CN110279845B - 记忆力、学习力、认知力提高用组合物 - Google Patents
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Abstract
本发明涉及记忆力、学习力、认知力提高用组合物，确认到本发明的C末端部以GAG结束的肽的记忆力具有改善效果，并确认到为了使肽具有效果，肽的长度需要至少由4个以上的氨基酸构成，并且，确认到C末端部以GAG结束的肽的长度由5个至9个以内的氨基酸构成的肽也具有相同的效果，由此将本发明的肽可用作记忆力、学习力、认知力提高用组合物。
Description
本申请是申请日为2016年5月3日、题为《记忆力、学习力、认知力提高用组合物》的中国发明专利申请201680013706.9的分案申请。
技术领域
本发明涉及记忆力、学习力、认知力提高用组合物。
背景技术
大脑具有的功能具有很多种，但是最为重要的应该是记忆及认知。在对于人类没有认知能力及记忆能力的情况下，难以进行日常生活且生存也成为问题。记忆及认知几乎与大脑的所有功能相关，与记忆及认知有关的大脑结构物为各种各样的，几乎与所有大脑部分密切相关。
记忆的阶段分为以下几种，包括注册信息并进行符号化的过程、储存过程、接近记忆的场所进行提取的过程。
符号化是指通过感觉器官来学习并记忆由大脑进入的信息的第一过程。通过符号化先储存信息，但为了继续维持所储存的信息并储存为更加明确的记忆，必须经过符号化后的过程，将此过程称为凝固化过程。若记忆没有好好凝固化，则可能会很快地发生记忆的遗忘，难以维持记忆。提取是指有意识地唤起长期储存的内容的过程。提取方法有回忆和再认。回忆是指有意识地唤起记忆的内容，再认是指通过暗示来唤起的。在大部分的情况下，回忆比再认难。但是，如前额叶损伤患者或皮质下血管痴呆，即使难以回忆，但存在擅长再认的情况，在此情况下，记忆的符号化和储存得好，但是意味着具有提取障碍。在具有记忆储存障碍的情况下，回忆和再认同时出现障碍。
并且，短期记忆也称为工作记忆，是指短期储存信息后利用此来可执行下一项任务的过程。从大脑进入的信息留在长期记忆之前暂时停留。工作记忆的特征在于，在执行特定的任务之后，则普通工作记忆会被删掉。
长期记忆是指学习新事物并过一段时间后可以再次进行记忆。时间流逝后再次记起我们在日常生活中所经历的事或所学习的多个内容大部分属于长期记忆。
记忆和认知的障碍为不能进行日常生活的一种非常严重的疾病，是基于老化、阿尔茨海默氏症、精神分裂症、帕金森氏病、亨廷顿氏病、匹克氏病、克罗伊茨费尔特-雅各布病、抑郁症、老化、头部外伤、腦卒中、中枢神经系统(CNS)低氧症、脑缺血症、脑炎、健忘症、创伤性脑损伤、低血糖症、韦尼克-科尔萨科夫综合征、药物中毒、癫痫、羊癫风、海马硬化症、头痛、脑衰老症、痴呆、额颞叶变性、肿瘤、正常压力脑积水、艾滋病(HIV)、脑血管疾病、脑神经疾病、心血管类疾病、遗忘症、辐射暴露、代谢性疾病、甲状腺功能减退症、轻度认知障碍、认知缺陷或注意力缺陷等多种原因及机制发病的疾病。为了解决这种记忆及认知障碍，现有技术已做出多种努力，但目前为止，实际上对于不仅以多种脑神经疾病为对象具有突出的神经保护疗效和脑功能提高效果的物质，而且对于具有正确的序列的合成肽的疗效报告及适用也不存在。
发明内容
技术问题
本发明基于上述必要性而提出的，本发明的目的在于提供记忆力、学习力、认知力提高用肽。
解决问题的方案
为了实现上述目的，本发明提供包含C末端部位包含GAG的氨基酸序列的肽。
在本发明的一实例中，上述肽优选为来源于作为丝素蛋白的水解产物，但并不限定于此。
在本发明的再一实例中，上述肽优选为人工合成的，但并不限定于此。
在本发明的另一实例中，上述肽的氨基酸残基数优选为4至6，但并不限定于此长度，上述肽的氨基酸序列优选为GGAG、AGAG、QGAG或SGAGAG，但并不限定于此氨基酸序列。
在本发明的还有一实例中，上述肽的氨基酸残基数优选为5至9，且上述肽的氨基酸序列优选为QAGAG、SGGAG或GAGGAGGAG，但并不限定于此。
