CN110709078A - 脑萎缩预防或治疗剂 - Google Patents
脑萎缩预防或治疗剂 Download PDFInfo
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- CN110709078A CN110709078A CN201880035394.0A CN201880035394A CN110709078A CN 110709078 A CN110709078 A CN 110709078A CN 201880035394 A CN201880035394 A CN 201880035394A CN 110709078 A CN110709078 A CN 110709078A
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- alzheimer
- brain atrophy
- dementia
- brain
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Abstract
本发明的课题为提供抑制阿尔茨海默型痴呆进展的药物及抑制阿尔茨海默型痴呆进展的方法。1‑(3‑(2‑(1‑苯并噻吩‑5‑基)乙氧基)丙基)氮杂环丁烷‑3‑醇或其盐具有抑制脑萎缩的效果,可用作脑萎缩的预防或治疗剂。通过施用1‑(3‑(2‑(1‑苯并噻吩‑5‑基)乙氧基)丙基)氮杂环丁烷‑3‑醇或其盐,能够预防或治疗在年龄增长或神经变性疾病等中观察到的脑萎缩。
Description
技术领域
本发明涉及含有1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇或其盐作为活性成分的脑萎缩的预防或治疗剂。
背景技术
痴呆为由于脑的萎缩、脑血管疾病等导致认知功能显著降低的神经变性疾病。痴呆根据原因不同而被分类为若干种,所有痴呆患者中的60%~80%为阿尔茨海默型痴呆(AD)(非专利文献1)。AD的发病机制复杂,认为原因为淀粉样蛋白β蛋白(Aβ)凝聚而形成老年斑、或经磷酸化的Tau蛋白(p-Tau)凝聚而导致神经原纤维变化(非专利文献2)。对AD的患者数量而言,推定在日本为约116万人以上。由于发病率为越至高龄变得越高,因此,预计随着社会的老龄化而今后患者数量急速增大,患者的家属的负担增加,医疗费用及护理费用暴涨(非专利文献3,4)。因此,治疗AD不仅防止患者自身的生活的品质降低,减轻其后家属的负担,对今后的老龄化社会的医疗费用的削减也是重要的。
在痴呆的症状中,存在以认知功能障碍为中心的核心症状、及如具有认知功能障碍的患者与周围发生关系的时候显示出的问题行为的外围症状(非专利文献5)。目前在日本国内使用的AD的治疗药,有作为乙酰胆碱酯酶抑制剂的多奈哌齐盐酸盐、加兰他敏氢溴酸盐、卡巴拉汀及N-甲基-D-天冬氨酸受体拮抗剂的美金刚盐酸盐这4种药物,均能够减轻核心症状或外围症状。但是,这些药物为对核心症状或外围症状进行一定时间改善的对症疗法,并不是抑制AD的神经变性的药物。这些药物即使在使用刚开始时显示出暂时性的认知功能改善效果,一般而言在经过48周以上时,认知功能比治疗前的认知功能更差(非专利文献6)。
已知1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇(以下称为“化合物A”)或其盐具有神经保护作用、神经再生促进作用及轴突生长作用,为作为中枢及外周神经疾病的治疗药有用的化合物(专利文献1)。另外,其给药量被记载为在口服施用的情况下,通常对于成人,可以每1天0.01~500mg以1次~分成多次进行施用(专利文献2)。
现有技术文献
专利文献
专利文献1:国际公开第2003/035647号公报
专利文献2:国际公开第2003/105830号公报
非专利文献
非专利文献1:2012 Alzheimer’s Disease Facts and Figures.(http://www.alz.org/downloads/facts_figures_2012.pdf)
非专利文献2:YAKUGAKU ZASSHI,2010年,第130卷,第4号,521-526页
非专利文献3:日本临床,2008年,第66卷(增刊号1),23-27页
