CN111386112A - 用于治疗寄生虫感染的含有莫昔克丁的组合物 - Google Patents
用于治疗寄生虫感染的含有莫昔克丁的组合物 Download PDFInfo
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- CN111386112A CN111386112A CN201880076021.8A CN201880076021A CN111386112A CN 111386112 A CN111386112 A CN 111386112A CN 201880076021 A CN201880076021 A CN 201880076021A CN 111386112 A CN111386112 A CN 111386112A
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- moxidectin
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Abstract
本发明涉及一种包含莫昔克丁或其盐的组合物,其供用于预防和/或治疗非人类哺乳动物的寄生虫感染,其中所述组合物每3到9个月局部给予。
Description
技术领域
本发明涉及一种包含莫昔克丁(moxidectin)或其盐的兽医学或医药组合物,其供用于预防和/或治疗非人类哺乳动物的寄生虫感染(infestation),其特征在于组合物每3到9个月局部给予。
其还涉及一种治疗和/或预防非人类哺乳动物的寄生虫感染的方法,其包含每3到9个月向所述非人类哺乳动物局部给予包含莫昔克丁或其盐的兽医学或医药组合物。
背景技术
非人类哺乳动物,例如伴侣动物,诸如狗、小狗、猫、小猫、兔、雪貂、马和猪,通常易受以血液为食的寄生虫感染,并且因此易受由这些寄生虫引起的感染(infection)。这些寄生虫可能是体外寄生虫,如扁虱、跳蚤、疥疮、虱子/虱卵、苍蝇、蚊虫或体内寄生虫。此外,这些寄生虫中的一些是体内寄生虫的中间宿主,例如扁虫(或扁形虫)、钩虫、鞭虫或蛔虫(或线虫)。
更确切地说,犬心丝虫是通过蚊虫(中间宿主)的叮咬从宿主扩散到宿主的寄生蛔虫(尤其犬恶丝虫(dirofilariaimmitis))。确定且最受影响的宿主为狗,但犬心丝虫也可感染猫、狼、草原狼、狐狸、雪貂、海狮和甚至牛科动物和人类。其在五大洲都有发现。
所述寄生虫通常被称为“犬心丝虫”,因为其生命周期的成虫繁殖阶段主要存在于其宿主的右心室中,在所述右心室中其可存活许多年。犬心丝虫感染可能引起宿主出现严重疾病:恶丝虫病(dirofilariasis),且更准确地说,犬心丝虫病。
当蚊虫叮咬感染动物时,被称作微丝虫的幼小犬心丝虫进入蚊虫系统。在两周内,微丝虫在蚊虫内部发育为感染性幼虫,且当蚊虫再次叮咬时,可将这些感染性幼虫转移到其它动物。
当经由此叮咬进入狗的血液系统时,幼虫发育(大丝虫(macrofilariae))并且迁移到狗的心脏,在所述心脏中,其成熟并且繁殖。当摄入的微丝虫在蚊虫中成熟为感染性幼虫时恶丝虫属生命周期完成。在狗中,幼虫发育成成虫需要约180天,而犬心丝虫的生命周期为约6个月。
犬恶丝虫呈现为白色线状圆虫,对于雄性成虫,其达到长达20cm长(12-20cm)并且对于雌性成虫为31cm(25-31cm),平均直径为1mm。
犬心丝虫主要发现于具有低寄生负荷(<50条虫)的狗中的肺动脉中。在具有高寄生负荷(>50条虫)的感染中,虫可能会到达右心室、右心房和(偶尔)腔静脉。初始反应包括小肺动脉的肿胀和血液凝结。犬心脏的肺动脉和右心室中犬心丝虫的实际存在,和所引起的组织破坏造成呼吸道和循环系统问题,在压力或剧烈运动的条件下可能致命。肺高血压和右侧心脏衰竭可能导致充血性心脏衰竭。
因为必须要有大量的犬心丝虫才会将血流堵塞到显著程度,所以在引起临床体症之前,犬心丝虫可在心脏内部存在长达2或3年。随着疾病进展,肺组织可被破坏,导致咳嗽加重,而肝和肾脏损伤可归因于器官中的血流减少而发生。如果放任不去治疗,那么犬心丝虫病可能导致死亡。人类也可能被感染为异常的宿主。但是,大多数引入人体的感染性幼虫死亡。
尽管在过去的两十年已有可用的安全、高效且适宜的预防策略,但犬心丝虫病,归因于犬恶丝虫,继续在世界的许多地方引起狗和其它哺乳动物(猫、牛科动物、人类、豚鼠和雪貂)的严重损伤和甚至死亡。此外,寄生虫和蚊媒(vector mosquito)继续扩散到先前尚未报告的地区中。
目前,仅两种砷衍生物可用于临床上感染的狗的治愈性治疗。第一种,硫乙胂胺(thiacetarsamide)(雅培实验室(Abbott Laboratories)),其为具有严重不良作用的老式药剂,以及第二种,美拉索明二氢氯化物(melarsomine dihydrochloride)(梅里亚(Merial)),其为具有较少副作用的更近期药物。对于化学防治,两种替代方案可用来预防狗的犬心丝虫病:每日给予柠檬酸二乙碳酰嗪或每月给予巨环内酯。
类似地,疥疮(蠕形螨种(Demodex sp.)、疥螨种(Sarcoptes sp.)、耳痒螨种(Otodectes sp.)……)难以控制/杀死,因为仅存在极少有效治疗,且已经常治疗受感染的动物。举例来说,耳螨为存活于动物和人类的耳部中的螨。狗和猫中的耳螨感染可引起在单耳或双耳中的剧烈瘙痒,且引发在受感染的耳部处的挠抓。还可产生异常深色的耳垢(earwax/cerumen)。与耳螨相关的最常见病变为在耳背部或基部处的裂开或结痂性皮肤创口,其由后肢爪对皮肤的擦伤所引起。此病变通常由普通皮肤细菌感染和结痂,使得耳螨的常见表现为呈现于单耳或双耳的背部或基部处的此类创口。最常见的耳螨治疗目前使用抗寄生虫塞拉菌素(selamectin)(其以一月一次的制剂形式给予,可局部施用到动物的皮肤)或伊维菌素(ivermectin)。
