的混合物。
在本发明的一个实施方案中,至少95%,更优选至少99%,甚至更优选所有的短双歧杆菌CNCM I-3865(NCC2950)是非复制性的。
出于该目的,可以通过任何本领域技术人员已知的方式致使其不复制。文献中描述的用于致使益生菌菌株不复制的技术包括例如热处理、γ-辐射、UV光照或化学剂(福尔马林、低聚甲醛)处理。优选的是不需要添加试剂的方法。特别是对于含有奶或奶化合物的制品,热处理是优选的,因为它们可以以任何方式进行,来降低细菌负载。该方式不需要任何额外的加工步骤。
非复制性的益生性微生物具有比其相应的活菌更易于处理的优点。额外的,它们储藏更加稳定,且需要的包装条件严格程度较低。
非复制性的益生性微生物允许开发大量的功能性食品,这些营养食品在没有额外的保护措施的条件下,本质上不允许添加活的益生菌。这在例如提供压块干粮、果汁、UHT饮料、耐贮存饮料等中发挥了作用。
此外,例如在免疫受损的消费者中,由于出现菌血症的潜在风险,因此使用活的益生菌可能受限制。免疫受损的个体也可以更好的耐受无繁殖能力的益生菌。
额外的,提供非复制性益生微生物允许热冲调,例如粉末状的营养组合物。
“非复制性”意指通过经典的涂板方法不能检测到可复制的细胞和/或集落形成单位。此类经典的涂板方法概括在微生物学书籍中:JamesMonroe Jay,Martin J.Loessner,David A.Golden.2005.Modern foodmicrobiology,第7版,Springer Science,New York,N.Y.第790页。典型的,缺少可复制的细胞可表现如下:在用不同浓度的细菌制品(“非复制性”样品)接种并在恰当的条件(好氧和/或厌氧气氛下至少24小时)下孵育后,在琼脂平板上没有可见的集落,或在液体生长培养基中没有增加的浑浊度。
组合物中可以添加益生元。益生元可以帮助短双歧杆菌CNCMI-3865(NCC2950)的生长。益生元还可以与组合物中存在的其他活的益生细菌,或者肠道中的有益细菌协同作用。
“益生元”意指促进肠道中的益生菌或促进健康的微生物生长的不可消化的食物物质。在摄入它们的个体中,在其胃和/或肠道上段不被降解,或在胃肠道中不被吸附,但却被胃肠道微生物丛和/或益生菌发酵。益生元是例如Glenn R.Gibson和Marcel B.Roberfroid,DietaryModulation of the Human Colonic Microbiota:Introducing the Conceptof Prebiotics,J.Nutr.1995 125:1401-1412定义的。
根据本发明使用的益生元没有特别的限制,包括促进肠道中的益生菌或促进健康的微生物生长的所有食物物质。优选的,可以选自寡糖,任选的含有果糖、半乳糖、甘露糖;膳食纤维,特别是可溶性纤维、大豆纤维;菊粉;或其混合物。优选的益生元是果糖低聚糖(FOS)、半乳糖低聚糖(GOS)、异麦芽糖低聚糖(IMO)、木糖低聚糖(XOS)、大豆的寡糖、葡萄糖基蔗糖(GS)、乳糖基蔗糖(LS)、半乳糖苷果糖(LA)、帕拉金糖(palatinose)寡糖(PAO)、麦芽糖低聚糖(MOS)、树胶和/或其水解产物、果胶和/或其水解产物。
组合物中可以添加其他的益生菌。
其他的益生菌可以是复制性的或非复制性的或两者的混合物。所有益生性微生物都可以与短双歧杆菌CNCM I-3865(NCC2950)组合。优选这样添加的益生菌可以选自双歧杆菌属(Bifidobacterium)、乳杆菌属(Lactobacillus)、乳球菌属(Lactococcus)、肠球菌属(Enterococcus)、链球菌属(Streptococcus)、丙酸杆菌属(Propionibacterium)、片球菌属(Pediococcus)、大肠杆菌(Escherichia coli)、德巴利酵母属(Debaryomyces)、克鲁维酵母属(Kluyveromyces)、酵母属(Saccharoymces)、裂殖酵母属(Schizosaccharomyces)、接合酵母属(Zygosaccharomyces)、耶氏酵母属(Yarrowia)、假丝酵母属(Candida),特别是选自长双歧杆菌(Bifidobacterium longum)、乳酸双歧杆菌(Bifidobacterium