非专利文献4:Seed Planning Press Release(2010年12月28日)(http://www.seedplanning.co.jp/press/2010/2010122801.html)
非专利文献5:临床精神药理,2011年,第14卷,第7号,1123-1129页
非专利文献6:临床精神药理,2012年,第15卷,第3号,311-321页
发明内容
发明所要解决的问题
需要早期开发通过抑制神经变性而抑制AD的进展的药物。本发明的目的是提供用于抑制AD进展的药物及抑制AD进展的方法。
解决问题的方法
在这样的状况下,本发明人发现化合物A或其盐具有抑制脑萎缩的效果,从而完成了本发明。
根据本发明,提供以下发明。
(1)含有化合物A或其盐作为活性成分的脑萎缩预防或治疗剂。
(2)根据(1)所述的脑萎缩预防或治疗剂,其以每次以化合物A计100mg~400mg、1天1次口服施用。
(3)根据(1)所述的脑萎缩预防或治疗剂,其以每次以化合物A计160mg或320mg、1天1次口服施用。
(4)根据(1)~(3)中任一项所述的脑萎缩预防或治疗剂,其用于对患有神经变性疾病的患者施用。
(5)根据(1)~(3)中任一项所述的脑萎缩预防或治疗剂,其用于对患有AD、基本确定的(Probable)AD、存疑的(Possible)AD、处于临床前阶段的(Preclinical)AD、前驱期(Prodromal)阿尔茨海默型痴呆、阿尔茨海默型痴呆所致的轻度认知障碍(AD所致的MCI)或轻度认知障碍(MCI)的患者施用。
(6)根据(1)~(3)中任一项所述的脑萎缩预防或治疗剂,其用于对患有AD、AD所致的MCI或MCI的患者施用。
(7)根据(1)~(3)中任一项所述的脑萎缩预防或治疗剂,其用于对患有AD的患者施用。
(8)根据(1)~(3)中任一项所述的脑萎缩预防或治疗剂,其用于对患有AD所致的MCI的患者施用。
另外,根据本发明也提供以下发明。
(a)含有化合物A或其盐作为活性成分的药物组合物,其用于预防或治疗脑萎缩。
(b)用于在脑萎缩的预防或治疗中使用的化合物A或其盐。
(c)预防或治疗脑萎缩的方法,包括向患者施用化合物A或其盐。
(d)化合物A或其盐用于制造脑萎缩预防或治疗剂的用途。
(e)脑萎缩抑制剂,其含有化合物A或其盐作为活性成分。
(f)用于在脑萎缩的抑制中使用的化合物A或其盐。
(g)对患者施用化合物A或其盐而抑制脑萎缩的方法。
(h)化合物A或其盐用于制造脑萎缩抑制剂的用途。
发明的效果
通过施用化合物A或其盐,可以预防或治疗在年龄增长或AD、进行性核上性麻痹及额颞叶痴呆等神经变性疾病中观察到的脑萎缩。
附图说明
[图1]示出来自试验例1的52周的筛选的脑体积(全脑)的变化的图。“n.s.”指统计学上没有有意义的差异。
[图2]示出来自试验例1的52周的筛选的脑体积(海马)的变化的图。“n.s.”指统计学上没有有意义的差异。
[图3]示出来自试验例2的52周中的筛选的脑体积(全脑)的变化的图。
[图4]示出来自试验例2的52周中的筛选的脑体积(海马)的变化的图。
具体实施方式
以下对本发明进行详细说明。
在本说明书中,如果没有特指,则各术语具有以下含义。
在本说明书中使用“~”示出的数值范围,意味着将“~”的前后记载的数值分别作为最小值及最大值而包含的范围。
化合物A是指1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇。
作为化合物A的盐,可列举通常已知的氨基等碱性基团或羟基或者羧基等酸性基团的盐。
作为碱性基团的盐,可列举例如:与盐酸、氢溴酸、硝酸及硫酸等无机酸的盐;与甲酸、乙酸、柠檬酸、乙二酸、富马酸、马来酸、琥珀酸、苹果酸、酒石酸、天冬氨酸、三氯乙酸及三氟乙酸等有机羧酸的盐;以及与甲磺酸、苯磺酸、对甲苯磺酸、均三甲苯磺酸及萘磺酸等磺酸的盐。
作为酸性基团的盐,可列举例如:与钠及钾等碱金属的盐;与钙及镁等碱土金属的盐;铵盐;以及与三甲胺、三乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二乙胺、二环己胺、普鲁卡因、二苄胺、N-苄基-β-苯乙胺、1-二苯羟甲胺及N,N′-二苄基乙二胺等含氮有机碱的盐等。