控制此类体内和体外寄生虫已经被公认为人类和动物健康方案的重要方面。尽管许多控制感染的替代方案在使用中,但其受许多问题困扰,包括有限的活动范围、需要重复治疗(不具有顺应性)和在一些罕见的情况下,寄生虫的抗性,尤其是在使用氨基甲酸酯、有机磷化合物或拟除虫菊酯(pyrethroid)的情况下。这就是为何开发新的有效治疗非常重要的原因。
许多治疗已经商业化以治疗此类寄生虫。举例来说,含有伊维菌素(梅里亚)的咀嚼片剂已经商业化,以通过在感染之后消除犬心丝虫幼虫(犬恶丝虫)的组织阶段持续一个月(30天)来预防犬心丝虫病(6.0微克/千克体重,最小值)。但所述治疗具有两个局限性:其可仅一月一次使用,并且因此仅具有一个月的有效性,且其为经口药剂:由肝脏或胃液降解、延迟作用以及药物相互作用。
作为另一实例,一种皮下注射的莫昔克丁-浸染的脂质微球的缓慢释放调配物(在单次给药给药给予之后提供针对六个月的恶丝虫属的连续保护)已经由硕腾(Zoetis)以MoxidectinProHeart或Guardian的名称出售。其具有许多缺点:其为在一般兽医学实践中需要复杂制备和使用的悬浮液,且因为其为可注射产品,所以其必须由兽医用注射器给予,最终可引起局部耐受性问题。此外,由于与安全性有关的问题,此产品已在2004年9月自美国市场自愿撤出,并且目前在风险最小化和限定分配方案下,已经由FDA再次允许。
吡虫啉(imidacloprid)和莫昔克丁的组合物由拜耳(或Advantage)商品化以预防恶丝虫病,其局部施用,但吡虫啉可对一些动物(例如鸟类)有毒,且产品必须每月给予,在数月期间,不得错过任何给药,这是限制性的。Advantage注意事项详述许多缺点:“为预防犬心丝虫病,应每隔一月投予狗用Advantage狗用Advantage可以全年给予,或至少应在第一次预期暴露于蚊虫之前一个月开始,且应每隔一月继续直到最后暴露于蚊虫之后一个月。如果错过给药且各给药之间间隔超过30天,那么立即给予狗用Advantage且恢复每月给药时程。当在犬心丝虫预防方案中替换另一犬心丝虫预防性产品时,应在前一药剂最后一次给药的一月内给予狗用Advantage Multi的第一治疗。此外,鲍曼D.(Bowman D.)等人.(寄生虫和载体(Parasites&Vectors)(2016)9:12)证实,当狗只在最后一次每月治疗后28天受感染时,预防的功效为100%。当狗按规定接受Advantage的连续给药时,在若干每月剂量的给予之后的整个每月给药间隔预防犬心丝虫感染。
司拉克丁点滴剂(spot-on)由硕腾商品化,以预防由犬恶丝虫引起的犬心丝虫病,并且治疗且控制耳螨(耳疥虫(Otodectescynotis))感染。所建议的最小剂量为每磅体重2.7mg塞拉菌素(6mg/kg)。同样,此产品受到约束,因为其必须每月一次施用。
US2013231371涉及一种点滴式杀虫组合物,其包含约0.25%到约60%(w/w)的拟除虫菊酯和约0.01%到约10%(w/w)的巨环内酯。每四周一次施用组合物。
WO2016161369描述一种缩酚酸肽(depsipeptide)和一种巨环内酯的组合物,其用作寄生虫感染的治疗或防治,其中寄生虫感染包含对单独用巨环内酯治疗或防治具有抗性的寄生虫,所述寄生虫为犬恶丝虫。每隔一月给予环缩酚酸肽和巨环内酯五次。根据本专利申请,单独使用莫昔克丁无法预防犬恶丝虫。此外,本申请指明,近年来已报告缺乏功效的案例数目增加,其中狗尽管接受每月防治性剂量的巨环内酯药物却仍罹患熟犬心丝虫感染,且测试犬心丝虫抗原阳性的同时接受犬心丝虫预防性药剂的狗的案例数目增加,所述药剂推测犬恶丝虫已形成对犬心丝虫预防的抗性。
现有产品和最新发展的主要缺点是缺乏有效性、由于给予模式(点滴式)所致的非长效功效、点滴组合物的基本每月施用,在至少4个月期间重复以产生长效组合物,其为体内外杀虫剂(endectocide)并且防御犬心丝虫。长效产品是可注射的且并非点滴式产品。
实际上,现有技术文献均未公开一种根据本发明的包含莫昔克丁或其盐的组合物,其适用于治疗和/或预防非人类哺乳动物的体内寄生虫(更确切地说,犬心丝虫)和耳螨感染(其长效(至少3个月)且易于局部施用),且一种单一施用足够且具有药物的优化的胞质浓度以使动物中的长期毒性问题减到最少。
发明内容
因此,为了解决前述问题,包括建议每月施用点滴式组合物来治疗犬心丝虫或注射长效产品,以便产生针对体内寄生虫和耳螨具有提高的杀灭有效性的组合物,根除恶丝虫病,并且提供更可预测的性能,在本领域中需要在更低的最大血浆浓度下提供改进的吸收和生物可用性的新颖组合物和新颖治疗方法。
因此,本发明旨在提供一种包含莫昔克丁的组合物的新颖用途,所述组合物防御体内寄生虫,如虫(蛔虫、钩虫、犬心丝虫、绦虫和鞭虫)和耳螨,非常容易给予(点滴式或管线式(line-on))并且能够以独特的局部施用在长时间段内维持有效血浆浓度。
与现有技术相比,使用根据本发明的包含莫昔克丁的组合物具有许多优点。其是安全的、无毒的、化学稳定的且公认的。与现有产品不同,仅需要一种活性成分来治疗和/或预防犬恶丝虫和耳螨,不需要两种活性成分(或更多)的协同结合。因此,调配物易于制造。由于使用了所述组合物,既没有相关的局部临床体症(没有红斑,没有脱发,没有瘙痒,没有结垢,有限的美容效果……),也没有一般的阴性临床体征(生物化学/生物学),但有可接受的局部和普遍非人类哺乳动物的耐受性。
这种类型的“一次性调配物”已经优化,以便通过小心地选择活性成分、赋形剂、给予形式和浓度来实现良好稳定性和良好可涂抹性而在毛皮上无任何固体沉积物。
不同于建议或现有技术产品,根据本发明的组合物的仅单次局部施用对于数月期间的功效为有用的。组合物具有良好的莫昔克丁的皮肤渗透率(比市场产品高)。