本发明的肽其本身具有优秀的稳定性，但为了进一步提高稳定性，可与多种保护基(protection group)相结合。保护基的例包括氨基酸，乙酰基，芴基甲氧基羰基，甲酰基，十六烷酰基，十四烷基，十八烷基及聚乙二醇(PEG)。上述保护基可与本发明的肽的多种氨基酸残基相结合，但是优选地与N-或C-末端相结合。
本发明提供包含本发明的上述肽作为有效成分的用于记忆、认知或学习障碍的预防或治疗的药学组合物。
在本发明的一实例中，上述记忆、认知或学习障碍优选为基于老化、阿尔茨海默氏症、精神分裂症、帕金森氏病、亨廷顿氏病、匹克氏病、克罗伊茨费尔特-雅各布病、抑郁症、老化、头部外伤、腦卒中、中枢神经系统低氧症、脑缺血症、脑炎、健忘症、创伤性脑损伤、低血糖症、韦尼克-科尔萨科夫综合征、药物中毒、癫痫、羊癫风、海马硬化症、头痛、脑衰老症、痴呆、额颞叶变性、肿瘤、正常压力脑积水、艾滋病、脑血管疾病、脑神经疾病、心血管类疾病、遗忘症、辐射暴露、代谢性疾病、甲状腺功能减退症、轻度认知障碍、认知缺陷及注意力缺陷的记忆、认知或学习障碍，但并不限定于此。
上述组合物可包含药学上可接受的载体。包含在上述组合物的药学上可接受的载体为通常利用在制剂，包含乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油等，但并不限定于此。上述药学组合物除了包含上述成分之外，还可包含润滑剂、湿润剂、甜味剂、调味剂、乳化剂、悬浮剂、保存剂等。
可以将上述药学组合物口服或非口服方式给药。在非口服给药的情况下，可以以静脉内注入、皮下注入、肌肉注入、腹腔注入、内皮给药、局部给药、鼻内给药、肺内给药及直肠给药等方式给药。
当口服给药时，由于蛋白质或肽被消化，因此可对口服用组合物进行剂型化，以使涂敷活性药剂或保护胃中的分解。并且，上述组合物可借助活性物质向靶细胞移动的任何装置来进行给药。
上述药学组合物的合适的给药量可根据如制剂化方法、给药方式、患者的年龄、体重、性别、病态、饮食、给药时间、给药途径、排泄速度及反应感应性等的要素来开多种处方。以成人为基准，上述组合物的优选给药量在0.001～100㎎/kg的范围内。术语“药学有效量”是指用于预防或治疗记忆障碍、认知障碍或学习障碍的充足的量。
根据本领域的技术人员可容易实施的方法，对上述组合物利用药学上可接受的载体和/或赋形剂进行制剂化，从而可制备成单位用量形态或注入多用量容器内来进行制备。此时，剂型可以是油或水性介质中的溶剂、悬浮液、糖浆剂或乳化剂形态或者也可以是浸膏剂、散剂、粉末剂、颗粒剂、片剂或胶囊剂形态，还可包含分散剂或稳定化剂。并且，上述组合物可以作为单独治疗剂来进行给药或与其他治疗剂联用来进行给药，可以与现有的治疗剂依次或同时给药。
并且，本发明提供包含上述本发明的肽作为有效成分的、用于提高大脑或认知功能的食品组合物。
在本发明的一实例中，上述大脑或认知功能优选为学习能力、记忆能力或集中力，但并不限定于此。
本发明的食品或饮料中的上述肽的添加量可为总食品重量的0.01重量百分比至15重量百分比，健康饮料组合物可以以100ml为基准添加0.02g至5g，优选地，以0.3g至1g的比率添加，或者可由本领域的技术人员容易地确定以使符合产品。
上述食品组合物除了包含上述肽之外，还可包含食品学上可接受的食品辅助添加剂，可制备成片剂、胶囊剂、丸剂、液剂、凝胶剂、粉末剂、颗粒剂等的形态。
本发明的食品组合物作为必须成分除了包含上述肽之外，对于其他成分没有特别限制，如普通的饮料，可包含各种调味剂或天然碳水化物等作为附加成分。所述的天然碳水化物的例有单糖，例如，葡萄糖、果糖等；二糖，例如，麦芽糖、蔗糖等；及多糖，例如，糊精、环糊精等的通常的糖及木糖醇、山梨糖醇、赤藓糖醇等的糖醇。作为除了如上所述的成分之外的调味剂，可有效使用天然调味剂(索马甜，甜菊提取物(例如，甜叶菊甙A、甘草甜素等))及合成调味剂(糖精、阿斯巴甜等)。上述天然碳水化物的比率以每100ml的本发明的组合物为通常为约1g至20g，优选地，为约5g至12g。
