CN109414418B - 包含美金刚和褪黑素的组合的药物组合物 - Google Patents
包含美金刚和褪黑素的组合的药物组合物 Download PDFInfo
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- CN109414418B CN109414418B CN201780040543.8A CN201780040543A CN109414418B CN 109414418 B CN109414418 B CN 109414418B CN 201780040543 A CN201780040543 A CN 201780040543A CN 109414418 B CN109414418 B CN 109414418B
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Abstract
本发明涉及化学‑制药工业,并且特别地涉及片剂形式的药物组合物,其包括:2.0至15.0wt%的美金刚;1.5至10.0wt%的褪黑素;65.0至80.0wt%的选自甘露醇或甘露醇和共聚维酮的混合物的填料;4.0至15.0wt%的选自交聚维酮的崩解剂;1.0至2.0wt%的选自山梨糖醇的粘合剂;1.0‑2.5wt%的选自麦芽糖醇、糖精钠或其混合物的甜味剂;0.5至1.0wt%的选自胶态二氧化硅、硬脂酸、硬脂酸镁、滑石或其混合物的助流剂;1.5‑3.0wt%的加香剂;并且还涉及获得所述药物组合物的方法。本发明使得包含美金刚和黑色素的组合的药物组合物的范围扩大,并使得其储存稳定性和溶出速率提高。
Description
本发明涉及化学-制药工业领域,特别地涉及一种新型的褪黑素和美金刚组合的制剂。
美金刚(或3,5-二甲基金刚烷-1-胺)是具有以下结构的金刚烷衍生物:
作为N-甲基-D-天冬氨酸(NMDA)受体的非竞争性拮抗剂,它对谷氨酸能系统具有调节作用。它调节离子转运、阻断钙通道、使膜电位正常化、改善神经冲动的传递。它具有益智、脑血管扩张、抗缺氧和精神活性作用、改善认知过程、增加日常生活活力、减少疲劳和抑郁症状、减少因脑部疾病和损伤引起的痉挛[医药产品注册页:http://www.rlsnet.ru/ mnn_index_id_2206.html]
褪黑素(或N-乙酰基-5-甲氧基色胺)是具有以下结构的合成骨骺激素类似物:
在生理条件下,褪黑素的分泌在夜幕降临后很快增加,在凌晨2点到4点达到最大值,并且在下半夜降低。内源性褪黑素的含量随着年龄的增长而降低。褪黑素控制昼夜节律和昼夜循环感知,具有镇静作用并且改善入睡,使身体适应快速变化的时区,减少应激反应,表现出免疫刺激和显著的抗氧化特性,抑制促性腺激素以及在较小程度上其他腺垂体激素(促肾上腺皮质激素、促甲状腺激素和生长激素)的分泌[医药产品注册页:http://www.rlsnet.ru/mnn_index_id_2278.html]。从现有技术[专利RU2536270C1.公开12/20/2014]中已知美金刚和褪黑素组合物有效对抗了具有脑病理状况的患者的疾患,用于预防、管理和治疗淀粉样蛋白中毒体征的用途。参考现有技术表明,美金刚和褪黑素的组合具有协同作用,以改善认知功能障碍并减少在患有阿尔茨海默病的患者的脑中形成淀粉样斑块的β-淀粉样蛋白聚集体的浓度。包含美金刚和褪黑素的组合的药物组合物可以片剂、胶囊、可注射形式等提供,并且还可以包括药学上可接受的赋形剂。
然而,参考现有技术未公开包含美金刚和褪黑素的组合的药物组合物的具体实施方式,此外,药学上可接受的赋形剂以一般术语描述而不以任何优选的术语描述。
本发明最接近的类似物(现有技术)是固体剂型的药物组合物[专利RU2488388C1,公开07/27/2013;申请号WO2015060746 A1,公开30/04/2015],其包含美金刚和褪黑素的组合,以及以以下组分比例的药学上可接受的赋形剂,wt%:
稀释剂选自乳糖、淀粉、淀粉衍生物、微晶纤维素、蔗糖、转化糖、右旋糖和葡萄糖结合剂(dextrate);崩解剂选自羧甲基纤维素钠、交联羧甲基纤维素、预胶化淀粉;粘合剂选自聚乙烯吡咯烷酮、明胶、纤维素衍生物、天然树胶、聚乙二醇类、海藻酸钠;抗摩擦剂选自硬脂酸和/或其盐、胶态二氧化硅、滑石、苯甲酸钠、乙酸钠和油酸钠。