此外,根据本发明的组合物的用途允许莫昔克丁在血浆/组织脂肪中具有较长半衰期,并且被良好吸收、良好分布。因此,其对于体内寄生虫(如虫)极有效,被身体充分代谢且充分消除(生物可蚀解、生物可吸收)。
本发明中使用的组合物也是即用型的。容易将其用作兽医学药品:使用者既不需要制备任何悬浮液或溶液,也不需要根据动物的重量测量/计算并从注射器提取适宜量的药物,因此,组合物可在单一施用时由动物主人容易地局部施用,且不再由兽医施用。由于注射,不存在更多的风险(感染)。其为即用型点滴式/管线式组合物。因此,不存在剂量误差的风险。归功于即用型移液管而完全控制给药方案,产生治疗的较好观察结果。组合物将可注射现有产品的长效有效性与局部产品的给予简易性组合。
此外,根据本发明的组合物的用途允许在哺乳动物中,尤其在狗和猫中获得良好药物动力学概况,且具有针对胃肠和呼吸道线虫的巨大效用。
此外,局部(点滴式、管线式)给予增加组合物有效性:与每月经口给予相比,存在更好的保护(布莱格伯恩(Blagburn),2011)。更确切地说,“管线式”施用允许控制活性成分扩散:组合物针对动物的纹理外部给予且连续施用。
本发明人出人意料地发现,不同于现有技术结论,如此频繁的每月施用不可用于实现有效血浆浓度:根据本申请的组合物的用途在至少3个月期间是有效的。此外,在动物中不存在药物累积,因此毒性和生态毒性降低(环保)。
因此,本发明解决的问题为提供一种新颖治疗方法,其包含给予兽医学或医药组合物,所述组合物易于局部施用且用于治疗和/或预防非人类哺乳动物的寄生虫感染,更确切地说,犬心丝虫和耳螨,具有比现有商业产品要高的功效,且在至少三个月或更久期间实现有效血浆浓度。
在第一方面,本发明的目标为提供一种包含莫昔克丁或其盐的兽医学或医药组合物,其供用于预防和/或治疗非人类哺乳动物的寄生虫感染,其特征在于组合物每3到9个月局部给予。如本文所定义的兽医学或医药组合物可被视为长效组合物。
本发明的另一目标为一种治疗和/或预防非人类哺乳动物的寄生虫感染的方法,其包含每3到9个月向所述非人类哺乳动物局部给予包含莫昔克丁或其盐的兽医学或医药组合物。
附图说明
图2为展示在比格犬(Beagle dog)中单一局部用根据本发明的组合物(调配物7-10)之后所观察到的血浆浓度-时间概况的图式。
发明详述
在第一方面,本发明涉及一种包含莫昔克丁或其盐的兽医学或医药组合物,其供用于预防和/或治疗非人类哺乳动物的寄生虫感染,其特征在于组合物每3到9个月局部给予。
在本发明的上下文内,“医药组合物”是指含有用于治疗和/或诊断和/或治愈和/或预防疾病的药物的组合物。此外,药物为呈现为具有治疗和/或预防人类疾病的特性的任何物质或物质组合(组合物);或可在人类中使用或向人类给予的任何物质或物质组合,考虑到通过发挥药理学、免疫或代谢作用来恢复、校正或调节生理功能,或进行医疗诊断(根据指令2004/27/EC)。
根据FDA词汇表,在本发明的上下文内,“医药组合物”还指“药物产品”,其为含有药物物质的成品剂型,通常但不一定与其它活性或非活性成分结合。
药物定义为由官方药典或处方集所认可的物质、旨在用于诊断、治愈、缓解、治疗或预防疾病的物质、意图影响身体的结构或任何功能的物质(除食物以外)、旨在用作药品的组分但并非装置或装置的组件、零件或附件的物质(生物产品包括在此定义内,且通常由相同法律和法规所涵盖,但关于其制造方法-化学方法对比生物方法-存在不同之处)。
根据本发明,术语“兽医学”具有与“医药上”相同的定义,但适于动物(意指非人类):“动物”意指任何存活阶段的除人类以外的动物界的任何成员。更准确地说,根据本发明的“兽医学药物”(或“药品或组合物”)意指使用或制造、销售或表示为适合用于诊断、治疗、控制、根除、缓解或预防动物的疾病或异常身体或精神状态或其症状;或恢复、校正、控制或调节动物中的任何身体、精神或器官功能的任何物质或物质的混合物。
如本文所使用,术语“包含”可包括其它活性成分和任何其它赋形剂的存在。术语“包含”还可指示“由……组成”,且反之亦然。
在另一实施例中,根据本发明的供使用的兽医学或医药组合物包含作为唯一活性成分的莫昔克丁或其盐。其意指本发明的组合物仅包含一种活性成分,其为莫昔克丁或其盐,进而不包含活性成分的组合。因此,本发明的一个目标为一种包含作为唯一活性成分的莫昔克丁或其盐的兽医学或医药组合物,其供用于预防和/或治疗非人类哺乳动物的寄生虫感染,其特征在于组合物每3到9个月局部给予。另一目标为包含由莫昔克丁或其盐组成的活性成分的兽医学或医药组合物,其供用于预防和/或治疗非人类哺乳动物的寄生虫感染,其特征在于组合物每3到9个月局部给予。
莫昔克丁为巨环内酯,并且巨环内酯分类为结构上相关分子的两个群组中:米尔倍霉素(milbemycins)和阿维菌素(avermectins)(伊维菌素、多拉菌素(doramectin)、阿维菌素(abamectin)、依普菌素(eprinomectin)和塞拉菌素)。1981年,兽医学巨环内酯伊维菌素作为抗寄生虫药物被第一次引入,且其对线虫和节肢动物的巨大功效将寄生虫控制提升到一个新水平。犬心丝虫(L3和L4幼虫)对巨环内酯特别敏感。
然而,早期发现具有MDR-1缺乏的某些品种的狗对巨环内酯的毒性作用高度敏感。众所周知的敏感品种是牧羊犬(collie dog)。因此,牧羊犬和相关狗中的最大耐受剂量决定可接受的治疗剂量范围。
更确切地说,伊维菌素具有狭窄的安全界限。因此,其用途限于预防犬心丝虫(6μg/kg(口服)或80μg/kg(局部))。当每隔一周施用四次时,米尔贝肟(Milbemycin oxime)也用于控制法国犬心丝虫(French heartworm)(血管圆线虫(Angiostrongylus vasorum))。经口施用莫昔克丁以预防犬心丝虫(3μg/kg)且局部用于控制胃肠和呼吸道线虫。在牧羊犬中局部施用是安全的。莫昔克丁具有针对胃肠和呼吸道线虫(成虫、不成熟成虫和L4期)的巨大功效。所建议的每月施用也对呼吸道线虫有效。