在上述盐中,作为优选的盐,可列举药理学上允许的盐,作为更优选的盐,可列举与马来酸的盐。
在化合物A或其盐中,在存在异构体(例如,光学异构体、几何异构体及互变异构体等)的情况下,本发明包括它们的全部异构体,另外,包括水合物、溶剂合物及全部晶形。
预防是指防止特定的疾病或由该疾病产生的1个以上的症状的发病。
治疗是指对于对象罹患的特定的疾病,减轻或改善由该疾病产生的1个以上的症状,以及延迟该疾病的进展。
在本发明的实施方式中,例如,在患有神经变性疾病等疾病的患者中,预防是指阻止或者延迟脑萎缩的产生或进展。治疗是指阻止或延迟脑萎缩的进展。
轻度~中度AD为,依照国立神经疾病脑卒中研究所/阿尔茨海默病相关疾病协会(National Institute of Neurological and Communicative Disorders and Stroke/the Alzheimer‘s Disease and Related Disorders Associations)(NINCDS-ADRDA)的诊断基准能够临床诊断为“基本确定的(probable)阿尔茨海默病”。
对“轻度~中度”的诊断而言,使用标准的基准,普通医生能够足以进行。例如,参考标准化的简易精神状态检查(Mini-Mental State Examination)(MMSE;0~30分的打分)的数值,临床诊断轻度~中度、中度、及中度~重度AD。MMSE(Folstein,Folstein andMcHugh,1975)为基于对患者的询问法的简便的认知功能检查。对于定向力、记忆、计算、注意力,语言功能等进行评价。合计打分为30分,得分越低,认知功能的障碍的程度越高。
在本发明的试验例中,将在试验开始(筛选)时间点的MMSE打分为12~22的患者定义为轻度~中度AD。需要说明的是,应该注意MMSE不是用于临床诊断AD的等级的唯一方法,而是简单的方法。
载脂蛋白E(ApoE)为构成脂蛋白,参与脂蛋白的识别及脂质代谢的载脂蛋白之一。在ApoE中存在ApoE2、ApoE3及ApoE4这3个亚型,报告称编码ApoE4的ApoE4基因型与脑内的淀粉样蛋白β蛋白的沉积量相关,及ApoE4基因型为阿尔茨海默病的风险基因。
脑的结构变化虽然在正常的老化中也可以观察到,但由于神经变性疾病的发病而加速。在本发明的实施方式中,作为神经变性疾病,可列举例如:AD、基本确定的AD、存疑的AD、处于临床前阶段的AD、前驱期AD、AD所致的MCI、MCI、进展性核上性麻痹及额颞叶痴呆等,优选可列举AD、基本确定的AD、存疑的AD、处于临床前阶段的AD、前驱期AD、AD所致的MCI及MCI,更优选可列举AD、AD所致的MCI及MCI,进一步优选可列举AD及AD所致的MCI。需要说明的是,对于基本确定的AD、存疑的AD、处于临床前阶段的AD、前驱期AD及AD所致的MCI的诊断,记载于Alzheimers Dement,2011年5月,第7卷,第3号,第263~292页。
在AD中的脑的萎缩,发生从嗅觉皮层开始的神经元及突触的丧失。之后,病变扩展到包含海马形成的颞叶的边缘区域整体,神经元的丧失及萎缩在颞叶、顶叶及额叶的新皮层相关区域的全部中可观察到。
容积磁共振成像(Volumetric MRI(vMRI))能够实现脑结构体积的体内评价,提供萎缩速度的量度。vMRI研究结果提示能够将反映AD病理学进展的脑萎缩的模式与时间的经过一起进行切实地检测,进行追踪(Atiya et al.2003)。根据AD的vMRI研究,长期报告了包含海马及嗅觉皮层的内颞叶的萎缩(Jack et a1.1997)。根据vMRI得到的海马的体积,与组织学的海马的体积、神经元的丧失及AD的程度相关(Jack et al.2002),认为嗅觉皮层的厚度的变化为与AD相关的神经变性的早期且敏感的指标(Knight et al.2009;Holland etal.2009)。局部及全脑容积变化的纵向的vMRI测定,在不受暂时性的症状的改善的影响的方面补全了认知评价,提供对于基于AD的萎缩造成影响的药物的能力的早期指标。
本发明中使用的化合物A或其盐可以通过本身公知的方法或将它们适当组合,以及专利文献1中记载的方法而制造。
