CN117323327A - 胆绿素或其衍生物在制备预防或延缓衰老药物中的用途 - Google Patents
胆绿素或其衍生物在制备预防或延缓衰老药物中的用途 Download PDFInfo
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- CN117323327A CN117323327A CN202311337685.4A CN202311337685A CN117323327A CN 117323327 A CN117323327 A CN 117323327A CN 202311337685 A CN202311337685 A CN 202311337685A CN 117323327 A CN117323327 A CN 117323327A
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- medicament
- biliverdin
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Abstract
本发明属于生物医药技术领域,公开了胆绿素或其衍生物在制备预防或延缓衰老药物中的用途以及用于预防或延缓衰老的药物,所述药物包括有效剂量的包含胆绿素和/或其衍生物以任何比例作为活性成分的药物和其他预防或延缓衰老的药物。本发明使用胆绿素盐酸盐配制的药剂灌胃老年布氏田鼠,分别测试了田鼠的认知能力、记忆能力、抓握能力、衰老相关分泌表型和β‑半乳糖苷酶阳性细胞数。结果表明,胆绿素均显著提高了田鼠的认知能力、记忆能力和抓握能力,并显著降低了衰老相关分泌表型和β‑半乳糖苷酶阳性细胞数。因此,本发明所公开的胆绿素制剂具有良好的预防或延缓衰老的效果。
Description
技术领域
本发明属于生物医药技术领域,本发明涉及胆绿素或其衍生物在制备预防或延缓衰老药物中的用途,本发明还涉及用于预防或延缓衰老的药物,所述药物包括有效剂量的包含胆绿素和/或其衍生物以任何比例作为活性成分的药物和其他预防或延缓衰老的药物。
背景技术
人口老龄化已成为一个日益增长的全球趋势,也是全世界高度关注的问题。了解老龄化过程和机制对于应对我们社会的老龄化挑战至关重要。此外,衰老是调节自然和养殖状态下动物个体生长发育、种群增长的重要过程。揭示动物衰老调节的关键因素和机制将有利于加深我们对生命系统的生态和进化模式和过程的理解,并有利于人类和动物健康的管理。
衰老(Aging或Senescence)指随着年龄增加,机体逐渐出现的退行性变化。例如,记忆力减退、认知能力下降、肌肉和骨骼质量的丧失导致运动表现低下。免疫系统会随着年龄的增长而退化,衰老的一个主要标志是炎症水平升高,即出现一种称为衰老相关分泌表型(Senescence Associated Secretory Phenotype,SASP)的促炎症表型。SASP由分泌的细胞因子(TNF-α,IL-6,成熟的IL-1β)、趋化因子、生长因子和蛋白酶的高度复杂混合物组成。细胞衰老的过程中,一个主要特征就是溶酶体β-半乳糖苷酶的活性增加,被称作衰老相关的β-半乳糖苷酶(Senescence-Associatedβ-galactosidase,SA-β-gal)。在不同类型的衰老细胞中以及在体内和体外的实验里,SA-β-gal都是识别衰老的广泛使用的标志物。
胆绿素的英文名称为Biliverdin,分子式为C33H34N4O6,其结构式如下式(I)所示。
