CN113842460A - 一种他汀类药物纳米晶及其制备方法和用途 - Google Patents
一种他汀类药物纳米晶及其制备方法和用途 Download PDFInfo
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- CN113842460A CN113842460A CN202111338585.4A CN202111338585A CN113842460A CN 113842460 A CN113842460 A CN 113842460A CN 202111338585 A CN202111338585 A CN 202111338585A CN 113842460 A CN113842460 A CN 113842460A
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Abstract
本发明提供了一种他汀类药物纳米晶及其制备方法和用途。本发明的他汀类药物的纳米晶,主要由他汀类药物、稳定剂和冻干保护剂为原料制成;所述的他汀类药物、稳定剂、冻干保护剂重量的比例为(1~10):(2~12):(0~40)。本发明具有如下技术效果:本发明的他汀类药物纳米晶,相对于他汀类游离药物,显示出在组织缺血部位的血管密度显著增加,特别是增加了在肺部的蓄积并增强肺部血管密度,具有显著性的治疗组织缺血性疾病疗效,可以增加缺血组织的血管密度,疏通血管。
Description
技术领域
本发明涉及一种他汀类药物纳米晶、其制备方法及其应用,属于医药技术领域。
背景技术
组织缺血性疾病,常见肺动脉高压,心肌缺血、下肢缺血、脑梗死、脑栓塞等疾病,其特征为组织和器官的血管病变,进而引起组织的缺血性病变。目前暂没有很好的治疗方法。以肺动脉高压为例,其主要特征是肺血管阻力进行性升高,最终导致患者右心衰竭而死亡。病因复杂、诊断治疗棘手是该领域长期发展缓慢的主要原因。在西方国家,肺动脉高压已成为逐渐得到重视的一大类心血管疾病。肺动脉高压本身没有特异性临床表现,最常见的首发症状是活动后气短、晕厥或眩晕、胸痛、咯血等。需要强调:肺动脉高压患者首次出现症状需要认真记录,首次出现症状的时间,需要尽可能详细,因为首次出现症状的时间距离确诊为肺动脉高压的时间与预后有明确的相关性。最新研究表明,他汀类药物可治疗一氧化氮介导的血管舒张和血管松弛,还可以促进组织中的血管发生。但这些有益效果都是全身作用,并且需使用高剂量药物才能产生疗效,高剂量药物施用会增加副作用风险。因此,如果能进行局部给药或者施用具有靶向性的药物能降低副作用的发生。
纳米技术能够有效地提高难溶性药物的溶解度、促进药物溶出和提高生物利用度。近十几年,纳米晶体药物的研究逐渐成为纳米制剂研究的热点。纳米晶体药物无需载体材料,是将纯药物形成亚微米颗粒的胶状分散体系,依靠电荷保护剂和立体保护剂维持稳定。不论是难溶于水的药物,还是既难溶于水又难溶于油的药物,都可以通过纳米晶体技术增加药物的溶解度,提高药物的生物利用度。可通过分散法或沉淀法制备纳米晶药物。
中国专利申请CN201910261564.3,在背景技术中提到:纳米晶体技术是指通过控制活性成分晶体生长或者将活性成分晶体粉碎成其中任何一个维度小于1000nm的晶体的技术。纳米晶体一般包括活性成分和防止晶体生长的非活性成分。将难溶活性成分制备成纳米晶体后,比表面积大幅增加,晶体表面饱和蒸气压改变,导致溶解度和溶出速度均增加,进而提高生物利用度,改善治疗效果。
目前,现有技术主要报道了纳米晶具有能够提高生物利用度的效果,尚未有其他效果相关的报道。