本发明的食品组合物除了上述成分之外可包含各种营养剂、维生素、矿物(电解质)、合成风味剂及天然风味剂等的风味剂、着色剂及填充剂(奶酪、巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定化剂、防腐剂、甘油、酒精、使用于碳酸饮料的碳酸化剂等。除此之外，本发明的食品组合物可包含用于制备天然果汁及果汁饮料的果肉。可单独或组合使用这种成分。这种添加剂的比率通常对每100重量份的本发明的化合物选自0重量份至约20重量份的范围内。
并且，本发明提供编码上述本发明的肽的多核苷酸。
上述“多核苷酸(polynucleotide)”为以单链或双链形态存在的脱氧核糖核酸核苷酸或核糖核苷酸的聚合物。包括RNA基因组序列、DNA(gDNA及cDNA)及由此转录的RNA序列，没有特别说明时，包括天然的多核苷酸的类似物。
上述多核苷酸不仅包括上述核苷酸序列，还包括互补(compleme ntary)序列。上述互补序列不仅包括完全互补的序列，而且还包括实质上互补的序列。这在被技术领域中所公知的严格条件(stringent con ditions)下，是指可与上述核苷酸序列杂交的序列。
并且，上述多核苷酸可变形。上述变形包括核苷酸的添加、缺失或非保存性置换或保存性置换。将编码上述氨基酸序列的多核苷酸解释成还包含对于上述核苷酸序列显示实质性的相同性的核苷酸序列。上述实质上的相同性，可以是以最好相对应的方式对准上述核苷酸序列和任何其他序列，在利用本技术领域中所利用的算法分析所对准的序列的情况下，可为最少具有80％的同源性、最少具有90％的同源性或最少具有95％的同源性的序列。
并且，本发明提供包含上述本发明的多核苷酸的重组载体。
术语“载体(vector)”是指在宿主细胞中用于表达目的基因的方式。例如，包括病毒载体，如质粒载体、黏粒载体及噬菌体载体、腺病毒载体、逆转录病毒载体及腺相关病毒载体。可通过操作在本技术领域中往往使用的质粒(例如，pSC101、pGV1106、pACYC177、ColE1、pKT230、pME290、pBR322、pUC8/9、pUC6、pBD9、pHC79、pIJ61、pLAFR1、pHV14、pGEX系列、pET系列及pUC19等)、噬菌体(例如，λgt4λB、λ-Charon、λΔz1及M13等)或病毒(例如，CMV、SV40等)来制备可用作上述重组载体的载体。
在上述重组载体中，编码上述肽的多核苷酸可与启动子有效连接。
术语“有效连接(operatively linked)”是指核苷酸表达调节序列(例如，启动子序列)与其他核苷酸序列之间的功能性的结合。所以，由此上述调节序列可调节上述其他核苷酸序列的转录和/或翻译。
上述重组载体可构建成用于典型克隆的载体或用于表达的载体。作为上述用于表达的载体，可使用在本技术领域中在植物、动物或微生物中表达外来的蛋白质所使用的普通的载体。上述重组载体可通过在本技术领域中所公知的多种方法来进行构建。
上述重组载体可以以原核细胞或真核细胞为宿主进行构建。例如，所使用的载体为表达载体，在以原核细胞为宿主的情况下，通常包含可进行转录的强力的启动子(例如，pLλ启动子、trp启动子，lac启动子、tac启动子、T7启动子等)、用于开始翻译的核糖体结合位置及转录/翻译终止序列。在以真核细胞为宿主的情况下，在真核细胞中启动的复制起点包括f1复制起点、SV40复制起点、pMB1复制起点、腺病毒复制起点、AAV复制起点、CMV复制起点及BBV复制起点等，但并不限定于此。并且，可利用来源于哺乳动物细胞基因组的启动子(例如，金属硫蛋白启动子)或来源于哺乳动物病毒的启动子(例如，腺病毒病毒后期启动子、牛痘病毒7.5K启动子、SV40启动子、巨细胞病毒(CMV)启动子及单纯疱疹病毒(HSV)的tk启动子)，作为转录终止序列，通常具有聚腺苷酸化序列。
并且，本发明提供转化为上述本发明的重组载体的宿主细胞。