lactis)、动物双歧杆菌(Bifidobacterium animalis)、短双歧杆菌、婴儿双歧杆菌(Bifidobacterium infantis)、两歧双歧杆菌(Bifidobacterium bifidum)、青春双歧杆菌(Bifidobacteriumadolescentis)、嗜酸乳杆菌(Lactobacillus acidophilus)、干酪乳杆菌(Lactobacillus casei)、副干酪乳杆菌(Lactobacillus paracasei)、唾液乳杆菌(Lactobacillus salivarius)、植物乳杆菌(Lactobacillusplantarum)、发酵乳杆菌(Lactobacillus fermentum)、约氏乳杆菌(Lactobacillus johnsonii)、路氏乳杆菌(Lactobacillus reuteri)、戈氏乳杆菌(Lactobacillus gasseri)、鼠李糖乳杆菌(Lactobacillusrhamnosus)、乳球菌物种例如乳酸乳球菌(Lactococcus lactis)、乳脂乳球菌(Lactococcus cremoris)、(Lactococcus diacetylactis)、屎肠球菌(Enterococcus faecium)、粪肠球菌(Enterococcus faecalis)、酿酒酵母(Saccharomyces cerevisiae)、布拉氏酵母(Saccharomycesboulardii)、栗酒裂殖酵母(Schizosaccharomyces pombe)、乳酸克鲁维酵母(Kluyveromyces lactis)、Yarrowia lypolitica或其混合物,优选选自约氏乳杆菌(NCC533;CNCM I-1225)、长双歧杆菌(NCC490;CNCM I-2170)、长双歧杆菌(NCC2705;CNCM I-2618)、长双歧杆菌(NCC3001;ATCC BAA-999)、乳酸双歧杆菌(NCC2818;CNCMI-3446)、短双歧杆菌(菌株A)、副干酪乳杆菌(NCC2461;CNCMI-2116)、鼠李糖乳杆菌GG(ATCC53103)、鼠李糖乳杆菌LPR(NCC4007;CGMCC 1.3724)、屎肠球菌SF 68(NCIMB10415),及其混合物。所有这些益生菌都可以添加可复制性的或非复制的形式。
根据本发明的食品包括奶产品,例如发酵奶产品,如酸奶、酪乳等;冰激凌;浓缩奶;奶;奶酪;风味奶饮品;基于乳清的饮料;浇头(toppings);咖啡乳膏(coffee creamer);巧克力;基于奶酪的产品;糖;调味酱;法式浓汤;佐料(dressings);布丁;蛋奶冻;婴儿食品;营养配方,例如用于婴儿、儿童、青少年、成人或老年人的全营养配方;谷物和压块干粮。
饮料包括例如基于奶或基于酸奶的饮料、发酵奶、咖啡、蛋白质饮料、茶、能量饮料、大豆饮料、水果和/或蔬菜饮料、水果和/或蔬菜汁。
同样的,组合物可以口服的、肠道的和/或不经肠道的(例如,皮下、肌肉内)施用。
本发明的组合物可以进一步包括蛋白质源、碳水化合物源和/或脂肪源。
对于特殊的临床应用,特别是不经肠道的应用,理想的是提供不含碳水化合物源的组合物。
由于触发过敏反应的过敏原通常是食物蛋白质或其部分,因此,在预计用于过敏患者的组合物中的组合物蛋白质源需要引起特别注意。一般而言,组合物中存在的蛋白质类型应该不引发过敏反应。因此,所使用的蛋白质源可随本发明组合物将预防或治疗的过敏的类型而改变。
可以使用任何合适的膳食蛋白质,例如动物蛋白(例如奶蛋白、肉蛋白和蛋蛋白)或其水解产物;植物蛋白(例如大豆蛋白、小麦蛋白、稻蛋白和豌豆蛋白)或其水解产物;游离氨基酸的混合物;或其组合。奶蛋白(例如酪蛋白和乳清)和大豆蛋白或其水解产物对于一些应用是特别优选的。如果蛋白质源是奶蛋白或奶蛋白级分,则可以是例如甜乳清、酸乳清、α乳清蛋白、β乳球蛋白、牛血清白蛋白、酸酪蛋白、酪蛋白酸盐、α酪蛋白、β-酪蛋白、γ-酪蛋白。当然也可以使用不同蛋白质源的组合。
关于乳清蛋白,蛋白质源可以基于酸乳清或甜乳清或其混合物,可以包括以任何需要的比例的α乳清蛋白和β乳球蛋白。然而优选的,特别是如果组合物是婴儿喂养配方,则蛋白质源是基于修饰的甜乳清的。甜乳清是易于获得的奶酪生产的副产物,经常用于生产基于牛奶的婴儿配方中。