发明内容
经过大量的研究,发明人发现,采用特定配比的稳定剂、冻干保护剂和他汀类药物为原料制备得到的他汀类药物的纳米晶,相对于他汀类游离药物,显示出在缺血性组织中血管密度显著增加,改善组织缺血情况。以肺动脉高压为例,他汀类药物纳米晶能够显著增加肺部血管密度,从而在肺动脉高压的治疗中具有显著效果。而且他汀类药物的纳米晶易制备且副作用低,采用纳米沉淀法即可制备。
因而,本发明要解决的技术问题之一是他汀类药物的纳米晶体制备。本实施方案通过解决目前游离的他汀类药物在治疗中存在生物利用度低,对血管生成效果差等问题,通过一种纳米沉淀法制备的他汀类纳米晶。能够实现除提高生物利用度外,还具有显著增强血管密度的疗效,从而在组织缺血性疾病的治疗中具有显著效果。
本发明中,关于“纳米晶”的定义如下:纳米晶药物,是指尺寸小于1μm、无载体、含少量稳定剂,溶解速度和饱和溶解度提高,能够稳定存在的晶态或无定型态药物。
本发明的技术方案如下:
本发明的第一个目的是提供一种他汀类药物纳米晶。
本发明的他汀类药物纳米晶主要由他汀类药物、稳定剂和冻干保护剂为原料制成;所述的他汀类药物、稳定剂、冻干保护剂重量的比例为(1~10):(2~12):(0~40)。
优选地,
本发明中,所述的他汀类药物选自匹伐他汀或其钙盐、阿托伐他汀或其钙盐、辛伐他汀、洛伐他汀、氟伐他汀中的一种或多种。
在纳米晶生产过程中为了避免在固化过程中纳米晶粒重新聚集降低溶出速率和生物利用度,常常需要加入稳定剂。所选的稳定剂需要能够紧密吸附于纳米晶表面,同时具有适宜的亲水亲油平衡值。本发明中,所述的稳定剂选自HPMC、HPC、CMC-Na、聚乙烯醇、聚乙烯吡咯烷酮、泊洛沙姆、吐温-80、TPGS、十二烷基硫酸钠、磷脂、海藻酸钠、壳聚糖、Plantacare 2000、皂苷中的一种或多种。
由于在纳米晶冷冻干燥的过程中,会产生多种应力使其变性。为了保护药物的活性,通常在冻干过程中添加活性物质的保护剂,使其在冻干之后药物性质保持不变。本发明中,所述的冻干保护剂选自糖类、多羟基化合物、蛋白质、表面活性剂,优选自甘露醇、蔗糖和海藻糖。
进一步地,所述的纳米晶主要由他汀类药物、稳定剂、冻干保护剂及水化介质为原料制成,水化介质为注射用水或PBS缓冲液。
进一步地,所述的他汀类药物为匹伐他汀钙,所述的他汀类药物、稳定剂、冻干保护剂的重量比为(1~10):(2~12):(0~40)。更优选地,本发明的纳米晶中,所述的他汀类药物、稳定剂、冻干保护剂重量的比例为1:(6~10):(15~20)。
本发明中,他汀类药物纳米晶的给药方式为静脉注射或静脉滴注。
本发明中,他汀类药物纳米晶的给药剂量可以是临床上匹伐他汀类药物的常用剂量范围1~4mg/kg。
本发明的第二个目的是提供所述的他汀类药物纳米晶的制备方法。
本发明的他汀类药物纳米晶的制备方法采用纳米沉淀法。
优选地,本发明的制备方法,具体步骤如下:
(1)配制水相:稳定剂溶于注射用水中;
(2)配制有机相;称取他汀类药物溶于有机溶剂中;
(3)将有机相与水相混合,采用减压蒸发将有机相蒸发除去,加入冻干保护剂水溶液进行混合,充氮气,即制备得到他汀类药物纳米晶粗分散体系;
(4)将粗分散体系用超声分散,依次过0.45μm和0.22μm的滤膜,然后西林瓶灌装,氮气封装,冷冻干燥即得他汀类纳米晶冻干粉。
优选地,
所述的步骤1)中,所述有机溶剂选自丙酮、二氯甲烷、乙醇中的一种或者多种。
本发明的第三个目的是提供所述的他汀类药物纳米晶在制备治疗组织缺血性疾病的药物中的用途,所述组织缺血性疾病包括肺动脉高压、下肢缺血、心肌缺血、脑缺血及肾脏缺血等。