本发明中使用的化合物A或其盐可以配合:赋形剂、粘合剂、崩解剂、崩解抑制剂、防结块及粘连剂、润滑剂、吸收·吸附载体、溶剂、增量剂、等渗剂、助溶剂、乳化剂、悬浮剂、增稠剂、包衣剂、吸收促进剂、凝胶化·凝固促进剂、光稳定剂、保存剂、防潮剂、乳化·悬浊·分散稳定剂、防着色剂、脱氧·抗氧化剂、矫味·矫臭剂、着色剂、起泡剂、消泡剂、安抚剂、抗静电剂、缓冲·pH调节剂等各种药物添加物,而制成口服制剂(片剂、胶囊剂、散剂、颗粒剂、细粒剂、丸剂、悬浮剂、乳剂、液剂、糖浆剂等)、注射剂、滴眼剂、经鼻剂或透皮剂等药物制剂。需要说明的是,作为患有AD的患者中的口服施用制剂优选为片剂。
上述药物利用通常的方法制成制剂。
对化合物A的施用方法没有特别限定,根据制剂的形态、患者的年龄、性别、其它条件,患者的症状的程度而适当确定。
化合物A的给药量根据用法、患者的年龄、性别、疾病的形态、其它条件等而适当选择。
通常,对于成人,可以将以化合物A计1天40~500mg以1次~分成多次进行施用,更优选可以将以化合物A计1天100~400mg以1次~分成多次进行施用,进一步优选可以将以化合物A计1天160mg或320mg以1次进行施用。
在本发明中,化合物A或其盐的施用可以进一步包括基于乙酰胆碱酯酶抑制剂(AChEI)的施用的预防或治疗。作为AChEI,可列举:盐酸多奈哌齐、盐酸加兰他敏、酒石酸卡巴拉汀或盐酸他克林等。
在本发明中,对象可以在化合物A或其盐的施用前接受至少6个月期间的基于AChEI的施用的预备或治疗。
下面,通过试验例及制剂例说明本发明,但本发明并不限于这些。
作为试验化合物,使用了化合物A的马来酸盐。
试验例1在轻度到中度AD患者中的评价化合物A的有效性及安全性的II期多中心随机化双盲安慰剂对照试验
对象(选择基准):从临床试验药物设计安排的42天前至进行设计安排时,基于下述选择基准进行了患者的筛选。
·获得筛选的同意时为55岁以上且85岁以下,且为基本确定的(probable)AD的患者
·筛选时的MMSE打分为12~22的患者
·修改的Hachinski缺血量表(Modified Hachinski Ischemia Scale)打分为4以下的患者
·在基线前至少4个月期间及在基线前3个月期间以稳定的给药量,通过多奈哌齐盐酸盐或卡巴拉汀经皮系统接受了治疗的患者
·对于除了多奈哌齐盐酸盐或卡巴拉汀经皮系统以外还施用了美金刚的患者,在基线前至少4个月期间及在基线前3个月期间以稳定的给药量接受了美金刚的治疗的患者
·筛选时的脑MRI或CT与AD一致的患者
组的构成:将适合上述的患者(484名)随机分为下述3组,开始了试验。
(1)高用量施用组:224mg试验化合物(以化合物A计160mg)进行了1天1次口服施用4周之后,将448mg试验化合物(以化合物A计320mg)进行1天1次口服施用48周(158名)
(2)低用量施用组:224mg试验化合物(以化合物A计160mg)进行1天1次口服施用52周(166名)
(3)安慰剂施用组:将安慰剂进行1天1次口服施用52周(158名)
评价方法:
容积磁共振成像(Volumetric MRI)
在筛选及52周后利用vMRI扫描测定了对象的脑体积,将每个对象的全脑(全部脑)及海马的体积变化进行定量,根据从筛选起的变化而对脑的萎缩进行了评价。
另外,每个对象的全脑及101个区域(布罗德曼的脑图(1~52)中,在左脑及右脑中各个存在的区域分开而分成101个区域)的体积变化进行定量,根据从筛选起的变化而对脑的萎缩进行了评价。
统计分析:
将52周之后的全脑及海马体积的从基线的变化利用混合效应模型(Mixed-effectModel),在高用量施用组和安慰剂组,及低用量施用组和安慰剂施用之间进行了组间比较。在模型中,将施用组以固定效果、年龄、各脑体积(全部脑或海马)的基线,MMSE的基线及ApoE4基因型(阳性/阴性)作为协变量,包括临床试验实施设施作为变量效果。
另外,将52周之后的全脑及101个区域的各体积的从基线的变化,在高用量施用组和安慰剂组,及低用量施用组和安慰剂施用之间进行了组间比较。
结果:如下所示。
将来自在52周的筛选的基于vMRI扫描的脑体积的变化示于表1、图1及图2。
[表1]
对于来自52周的筛选的全部脑及海马体积的变化,与安慰剂施用组相比,在化合物A施用组中确认了体积的减少较少的倾向。对于相对于化合物A低用量施用组和安慰剂施用组的海马体积变化的效果的差为统计学有意义。