作为本发明的宿主细胞，可使用在本技术领域中所公知的任何宿主细胞，作为原核细胞，如E.coli JM109、E.coli BL21、E.coli RR1、E.coli LE392、E.coli B、E.coli X1776、E.coli W3110、枯草芽孢杆菌、苏云金杆菌等芽孢杆菌属菌株、如鼠伤寒沙门氏菌、灵杆菌及多种假单胞菌种等肠内菌科菌株等，在对真核细胞进行转化的情况下，作为宿主细胞，可利用酵母(酿酒酵母(Saccharomyce cerevisiae))、昆虫细胞、植物细胞及动物细胞，例如，SP2/0、中国仓鼠卵巢(Chinese hamster ovary，CHO)K1、CHO DG44、PER.C6、W138、BHK、COS-7、293、HepG2、Huh7、3T3、RIN及MDCK细胞株等。
并且，本发明提供本发明的肽的制备方法，包括培养上述本发明的宿主细胞的步骤。
可使用在本技术领域中众所周知的插入方法来向宿主细胞内插入上述多核苷酸或包含其的重组载体。在上述运输方法中，例如，在宿主细胞为原核细胞的情况下，可使用CaCl2方法或电穿孔法等，在宿主细胞为真核细胞的情况下，可使用微注入法、磷酸钙沉淀法、电穿孔法、脂质体介导转染法及基因枪法等，但并不限定于此。
可通过利用借助选择标记来表达的表达型，并根据本技术领域中众所周知的方法容易地实施筛选被转化的宿主细胞的上述方法。例如，在上述选择标记为特定抗生素耐性基因的情况下，可通过在含有上述抗生素的培养基中培养转化体来容易筛选出转化体。
发明的效果
通过本发明可知，确认到C末端部以GAG结束的肽的记忆力具有改善效果，并确认到为了使肽具有效果，肽的长度需要至少由4个以上的氨基酸构成，并且，确认到C末端部以GAG结束的肽的长度由5个至9个以内的氨基酸构成的肽也具有相同的效果，由此将本发明的肽可用作记忆力、学习力、认知力提高用组合物。
附图说明
图1为通过被动回避实验来示出C末端部位的氨基酸序列具有提高作为GAG的肽的记忆力的效果的图，y轴为时间(秒钟)。
图2为通过Y迷宫实验示出C末端部位的氨基酸序列具有提高作为GAG的肽的记忆力的效果的图，y轴为自发更迭(％)。
图3为通过被动回避实验示出由5～9个氨基酸构成的C末端部位的氨基酸序列具有提高作为GAG的肽的记忆力的效果的图。
图4为通过Y迷宫实验示出由5～9个氨基酸构成的C末端部位的氨基酸序列具有提高作为GAG的肽的记忆力的效果的图。
具体实施方式
以下，通过本发明实施例进行详细说明。但是，这些实施例仅用于例示性地说明本发明，而本发明的范围并不限定于此。
实施例1：肽的合成
所合成的肽从金斯瑞(Genscript)(美国新泽西州(New Jersey，USA))获取。利用柔性肽技术(Flexpeptide technology)方法来合成肽，并利用高效液相色谱及质量分析仪来确认。所合成的肽的氨基酸序列如以下表1所示。
表1
并且，本发明人进一步合成氨基酸序列5个至9个的肽(序列7至9)来进行额外实验。这些所合成的肽从金斯瑞(美国新泽西州)获取。利用柔性肽技术方法来合成肽，并利用高效液相色谱及质量分析机来确认。所合成的肽的氨基酸序列如下：
QAGAG(序列7)，
SGGAG(序列8)，
GAGGAGGAG(序列9)。
实施例2：试剂及动物
东莨菪碱(Scopolamine)购自西格玛奥德里奇(Sigma-Aldrich)(美国密苏里州圣路易斯市(St.Louis，MO，USA))。4周龄的雄性ICR小鼠购自韩国百聯公司(Korean BioLinkCo.)(韩国忠清北道(Chungbuk，Korea))。经过1周的适应期间后，使用于实验，所有试剂向腹腔内给药。借助在测试30分钟前的东莨菪碱的注入来诱导记忆障碍，在注入东莨菪碱30分钟前注入所合成的肽。
实施例3：确认被动回避反应测试(Passive Avoidance Test)中的肽的效果
被动回避反应测试在相同的亮的房间及暗的房间执行。各房间的地面以2mm的不锈钢棒以1cm的间距相隔的形态形成。亮的房间(20×20×20cm)具有100W的灯泡。这些房间与断头台门(guillotine door)相连接。