与现有技术相比,本发明具有如下有益效果:相对于他汀类游离药物,显示出在组织缺血部位的血管密度显著增加,特别是增加了在肺部的蓄积并增强肺部血管密度,具有显著性的治疗组织缺血性疾病疗效,可以增加缺血组织的血管密度,疏通血管。
具体来说,具有如下技术效果:
1)本发明通过优化稳定剂和他汀类药物的配比,同时采用纳米沉淀法制备了纳米晶,粒度在190nm左右。这有利于增强药物局部释放并减少毒副作用,满足临床需求。
2)本发明制备的纳米晶体,工艺稳定,可控性和重现性好,易于工业化生产。
3)本发明制备的他汀类药物纳米晶,相对于他汀类游离药物,显示出在缺血性组织中血管密度显著增加,改善组织缺血情况。
4)本发明通过测定了他汀类药物纳米晶在肺动脉高压模型中的治疗效果,相比于游离的他汀类药物,其治疗效果更佳,肺部血管密度显著增加。
5)本发明通过大鼠活体成像分析和大鼠肺部血管造影分析发现,在相同剂量下,匹伐他汀类药物的纳米晶,相对于匹伐他汀类游离药物,显示出显著增强的肺部蓄积并增强血管密度的疗效,具有显著的扩张血管效果,治疗3周后匹伐他汀纳米晶治疗组右心室压力降至42mm Hg,阿托伐他汀纳米晶治疗组右心室压力为48mmHg,正常组右心室压力为34mmHg,PBS治疗组右心室压力为80mm Hg,游离匹伐他汀钙治疗组为75mm Hg。以上结果显示他汀类药物纳米晶在肺动脉高压的治疗中具有诱导肺部血管新生,且肺部血管密度增加能有效降低右心室压即降低肺动脉压力,对肺动脉高压具有显著治疗效果。
附图说明
图1是实施例1中纳米晶的粒径分布、zeta电位和TEM电镜图。
图2是实施例2中纳米晶的粒径分布和TEM电镜图。
图3是实施例3中纳米晶的粒径分布、zeta电位和TEM电镜图。
图4是实施例4中纳米晶的粒径分布和TEM电镜图。
图5是实施例5中纳米晶的粒径分布和TEM电镜图。
图6是匹伐他汀钙纳米晶和阿托伐他汀钙纳米晶的体外释放曲线。
图7是模型大鼠的生存率分析。
图8为大鼠活体成像分析。
图9为大鼠肺部血管造影分析。
图10为大鼠肺部HE染色分析。
图11是大鼠心脏心室壁厚度。
具体实施方式
本发明中材料来源如下:
匹伐他汀钙购买于日产化学工业。
阿托伐他汀钙购买于上海阿拉丁生化科技股份有限公司。
聚乙烯醇、泊洛沙姆、甘露醇、海藻糖购买于麦克林试剂有限公司。
乙醇和丙酮购买于中国国药有限公司。
磷钨酸购买于国药集团化学试剂有限公司。
6周大的SD雄性大鼠是从上海吉辉实验动物饲养有限公司处购买。
实施例1匹伐他汀钙纳米晶的制备
采用纳米沉淀法制备。
具体步骤如下:
1)水相溶液配制:注射用水,40℃保温;称取聚乙烯醇(黏度5.0mPa.S)800mg溶于其中,加热至70℃直至聚乙烯醇溶解。后降温至40℃备用。
2)有机相配制:称取匹伐他汀钙100mg溶于有机溶剂丙酮30ml中直至完全溶解。
3)将有机相缓慢滴加至水相中,连接旋转蒸发仪,转速为100rpm/min,水浴温度为35℃,待有机相蒸发完全后,加入甘露醇水溶液300mL(水溶液中含1500mg甘露醇)于25℃进行混合,充氮气,即制备得到匹伐他汀类药物纳米晶粗分散体系。
4)将粗分散体系用超声分散5min,依次过0.45μm和0.22μm的滤膜,然后西林瓶氮气封装,冷冻干燥即得匹伐他汀类纳米晶冻干粉。
实施例2匹伐他汀钙纳米晶的制备
采用纳米沉淀法制备。
具体步骤如下:
1)水相溶液配制:注射用水,40℃保温;称取泊洛沙姆645mg溶于其中,超声直至泊洛沙姆溶解。
2)有机相配制:称取匹伐他汀钙100mg溶于有机溶剂丙酮30ml中直至完全溶解。