对于来自52周的筛选的基于vMRI扫描的各脑体积的变化,将在试验化合物的低用量施用组和安慰剂施用组的组间比较中,存在统计学有意义的差异的区域(P值<0.05)的结果示于表2。
[表2]
在对全部脑及101个区域逐个进行了分析的结果中,也确认了与安慰剂施用组相比,在化合物A的低用量施用组中全脑及海马的体积减少被抑制的倾向(表2的编号6及14)。
另外,在化合物A的高用量施用组中,也确认了与低用量施用组相同的倾向。
试验例2在轻度到中度AD患者中的评价化合物A的有效性及安全性的前期临床II期多中心随机化双盲安慰剂对照试验
从临床试验药物设计安排28天前至进行设计安排时,基于下述选择基准进行了患者的筛选。将适合的患者(373名)随机分为下述2组,开始了试验。
对象(选择基准):
·获得筛选的同意时为50岁以上且90岁以下,且为基本确定的(probable)AD的患者
·筛选时的MMSE打分为15~24的患者
·修改的Hachinski缺血量表(Modified Hachinski Ischemia Scale)打分为4以下的患者
·在基线前至少6个月期间及在基线前3个月期间以稳定的给药量,接受多奈哌齐盐酸盐治疗的患者
·筛选时的脑MRI或CT与AD一致的患者
组的构成:
(1)真药施用组:224mg的试验化合物(以化合物A计160mg)以1天1次口服施用52周(176名)
(2)安慰剂施用组:安慰剂以1天1次口服施用52周(178名)
评价方法:
容积磁共振成像(Volumetric MRI)
在筛选及52周后利用vMRI扫描测定了对象的脑体积,将每个对象的全脑及海马的体积变化进行定量,根据从筛选起的变化而对脑的萎缩进行了评价。
统计分析:
算出了52周之后的全脑及海马体积的从基线的变化量的平均值、标准偏差及与安慰剂施用组的差。
结果:如下所示。
将来自在52周的筛选的基于vMRI扫描的脑体积的变化示于表3、图3及图4。
[表3]
对于来自52周的筛选的全部脑及海马体积的变化,与安慰剂施用组相比,在化合物A施用组中确认到了体积的减少较少的倾向。
制剂例1
在化合物A的马来酸盐174.03g中加入硬脂酸镁(硬脂酸镁,默克)0.9726g,混合了30分钟。将该混合粉末利用干式造粒机(TF-LABO(辊加压3MPa),Freund产业)压缩成形,对成形而成的固态物进行整粒。向得到的整粒粉末60.0g中,分别利用网眼850μm的筛过筛而加入乳糖(Flowlac90,Meggle Japan)49.51g,结晶纤维素(Ceolus PH302,旭化成chemicals)16.50g及交联羧甲纤维素钠(primellose,DMV Japan)6.67g,混合了10分钟。向该混合粉末中加入硬脂酸镁0.6667g,混合了30分钟。将该混合粉末使用片剂径8.5mm的双弧面的杵,在压片压约12kN下,利用压片机(HT-P18A,畑铁工所)进行压片,得到了250mg 1片的圆形裸片。利用包衣机:DRC-200(powrex)对裸片以包衣剂每1片8mg的比例进行包衣后,添加微量的棕榈蜡(抛光蜡-105,日本Wax),得到了薄膜衣片(film coating tablet)。
制剂例2
向化合物A的马来酸盐53.70g中加入甘露醇(Parteck M200,默克)60.90g及交联羧甲纤维素钠3.60g,混合了10分钟。向该混合粉末中加入硬脂酸镁1.80g,混合了30分钟。将该混合粉末使用片剂径8.5mm的双弧面的杵,在压片压约10kN条件压片,得到了250mg 1片的圆形的裸片。对裸片将包衣剂(欧巴代03F44057,00F440000(羟丙甲纤维素2910:71.5%、PEG 6000:14.166%、滑石:7.167%、氧化钛:7.067%、氧化铁:0.1%),日本卡乐康)以每1片8mg的比例包衣之后,添加微量的棕榈蜡,得到了薄膜衣片。
制剂例3