在代谢过程中,血红素被血红素氧合酶催化成胆绿素、一氧化碳和铁离子。胆绿素被胆绿素还原酶还原成胆红素。在胆绿素和胆红素相互转化过程中可以不断的消耗自由基,形成一个抗氧化还原系统,所以胆绿素抗氧化是近年来的研究热点。胆绿素可以通过NF-κB和MAPK等信号通路发挥抗炎作用,减轻缺血再灌注导致的器官损伤。此外,胆绿素还可减轻同种异体器官移植的免疫排斥,抑制血管平滑肌细胞增殖以及延缓细胞衰老。因此,胆绿素有望开发成预防或延缓衰老药物,为衰老干预提供一个新思路。
发明内容
一方面,本发明涉及一种胆绿素或其衍生物在制备预防或延缓衰老药物中的用途,所述胆绿素(下文也称“化合物”)的结构如下式(I)所示。
另一方面,本发明涉及一种用于预防或延缓衰老的药物,所述药物包括有效剂量的包含胆绿素和/或其衍生物以任何比例作为活性成分的药物和其他预防或延缓衰老的药物。
与现有技术相比,本发明的优点和有益效果特别是在于:
1.本发明发现了胆绿素在制备预防或延缓衰老药物中的新用途。
2.本发明为衰老干预提供了一个新思路。
附图说明
图1为胆绿素实验组(简称“胆绿素组”)与对照组认知行为的差异。
图2为胆绿素实验组与对照组记忆行为的差异。
图3为胆绿素实验组与对照组抓握能力(简称“抓力”)的差异。
图4为Elisa检测胆绿素实验组与对照组对老年田鼠衰老相关分泌表型的影响。
图5为β-半乳糖苷酶染色检测胆绿素实验组与对照组对老年田鼠β-半乳糖苷酶的阳性细胞数量。
具体实施方式
一般定义
本文所用术语“预防或延缓”是指当用于疾病或病症时,与未给予化合物或药物的哺乳动物(特别是人、鼠)相比,所述化合物或药物能降低体内的医学病症症状的频率或推迟其发病。
本文所用术语“有效剂量”是指足够量的药剂,以提供所期望的生物学或治疗结果。该结果可以是疾病的征象、症状或原因中的一种或多种的减少、改善、缓解、减轻、延缓和/或缓和,或生物系统的任何其他所期望的改变。例如,用于预防或延缓用途的“有效剂量”是指提供以使疾病或病症的临床症状显著减轻、而不产生过度的毒副作用的化合物或药物的量。
本文所用术语“剂量”是指每千克(kg)哺乳动物体重的活性物质的重量(例如,毫克(mg)、克(g))。
本文所用术语“药学上可接受的”是指在合理的医学判断范围内,适合与哺乳动物(特别是人、鼠)的组织接触,无过度的毒性、刺激性、过敏反应和其他与合理的效益/风险比相当的问题并发症的那些化合物、材料、组合物和/或剂型。
本文所用术语“药学上可接受的辅料”是指将本发明的化合物或药物中的活性成分传送给哺乳动物(特别是人、鼠)的药学上可接受的载体、溶剂、悬浮剂或赋形剂。
本文所用术语“老年布氏田鼠”是指20月龄以上的布氏田鼠。
根据世界卫生组织对老年人的定义,本文所用术语“老年人”是指60周岁以上的人。
一方面,本发明涉及一种胆绿素或其衍生物在制备预防或延缓衰老药物中的用途,所述胆绿素的结构如下式(I)所示。
在本发明的具体实施方案中,所述衍生物为在式(I)的基础结构上添加一种或多种化学基团而来;优选地,所述衍生物为对所述式(I)的基础结构进行化学上可接受的改造而来,优选地,所述化学上可接受的改造为对所述式(I)的基础结构进行一个或多个组成元素的替换、或元素间化学键的改造;优选地,所述衍生物为在所述式(I)的基础结构上添加一种或多种化学基团并同时对所述式(I)的基础结构进行化学上可接受的改造而来;优选地,所述化学上可接受的改造为对所述式(I)的基础结构进行一个或多个组成元素的替换、或元素间化学键的改造。
在本发明的具体实施方案中,所述衍生物为式(I)的药学上可接受的立体异构体、N-氧化物、溶剂合物、盐或酯,或它们的混合物。优选地,所述衍生物为式(I)的药学上可接受的盐。
本发明包括本发明化合物作为单一立体异构体,或作为所述立体异构体的任何混合物(例如,以任何比例的(R)或(S)异构体)的所有可能的立体异构体。本发明化合物的单一立体异构体(例如,单一对映异构体或单一非对映异构体)的分离可通过任何合适的现有技术方法,例如色谱法,尤其是手性色谱法来实现。
