CN114599231A - 反刍动物的胰岛素抵抗性抑制剂 - Google Patents
反刍动物的胰岛素抵抗性抑制剂 Download PDFInfo
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- CN114599231A CN114599231A CN202080075548.6A CN202080075548A CN114599231A CN 114599231 A CN114599231 A CN 114599231A CN 202080075548 A CN202080075548 A CN 202080075548A CN 114599231 A CN114599231 A CN 114599231A
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- cashew nut
- nut shell
- shell oil
- insulin resistance
- cardanol
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Abstract
本发明提供一种反刍动物的胰岛素抵抗性抑制剂，其特征在于，含有腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
Description
技术领域
本发明涉及用于抑制反刍动物的胰岛素抵抗性的制剂及饲料、以及使用它们的胰岛素抵抗性抑制方法。
背景技术
在使用反刍动物作为家畜时，为了提高其生产率，畜产物的健康状态的维持及疾病对策成为重要的要素。
胰岛素抵抗性是指糖摄取促进作用等胰岛素的作用降低的状态，可能成为糖尿病、高脂血症等的原因。特别是在围产期的反刍动物中，存在容易因能量代谢的变化、激素平衡的变化而引起胰岛素抵抗性的危险。
然而，在反刍动物中对于抑制胰岛素抵抗性有效的饲料成分基本上不为人所知。
作为腰果壳油对反刍动物的效果，已知有瘤胃发酵改善效果(专利文献1)、鼓胀病防除效果(专利文献2)、球虫病防除效果(专利文献3)、酸中毒防除效果(专利文献4)等。但是，迄今为止，完全没有关于利用腰果壳油来抑制反刍动物的胰岛素抵抗性的见解。
现有技术文献
专利文献
专利文献1：WO2008/149992
专利文献2：WO2008/149994
专利文献3：WO2009/139468
专利文献4：WO2010/053085
发明内容
发明所要解决的课题
本发明的课题在于，提供用于抑制反刍动物的胰岛素抵抗性的材料。
用于解决课题的手段
本发明人等为了解决上述课题进行了深入研究，结果发现，通过向反刍动物施用腰果壳油(以下有时也简称为CNSL)，能够抑制胰岛素抵抗性。本发明人等基于此种见解完成了本发明。
即，本发明如下所示。
(1)一种反刍动物的胰岛素抵抗性抑制剂，其特征在于，含有腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
(2)根据(1)中记载的胰岛素抵抗性抑制剂，其中，反刍动物为牛。
(3)根据(1)或(2)中记载的胰岛素抵抗性抑制剂，其中，反刍动物为雌性的反刍动物。
(4)根据(3)中记载的胰岛素抵抗性抑制剂，其中，雌性的反刍动物为分娩前30天到分娩后30天的雌性的反刍动物。
(5)根据(1)～(4)中任一项记载的胰岛素抵抗性抑制剂，其具有将胰岛素抵抗性指标抑制30％以上、并使血中的游离脂肪酸和/或酮体浓度减少的效果。
(6)一种反刍动物的胰岛素抵抗性抑制用饲料，其特征在于，含有腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
(7)根据(6)中记载的饲料，其中，粗蛋白质(CP)含量为12％DM(％干燥质量)以上。
(8)根据(6)或(7)中记载的饲料，其中，中性洗涤纤维(NDF)含量为20％DM以上。
(9)一种抑制胰岛素抵抗性的方法，其特征在于，对非人动物施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
(10)一种抑制反刍动物的胰岛素抵抗性的方法，其特征在于，对反刍动物施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
(11)根据(10)中记载的方法，其中，反刍动物为牛。
(12)根据(10)或(11)中记载的方法，其中，反刍动物为雌性的反刍动物。
(13)根据(12)中记载的方法，其中，在从分娩前30天到分娩后30天的任意时刻施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
(14)根据(12)中记载的方法，其中，在从分娩前30天到分娩时为止的任意时刻施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
(15)根据(10)～(14)中任一项记载的方法，其中，施用期间至少为14天。
(16)根据(10)～(15)中任一项记载的記載的方法，其中，以0.1～50g/头/天施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