3)将有机相缓慢滴加至水相中,连接旋转蒸发仪,转速为100rpm/min,水浴温度为35℃,待有机相蒸发完全后,加入甘露醇水溶液300mL(水溶液中含1500mg甘露醇)于25℃进行混合,充氮气,即制备得到匹伐他汀类药物纳米晶粗分散体系。
4)将粗分散体系用超声分散5min,依次过0.45μm和0.22μm的滤膜,然后西林瓶氮气封装,冷冻干燥即得匹伐他汀类纳米晶冻干粉。
实施例3匹伐他汀钙纳米晶的制备
采用纳米沉淀法制备。
具体步骤如下:
1)水相溶液配制:注射用水,40℃保温;称取泊洛沙姆645mg溶于其中,超声直至泊洛沙姆溶解。
2)有机相配制:称取匹伐他汀钙100mg溶于有机溶剂丙酮30ml中直至完全溶解。
3)将有机相缓慢滴加至水相中,连接旋转蒸发仪,转速为100rpm/min,水浴温度为35℃,待有机相蒸发完全后,加入海藻糖水溶液300mL(水溶液中含1500mg海藻糖)于25℃进行混合,充氮气,即制备得到匹伐他汀类药物纳米晶粗分散体系。
4)将粗分散体系用超声分散5min,依次过0.45μm和0.22μm的滤膜,然后西林瓶氮气封装,冷冻干燥即得匹伐他汀类纳米晶冻干粉。
实施例4阿托伐他汀钙纳米晶的制备
采用纳米沉淀法制备。
具体步骤如下:
1)水相溶液配制:注射用水,40℃保温;称取聚乙烯醇(黏度5.0mPa.S)800mg溶于其中,加热至70℃直至聚乙烯醇溶解。后降温至40℃备用。
2)有机相配制:称取阿托伐他汀钙80mg溶于有机溶剂丙酮30ml中直至完全溶解。
3)将有机相缓慢滴加至水相中,连接旋转蒸发仪,转速为100rpm/min,水浴温度为35℃,待有机相蒸发完全后,加入甘露醇水溶液300mL(水溶液中含1500mg甘露醇)于25℃进行混合,充氮气,即制备得到匹伐他汀类药物纳米晶粗分散体系。
4)将粗分散体系用超声分散5min,依次过0.45μm和0.22μm的滤膜,然后西林瓶氮气封装,冷冻干燥即得阿托伐他汀类纳米晶冻干粉。
实施例5阿托伐他汀钙纳米晶的制备
采用纳米沉淀法制备。
具体步骤如下:
1)水相溶液配制:注射用水,40℃保温;称取泊洛沙姆800mg溶于其中,超声直至溶解。
2)有机相配制:称取阿托伐他汀钙80mg溶于有机溶剂丙酮30ml中直至完全溶解。
3)将有机相缓慢滴加至水相中,连接旋转蒸发仪,转速为100rpm/min,水浴温度为35℃,待有机相蒸发完全后,加入甘露醇水溶液300mL(水溶液中含1500mg甘露醇)于25℃进行混合,充氮气,即制备得到匹伐他汀类药物纳米晶粗分散体系。
4)将粗分散体系用超声分散5min,依次过0.45μm和0.22μm的滤膜,然后西林瓶氮气封装,冷冻干燥即得阿托伐他汀类纳米晶冻干粉。
对照例1游离匹伐他汀钙的制备
将匹伐他汀钙溶于CMC-Na中,加热至40℃保温5分钟,然后超声10分钟,直至无沉淀物,否则继续超声。
对照例2游离阿托伐他汀钙的制备
将阿托伐他汀钙溶于CMC-Na中,加热至40℃保温5分钟,然后超声10分钟,直至无沉淀物,否则继续超声。
试验例1纳米晶的表征
将实施例1-5制得的样品分别稀释至合适浓度,分别使用马尔文动态光散射仪测定纳米晶的粒径分布和zeta电位。将稀释后的样品滴加到铜网上再用2%磷钨酸负染,使用透射电镜捕获纳米粒子的图像信息。使用透射电子显微镜拍摄的纳米晶证实了纳米晶的粒径为190nm左右,实施例1-5制得的样品TEM图像结果见图1~图5。
可以看出,他汀类药物纳米晶平均粒径大小为190nm左右,Zeta电位为0~-2.99mv。TEM图像显示纳米晶的粒径大小约为190nm。
试验例2体外药物释放测定