此外,本发明的化合物可以作为N-氧化物存在,其定义为本发明的化合物的至少一个氮被氧化。本发明包括所有这些可能的N-氧化物。
本发明还涉及本发明化合物的有用形式,例如代谢物、溶剂合物、前药、盐,特别是药学上可接受的盐和/或共沉淀物。
此外,本发明的化合物可能以游离形式存在,例如作为游离碱,或作为游离酸,或作为两性离子,或以盐的形式存在。所述盐可以是任何盐,有机或无机加成盐,特别是任何药学上可接受的有机或无机加成盐,其通常用于药学,或用于例如分离或纯化本发明的化合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂缔合的化合物或其盐的形式。这种物理缔合可包括氢键键合。常规溶剂包括甲醇、DMSO、DMF和乙醚等。本文所述的化合物可制备成,例如,结晶形式,且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下,所述溶剂合物将能够分离,例如,当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括甲醇合物。
术语“药学上可接受的盐”是指本发明化合物的无机或有机酸加成盐。例如,参见S.M.Berge等人“Pharmaceutical Salts,”J.Pharm.Sci.1977,66,1-19。
合适的药学上可接受的盐可以是本发明化合物的酸加成盐,例如与无机酸或“矿物酸”的酸加成盐,所述酸例如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、双硫酸、磷酸或硝酸;或与有机酸的酸加成盐,所述酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、十二烷酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基-2-萘甲酸、烟酸、帕莫酸、果胶酸、3-苯基丙酸、特戊酸、2-羟基乙磺酸、衣康酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡萄糖庚酸、甘油磷酸、天冬氨酸、磺基水杨酸或硫氰酸。
此外,具有足够酸性的本发明化合物的另一种合适的药学上可接受的盐是碱金属盐,例如钠盐或钾盐;碱土金属盐,例如钙盐、镁盐或锶盐;或铝盐或锌盐;或衍生自氨或衍生自具有1至20个碳原子的有机伯胺、仲胺或叔胺的铵盐,所述伯胺、仲胺或叔胺例如乙胺、二乙胺、三乙胺、乙基二异丙胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己基胺、二甲基氨基乙醇、二乙基氨基乙醇、三(羟基甲基)氨基甲烷、普鲁卡因、二苄胺、N-甲基吗啉、精氨酸、赖氨酸、1,2-乙二胺、N-甲基哌啶、N-甲基-葡糖胺、N,N-二甲基-葡糖胺、N-乙基-葡糖胺、1,6-己二胺、葡萄糖胺、肌氨酸、丝氨醇、2-氨基-1,3-丙二醇、3-氨基-1,2-丙二醇、4-氨基-1,2,3-丁三醇;或具有1至20个碳原子的季铵离子的盐,所述季铵离子例如四甲基铵、四乙基铵、四(正丙基)铵、四(正丁基)铵、N-苄基-N,N,N-三甲基铵、胆碱或苯扎氯铵。
本领域技术人员将进一步认识到要求保护的化合物的酸加成盐可以通过多种已知方法中的任一种使本发明的化合物与合适的无机或有机酸反应进行制备。或者,本发明的酸性化合物的碱金属盐和碱土金属盐可以通过各种已知方法使本发明的化合物与合适的碱反应进行制备。
本发明包括本发明化合物作为单一盐,或作为所述盐以任何比例的任何混合物的所有可能的盐。
在本文(特别是在实施例部分)中,对于本发明的实施例,当化合物作为与相应的碱或酸的盐形式被提及时,通过相应的制备和/或纯化方法获得的所述盐形式的确切化学计量组成在大多数情况下是未知的。