(17)腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚在制造反刍动物的胰岛素抵抗性抑制剂中的应用。
发明效果
根据本发明，通过对反刍动物施用包含腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚、和/或腰果二酚的制剂或饲料，能够抑制胰岛素抵抗性。由此，能够维持反刍动物的健康状态，能够提高培育效率。
具体实施方式
本发明的反刍动物的胰岛素抵抗性抑制剂的特征在于，含有腰果壳油(CNSL)、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
本发明中，所谓胰岛素抵抗性的抑制，是指抑制陷于糖摄取促进作用等胰岛素作用降低的状态的情况。
胰岛素抵抗性可以利用下述的RQUIKI值进行评价，该值越低，则可以评价胰岛素抵抗性越高。因而，若通过施用CNSL等，与不施用时相比能够抑制RQUIKI值的降低，则可以说能够抑制胰岛素抵抗性。对于RQUIKI值等胰岛素抵抗性的指标，优选通过本发明的胰岛素抵抗性抑制剂的施用，与不施用时相比抑制30％以上，更优选抑制50％以上。
RQUIKI＝1/[Log(Glu)+Log(Insulin)+Log(NEFA)]
此处，Glu、Insulin、NEFA各自表示血中的葡萄糖浓度(mg/dL)、胰岛素浓度(μU/mL)、游离脂肪酸浓度(mmol/L)。
腰果壳油是腰果树(Anacardium occidentale L.)的果实的壳中含有的油状的液体。腰果壳油包含漆树酸、腰果酚、腰果二酚作为其成分。漆树酸因进行加热处理而转换为腰果酚，也可以使用因加热处理而变成仅为腰果酚和腰果二酚的腰果壳油(加热腰果壳油)。
通过压榨腰果的壳而提取出的腰果壳油(非加热)如J.Agric.Food Chem.2001，49，2548-2551中记载所示，包含55～80质量％的漆树酸、5～20质量％的腰果酚、5～30质量％的腰果二酚。
对非加热腰果壳油进行加热处理(例如为70℃以上、优选为130℃以上)而得的加热腰果壳油中，因作为非加热腰果壳油的主成分的漆树酸发生脱羧而变为腰果酚，从而包含0～10质量％的漆树酸、55～80质量％的腰果酚、5～30质量％的腰果二酚。
腰果壳油可以作为通过压榨腰果的壳而提取出的植物油得到。另外，也可以对腰果壳进行干馏或溶剂提取而得到。另外，例如也可以利用日本特开平8-231410号公报中记载的方法得到腰果壳油。腰果壳油也可以使用市售品。
本发明的胰岛素抵抗性抑制剂可以取代腰果壳油而包含漆树酸、腰果酚和/或腰果二酚本身。
作为漆树酸，可以举出天然物漆树酸、合成漆树酸、它们的衍生物。另外，也可以使用市售的漆树酸。漆树酸可以通过像日本特开平8-231410号公报中记载的那样操作而得到，即，对腰果的壳用有机溶剂进行提取处理，将所得的腰果油例如使用硅胶柱色谱改变正己烷、乙酸乙酯及乙酸的混合溶剂的比率地进行洗脱(日本特开平3-240721号公报、日本特开平3-240716号公报等)。
作为腰果酚，可以举出天然物腰果酚、合成腰果酚、它们的衍生物。另外，本发明中使用的腰果酚可以通过对作为腰果壳油的主成分的漆树酸进行脱羧而得到。
作为腰果二酚，可以举出天然物腰果二酚、合成腰果二酚、它们的衍生物。另外，本发明中使用的腰果二酚可以通过由腰果壳油进行纯化而得到。
对于本发明的胰岛素抵抗性抑制剂中的腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚的含量，以制剂的总量基准计，优选为0.1质量％～100质量％，更优选为0.5质量％～95质量％，特别优选为1质量％～90质量％。
作为本发明的胰岛素抵抗性抑制剂，也可以直接经口施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚的原液。
另一方面，本发明的胰岛素抵抗性抑制剂可以在包含腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚以外，例如还包含乳糖、白糖、D-甘露醇、α淀粉、淀粉、玉米淀粉、微晶纤维素、膨润土、硅胶、轻质硅酸酐等饲料或医药品中可以使用的赋形剂等成分。
另外，本发明的胰岛素抵抗性抑制剂可以在包含腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚以外，还包含对促进反刍动物的生长有效的成分、营养补充成分、提高保存稳定性的成分、包衣剂成分等任意成分。作为此种任意成分，可以举出麦糠、紫花苜蓿、梯牧草等饲料的原料、饲料添加物、食品原料、食品添加物、医药品原材料、动物用补充剂(以下称作补充剂。)中使用的其他补充剂成分等。例如可以举出肠球菌属细菌、杆菌属细菌、双歧杆菌等生菌剂；淀粉酶、脂肪酶等酶；L-抗坏血酸、氯化胆碱、肌醇、叶酸等维生素；氯化钾、柠檬酸铁、氧化镁、磷酸盐类等矿物质；DL-丙氨酸、DL-蛋氨酸、L-赖氨酸等氨基酸；富马酸、丁酸、乳酸、乙酸等有机酸及它们的盐；乙氧基喹啉、二丁基羟基甲苯、丁基羟基茴香醚、阿魏酸、维生素C、维生素E等抗氧化剂；丙酸钙等防霉剂；羧甲基纤维素(CMC)、酪蛋白钠、聚丙烯酸钠等粘结剂；卵磷脂、脂肪酸甘油酯、失水山梨醇脂肪酸酯等乳化剂；虾青素、斑蝥黄等色素；各种酯、醚、酮类等添香剂。对于补充剂的种类、除腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚以外的成分没有特别限制。