体外释放是以生理盐水为介质使用透析法考察的。
将实施例1,实施例4中制备的匹伐他汀钙纳米晶和阿托伐他汀钙纳米晶加入到截留分子量为3000Da的透析袋中,将透析袋置于西林瓶中,加入释放介质,将西林瓶置于37℃水浴振荡器中每分钟震荡100次。在预定设计好的时间点(0.25h,0.5h,1h,2h,4h,6h,8h,12h,24h,36h)取300μL样品并加入等温新鲜介质。药物含量使用高效液相进行测定,所有的实验都设置平行三组重复实验,结果取三组平均值。
匹伐他汀钙定量方法:在波长为245nm下进样10μL样品,使用0.3%稀醋酸和甲醇(1:3)作为流动相用于测定匹伐他汀钙的含量。
阿托伐他汀钙定量方法:在波长为245nm下进样10μL样品,使用40:60的乙腈:0.02mol/L醋酸铵缓冲溶液(冰醋酸调至pH=5.2)作为流动相用于测定阿托伐他汀钙的含量。
结果见图6。
从图6可以看出,在生理盐水37℃匹伐他汀钙纳米晶与阿托伐他汀钙纳米晶的释放行为相似,在24h内完全释放。
试验例3体内肺动脉高压治疗效果
本实施例考察匹伐他汀钙纳米晶在肺动脉高压模型上的治疗效果。本发明采用血管造影来测定纳米晶对肺动脉高压治疗的效果。
药效学实验:
所有动物实验均获华东师范大学动物伦理审查委员会登记审查并按照制度程序进行。SD大鼠皮下注射60mg/kg的野百合碱,16天后观察大鼠呼吸是否顺畅。大鼠心率加快、呼吸不畅且口鼻周有分泌物表示造模型成功。选择造模型成功的大鼠进行治疗。
1.实验动物:
SD大鼠28只,体重250g左右,雄性。
2.实验分组:
将实验动物随机分成4组,每组7只。分别通过尾静脉注射3mg/kg匹伐他汀钙纳米晶(实施例1制备)、3mg/kg游离匹伐他汀钙(对照例1制备)、3mg/kg阿托伐他汀钙纳米晶(实施例4制备)和PBS。每隔三天给药一次,一共给药3次。
3.实验方法:
(1)生存期:每隔两天测量大鼠体重,记录大鼠存活时间,38天后将动物安乐死。使用对数秩检验对生存曲线进行统计分析。*表示有显着差异(*,p<0.05;**,p<0.01;***,p<0.001;****,p<0.0001)。
(2)检测右心室收缩压:野百合碱给药3周后,各组动物用戊巴比妥钠麻醉,将大鼠仰位固定于手术台,使用聚乙烯导管通过颈静脉插入右心室,用血流动力学测量系统测量右心室收缩压并记录。
(3)肺部血管造影:各组动物用戊巴比妥钠麻醉,将大鼠仰位固定于手术台,开胸后暴露心脏,将稀释的肝素钠(5U/mL,20mL)经右心室和心脏注射。使用聚乙烯导管插入肺动脉并用手术线固定。在左心房做了一个小切口,加入2mL稀释的肝素钠,使用连续注射泵以2毫升/分钟的速度泵送。将microfil中的固化剂混合黄色纤维素(体积比4:5)以0.1mL/min的速度泵入导管,直到黄色造影剂在肺表面均匀可见。在4℃下聚合24小时,将肺取出浸泡在乙醇中,用立体显微镜拍摄。
(4)活体成像:制备包裹Dir的匹伐他汀钙纳米晶,将动物经过尾静脉分别注射包裹Dir的匹伐他汀钙纳米晶、游离Dir,在24小时内将小鼠麻醉,并使用小动物活体成像仪对动物进行全身成像。
(5)测量右心室壁厚度和组织HE染色:38天后将动物安乐死,取出心和肺组织并浸泡在10%福尔马林溶液中。通过石蜡切片机和HE染色液对组织进行HE染色。在显微镜下拍摄染色切片。
4.实验结果:
(1)生存期:从图7可以看出,生存率曲线显示:PBS组的中位生存期为29天,游离匹伐他汀钙组的中位生存期为35天。而匹伐他汀钙纳米晶组和阿托伐他汀钙纳米晶组中位生存期大于PBS组和游离匹伐他汀钙组,说明注射纳米晶能够提高大鼠存活率。