除非另有说明,否则与盐有关的化学名称或结构式的后缀,例如“盐酸盐”、“三氟乙酸盐”、“钠盐”或“×HCl”、“×CF3COOH”、“×Na+”,表示一种盐形式,其盐形式的化学计量未指定。
此外,本发明包括本发明化合物所有可能的结晶形式或多晶型物,或者作为单一多晶型物,或者作为多于一种多晶型物以任何比例的混合物。
此外,本发明还包括本发明化合物的前药。术语“前药”在此表示其本身可以是生物活性的或无生物活性的,但是它们在体内的停留时间期间转化(例如代谢或水解)为本发明的化合物。
在本发明的具体实施方案中,根据本发明所制备的药物用于提高衰老导致的认知能力的降低。
在本发明的具体实施方案中,根据本发明所制备的药物用于提高衰老导致的记忆能力的降低。
在本发明的具体实施方案中,根据本发明所制备的药物用于降低衰老导致的衰老相关分泌表型TNF-α、IL-6和成熟的IL-1β的升高。
在本发明的具体实施方案中,根据本发明所制备的药物用于降低衰老导致的β-半乳糖苷酶阳性细胞数的增多。
在本发明的具体实施方案中,根据本发明所制备的药物用于预防或延缓老年哺乳动物,特别是老年人、鼠的衰老。
在本发明的具体实施方案中,根据本发明所制备的药物包括胆绿素和/或其衍生物以任何比例作为活性成分。
在本发明的具体实施方案中,根据本发明所制备的药物还包括药学上可接受的辅料,优选地,所述药物包括载体或赋形剂。
在本发明的优选实施方案中,药学上可接受的辅料可以是液体或固体,包括但不限于:pH调节剂、表面活性剂、碳水化合物、佐剂、抗氧化剂、螯合剂、离子强度增强剂、防腐剂、载剂、助流剂、甜味剂、染料/着色剂、增味剂、润湿剂、分散剂、悬浮剂、稳定剂、缓冲剂、等渗剂、溶剂、乳化剂、喷雾剂、压缩空气或其它适宜的气体,或其它适宜的与药物化合物合用的非活性成分。更具体而言,合适的辅料可以是本领域常用于小分子化合物给药的辅料。辅料的实例包括各种乳糖、甘露醇、油类(如玉米油)、缓冲剂(如PBS、生理盐水、聚乙二醇、甘油、聚丙二醇、二甲亚砜)、酰胺类(如二甲基乙酰胺)、蛋白质(如白蛋白)、去污剂(如吐温80)以及单糖和低聚多糖(如葡萄糖、乳糖、环糊精和淀粉)。
在本发明的具体实施方案中,根据本发明所制备的药物用于配制为口服制剂或注射制剂。
在本发明的某些实施方案中,根据本发明所制备的注射制剂为冻干制剂。
在本发明的某些实施方案中,所述注射制剂的给药方式包括静脉注射、肌肉注射、皮下注射或其他药物递送方式。
在本发明的某些实施方案中,根据本发明所制备的口服制剂为口服液、片剂、胶囊剂、颗粒剂、软胶丸、粉剂和滴丸剂。
在本发明的某些实施方案中,所述口服液可以制成水和油的悬浮液、溶液、乳浊液、糖浆,也可以制成干品,用前补充水或其他合适的媒质。如需要可添加调味剂或着色剂。
另一方面,本发明涉及一种用于预防或延缓衰老的药物,所述药物包括有效剂量的前述任一项包含胆绿素和/或其衍生物以任何比例作为活性成分的药物和其他预防或延缓衰老的药物。
在本发明的某些实施方案中,胆绿素和/或其衍生物可以与其他活性成分或药物联合给药,额外预防或延缓衰老的成分或药物选自:雷帕霉素、senolytics、二甲双胍、阿卡波糖、亚精胺、NAD+补充剂、锂、白藜芦醇、达沙替尼、槲皮素、姜黄素、虾青素、熊果苷等。
下面将结合具体实施例,对本发明作进一步说明。本领域技术人员将会理解,提供这些实施例的目的仅用于说明本发明而非用于限定本发明的范围。除非特别说明,本发明采用的试验方法、试剂以及设备均为本技术领域的常规方法、试剂和设备。
实施例
一般说明