本发明的胰岛素抵抗性抑制剂可以包含氧化镁、硬脂酸盐、滑石、沸石、硅藻土及二氧化硅等吸油剂，吸油剂优选为粒子状。作为吸油剂，优选为每100g吸附50～300g的油的吸油剂。另外，若粒径大于300μm，则粒子变粗而逐渐分离，因此优选粒径为2～300μm的粒子。
在本发明的胰岛素抵抗性抑制剂的一个方式中，吸油剂与腰果壳油(CNSL)、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚的优选的质量比为100：20～100：180。另外，吸油剂与腰果壳粉碎物的情况下的优选的质量比为15：100～60：100。
本发明的胰岛素抵抗性抑制剂的剂形没有特别限制，例如可以举出液剂、粉剂、固体、片剂、胶囊剂、乳剂、颗粒剂、片剂、包衣剂等任意的形态，优选液剂、粉剂、胶囊剂、颗粒剂、片剂。
作为液剂，可以直接使用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚，也可以将腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚溶解于乙醇等溶剂中，或者也可以添加上述赋形剂或任意成分后使用。另外，也可以使以下的粉剂、胶囊剂、颗粒剂、片剂混悬、漂浮在液体中。
作为粉剂，也可以向腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚中添加上述赋形剂并进行粉末化。
作为胶囊剂，可以将腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚直接填充到胶囊中，或者也可以添加上述赋形剂或任意成分。
作为颗粒剂，可以向腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚中添加上述赋形剂，进行造粒，使之颗粒化。
作为片剂，也可以向腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚中添加上述赋形剂，进行造粒，使之片剂化。
需要说明的是，在含有二氧化硅等吸油剂的情况下，优选以粉剂、片剂、颗粒剂的形式进行制剂化。
如上所述，本发明的胰岛素抵抗性抑制剂可以通过将腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚及根据需要使用的赋形剂或任意成分混合、并进行制剂化来制造。需要说明的是，根据制剂的形态，可以将所述的腰果壳的粉碎、破碎物、或者不进行任何处理地将腰果壳直接与其他任意成分混合后作为本发明的胰岛素抵抗性抑制剂。此外，可以不与其他任意成分混合，而是将粉碎、破碎物本身或腰果壳本身作为胰岛素抵抗性抑制剂。
本发明的饲料的特征在于，含有腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
对于本发明的饲料中的腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚的含量，相对于饲料的干物质量，以总量基准计优选为0.5～500000质量ppm，更优选为5～300000质量ppm，特别优选为50～100000质量ppm。若为0.5质量ppm以上，则可以期待胰岛素抵抗性抑制效果。若为5质量ppm以上、特别优选为50质量ppm以上，则该趋势变得显著，所以优选。另一方面，虽然即使是500000质量ppm也能够发挥胰岛素抵抗性抑制，然而优选为300000质量ppm以下，特别优选为100000质量ppm以下。
本发明的饲料中，粗蛋白质(CP)含量优选为12％DM(％干燥质量)以上，更优选为15％DM以上，进一步优选为17％DM以上。CP含量的上限例如为30％DM。CP含量可以利用凯氏法(wet分析)测定。
另外，本发明的饲料中，中性洗涤纤维(NDF)含量优选为20％DM以上，更优选为25％DM以上，进一步优选为30％DM以上。NDF含量的上限例如为50％DM。NDF含量可以利用洗涤分析法(wet分析)测定。
CP、NDF的分析法也记载于饲料分析法·解说2004(日本科学饲料协会2004.3)中。
在包含腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚的本发明的饲料中，通过增加蛋白质、中性洗涤纤维含量，特别是在分娩前后的雌性的反刍动物中，可以在维持健康状态的同时还一并地提高胰岛素抵抗性抑制效果。
本发明的饲料可以通过将腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚或者包含它的本发明的胰岛素抵抗性抑制剂添加到饲料成分中、并进行混合而制造。