(2)活体成像:注射包裹Dir的纳米晶后,药物能够进入肺部,而游离的DIR并未能进入大鼠肺部(图8)。
(3)肺部血管造影:从图9和图10看出,使用匹伐他汀钙纳米晶组或阿托伐他汀钙纳米晶组治疗之后肺部血管密度明显增加。
(4)右心室收缩压:正常大鼠平均右心室收缩压为34mm Hg,匹伐他汀钙纳米晶治疗组治疗3周后右心室收缩压平均降至42mm Hg,阿托伐他汀纳米晶治疗组右心室压力为48mmHg,PBS组右心室平均收缩压为80mm Hg,游离匹伐他汀钙治疗组平均为75mm Hg。结果显示纳米晶治疗能有效降低右心室收缩压即降低肺动脉压力,对肺动脉高压具有显著治疗效果。
(5)右心室壁厚度:从图11可以看出,经过纳米晶治疗后,肺动脉高压大鼠的右心室壁厚度显著低于PBS组。证明治疗具有显著的治疗效果。
结果表明:与PBS组进行对比,匹伐他汀钙纳米晶及阿托伐他汀纳米晶能有效的治疗肺动脉高压,游离的匹伐他汀钙和PBS组之间没有显著差异性。在相同剂量下,匹伐他汀钙纳米晶,与游离的匹伐他汀钙以及PBS对照组相比,显示出显著增强的肺部蓄积并增强血管密度和降低右心室收缩压。
以上所述仅为本发明的较佳实施例而已,并不用于限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种他汀类药物纳米晶,其特征在于,主要由他汀类药物、稳定剂和冻干保护剂为原料制成;所述的他汀类药物、稳定剂、冻干保护剂重量的比例为(1~10):(2~12):(0~40)。
2.根据权利要求1所述的他汀类药物纳米晶,其特征在于,所述的他汀类药物选自匹伐他汀或其钙盐、阿托伐他汀或其钙盐、辛伐他汀、洛伐他汀、氟伐他汀中的一种或多种。
3.根据权利要求1所述的他汀类药物纳米晶,其特征在于,所述的稳定剂选自HPMC、HPC、CMC-Na、聚乙烯醇、聚乙烯吡咯烷酮、泊洛沙姆、吐温-80、TPGS、十二烷基硫酸钠、磷脂、海藻酸钠、壳聚糖、Plantacare 2000、皂苷中的一种或多种。
4.根据权利要求1所述的他汀类药物纳米晶,其特征在于,所述的冻干保护剂选自糖类、多羟基化合物、蛋白质、表面活性剂。
5.根据权利要求1所述的他汀类药物纳米晶,其特征在于,所述的纳米晶主要由他汀类药物、稳定剂、冻干保护剂及水化介质为原料制成,水化介质为注射用水或PBS 缓冲液。
6.根据权利要求2所述的他汀类药物纳米晶,其特征在于,所述的他汀类药物为匹伐他汀钙,所述的他汀类药物、稳定剂、冻干保护剂的重量比为(1~10):(2~12):(0~40)。
7.如权利要求1-6任意一项所述的他汀类药物纳米晶的制备方法,其特征在于,采用纳米沉淀法。
8.根据权利要求7所述的制备方法,其特征在于,具体步骤如下:
(1) 配制水相:稳定剂溶于注射用水中;
(2) 配制有机相;称取他汀类药物溶于有机溶剂中;
(3) 将有机相与水相混合,采用减压蒸发将有机相蒸发除去,加入冻干保护剂水溶液进行混合,充氮气,即制备得到他汀类药物纳米晶粗分散体系;
(4) 将粗分散体系用超声分散,依次过0.45 μm和0.22 μm的滤膜,然后西林瓶灌装,氮气封装,冷冻干燥即得他汀类纳米晶冻干粉。
9.根据权利要求8所述的制备方法,其特征在于,所述有机溶剂选自丙酮、二氯甲烷、乙醇中的一种或者多种。
10.如权利要求1-6任意一项所述的他汀类药物纳米晶在制备治疗组织缺血性疾病的药物中的用途,所述组织缺血性疾病包括肺动脉高压、下肢缺血、心肌缺血、脑缺血、肾脏缺血等。
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