作为不利的特征,可以注意到,所述参考文献未公开关于所提供的固体剂型的药物组合物获得的稳定性和溶出速率的研究结果。
本发明的目的是扩大包含美金刚和黑色素的组合的药物组合物的范围,并制备与现有技术相比具有改善的性能的药物组合物。
本发明的技术结果是提高包含美金刚和褪黑素的组合的药物组合物的安全性、储存稳定性和溶出速率。
本发明的目的和技术结果是通过用于预防和治疗精神、行为、认知障碍(cognitive disorders)的固体形式的新型药物组合物实现的,该组合物包括:
-从2.0至15.0wt%的美金刚;
-从1.5至10.0wt%的褪黑素;
-从75.0至96.5wt%的赋形剂。
在本发明的优选实施方式中,药物组合物包括:
-从2.0至15.0wt%的美金刚;
-从1.5至10.0wt%的褪黑素,以及
-从65.0至80.0wt%的载体,和/或
-从4.0至15.0wt%的崩解剂,和/或
-从1.0至2.0wt%的粘合剂,和/或
-从1.0至2.5wt%的甜味剂,和/或
-从0.5至1.0wt%的助流剂,和/或
-从1.5至3.0wt%的调味剂。
载体优选选自但不限于甘露醇或甘露醇和共聚维酮混合物。
崩解剂优选选自但不限于交聚维酮、羧甲基纤维素钠、交联羧甲基纤维素、预胶化淀粉。
粘合剂优选选自但不限于山梨糖醇、聚乙烯吡咯烷酮、明胶、纤维素衍生物、天然树胶、聚乙二醇类、海藻酸钠。
该组合物可任选地包括甜味剂。甜味剂选自但不限于麦芽糖醇、糖精钠或其混合物、三氯蔗糖、乙酰磺胺酸钾。
助流剂选自但不限于胶态二氧化硅、硬脂酸和/或其盐、滑石或其混合物、苯甲酸钠、乙酸钠和油酸钠。
作为调味剂,可以使用通常用于制备片剂形式的药物组合物的任何剂。优选地,调味剂选自薄荷、薄荷脑、草莓、橙子或柠檬调味剂。这种剂的选择优选的但不限于上述选项。
在优选的实施方式中,片剂是口腔崩解片剂。
在又一实施方式中,美金刚的量为2.5至10.0wt%,优选2.5wt%,并且褪黑素的量为1.5至6.0wt%,优选1.5wt%。
在又一实施方式中,美金刚和褪黑素的量可以包括任何上述子范围,即美金刚的量的范围可以是但不限于,例如2.5至10.0wt%、或2.5至9.5wt%、或2.5至9.0wt%、2.5至8.5wt%、2.5至8.0wt%、2.5至7.5wt%、2.5至7.0wt%、2.5至6.5wt%、2.5至6.0wt%、2.5至5.5wt%、2.5至5.0wt%、2.5至4.5wt%、2.5至4.0wt%、2.5至3.5wt%、2.5至3.0wt%、并且褪黑素的量的范围可以是但不限于,例如1.5至6.0wt%、1.5至5.5wt%、1.5至5.0wt%、1.5至4.5wt%、1.5至4.0wt%、1.5至3.5wt%、1.5至3.0wt%、1.5至2.5wt%、1.5至2.0wt%。
本发明的药物组合物用于预防和治疗精神、行为、认知障碍和损伤,包括不同严重程度的痴呆。该剂可用于与器质性精神综合症的临床体征相关的医学病症(并且它是最关键的组分——痴呆)如下:阿尔茨海默病、血管性(多发梗塞)痴呆、轻度认知损伤、酒精中毒、颅内容积过程——肿瘤、硬脑膜下血肿和脑脓肿、缺氧、颅脑外伤、正常压力脑积水、帕金森病、亨廷顿病、进行性核上性麻痹、皮克氏病、肌萎缩侧索硬化、脊髓小脑变性、与异染性脑白质营养不良(成人型)相关的眼肌麻痹,Gellervorden-Spatz病、大麻性精神病、晚期(advanced)、感染、克雅二氏症(Creutzfeldt-Jacob disease)、病毒性脑炎、进行性多灶性脑白质病、神经梅毒、白塞氏病(Behcet's disease)、慢性细菌性和真菌性脑膜炎;缺乏症、韦尼克-科尔萨科夫综合征、硫胺素缺乏症、维生素B12缺乏症、叶酸缺乏症、维生素B3缺乏症、糙皮病;代谢紊乱、透析性痴呆、甲状腺功能衰退和亢进、严重肾功能衰竭、库欣综合征、肝功能衰竭、甲状旁腺病、系统性红斑狼疮和其他与脑血管炎症相关的胶原蛋白依赖性疾病、多发性硬化症、惠普尔病。
用于制备片剂形式的所述药物组合物的方法包括称重和筛分起始材料,对其进行混合和压片。优选地,使用直接压缩技术执行压片。成品片剂可以包装在泡罩中,并且泡罩可以包装在硬板盒中。