蛋白质可以是完整的或水解的或完整和水解蛋白质的混合物。理想的是提供充分或部分水解的蛋白质(水解程度在2至20%之间)。水解步骤可以消化潜在的过敏性食物蛋白质。因此,提供水解的蛋白质对过敏患者或有风险出现过敏的个体是有益的。
如果需要水解的蛋白质,则可以根据需要和本领域已知的进行水解过程。例如,可以通过在一个或多个步骤中酶促水解乳清级分,制备乳清蛋白水解产物。
如果本发明的组合物含有蛋白质源,则组合物中的蛋白质或蛋白质等价物的量典型的在1.6-7.5g/100kcal组合物的范围内。
特别是对于营养配方,蛋白质源应该提供满足必需氨基酸的最低要求。
如果组合物含有碳水化合物源,则使用的碳水化合物的种类没有特别的限制。可以使用任何合适的碳水化合物,例如蔗糖、乳糖、葡萄糖、果糖、玉米糖浆固形物、麦芽糊精、淀粉及其混合物。可以使用不同的碳水化合物源的组合。碳水化合物可优选的提供30%至80%的组合物能量。例如,组合物可包括9-18g/100kcal组合物的量的碳水化合物源。
如果组合物含有脂类源,则使用的脂类的种类没有特别的限制。如果组合物包括脂类源,则脂类源可提供5%至70%的组合物能量。可以添加长链n-3和/或n-6多不饱和脂肪酸,例如DHA、ARA和/或EPA。可以使用芥花籽油、玉米油、高油酸向日葵油和中链甘油三酯油的掺合物获得合适的脂肪谱。组合物可以包含1.5-7g/100kcal组合物的量的脂类源。
组合物还可以含有认为对日常膳食是必需的营养上显著量的所有维生素和矿物质。具体的矿物质和其他维生素的存在和量根据治疗对象而改变。
需要时,组合物可含有乳化剂和稳定剂,例如大豆卵磷脂、单甘油和二甘油柠檬酸酯,等
组合物可任选的含有其他具有有益效应的物质,例如纤维、乳铁蛋白、核苷酸、核苷等。
可以根据任何合适的方法培养短双歧杆菌CNCM I-3865(NCC2950),并通过例如冷冻干燥或喷雾干燥制备用于向组合物中添加的短双歧杆菌CNCM I-3865(NCC2950)。
额外的或可选的,可以以封装的形式提供活的益生微生物。
已发现封装的细菌具有治疗和技术优势。封装增加了细菌的存活,因而增加了到达肠道的活细菌的数量。此外,细菌是逐渐释放的,允许延长细菌对对象健康的作用。细菌可以是微封装的,例如FR2443247描述的(Sociétédes Produits Nestlé),其通过引用整合到本文中。简而言之,细菌可以是冷冻干燥的或喷雾干燥的,并整合到凝胶中。
在不脱离公开的本发明的范围的条件下,本领域技术人员可以理解他们可以自由的组合本文所述的本发明的所有特征。特别的是,描述用于本发明用途的特征可用于本发明的组合物,反之亦然。
根据下列实施例和附图,本发明的其他优势和特征是显而易见的。
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Claims (9)
1.包含短双歧杆菌CNCM I-3865(NCC2950)的组合物,用于治疗或预防过敏性腹泻。
2.根据权利要求1使用的组合物,其是药物、治疗性营养组合物、婴儿喂养配方、高段配方、成长奶、食品、动物食品、营养食品、饮料和/或食品添加剂。
3.根据任一项前述权利要求使用的组合物,包括等价于在干重基础上的103至1012cfu/g量的短双歧杆菌CNCM I-3865(NCC2950)。
4.根据任一项前述权利要求使用的组合物,包括等价于107至1011cfu/g量的短双歧杆菌CNCM I-3865(NCC2950)。
5.根据任一项前述权利要求使用的组合物,其中至少95%,优选99%,甚至更优选所有的短双歧杆菌CNCM I-3865(NCC2950)是非复制性的。
6.根据任一项前述权利要求使用的组合物,进一步包括至少一种益生元,其量按组合物的重量计量为0.3至6%。
7.根据任一项前述权利要求使用的组合物,其是添加物,并且包括每单位剂量106至1012cfu短双歧杆菌CNCM I-3865(NCC2950)。
8.权利要求1-8的任一项要求保护的组合物的用途,用于生产预防或治疗过敏性腹泻的组合物。
9.根据权利要求9的用途,其中所述组合物选自药物、治疗性营养组合物、婴儿喂养配方、高段配方、成长奶、食品、动物食品、营养食品、饮料和/或食品添加剂。