实验动物:以下实施例使用雄性老年(20月龄)布氏田鼠(以下简称田鼠),平均体重为30-40g,由中国科学院动物研究所饲养,饲养条件为:将田鼠在聚乙烯塑料笼(30×15×20cm)中以玉米芯为垫料单笼饲养,并提供标准兔颗粒(购自北京科奥生物科技有限公司)和水,供它们自由饮食。所有田鼠均饲养在温度为23±0.5℃、光暗比14h:10h的室内。
实施例1:胆绿素的配制
将胆绿素盐酸盐(购自Sigma-Aldrich,货号30891,纯度≥97.0%(TLC))溶解于0.1mol/L的NaOH水溶液,用1mol/L的HCL调pH值至7.4,根据所选田鼠的平均体重、灌胃体积300μL以及灌胃胆绿素12.5mg/kg的剂量,计算用生理盐水倍比稀释的实验浓度并稀释至该实验浓度,用0.2μM的滤膜过滤除菌,分装至5mL无菌离心管后,用锡箔纸包裹,贮存于-20℃备用。
实施例2:胆绿素灌胃给予老年田鼠。
将20月龄的雄性田鼠分为两组,实验组9只,对照组8只,其中在实验组中,将实施例1中配制的胆绿素溶液用无菌注射器以300μL的体积每天给予田鼠灌胃一次,持续6周。在对照组中,灌胃田鼠300μL的生理盐水。
实施例3:测试胆绿素处理后老年田鼠的认知能力。
采用新物体识别测试来分别评估实验组和对照组田鼠的认知能力。首先,在一个开阔的长方形测试箱里放入两个相同的物体,所述两个相同的物体间有一定的间距并均匀分布在测试箱中。然后,将田鼠放入箱子中接受训练,使它们适应并熟悉物体的位置和形状。适应10分钟后,移走田鼠,使用75%酒精擦拭测试箱内侧以及物体。将测试箱中的一个物体替换为另一个高度和体积基本一致但形状和外观不同的物体。1小时后,再次移进田鼠进行测试,测试持续5分钟。记录田鼠探索每个物体所花费的时间。该行为依赖于啮齿动物自发的倾向,即花更多的时间探索一个新奇的物体,而不是熟悉的物体。认知指数的计算公式为:
检测结果如图1所示,结果表明,经胆绿素处理后,老年田鼠的认知能力显著增强。
实施例4:测试胆绿素处理后老年田鼠的记忆能力。
采用Y迷宫装置测试来分别评估实验组和对照组田鼠的记忆能力。Y迷宫装置由三只臂(长宽高分别为40cm、8cm、30cm)和一个连接区组成,三臂相互夹角为120°,三只臂分别为:“起始”臂、“食物”臂和“新异”臂,我们将三只臂连接Y迷宫连接区的一端称之为“连接端”,另一端称之为“末端”。在每只臂的末端内侧处的相同位置关联不同形状相同颜色的标记物。实验前,将田鼠禁食12小时。首先,我们把食物放进“食物”臂的末端,打开“起始”臂和“食物”臂的连接端,并将“新异”臂的连接端保持关闭状态。然后,将田鼠面壁放在“起始”臂的末端,计时5分钟,使田鼠以适应并了解食物位置以及形状标记。随后,将田鼠从Y迷宫中移出,取出食物,使用75%酒精擦拭Y迷宫装置内侧。1小时后,打开“新异”臂的连接端。将田鼠面壁放在“起始”臂的末端,自由活动5分钟,记录田鼠访问“食物”臂和“新异”臂上花费的累计时间。记忆指数的计算公式为:
检测结果如图2所示,结果表明,经胆绿素处理后,老年田鼠的记忆能力显著增强。
实施例5:测试胆绿素处理后老年田鼠的抓握能力。
采用抓力计(购自ugo-basile Italy,型号47200)分别评估实验组和对照组田鼠的抓握能力。具体是将田鼠的两只前爪握住抓力计的把手,实验者用手抓住田鼠的尾巴以恒定的速度向后拖动,直到田鼠的前爪松开把手,抓力计自动记录田鼠的最大抓力值,每只田鼠测试6次,取平均值。
检测结果如图3所示,结果表明,经胆绿素处理后,老年田鼠的抓握能力显著增强。本实验无田鼠死亡,并且未发现毒性以及副作用。
实施例6:测试胆绿素处理后老年田鼠的衰老相关分泌表型。