此时，在使用粉末状、固体状的制剂的情况下，为了使混合容易，可以使用液体载体将制剂制成液状或凝胶状的形态。该情况下，可以使用水、植物油、液体动物油、矿物油、合成油、水溶性高分子化合物等流动性液体作为液体载体。另外，为了确保饲料中的腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚的均匀性，也优选配合海藻酸、海藻酸钠、黄原胶、羧甲基纤维素、α淀粉、酪蛋白钠、阿拉伯胶、瓜尔胶、罗望子种子多糖类等水溶性多糖类。
本发明的饲料中与本发明的制剂配合的饲料成分的种类、配合比例等没有特别限制，只要是以往提供给各个动物的饲料即可，例如可以使用玉米粒、玉米粉、高粱、麦糠、豆粕、燕麦、小麦低筋粉、小麦粗粉、紫花苜蓿、梯牧草、三叶草、脱脂米糠、北洋鱼粉、沿岸鱼粉、酵母、糖蜜、肉片、骨粉、碳酸钙、磷酸氢钙、黄脂膏(Yellow Grease)、维生素类、矿物质类等来制备。
摄取本发明的胰岛素抵抗性抑制剂或饲料的反刍动物的种类没有特别限制，例如可以举出牛、水牛、山羊、绵羊、牦牛等反刍动物。其中特别适合使牛摄取，作为优选的牛种，可以举出雌性荷尔斯坦因种、泽西种、黑毛和种、日本短角种、亚伯丁安格斯种。摄取的胰岛素抵抗性抑制剂或饲料的量可根据动物的种类、体重、年龄、性别、健康状态、饲料成分等适当调节，此时饲料中含有的腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚例如为0.01～500g/头/天，优选为0.1～200g/头/天，更优选为0.1～50g/头/天，进一步优选为0.5～5g/头/天。
另外，由于摄取本发明的胰岛素抵抗性抑制剂或饲料的牛的体重范围通常为500～900kg，因此作为每1kg牛体重的、一天给与的饲料中含有的腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚的量，为0.000011g～1g，优选为0.00011g～0.4g，更优选为0.0011g～0.2g。
本发明的胰岛素抵抗性抑制剂或饲料的施用时期没有特别限制，在奶牛的情况下，优选向适宜产乳的月龄的奶牛(通常为20～144月龄，优选为20～132月龄，更优选为20～108月龄)给与。
另外，本发明的胰岛素抵抗性抑制或饲料优选向围产期的反刍动物、优选过渡期的反刍动物给与。例如，可以在分娩前60天～分娩后30天、优选在分娩前30天～分娩后30天、更优选在分娩前14天～分娩后14天的任意时刻给与。特别是为了抑制因分娩而产生的胰岛素抵抗性，优选从分娩前起给与，例如可以在分娩前60天～分娩时、优选在分娩前30天～分娩时、更优选在分娩前14天～分娩时的任意时刻给与。该情况下，可以从分娩前延及分娩后地给与。给与期间没有特别限制，优选为14天以上，更优选为30天以上，进一步优选为60天以上。
实施例
以下，举出实施例而对本发明进行具体的说明。但是，本发明的方式并不限定于以下的实施例。
胰岛素抵抗性抑制效果的评价
将对照组5头、给与组4头共计9头用于试验，给与组中从分娩前14天起给与包含5.0g的腰果壳油(含有漆树酸61.8质量％、腰果酚8.2质量％、腰果二酚19.9质量％)的饲料。
需要说明的是，饲料中的粗蛋白质(CP)含量为12％DM以上，中性洗涤纤维(NDF)含量为20％DM以上。
供试牛为雌性的荷尔斯坦因成牛(平均57.5月龄、范围25月龄～90月龄)，是表示肥胖度的体况评分(BCS)显示为3.5～4.0的过肥牛，是胰岛素抵抗性获得风险高的个体。
在分娩前14天、分娩后3天及7天进行采血，测定与胰岛素抵抗性相关的项目和与体内炎症相关的项目。将结果表示于表1中。
[表1]
<结果、考察>
显而易见，在测定值中在分娩后第3天可以观测到差异，给与组中表示胰岛素抵抗性的RQUIKI值显著地高，没有显示出胰岛素抵抗性。
Claims (17)
1.一种反刍动物的胰岛素抵抗性抑制剂，其特征在于，
含有腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
2.根据权利要求1所述的胰岛素抵抗性抑制剂，其中，
反刍动物为牛。
3.根据权利要求1或2所述的胰岛素抵抗性抑制剂，其中，
反刍动物为雌性的反刍动物。
4.根据权利要求3所述的胰岛素抵抗性抑制剂，其中，
雌性的反刍动物为分娩前30天到分娩后30天的雌性的反刍动物。
5.根据权利要求1～4中任一项所述的胰岛素抵抗性抑制剂，其具有将胰岛素抵抗性指标抑制30％以上、并使血中的游离脂肪酸和/或酮体浓度减少的效果。
6.一种反刍动物的胰岛素抵抗性抑制用饲料，其特征在于，
含有腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
7.根据权利要求6所述的饲料，其中，
粗蛋白质即CP的含量为12％DM以上，所述％DM为％干燥质量。
8.根据权利要求6或7所述的饲料，其中，
中性洗涤纤维即NDF的含量为20％DM以上。
9.一种抑制胰岛素抵抗性的方法，其特征在于，
对非人动物施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
10.一种抑制反刍动物的胰岛素抵抗性的方法，其特征在于，
对反刍动物施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
11.根据权利要求10所述的方法，其中，
反刍动物为牛。
12.根据权利要求10或11所述的方法，其中，