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CH637297A5 (fr) | 1978-12-05 | 1983-07-29 | Nestle Sa | Microbille comprenant un microorganisme et son procede de fabrication. |
JP2617758B2 (ja) | 1988-03-25 | 1997-06-04 | 株式会社ヤクルト本社 | 抗体産生増強型免疫賦活剤 |
US5902578A (en) * | 1996-03-25 | 1999-05-11 | Abbott Laboratories | Method and formula for the prevention of diarrhea |
ES2314461T3 (es) * | 2003-10-24 | 2009-03-16 | N.V. Nutricia | Composicion simbiotica para bebes. |
PL1855550T3 (pl) * | 2005-02-28 | 2012-03-30 | Nutricia Nv | Kompozycje żywieniowe z probiotykami |
EP2140772A1 (en) * | 2008-07-03 | 2010-01-06 | Nestec S.A. | Temperature-induced delivery of nutrients by micro-organisms in the gastrointestinal tract |
ATE546149T1 (de) | 2009-05-11 | 2012-03-15 | Nestec Sa | Prävention und behandlung von allergischer diarrhöe |
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CN114146100A (zh) * | 2021-11-22 | 2022-03-08 | 微康益生菌(苏州)股份有限公司 | 动物双歧杆菌乳亚种BLa80在制备抗轮状病毒感染致腹泻的药物或食物中的应用 |
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JP5632460B2 (ja) | 2014-11-26 |
US20120183506A1 (en) | 2012-07-19 |
CN102869366B (zh) | 2015-02-18 |
CA2761238C (en) | 2017-03-21 |
RU2522240C2 (ru) | 2014-07-10 |
WO2010130661A1 (en) | 2010-11-18 |
EP2429542A1 (en) | 2012-03-21 |
RU2011150189A (ru) | 2013-06-20 |
BRPI1010837A2 (pt) | 2016-04-05 |
TW201105252A (en) | 2011-02-16 |
ATE546149T1 (de) | 2012-03-15 |
ES2382263T3 (es) | 2012-06-06 |
MX2011012071A (es) | 2012-02-23 |
EP2251021A1 (en) | 2010-11-17 |
UA107081C2 (uk) | 2014-11-25 |
MY158310A (en) | 2016-09-30 |
US9498502B2 (en) | 2016-11-22 |
EP2251021B1 (en) | 2012-02-22 |
CA2761238A1 (en) | 2010-11-18 |
ZA201109086B (en) | 2013-05-29 |
TWI407918B (zh) | 2013-09-11 |
JP2012526750A (ja) | 2012-11-01 |
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