尽管已经通过各种典型的实际应用方法描述了本发明,但应该注意,这些实际实施方式仅描述了本发明的构思及其应用。本领域技术人员将理解,可以在实践本发明中由典型实施方式进行许多修改,而不脱离本发明的范围。
此外,应该意识到,可以组合本发明的各种实践的各种特征和/或特点。因此,应该理解,除了所描述的实践实施方式之外,可以对其进行许多修改,并且可以开发其他应用方法,而不脱离本发明的范围。
另外,在阅读了本说明书和实践了本文提供的发明之后,本领域技术人员可以想到实践本发明的其他实施方式。说明书部分和实施例仅旨在用于说明基于本领域的知识和本文提供的指导的典型实践。
通过以下实施例可以说明本发明。
实施例提供了片剂形式的包含美金刚和褪黑素的组合的药物组合物,它们是说明性的,并且决不限制本发明的范围。
实施例1:组合物变体的制备
片剂形式的药物组合物的制备包括称重和筛分起始材料,对其进行混合,并使用直接压片技术压片。
如下表1-表5中所示制备以下组合物变体。
表1:变体1至3。
表2:变体4至6。
表3:变体7至9。
表4:变体10-12。
表5:变体13-15。
实施例2:通过加速老化技术测定片剂稳定性。
基于褪黑素的含量评价变体1至15的片剂的储存稳定性,并与现有技术的片剂的稳定性进行比较[专利RU 2488388 C1,公开07/27/2013.实施例1]。
现有技术美金刚和褪黑素片剂制剂.
将变体1至15和现有技术的片剂装入铝箔泡罩('Alu-Alu')中并在加速试验条件下放入稳定性室中。使用标准品通过HPLC分析了褪黑素含量。
“加速老化”技术涉及在处理期间将测试药物保持在高于其储存的温度和湿度的温度和湿度下。在升高的温度下,药物中进行的物理化学过程通常会加速,随着时间的推移导致不期望的质量变化。因此,在升高的温度下,当药物中受控质量测量值保持在可接受范围(实验保质期)内的时间段,与储存温度下的保质期相比人为地减少了一段时间。这使得确定保质期所需的时间显著减少。
基于在药物“加速老化”过程中获得的结果,还可以解决相反的问题,即确定保证任何所需保质期的储存温度。
储存温度(tst)下的保质期(S)与实验储存的高温(texp)下的实验保质期(Sexp)有如下关系:
S=K·Sexp
化学反应速率(А)的温度系数假定为2.5。上述关系基于范特-荷夫(Vant-Hoff)规则,随着温度增加10℃,化学反应速率增加约2至4倍。
根据GM 1.1.0009.15,取决于所选的等于30℃的温度区间(texp-tst)的一致性系数(K)的值为15.6。选定的3年保质期的实验储存期为71天。
参数的统计处理和研究结果的呈现是根据欧亚经济联盟的良好临床实践规则(Rules of Good Clinical Practice of the Eurasian Economic Union)使用SPSSStatistics 19.0统计软件套件进行的。
在加速老化技术条件下储存71天后,发现变体1至15的片剂具有相同的稳定性并保持化学纯度。现有技术的片剂保持化学纯度少于10天,此外褪黑素含量降低超过3%。换句话说,与现有技术相比,本发明的变体1至15的片剂更稳定。
实施例3:使用长时间测试技术测定片剂稳定性
基于褪黑素的含量评价变体1至15的片剂的储存稳定性,并与现有技术的片剂的稳定性[专利RU 2488388 C1,公开07/27/2013,实施例1]进行比较。
现有技术美金刚和褪黑素的片剂制剂
将变体1至15和现有技术的片剂装入铝箔泡罩('Alu-Alu')中,并在长时间测试条件下放入稳定性室中。使用标准品通过HPLC分析了褪黑素含量。
在实时条件下储存12个月后,发现变体1至15的片剂具有相同的稳定性并保持化学纯度。现有技术的片剂保持化学纯度少于6个月,此外褪黑素含量降低超过0.7%。换句话说,与现有技术相比,本发明的变体1至15的片剂更稳定。
发明人提出,与现有技术相比,变体1至15的固体剂型的改善的稳定性的意外效果可能是由于固体剂型中美金刚含量的降低。在现有技术的固体剂型中,高含量(超过40wt%)的美金刚(其化学性质为碱)可能对剂型的第二活性组分褪黑素具有去稳定作用,其含量在以下实施例中确定。
实施例4:变体1至15和现有技术的片剂的溶出曲线的比较。
基于物质的含量评价变体1至15的片剂中的溶出动力学,并与现有技术的片剂中的溶出动力学[专利RU 2488388 C1,公开07/27/2013,实施例1]进行比较。