莫昔克丁(或米尔倍霉素B)具有结构式(米尔倍霉素B,casn°11350706-5,分子量639.8g.mol-1):
更确切地说,对于根据本发明的用途,莫昔克丁或其盐的量介于总组合物体积的1.0与4%重量/体积(%w/v)之间,尤其在1.5-3.5%w/v之间,尤其在2.0-3.5%w/v之间,尤其在2.0-3.0%w/v之间,尤其在2.5-3.0%w/v之间。更优选地,莫昔克丁的浓度介于2.0-3.5%w/v之间,更优选地莫昔克丁以总组合物的2.5%w/v的量存在,并且甚至更优选地以3.0%w/v的量存在。
在本发明的上下文内,%重量/体积或%w/v为定义为组分的质量(g)除以总组合物的体积(100mL)的质量浓度。举例来说,25mg/mL相当于2.5%w/v。
术语莫昔克丁还包含其医药上可接受的盐。盐可以是盐酸盐、氢溴酸盐、磷酸盐、硝酸盐、反丁烯二酸盐、柠檬酸盐、酒石酸盐、乙酸盐、顺丁烯二酸盐、甲苯磺酸盐、甲磺酸盐或其混合物等。
此外,根据本发明的供使用的组合物可进一步包括以医药学上可接受的量的以下其它赋形剂中的任一个,例如一种或多种:成膜剂、溶剂、抗氧化剂、流动剂、润滑剂、稀释剂、防腐剂、结晶抑制剂、胶体、粘合剂、增稠剂、触变剂、渗透剂、稳定剂、增溶剂、流化剂、络合剂、维生素、矿物质、防腐剂或其组合。更一般来说,活性成分可与对应于调配物开发的常见技术的任何液体添加剂组合。更优选地,根据本发明的组合物进一步包含赋形剂,如溶剂和抗氧化剂。
赋形剂或辅助物质是指根据药典不是活性物质的任何药物组分(如佐剂、稳定剂、稀释剂、抗氧化剂、抗微生物防腐剂……)。
溶剂(极性、非极性、质子、非质子)可选自:苯甲醇、异丙醇、中链甘油三酯(具有6至12个碳原子的链)、碳酸亚丙酯、二丙二醇单甲醚(DPGME,)、二甲基亚砜(DMSO)、N-辛基-2-吡咯烷酮(NOP)、N-甲基-2-吡咯烷酮(NMP)、卡必醇P(transcutol P)或(2-(2-乙氧基乙氧基)乙醇或高纯度二甘醇单乙醚)、丙酮、2-丁酮、3-甲基-2-丁酮、环己酮、乙腈、二甲苯、氯苯、二氯甲烷、氯仿三氯乙烷、苯甲醛乙烯氯化物、环丁砜、甲基叔丁基醚、二丁醚、乙酸乙酯、乙酸甲基丙烯酸丙酯、乙酸戊酯、乙酸丙酯、二甲基甲酰胺(DMF)、二甲基乙酰胺(DMAC)、碳酸二乙亚丙酯、碳酸亚乙酯、乙腈、三乙胺、吡啶、甲醇、乙醇、异丙醇、六氟异丙醇、羧酸诸如甲酸和乙酸、伯胺和仲胺、丙烯烷基醚、乙烯烷基醚、聚乙二醇烷基醚、二聚乙二醇烯丙基、聚丙二醇、聚乙二醇和其混合物。优选的溶剂为苯甲醇、异丙醇、中链甘油三酯、碳酸亚丙酯、二丙二醇单甲醚和其混合物。溶剂或溶剂混合物以总组合物的95.5%w/v与98.99%w/v之间的量存在,更优选地以总组合物的96.95%w/v与97.45%w/v之间的量存在。
根据本发明,碳酸亚丙酯和DPGME的量介于组合物的约15%与20%w/v之间。碳酸亚丙酯的优选量为16%w/v。DPGME的优选量为20%w/v。苯甲醇和异丙醇的量介于约75.5%w/v与83.99%w/v之间。中链甘油三酯的量在组合物的10%与40%w/v之间,优选地在16%与32%w/v之间,更优选地为16%或32%w/v。
抗氧化剂可以选自:2,6-二叔丁基-4-甲基苯酚(丁基羟基甲苯或BHT)、维生素E(DL-α-生育酚,E307)、维生素E磷酸酯、维生素A、抗坏血酸(维生素C)、维生素B12、多酚、丁基羟基茴香醚(BHA)、没食子酸丙酯(propylgallate)、生育酚、抗坏血酸、柠檬酸、磷酸二-α-生育酚酯、β-胡萝卜素、胡萝卜素、类胡萝卜素、硫酸酯化合物、L-半胱氨酸、硫代二丙酸、硫代乳酸、单硫代甘油、没食子酸丙酯(propyl galate)、偏亚硫酸氢钠、甲醛钠、次硫酸乙酸盐和其混合物。优选的抗氧化剂为BHT。一种或多种抗氧化剂以组合物的0.001与0.5%之间的量存在,更优选地以0.05%w/v的量存在。
更优选地,抗氧化剂为BHT并且溶剂为苯甲醇、异丙醇、碳酸亚丙酯、中链甘油三酯和/或DPGME。
更优选地,对于根据本发明的用途,成膜剂选自聚乙烯吡咯烷酮和其衍生物、多醣、纤维素和纤维素的衍生物,如乙基纤维素、树胶、聚乙烯醇、丙烯酸聚合物和共聚物、聚丙烯酰胺和其混合物。成膜剂以组合物的介于0与2%w/v之间的量存在,更优选以1%w/v的量存在。
防腐剂可以选自:对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、苯酚、山梨酸、甲酚和氯甲酚和其混合物。
说明性增稠剂包括甲基纤维素、乙基纤维素、羟乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮和其混合物。
说明性络合剂包括EDTA和其盐,磷酸盐、硝酸盐、乙酸盐、柠檬酸盐和其混合物。
说明性防腐剂包括对氧基苯甲酸甲酯、对氧基苯甲酸丙酯、PHB酯、氯丁醇、苯甲醇、丁醇、丁-1,3-二醇、氯己定盐(chlorohexidin salt)、苯甲酸及其盐、山梨酸和其混合物。
如本文所公开的赋形剂可以分类为一种或数种类别。举例来说,成膜剂(如乙基纤维素)也可被视为增稠剂。
优选的成膜剂和/或增稠剂为乙基纤维素,优选地7级、20级或100级的乙基纤维素。7级的乙基纤维素的粘度介于6与8mPa.s之间。20级的乙基纤维素的粘度介于18mPa.s与22mPa.s之间。100级的乙基纤维素的粘度介于90mPa.s与100mPa.s之间。在一个优选实施例中,乙基纤维素的量在组合物的0.1%与2%w/v之间,优选地在0.5%与1.5%w/v之间,更优选地为1.0%w/v。
根据本发明的供使用的优选兽医学或医药组合物包含:
-约3w/v%莫昔克丁、
-约1w/v%乙基纤维素、