为了采集试验(acquisition trial)，向小鼠注入试剂后置于亮的房间并在10秒钟后敞开门。当小鼠完全进入暗的房间时，关门并进行3秒钟的电击。在采集试验24小时后执行保留试验(retention trial)，将小鼠置于亮的房间。采集试验及保留试验的反应时间(Latency time)以在门敞开后直到进入箱子的暗的房间时的时间测定。
在被动回避反应测试中的保留反应(Retention latency)在啮齿类动物中示出长期记忆功能。由此，利用逐步被动回避测试(step-through passive avoidance test)来确认对东莨菪碱-诱导记忆损伤的作为丝素蛋白的肽的效果，其结果如图1所示。
如图1所示，在保留试验中，生理食盐水处理小鼠的反应时间为180秒(最大的截止时间)。与生理食盐水组相比，确认因东莨菪碱的注入而记忆力下降的东莨菪碱-注入组的逐步反应的平均明显下降。在给药东莨菪碱之前给药合成肽的组中，与东莨菪碱给药组相比，在由2个氨基酸组成的肽-1给药组中具有一定的改善，与东莨菪碱给药组相比，在肽-3给药组中，几乎没有效果。但是，在肽-2及肽-4至6给药组中，确认将因东莨菪碱而下降的记忆力改善成接近给药食盐水的正常组。由以上的结果，确认C末端部以GAG结束的肽的记忆力改善效果，确认为了使肽具有效果，肽应该是肽的长度至少由4个以上的氨基酸构成的肽。
并且，如图3所示，在保留试验中，生理食盐水处理小鼠的反应时间为180秒(最大的截止时间)。与生理食盐水组相比，确认因东莨菪碱的注入记忆力下降的东莨菪碱-注入组的逐步反应的平均明显下降。在给药东莨菪碱之前给药本发明的由5～9个的氨基酸构成的肽给药组中，确认将因东莨菪碱而下降的记忆力改善成接近给药食盐水的正常组。由以上的结果，确认C末端部以GAG结束的肽的记忆力具有改善效果。
实施例4：确认Y迷宫测试(Y Maze Test)中的肽的效果
将小鼠放置一条路的长度为30cm、宽度为5cm、高度为13cm组成的Y迷宫的一侧端，并记录进入各条路的顺序。更迭(alternation)是判断在依次进入3种不同路的情况下成功的现象。通过下述数学式定义自发更迭(spontaneous alternation)。
自发更迭(％)＝更迭次数/(总入场次数-2)×100
如图2所示，确认与生理食盐水相比，因东莨菪碱的注入而记忆力下降的东莨菪碱-注入组的自发更迭的平均显著下降。在给药东莨菪碱之前给药合成肽的组中，与东莨菪碱给药组相比，由2个及3个氨基酸组成的肽-1及2给药组中，具有一定的改善，与其相反，由4个及6个氨基酸构成的肽-3至6给药组中，确认显著改善因东莨菪碱而下降的记忆力。由以上结果，确认C末端部以GAG结束的肽具有可改善记忆力的效果，为了使肽具有效果，肽应该是肽的长度至少由4个以上的氨基酸构成的肽。
并且，如图4所示，确认与生理食盐水相比，因东莨菪碱的注入而记忆力下降的东莨菪碱-注入组的自发更迭平均显著下降。确认给药东莨菪碱之前给药本发明的由5～9个氨基酸构成的肽给药组中，明显改善因东莨菪碱而下降的记忆力，在给药序列2及3的肽给药组中，反而与对照组相比具有更优秀的效果。由以上的结果，确认C末端部以GAG结束的肽可具有可改善记忆力的效果。
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Claims (4)
1.具有C末端部为GAG的氨基酸序列的肽在制备用于治疗由老化、阿尔茨海默氏症、匹克氏病、克罗伊茨费尔特-雅各布病、健忘症、韦尼克-科尔萨科夫综合征、药物中毒、额颞叶变性、脑神经疾病、轻度认知障碍、认知缺陷或注意力缺陷引起的记忆、认知或学习障碍的药物中的用途，其中所述肽选自GGAG、AGAG、QGAG、QAGAG、SGGAG和GAGGAGGAG。
2.具有C末端部为GAG的氨基酸序列的肽在制备用于治疗由帕金森氏病、亨廷顿氏病、脑衰老症、痴呆或遗忘症引起的记忆、认知或学习障碍的药物中的用途，其中所述肽选自GGAG、AGAG、QGAG、QAGAG、SGGAG和GAGGAGGAG。