采用Elisa检测分别评估实验组和对照组田鼠血清中的衰老相关分泌表型。具体是在摘除田鼠眼球后,从田鼠的眼眶处使用血清分离管收集血液样品,分离血清前需让样品凝结30分钟,然后在1000×g下离心10分钟并及时检测。分别使用小鼠TNF-αELISA试剂盒(Mouse TNF-alpha ELISAKit,购自ABclonal,货号RK00027)、小鼠IL-6ELISA试剂盒(MouseIL-6ELISAKit,购自ABclonal,货号RK00008)和小鼠IL-1βELISA试剂盒(Mouse IL-1betaELISA Kit,购自ABclonal,货号RK00006)在酶标仪(购自美国BIOTEK,型号ELX-800)上使用上述血清样品测定田鼠血清中TNF-α、IL-6和成熟的IL-1β的含量。
检测结果如图4所示,结果表明,经胆绿素处理后,老年田鼠血清中的衰老相关分泌表型TNF-α、IL-6和成熟的IL-1β的含量显著下降。
实施例7:测试胆绿素处理后老年田鼠的β-半乳糖苷酶阳性细胞数。
采用β-半乳糖苷酶染色试剂盒(购自Solarbio,货号G1580)分别评估实验组和对照组田鼠脑、肝脏和肌肉组织中β-半乳糖苷酶阳性细胞数。具体是在前述实验结束后,处死田鼠,分别取出田鼠的脑、肝脏和肌肉组织,并分别制作冷冻切片,然后使用β-半乳糖苷酶染色试剂盒进行染色。
检测结果如图5所示,结果表明,经胆绿素处理后,老年田鼠脑、肝脏和肌肉组织中β-半乳糖苷酶阳性细胞数显著下降。
Claims (14)
1.胆绿素或其衍生物在制备预防或延缓衰老药物中的用途,所述胆绿素的结构如下式(I)所示。
2.根据权利要求1所述的用途,其特征在于,所述衍生物为在式(I)的基础结构上添加一种或多种化学基团而来;优选地,所述衍生物为对所述式(I)的基础结构进行化学上可接受的改造而来,优选地,所述化学上可接受的改造为对所述式(I)的基础结构进行一个或多个组成元素的替换、或元素间化学键的改造;优选地,所述衍生物为在所述式(I)的基础结构上添加一种或多种化学基团并同时对所述式(I)的基础结构进行化学上可接受的改造而来;优选地,所述化学上可接受的改造为对所述式(I)的基础结构进行一个或多个组成元素的替换、或元素间化学键的改造。
3.根据权利要求1所述的用途,其特征在于,所述衍生物为式(I)的药学上可接受的立体异构体、N-氧化物、溶剂合物、盐或酯,或它们的混合物,优选地,所述衍生物为式(I)的药学上可接受的盐。
4.根据权利要求1-3中任一项所述的用途,其特征在于,所述药物用于提高衰老导致的认知能力的降低。
5.根据权利要求1-3中任一项所述的用途,其特征在于,所述药物用于提高衰老导致的记忆能力的降低。
6.根据权利要求1-3中任一项所述的用途,其特征在于,所述药物用于降低衰老导致的衰老相关分泌表型TNF-α、IL-6和成熟的IL-1β的升高。
7.根据权利要求1-3中任一项所述的用途,其特征在于,所述药物用于降低衰老导致的β-半乳糖苷酶阳性细胞数的增多。
8.根据权利要求1-3中任一项所述的用途,其特征在于,所述药物用于预防或延缓老年哺乳动物,优选老年人、鼠的衰老。
9.根据权利要求1-3中任一项所述的用途,其特征在于,所述药物包括胆绿素和/或其衍生物以任何比例作为活性成分。
10.根据权利要求9所述的用途,其特征在于,所述药物还包括药学上可接受的辅料,优选地,所述药物包括载体或赋形剂。
11.根据权利要求10所述的用途,其特征在于,所述药物用于配制为口服制剂或注射制剂。
12.根据权利要求11所述的用途,其特征在于,所述注射制剂为冻干制剂。
13.根据权利要求11所述的用途,其特征在于,所述口服制剂为口服液、片剂、胶囊剂、颗粒剂、软胶丸、粉剂和滴丸剂。
14.一种用于预防或延缓衰老的药物,其特征在于,所述药物包括有效剂量的权利要求9-13中任一项所述药物和其他预防或延缓衰老的药物。
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