-约0.05w/v%BHT、
-约32w/v%中链TG,以及
-苯甲醇QS 1mL。
在极特定的实施例中,供使用的组合物可进一步包含一种或多种额外活性物质,如体外寄生虫或体内寄生虫控制剂、抗生素、非类固醇消炎药。
活性物质是指旨在用于制备药品的任何物质,并且当其用于药品的制造时,其变为这种药品的活性物质,此类物质旨在提供疾病诊断、愈合、减弱、治疗或预防的药理学活性或另一直接作用,或产生对身体结构和功能的作用(如药典中所定义)。
作为体外寄生虫剂的实例,其可列举有有机氯、有机磷酸酯、甲脒、脒、氨基甲酸酯、拟除虫菊酯(氯氰菊酯(cypermethrin)、溴氰菊酯(deltamethrin)、氟氯苯菊酯(lumethrin)、苄氯菊酯(permethrin)、氟氯氰菊酯(cyfluthrin)、氟氯苯菊酯(flumethrin)、甲氧苄氟菊酯(metofluthrin)、住友化学杀虫剂(momfluorothrin))、除虫菊酯(pyrethrins)、苯基吡唑(芬普尼(fipronil)、派瑞乐(pyriprole))、苯甲酰基脲、新烟碱类似物(呋虫胺(dinotefuran)、吡虫啉、烯啶虫胺(nitenpyram))、噁二嗪、多杀霉素(spinosyn)(赐诺杀(spinosad)、艾绿士(spinetoram))、异噁唑啉(阿福拉纳(afoxolaner)、氟雷拉纳(fluralaner)、洛替拉纳(lotilaner)、沙罗拉纳(sarolaner))、胆碱酯酶抑制剂、昆虫生长调节剂(吡虫隆(fluazuron)、烯虫酯(methoprene)、吡丙醚(pyriproxifen)、杀铃脲(triflumuron)、虱螨脲(lufenuron)、敌草胺(novaluron)、氟啶脲(chlorfluazuron)、烯虫乙酯(hydroprene))等,或其混合物。
作为内部寄生虫剂的实例,其可列举有:苯并咪唑(恩达唑(enbendazole)、奥芬达唑(oxfendazole)、阿苯达唑(albendazole)、三氯苯达唑(triclabendazole))、咪唑并噻唑(左旋咪唑(levamisole)、四咪唑)、嘧啶(噻嘧啶、酒石酸噻嘧啶)、异喹啉(吡喹酮、依西太尔(epsiprantel))、水杨酰苯胺(salicylanilide)(氯氰碘柳胺(closantel)、氯硝柳胺(niclosamide)、五氯柳胺(oxyclozanide)、碘醚柳胺(rafoxanide))、四氢嘧啶、氨基-乙腈衍生物、缩酚酸肽、螺环吲哚(spiroindole)、巨环内酯(伊维菌素、塞拉菌素……)等,或其混合物。优选的内寄生虫剂为伊维菌素或塞拉菌素。
根据本发明,非人类哺乳动物是指伴侣动物或宠物或任何家养的动物,并且包括但不限于狗、小狗、猫、小猫、兔、绵羊、山羊、猪、牛、沙鼠、马、小鼠、雪貂、仓鼠、马等。在一个优选实施例中,非人类哺乳动物为宠物,如犬,或如猫,更优选地为犬。狗可以是小型狗、中型狗或大型狗。
如本文所使用的“预防和/或治疗”包括控制、减少、减缓进展、根除、治愈和/或避免寄生虫感染。
在一个特定实施例中,组合物每3到6个月,更优选地3到9个月,更优选地每4到9个月,更优选地每5到9个月,更优选地每6到9个月,更优选地每6到8个月,更优选地每3个月,更优选地每4个月,更优选地每5个月,更优选地每6个月,更优选地每7个月,更优选地每8个月,且更优选地每9个月给予,更准确地说,局部给予。其具有3个月、6个月或更久,至多9个月的功效。本文所使用的“功效”是指治疗有效量的治疗和/或预防疾病的活性物质。在狗中的有效剂量(移液管体积)的实例为:
对于30mg/mL的莫昔克丁,在移液管(移液管体积)中:
-特小狗(等于<4kg):0.4mL,
-小狗(>4-10kg):1mL,
-中型狗(>10-25kg):2.5mL,
-大狗(>25-40kg):4mL,
-特大狗(>40-60kg):6mL,
-超大狗>75kg(>165lbs:7.5mL。
对于20mg/mL的莫昔克丁,在移液管(移液管体积)中:
-特小狗(等于<4kg):0.5mL,
-小狗(>4-10kg):1.25mL,
-中型狗(>10-25kg):3.125mL,
-大狗(>25-40kg):5mL,
-特大狗(>40-60kg):7.5mL,
-超大狗>75kg(>165lbs):11.25mL。
根据本发明,组合物旨在每3到9个月局部给予。根据特定实施例,组合物在时间T0以单一剂量向非人类哺乳动物给予,且接着在时间T1,至少3、4、5、6、7、8或9个月后再次给予。确切地说,可以每3个月、每4个月、每5个月、每6个月、每7个月、每8个月或每9个月重复治疗。根据此实施例,术语“每”意指重复治疗。
在另一特定实施例中,组合物在时间T0以单一剂量向非人类哺乳动物给予且稍后不重复。根据此特定实施例,术语“每”意指独特治疗,其中组合物有效至多3个、4个、5个、6个、7个、8个并且优选至多9个月。因此,本发明还涉及如本文所公开的包含莫昔克丁或其盐的兽医学或医药组合物,其优选地作为唯一活性成分,供用于预防和/或治疗非人类哺乳动物的寄生虫感染。优选地,兽医学或医药组合物为3、4、5、6、7、8或9个月长效组合物。
在一个优选实施例中,以2.5mg/kg莫昔克丁给药的动物中的血浆浓度高于0,025ng/mL,持续至少3个月或3个月的时段,持续至少6个月或6个月的时段,或持续至少7个月或7个月的时段,或持续至少8个月或8个月的时段,或持续至少9个月或9个月的时段。
在本申请的特定实施例中,莫昔克丁以介于1.5mg/kg体重(BW)与15mg/kg BW之间,尤其介于1.5mg/kg体重(BW)与3.5mg/kg BW之间,更尤其为2.5mg/kg BW,甚至更优选地为3.0mg/kg BW的量给予。