现有技术美金刚和褪黑素的片剂制剂
用于确定溶出速率的装置是1L的三颈烧瓶。将温度计引入其中的一个瓶颈,将用于取样和样品加入的玻璃管引入另一个瓶颈,并且将装置的主要部分,即如具有直径(约0.351mm)上40目的开口的网格的3.6cm高,2.5cm直径的圆柱形不锈钢篮引入第三个瓶颈。篮子安装在电机轴上。
将溶剂介质加入烧瓶(1000mL)中,在该实验中,它是对应于人唾液培养基的胰酶的碱性溶液,并且其对于确定舌下(口腔分散的)剂型的溶解度是重要的。将测试样品放入圆柱形篮子中,该篮子安装在距离烧瓶底部2cm的位置。
在实验期间,溶解介质的温度保持恒定(37±0.5℃)。介质中的篮子旋转速率在±5%范围内调节,并且为200rpm。在预定的时间点,取样1至2mL样本以确定溶质的含量。立即用新的溶剂补充溶剂的取样体积。
溶出是基于所选择的组分即美金刚来控制的。对于对比样品,使用变体1至15和现有技术的250mg片剂以在完全溶解时提供变体1至15的包括6.25mg/L、20mg/L、37.5mg/L美金刚的溶液,以及现有技术的100mg/L溶液。
在表8中示出了所得到的以最大浓度计的溶解活性成分的百分比结果。
结果表明,本发明的变体1至15的片剂的溶出速率显著高于现有技术的片剂的溶出速率,特别是本发明的变体1至15的片剂的50%的溶出时间为现有技术的一半,这对于制备口腔分散片剂特别有用。
所得结果表明,所选择的赋形剂制剂和比例对于包含美金刚和褪黑素的组合的口腔崩解制剂是最佳的。
实施例5:制品的急性毒性研究
为了研究新型组合物的急性毒性,如下表9中所示进一步制备以下组合物变体。
表9:变体16至17。
测试组特点
在急性毒性研究中,10只雄性Wistar大鼠的组用于每个剂量。
给大鼠胃内给药变体1、16和17以及现有技术的组合物[专利RU2488388 C1,公开07/27/2013,实施例1]。
计算LD50所需的剂量通过实验确定。根据Prozorovsky方法,使用概率分析计算LD50。
致死剂量的确定
在急性毒性研究中,通过实验选择了剂量,剂量以作为毒性更强的组分的美金刚计算。
表10中提供了变体1、16和17以及现有技术的组合物的急性毒性研究的组、剂量和结果。
表10:胃内给药的大鼠的LD50值
以对应于变体1、16和17的比例以及以获得现有技术的比例制备的物质的组合物的急性毒性研究结果的分析示出了,胃内给药的物质的组合物在允许对其根据Hodge和Sterner对具有第3毒性水平(中等毒性)物质的分类来进行归类的剂量内表现出毒性性能。根据K.K.Sidorov的分类,腹部给药的物质的组合属于第4级——低毒性物质。
变体1、16和17的组合物的毒性显著低于用相同美金刚剂量给药的现有技术的组合物。不希望受任何特定理论的束缚,发明人相信这种效果可能与本发明组合物中美金刚与褪黑色的最佳比例有关。
基于测试锭剂中的活性成分含量、毒性测定结果、实验动物在急性给药后为期14天的观察和尸检数据,(成品剂型)胃内给药的本发明组合物可归类为实际上无毒药物的第5级(II Hodge et all Clinical Toxicology of Commercial Products.AcutePoisoning.Ed.IV,Baltimore,1975,427p.;K.K.Sidorov,1977)。
实施例6:多剂量毒性
使用远交Wistar大鼠(90只雄性和90只雌性,总共180只大鼠)进行慢性(180天)毒性的研究。在慢性毒性研究中,将动物分成9组,每组20只动物(10只雌性和10只雄性)。胃内给药制剂。
慢性毒性数据分析显示,对比组(变体1、16、17的本发明组合物和现有技术的组合物)表现出零星的死亡率,死亡可能与心肺失代偿的发展有关。动物体重值、饲料和水消耗均在生理学正常范围内。
变体1、16和17的本发明测试组合物对动物行为没有不利影响。
当给药变体1、16、17的本发明组合物时,心脏生物电活动中的干扰频率对应于由药物美金刚给药引起的类似干扰的频率,这表明变体1、16、17的本发明组合物的组分之间不存在增强效应。
变体1、16、17的本发明组合物的给药对造血没有不利影响。相对于对照的记录的显著偏差(白细胞、单核细胞、红细胞、血红蛋白、血细胞比容、MCV、MCH、血小板)在生理学正常范围内。变体1、16、17的测试的本发明组合物中的药物物质之间没有毒性效应增强。