3.具有C末端部为GAG的氨基酸序列的肽在制备用于提高脑或认知功能的食物中的用途，其中所述肽选自GGAG、AGAG、QGAG、QAGAG、SGGAG和GAGGAGGAG。
4.如权利要求3所述的用途，其中所述脑或认知功能是学习能力、记忆能力或集中力。
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2019
- 2019-01-23 AU AU2019200449A patent/AU2019200449A1/en not_active Abandoned
-
2022
- 2022-05-26 US US17/825,064 patent/US20220296673A1/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1430674A (zh) * | 2000-05-25 | 2003-07-16 | 纳幕尔杜邦公司 | 在植物中生产丝状蛋白 |
Non-Patent Citations (1)
| Title |
|---|
| Memory-Enhancing Effects of Silk Fibroin-Derived Peptides in Scopolamine-Treated Mice;Yong Koo Kang等;《J. Microbiol. Biotechnol》;20130917;第23卷(第12期);1779-1784页 * |
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| EP3255055A4 (en) | 2018-04-18 |
| EP3255055A1 (en) | 2017-12-13 |
| BR112018012527A2 (pt) | 2018-12-11 |
| SG11201804902UA (en) | 2018-07-30 |
| US20180327452A1 (en) | 2018-11-15 |
| US20180201645A1 (en) | 2018-07-19 |
| EP3255055C0 (en) | 2024-06-05 |
| PH12017550079A1 (en) | 2018-02-12 |
| US10435436B2 (en) | 2019-10-08 |
| MY197348A (en) | 2023-06-14 |
| US20180327451A1 (en) | 2018-11-15 |
| US20220296673A1 (en) | 2022-09-22 |
| JP6463499B2 (ja) | 2019-02-06 |
| CN110279845A (zh) | 2019-09-27 |
| CA2965840C (en) | 2021-11-30 |
| CN107406482A (zh) | 2017-11-28 |
| EP3255055B1 (en) | 2024-06-05 |
| AU2016376059A1 (en) | 2017-10-05 |
| RU2694064C1 (ru) | 2019-07-09 |
| AU2016376059B2 (en) | 2019-02-14 |
| JP2018517394A (ja) | 2018-07-05 |
| MX2018006823A (es) | 2018-11-29 |
| WO2017111215A1 (ko) | 2017-06-29 |
| TR201807610T1 (tr) | 2018-06-21 |
| CA2965840A1 (en) | 2017-06-29 |
| AU2019200449A1 (en) | 2019-02-07 |
| SA518391710B1 (ar) | 2022-11-09 |
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