根据本发明的供使用的组合物呈液体溶液、半液体溶液、悬浮液、糊剂、乳膏、泡沫、软膏或凝胶的形式。组合物通过点滴途径,更确切地说,管线式给予局部给予。优选管线式施用以限制产品损失的风险且增强莫昔克丁的皮肤吸收。
“给予”在本文中,并且更准确地说,“管线式”意指组合物施用于动物的皮肤,从尾巴基部沿着脊柱到肩胛骨,或从背部中间沿着脊柱到肩胛骨,或更小:“管线式”施用的长度可以例如是30cm、或20cm、或15cm、或10cm、或5cm,优选长度是10cm。将组合物调配成适于动物的重量和/或尺寸的单位剂量,且将整个剂量施用到动物。归功于管线式施用方法,已知且控制通过动物皮肤扩散的莫昔克丁的量。
根据本发明,寄生虫感染由虫引起,尤其由线虫(体内寄生虫)和/或螨(体外寄生虫)引起,更尤其由犬恶丝虫和/或耳螨引起。
在根据本发明的一个实施例中,体外寄生虫为螨。猫螨来自蠕形螨科(Demodicidae)、痒螨科(Psoroptidae)、疥螨科(Sarcoptidae)、肉食螨科(Cheyletidae)、皮刺螨科(Dermanyssidae)和/或恙螨科(Trombiculidae):
-蠕形螨种:猫(cati)
-耳痒螨种:犬猫(cynotis)
-耳螨种(Notoedresspp):猫
-疥螨种:疥疮(scabiei)
-姬螯螨种(Cheyletiella spp.):布氏(blakei)、寄食(parasitovorax)
-皮刺螨种:鸡(gallinae)
-新恙螨种:秋(autumnalis)
优选的螨为耳痒螨种(耳螨)。
猫和狗螨来自袋鼠鸟虱科(Boopidae)、肉食螨科、痒螨科、疥螨科、蠕形螨科、皮刺螨科和/或恙螨科:
-姬螯螨种:牙氏(yasguri)
-耳痒螨种:犬猫
-疥螨种:疥疮
-耳螨种:猫
-蠕形螨种:犬
-皮刺螨种:鸡
-新恙螨种:秋。
优选的螨为耳痒螨种(耳螨)。
根据本发明的组合物还可以用于针对除犬心丝虫之外的体内寄生虫,更尤其是钩虫、扁虫、绦虫、鞭虫,更尤其是胃-肠道线虫、心肺线虫进行治疗。
在本发明的一个实施例中,体内寄生虫为循环系统中的线虫和/或吸虫。猫虫来自裂体科(Schistosomatidae)和/或丝虫科(Filarioidae):
-裂体吸虫种(Schistosoma spp.):日本(japonicum)、罗氏(rodhaini)
-恶丝虫种(Dirofilaria spp.):犬(immitis)
-布鲁格线虫种(Brugia spp.):彭亨(pahangi),马来(malayi)
优选的循环系统虫为恶丝虫种.(犬:犬心丝虫)。
狗虫来自裂体科、后圆科(Metastrongylidea)和/或丝虫科:
-管圆线虫种(Angiostrongylus spp.):脉(vasorum)
-裂体吸虫种:日本、梭形(spindale)、不明(incognitum)
-异比吸虫种(Heterobilharzia spp.):美洲(americana)
-恶丝虫种:犬
-布鲁格线虫种:彭亨,马来。
优选的循环系统虫为恶丝虫种(犬:犬心丝虫)。
在本发明的另一实施例中,体内寄生虫为小肠中的线虫、绦虫、吸虫和/或棘头虫(acanthocephalan)。猫虫来自蛔虫科(Ascaridoidea)、钩虫科(Ancylostomoidea)、小杆科(Rhabditoidea)、绦虫科(Diphyllobotrhiidae)、双壳科(Dilepididae)、带绦虫科(Taeniidae)、裂头科(Diphyllobothriidae)、中殖孔科(Mesocestoididae)、双穴科(Diplistomatidae)、异形科(Heterophydiae)、棘口科(Echinostomatidae)、巨吻科(Pliganthorynchidae)和/或鞭虫科(Trichuroidea):
-弓蛔线虫种(Toxoscaris spp.):狮(leonina)
-弓蛔虫种(Toxocara spp.):猫(mystax),芒果(malayensis)
-钩虫种(Ancylostoma spp.):巴西(braziliense)、锡兰(ceylanicum)、管形(tibaeforme)
-钩虫种(Uncinaria spp.):狭头(stenocephala)
-类圆线虫种(Strongyloides spp.):粪(stercocoralis)、扁头(planiceps)、猫(felis)、肿胀(tumefaciens)
-裂头绦虫种(Diphyllobothrium spp.):阔节(latum)、犬(caninum)
-棘球绦虫种(Echinococcus spp.):多房(multilocularis)、少节(oligarthrus)
-叠宫种(Spirometra spp.):曼氏(masoni)、曼森(mansonoides)、猬(erinacei)
-带绦虫种(Taenia spp.):巨颈(taeniaeformis)
-中殖孔绦虫种:线状(lineatus)
-重翼吸虫种(Alaria spp.):有翼(alata)、米氏(minessotae)、马尔希安那(marcianae)
-异形吸虫种(Heterophyes spp.):异形(heterophyes)、诺氏(nocens)
-后殖吸虫种(Metagonimus spp.):横川(yokogawai)
-缺茎吸虫种(Apophallus spp.):同利(donicum)、木氏(mulhingi)
-隐穴吸虫种(Cryptocotyle spp.):舌形(lingua)
-棘隙吸虫种(Echinochasmus spp.):叶形(perfoliatus)
-真缘吸虫科(Euparyphium spp.):獾(melis)
-隐孔吸虫种(Nanophyetus spp.):鲑(salmincola)