止血曲线在生理学正常范围内。
在生化血液分析中,所获得的结果与其他测量之间没有明显的关系,这表明所确定的偏差的功能性质的没有导致对于本方案和药物给药的持续时间的显著的细胞溶解现象,如组织学研究所证实的。组分(美金刚+褪黑素)之间没有增强效应。
尿液分析显示,180天给药变体1、16、17的本发明的组合物导致尿液中出现蛋白质和血细胞。这些变化是持久的。获得的结果与先前在临床检查期间发现的那些结果一致,以及尿变色和尿道液溢的出现。组织学检查显示肾脏无病理过程。因此,实验数据表明损伤与肾结构和功能状态无关。组分(美金刚+褪黑激素)之间没有增强效应。
对内部器官组织形态结构的研究表明,在给药变体1、16、17的本发明组合物和现有技术的组合物后没有病理变化的迹象。
没有局部刺激作用。
关于制剂的一般毒性性能的所进行的研究的结果表明,在变体1、16、17的本发明组合物之间没有毒性作用增强。
对变体1、16、17的新型的本发明组合物的一般毒性性能进行的研究表明,组合制剂的组分之间没有毒性作用增强。
本发明可用于医药、化学、制药工业。
Claims (13)
1.一种用于预防和治疗精神、行为、认知障碍的固体形式的药物组合物,所述固体形式为口腔崩解片剂,其中,所述组合物包括:
-从2.0至15.0wt%的美金刚;
-从1.5至10.0wt%的褪黑素;
-从75.0至96.5wt%的赋形剂。
2.根据权利要求1所述的固体形式的药物组合物,其特征在于,所述组合物包括:
-从2.0至15.0wt%的美金刚;
-从1.5至10.0wt%的褪黑素,以及
-从65.0至80.0wt%的载体,所述载体包括选自甘露醇以及共聚维酮中的至少一种组分,和/或
-从4.0至15.0wt%的崩解剂,所述崩解剂包括选自交聚维酮、羧甲基纤维素钠、交联羧甲基纤维素以及预胶化淀粉中的至少一种组分,和/或
-从1.0至2.0wt%的粘合剂,所述粘合剂包括选自山梨糖醇、聚乙烯吡咯烷酮、明胶、纤维素衍生物、天然树胶、聚乙二醇类以及海藻酸钠中的至少一种组分,和/或
-从1.0至2.5wt%的甜味剂,所述甜味剂包括选自三氯蔗糖、麦芽糖醇、糖精钠中的至少一种组分,和/或
-从0.5至1.0wt%的助流剂,所述助流剂包括选自胶态二氧化硅、硬脂酸和/或其盐、滑石或其混合物、苯甲酸钠、乙酸钠和油酸钠中的至少一种组分,和/或
-从1.5至3.0wt%的调味剂。
3.一种用于预防和治疗精神、行为、认知障碍的固体形式的药物组合物,所述固体形式为口腔崩解片剂形式,其特征在于,所述组合物包括:
-从2.0至15.0wt%的美金刚;
-从1.5至10.0wt%的褪黑素;
-从65.0至80.0wt%的载体,所述载体选自甘露醇或甘露醇和共聚维酮混合物;
-从4.0至15.0wt%的崩解剂,所述崩解剂是交聚维酮;
-从1.0至2.0wt%的粘合剂,所述粘合剂选自山梨糖醇或聚乙烯吡咯烷酮,和/或
-从1.0至2.5wt%的甜味剂,所述甜味剂选自麦芽糖醇、糖精钠或其混合物、三氯蔗糖,和/或
-从0.5至1.0wt%的助流剂,所述助流剂选自胶态二氧化硅、硬脂酸、硬脂酸镁、滑石或其混合物;
-从1.5至3.0wt%的调味剂。
4.根据权利要求3所述的药物组合物,其特征在于,所述调味剂选自薄荷、薄荷醇、草莓、橙子或柠檬调味剂。
5.根据权利要求3所述的药物组合物,其特征在于,所述载体是甘露醇,所述甜味剂是三氯蔗糖,所述助流剂是胶态二氧化硅,所述调味剂选自薄荷或薄荷醇调味剂。
6.根据权利要求3所述的药物组合物,其特征在于,所述组合物包括量为2.5至10.0wt%的美金刚。
7.根据权利要求6所述的药物组合物,其特征在于,所述组合物包括量为2.5wt%的美金刚。
8.根据权利要求3所述的药物组合物,其特征在于,所述组合物包括量为1.5至6.0wt%的褪黑素。
9.根据权利要求8所述的药物组合物,其特征在于,所述组合物包括量为1.5wt%的褪黑素。
11.根据权利要求1-10中任一项所述的药物组合物,其特征在于,所述精神、行为、认知障碍是不同严重程度的痴呆症的认知损伤。
12.一种根据权利要求1-11中任一项所述的固体形式的药物组合物的制备方法,所述固体形式为口腔崩解片剂,包括称重和筛分起始材料,对其进行混合和压片。