反刍动物为雌性的反刍动物。
13.根据权利要求12所述的方法，其中，
在从分娩前30天到分娩后30天的任意时刻施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
14.根据权利要求12所述的方法，其中，
在从分娩前30天到分娩时为止的任意时刻施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
15.根据权利要求10～14中任一项所述的方法，其中，
施用期间至少为14天。
16.根据权利要求10～15中任一项所述的方法，其中，
以0.1g/头/天～50g/头/天施用腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚。
17.腰果壳油、经加热处理的腰果壳油、漆树酸、腰果酚和/或腰果二酚在制造反刍动物的胰岛素抵抗性抑制剂中的应用。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019-199095 | 2019-10-31 | ||
| JP2019199095 | 2019-10-31 | ||
| PCT/JP2020/040763 WO2021085584A1 (ja) | 2019-10-31 | 2020-10-30 | 反芻動物のインスリン抵抗性抑制剤 |
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| EP (1) | EP4052708A4 (zh) |
| JP (1) | JPWO2021085584A1 (zh) |
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| CN (1) | CN114599231A (zh) |
| AR (1) | AR120346A1 (zh) |
| AU (1) | AU2020376624A1 (zh) |
| BR (1) | BR112022008111A8 (zh) |
| CA (1) | CA3159225A1 (zh) |
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| US8349370B2 (en) | 2007-06-08 | 2013-01-08 | National University Corporation Hokkaido University | Bloat controlling agent for a ruminant |
| JPWO2009139468A1 (ja) | 2008-05-16 | 2011-09-22 | 出光興産株式会社 | コクシジウム症防除剤およびそれを含有する飼料 |
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| JP6241000B2 (ja) * | 2012-12-20 | 2017-12-06 | 国立研究開発法人産業技術総合研究所 | 耐糖能異常改善剤 |
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- 2020-10-30 WO PCT/JP2020/040763 patent/WO2021085584A1/ja active Application Filing
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- 2020-10-30 US US17/772,002 patent/US20220370532A1/en active Pending
- 2020-10-30 CN CN202080075548.6A patent/CN114599231A/zh active Pending
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| CA3159225A1 (en) | 2021-05-06 |
| US20220370532A1 (en) | 2022-11-24 |
| BR112022008111A8 (pt) | 2022-12-06 |
| JPWO2021085584A1 (zh) | 2021-05-06 |
| EP4052708A1 (en) | 2022-09-07 |
| AR120346A1 (es) | 2022-02-09 |
| KR20220092505A (ko) | 2022-07-01 |
| BR112022008111A2 (pt) | 2022-07-19 |
| AU2020376624A1 (en) | 2022-05-19 |
| EP4052708A4 (en) | 2023-11-08 |
| WO2021085584A1 (ja) | 2021-05-06 |
| MX2022004965A (es) | 2022-11-07 |
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