-巨吻棘头虫种(Macracanthorhynchus spp.):猪(hirudinaceus)、卡氏(catalinum)
-奥氏种(Onicola spp.):钟形(campanulatus)
-旋毛虫种(Trichinella spp.):锯缘(serrata)、狐(vulpis)、钟(campanula)。
狗虫来自蛔虫科、钩虫科、小杆科、绦虫科、双壳科、带绦虫科、裂头科、中殖孔科、双穴科、异形科、棘口科、巨吻科和/或鞭虫科:
-弓蛔虫种:犬、狮
-钩虫种:犬、巴西、锡兰
-钩虫种:狭头
-类圆线虫种:粪(stercoralis)
-裂头绦虫种:阔节、犬
-棘球绦虫种:细粒(granulosus)、奎氏(quinus)、俄氏(orteleppi)、多房、沃格氏(vogeli)
-叠宫种:曼氏、曼森
-带绦虫种:泡状(hydatigena)、多头(multiceps)、羊(ovis)、豆状(pisiformis)、锯齿(serialis)、肥头(crassiceps)
-中殖孔绦虫种:线状
-重翼吸虫种:有翼、美洲、犬、密西根(michiganensis)
-异形吸虫种:异形、诺氏
-后殖吸虫种:横川
-缺茎吸虫种:同利、木氏
-隐穴吸虫种:舌形
-棘隙吸虫种:叶形、伊族(ilocanum)
-隐孔吸虫种:鲑。
在本发明的另一实施例中,猫和狗体内寄生虫为皮下组织中的线虫:恶丝虫种(Dirofilariae spp.):重氏(repens)。
在本申请中,每一属包括所有相关联的物质。
在一个优选实施例中,寄生虫感染为恶丝虫病。
本发明的更优选实施例涉及一种包含莫昔克丁或其盐,其优选地作为唯一活性成分的兽医学或医药组合物,其供用于预防和/或治疗非人类哺乳动物(如狗或猫)的寄生虫感染,优选为恶丝虫病,其特征在于所述组合物以单次服用形式每3到9个月,优选地每3到6个月,更优选地每3个月局部给予所述非人类哺乳动物。优选地,莫昔克丁或其盐的量介于1.5mg/kg与3.5mg/kg BW之间,更优选地为约3mg/kg BW。
本发明的另一目标为一种治疗和/或预防非人类哺乳动物的寄生虫感染的方法,其包含每3到9个月向所述非人类哺乳动物局部给予包含莫昔克丁或其盐的兽医学或医药组合物。
本发明的一个更优选实施例是一种预防和/或治疗狗或猫的恶丝虫病的方法,其包含每3到9个月,更优选地每3到6个月,更优选地每3个月,以单次服用形式向所述狗或猫局部给予包含莫昔克丁或其盐,优选地作为唯一活性成分的组合物,其量介于1.5mg/kg与3.5mg/kg BW之间,更优选地约3mg/kg BW。
本发明的另一个目标为莫昔克丁或其盐用于制造兽医学或医药组合物的用途,其用以预防和/或治疗非人类哺乳动物的寄生虫感染,其中每3到9个月向所述非人类哺乳动物局部给予组合物。
本发明的更优选实施例为莫昔克丁或其盐,优选地作为唯一活性成分,用于制造兽医学或医药组合物的用途,其用以预防和/或治疗狗或猫的恶丝虫病,其中所述组合物包含介于1.5mg/kg与3.5mg/kg BW之间,更优选地约3mg/kg BW的量的莫昔克丁,并且所述组合物以单次服用的形式每3到9个月,优选地每3到6个月,更优选地每3个月向所述狗或猫局部给予。
本发明的另一个目标为一种适用于预防和/或治疗非人类哺乳动物的寄生虫的试剂盒,其包含如上所述的在配备有供液器尖端的移液管内的组合物。移液管可具有五个剂量:0.4mL、1mL、2.5mL、4mL和6mL。
上文对于组合物的用途所描述的所有实施例还适用于治疗方法和包含所述组合物的试剂盒,如下所述。
具体实施方式
本文中描述以下实例:制备根据本发明的组合物和其用途。这些实例为说明性的且绝不限制。
实例
实例1:调配物1
在制造容器中,已制备根据下文所描绘的组合物的莫昔克丁溶液。在搅拌一部分苯甲醇的情况下,已添加丁基羟基甲苯(BHT)、碳酸亚丙酯和莫昔克丁。然后,用苯甲醇补充体积。
实例2:调配物2
在制造容器中,已制备根据下文所描绘的组合物的莫昔克丁溶液。在搅拌一部分异丙醇的情况下,已添加BHT、二丙二醇单甲醚(DPGME)和莫昔克丁。然后,用异丙醇补充体积。
实例3:调配物3
已使用与实例1相同的方法。
实例4:调配物4
已使用与实例2相同的方法。
实例5:调配物5
在制造容器中,已制备根据下文所描绘的组合物的莫昔克丁溶液。在搅拌一部分苯甲醇的情况下,已添加丁基羟基甲苯、碳酸亚丙酯、聚乙烯吡咯烷酮和莫昔克丁。然后,用苯甲醇补充体积。
实例6:调配物6
在制造容器中,已制备根据下文所描绘的组合物的莫昔克丁溶液。在搅拌一部分异丙醇的情况下,已添加丁基羟基甲苯、DPGME、聚乙烯吡咯烷酮和莫昔克丁。然后,用异丙醇补充体积。
实例7:调配物7
在制造容器中,已制备根据下文所描绘的组合物的莫昔克丁溶液。在搅拌一部分苯甲醇的情况下,已添加丁基羟基甲苯(BHT)、中链甘油三酯和乙基纤维素。当溶液均匀时,添加莫昔克丁。然后,用苯甲醇补充体积。
实例8:调配物8
在制造容器中,已制备根据下文所描绘的组合物的莫昔克丁溶液。在搅拌一部分苯甲醇的情况下,已添加丁基羟基甲苯(BHT)、中链甘油三酯、PEG-35蓖麻油和莫昔克丁。然后,用苯甲醇补充体积。
实例9:调配物9
在制造容器中,已制备根据下文所描绘的组合物的莫昔克丁溶液。在搅拌一部分苯甲醇的情况下,已添加丁基羟基甲苯(BHT)、中链甘油三酯和乙基纤维素。当溶液均匀时,已添加莫昔克丁。然后,用苯甲醇补充体积。
实例10:调配物10
在制造容器中,已制备根据下文所描绘的组合物的莫昔克丁溶液。在搅拌一部分苯甲醇的情况下,已添加丁基羟基甲苯(BHT)、中链甘油三酯和乙基纤维素。当溶液均匀时,已添加莫昔克丁和PEG-35蓖麻油。然后,用苯甲醇补充体积。
实例11:狗中的药物动力学(参见图1)