向化合物A的马来酸盐1988.89g中加入硬脂酸镁11.11g,混合了30分钟。将该混合粉末利用干式造粒机压缩成形,对成形的固态物进行整粒。向得到的整粒粉末107.13g中加入甘露醇26.21g、乙基纤维素(ETHOCEL100FP premium,Dow Chemical)7.50g、结晶纤维素(ceolus KG-1000,旭化成Chemicals)3.75g、交联聚维酮(Kollidon CL-SF,BASF)3.75g及交联羧甲纤维素钠0.75g,混合了30分钟。向该混合粉末中加入硬脂酸镁0.90g,混合了5分钟。将该混合粉末使用片剂径8.5mm的双弧面的杵,在压片压约7kN条件压片,得到了315mg1片的圆形的裸片。对裸片将包衣剂以每1片9mg的比例进行包衣后,添加微量的棕榈蜡,得到了薄膜衣片。
Claims (8)
1.脑萎缩预防或治疗剂,其含有1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇或其盐作为活性成分。
2.根据权利要求1所述的脑萎缩预防或治疗剂,其以每次以1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇计100mg~400mg、1天1次口服施用。
3.根据权利要求1所述的脑萎缩预防或治疗剂,其以每次以1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇计160mg或320mg、1天1次口服施用。
4.根据权利要求1~3中任一项所述的脑萎缩预防或治疗剂,其用于对患有神经变性疾病的患者施用。
5.根据权利要求1~3中任一项所述的脑萎缩预防或治疗剂,其用于对患有阿尔茨海默型痴呆、基本确定的(Probable)阿尔茨海默型痴呆、存疑的(Possible)阿尔茨海默型痴呆、处于临床前阶段(Preclinical)的阿尔茨海默型痴呆、前驱期(Prodromal)阿尔茨海默型痴呆、阿尔茨海默型痴呆所致的轻度认知障碍(AD所致的MCI)或轻度认知障碍的患者施用。
6.根据权利要求1~3中任一项所述的脑萎缩预防或治疗剂,其用于对患有阿尔茨海默型痴呆、阿尔茨海默型痴呆所致的轻度认知障碍(AD所致的MCI)或轻度认知障碍的患者施用。
7.根据权利要求1~3中任一项所述的脑萎缩预防或治疗剂,其用于对患有阿尔茨海默型痴呆的患者施用。
8.根据权利要求1~3中任一项所述的脑萎缩预防或治疗剂,其用于对患有阿尔茨海默型痴呆所致的轻度认知障碍(AD所致的MCI)的患者施用。
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CN116473962A (zh) | 2023-07-25 |
IL270922A (en) | 2020-01-30 |
RU2019138166A (ru) | 2021-07-09 |
BR112019024851A2 (pt) | 2020-06-09 |
MX2019014310A (es) | 2022-06-10 |
AU2018276638B2 (en) | 2021-04-08 |
EP3632431A1 (en) | 2020-04-08 |
RU2019138166A3 (zh) | 2021-07-09 |
CA3067453C (en) | 2021-11-23 |
NZ759585A (en) | 2022-02-25 |
EP3632431A4 (en) | 2020-06-03 |
KR20190137936A (ko) | 2019-12-11 |
JP2023053337A (ja) | 2023-04-12 |
WO2018221729A1 (ja) | 2018-12-06 |
CN116492335A (zh) | 2023-07-28 |
RU2759727C2 (ru) | 2021-11-17 |
AU2018276638A1 (en) | 2019-12-19 |
US20200215030A1 (en) | 2020-07-09 |
SG11201911512SA (en) | 2020-01-30 |
US11951092B2 (en) | 2024-04-09 |
JPWO2018221729A1 (ja) | 2020-04-09 |
JP7282028B2 (ja) | 2023-05-26 |
CA3067453A1 (en) | 2018-12-06 |
ZA201907973B (en) | 2022-03-30 |
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