13.根据权利要求12所述的制备方法,其特征在于,所述压片使用直接压缩技术进行。
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CN101842085B (zh) * | 2007-10-31 | 2013-01-30 | 麦克内尔-Ppc股份有限公司 | 口腔崩解剂型 |
RU2488388C1 (ru) * | 2012-05-24 | 2013-07-27 | Ооо "Валента Интеллект" | Фармацевтическая композиция для профилактики и лечения психических, поведенческих, когнитивных расстройств |
RU2536270C1 (ru) * | 2013-10-21 | 2014-12-20 | Общество с ограниченной ответственностью ООО "ВАЛЕНТА ИНТЕЛЛЕКТ" | Комбинация для коррекции неврологического и психоэмоционального статуса при органических нарушениях цнс |
RU2557960C1 (ru) * | 2014-07-01 | 2015-07-27 | Аллан Герович Бениашвили | Ородисперсная таблетка дегидроэпиандростерона и/или комбинации дегидроэпиандростерона и l-тианина |
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2017
- 2017-06-28 WO PCT/RU2017/000458 patent/WO2018004391A1/ru unknown
- 2017-06-28 CA CA3029382A patent/CA3029382C/en active Active
- 2017-06-28 EP EP17820624.9A patent/EP3479822B1/en active Active
- 2017-06-28 CN CN201780040543.8A patent/CN109414418B/zh active Active
- 2017-06-28 AU AU2017288035A patent/AU2017288035B2/en active Active
- 2017-06-28 IL IL263976A patent/IL263976B2/en unknown
- 2017-06-28 KR KR1020197002770A patent/KR102280457B1/ko active IP Right Grant
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KR102280457B1 (ko) | 2021-07-23 |
IL263976A (en) | 2019-01-31 |
KR20190025647A (ko) | 2019-03-11 |
IL263976B2 (en) | 2023-09-01 |
CA3029382C (en) | 2021-10-12 |
EP3479822A4 (en) | 2020-03-04 |
CN109414418A (zh) | 2019-03-01 |
AU2017288035B2 (en) | 2020-12-03 |
UA123552C2 (uk) | 2021-04-21 |
EP3479822B1 (en) | 2023-06-07 |
WO2018004391A1 (ru) | 2018-01-04 |
AU2017288035A1 (en) | 2019-01-17 |
IL263976B1 (en) | 2023-05-01 |
CA3029382A1 (en) | 2018-01-04 |
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