调配物1的样品已以3mg/kg的莫昔克丁剂量向三只比格犬给予。药物动力学概况已与以0.17mg/kg的剂量给予的可注射产品进行比较。平均胞质概况展现大于5ng/ml的最大浓度(Cmax),其适合于肠道虫根除,和类似或高于的胞质持久性,其实现在6个月期间预防犬心丝虫。
在独特局部施用之后,对莫昔克丁敏感的大部分体内寄生虫可以得到靶向。
实例12:狗中的药物动力学(参见图2)
实例7-10中所描述的局部调配物A106、A73、A107和A108已经在狗中测试。已经用单一剂量(0.1ml/kg)的各调配物处理8只比格犬的群组,并且取样血液以用于药物动力学。局部调配物充分耐受。吸收是快速、持续且显著的。在治疗后超过210天期间观察到类似于Proheart(实例1和图1)的持续血液水平。
Claims (16)
1.一种兽医学或医药组合物,其包含莫昔克丁或其盐,所述组合物供用于预防和/或治疗非人类哺乳动物的寄生虫感染,其特征在于所述组合物每3到9个月局部给予。
2.一种兽医学或医药组合物,其包含作为唯一活性成分的莫昔克丁或其盐,所述组合物供用于预防和/或治疗非人类哺乳动物的寄生虫感染,其特征在于所述组合物每3到9个月局部给予。
3.根据权利要求1或2所述的供使用的兽医学或医药组合物,其中莫昔克丁的浓度介于1-4w/v%之间。
4.根据权利要求1到3中任一项所述的供使用的兽医学或医药组合物,其中所述非人类哺乳动物为宠物,如犬。
5.根据权利要求1到4中任一项所述的供使用的兽医学或医药组合物,其中所述寄生虫感染由线虫引起。
6.根据权利要求5所述的供使用的兽医学或医药组合物,其中所述线虫为犬恶丝虫(dirofilariaimmitis)。
7.根据权利要求1到6中任一项所述的供使用的兽医学或医药组合物,其中所述寄生虫感染由耳螨引起。
8.根据权利要求1到7中任一项所述的供使用的兽医学或医药组合物,其中所述组合物每3到6个月给予。
9.根据权利要求1到8中任一项所述的供使用的兽医学或医药组合物,其中所述组合物每9个月给予。
10.根据权利要求1到9中任一项所述的供使用的兽医学或医药组合物,其中所述组合物的局部给予为管线式给予。
11.根据权利要求1到10中任一项所述的供使用的兽医学或医药组合物,其中所述组合物的局部给予为点滴式给予。
12.根据权利要求1到11中任一项所述的供使用的兽医学或医药组合物,其中所述组合物进一步包含丁基羟基甲苯作为抗氧化剂。
13.根据权利要求1到12中任一项所述的供使用的兽医学或医药组合物,其中所述组合物进一步包含选自以下的溶剂:苯甲醇、异丙醇、中链甘油三酯、碳酸亚丙酯、二丙二醇单甲醚和其混合物。
14.根据权利要求1到13中任一项所述的供使用的兽医学或医药组合物,其中所述组合物包含:
约3w/v%莫昔克丁、
约1w/v%乙基纤维素、
约0.05w/v%BHT、
约32w/v%中链TG,以及
苯甲醇QS 1mL。
15.根据权利要求1到14中任一项所述的供使用的兽医学或医药组合物,其中所述莫昔克丁以介于约1.5mg/kg体重与3.5mg/kg体重之间,优选约3.0mg/kg体重的量给予。
16.一种治疗和/或预防非人类哺乳动物的寄生虫感染的方法,其包含每3到9个月向所述非人类哺乳动物局部给予包含莫昔克丁或其盐的兽医学或医药组合物。
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- 2018-11-23 KR KR1020207015258A patent/KR20200090165A/ko active Search and Examination
- 2018-11-23 AU AU2018372008A patent/AU2018372008B2/en active Active
- 2018-11-23 EP EP18804026.5A patent/EP3713567A1/en not_active Withdrawn
- 2018-11-23 BR BR112020010291-1A patent/BR112020010291A2/pt not_active Application Discontinuation
- 2018-11-23 WO PCT/EP2018/082437 patent/WO2019101961A1/en unknown
- 2018-11-23 CA CA3082048A patent/CA3082048A1/en active Pending
- 2018-11-23 US US16/765,301 patent/US20200281848A1/en not_active Abandoned
- 2018-11-23 JP JP2020528262A patent/JP7274479B2/ja active Active
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KR20200090165A (ko) | 2020-07-28 |
CA3082048A1 (en) | 2019-05-31 |
EP3713567A1 (en) | 2020-09-30 |
AU2018372008B2 (en) | 2024-03-28 |
BR112020010291A2 (pt) | 2020-11-17 |
WO2019101961A1 (en) | 2019-05-31 |
US20200281848A1 (en) | 2020-09-10 |
JP7274479B2 (ja) | 2023-05-16 |
AU2018372008A1 (en) | 2020-05-28 |
JP2021504350A (ja) | 2021-02-15 |
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