CN112451653A - 谷胱甘肽在制备防治葛根素注射剂诱发的血管内溶血的药物上的应用 - Google Patents
谷胱甘肽在制备防治葛根素注射剂诱发的血管内溶血的药物上的应用 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
本发明涉及谷胱甘肽与葛根素的配伍应用方法,该应用方法是将谷胱甘肽与葛根素配伍制成含葛根素的注射剂,或者先用谷胱甘肽,再用葛根素,有效克服了葛根素注射剂的偶发性溶血不良反应,提高了葛根素注射给药的安全性。
Description
技术领域
本发明涉及谷胱甘肽的医药用途,具体涉及在葛根素注射剂中的应用。
背景技术
红细胞在血液循环中至关重要 ,维持红细胞正常生物功能须依赖红细胞膜的完整和弹性。一旦膜发生缺失或脆性增加, 红细胞就可能破裂, 形成溶血。而红细胞膜在自由基介导下的氧化被认为是造成红细胞损伤的重要原因。细胞中的氧自由基会攻击膜磷脂层会诱发链式反应, 发生脂质过氧化 ,膜脆性增加,细胞肿胀 、破裂,发生溶血。已知红细胞的生存和功能依赖抗氧化保护***的完整性。一旦遭受氧化损伤,红细胞就破裂、破坏,呈现溶血现象。谷胱甘肽上的-SH 更易氧化, 从而能保护细胞内的血红蛋白,CAT 及细胞膜上脂蛋白的-SH 不致氧化。缺乏GSH 一方面造成红细胞中的生物大分子如 CAT ,膜上的脂蛋白 , 血红蛋白的-SH 极易氧化 , 导致膜上脂质过氧化产物积聚、血红蛋白变性 、海恩茨氏体(Heinz bodies)形成 ,从而影响了红细胞的变形性和流动性, 最终发生溶血。谷胱甘肽缓解膜脂蛋白的氧化和血红蛋白的变性进程 ,从而抑制红细胞氧化性溶血。提示,谷胱甘肽水平与氧化性溶血成负相关关系。镰刀性贫血,溶血的发生也与谷胱甘肽的耗竭有关(E. E. Onukak , E. C. Akwiwu , J. O. Akpotuzor et al. Glutathione andBilirubin Concentrations as Markersof Oxidative Stress Measured among SickleCell Anaemia Subjects Attending University of Calabar Teaching Hospital,Calabar Nigeria. International Blood Research & Reviews, 2019,10(2): 1-6)。乙酰苯肼是一种强氧化剂 ,在体内 APH 与氧合血红蛋白作用, 产生苯二嗪自由基 ,后者能使血红蛋白分子变性 ,并激起膜脂类的脂质过氧化作用, 促使红细胞膜崩溃, 最后引起溶血。乙酰苯肼还可使谷胱甘肽含量明显降低。实验结果提示,一些具有抗氧化的生物活性肽,能够减轻氧化性溶血,保护红细胞(Qiao-Hui Zeng, Jing Jing Wang, Ying-HuiZhang et al. Recovery and identification bioactive peptides from proteinisolate of Spirulina platensis and their in vitro effectiveness againstoxidative stress-induced erythrocyte hemolysis. J Sci Food Agric,2020, 100:3776–3782)。轻度耗竭谷胱甘肽过氧化物酶,能够引起红细胞的氧化,产生溶血性贫血。维持谷胱甘肽过氧化物酶的活性,能够抑制红细胞的氧化应激,抵抗红细胞的溶血(K.Rankaljeet, G.Preety , R. Pulkit et al. Protective Role of Selenium AgainstHemolytic Anemia Is Mediated Through Redox Modulation. Biological TraceElement Research, 2019, 189:490–500)。因此,谷胱甘肽在防止红细胞的溶血上具有一定作用。
葛根素是从豆科植物野葛的干燥根中提取的单体—异黄酮化合物,4’,7一二羟基-8-β-D葡萄糖基异黄酮。临床上广泛用于心血管疾病的治疗。目前应用于临床的含有葛根素的药物制剂主要是注射剂。随着葛根素的广泛使用,近年来有关葛根素不良反应的报道也越来越多,引起医药界广泛关注。通过分析近20年中药不良反应,葛根素注射液位列第18位。国家药品不良反应监测中心曾在2003年1月第3期《药品不良反应信息通报》中通报了葛根素注射液的不良反应。大多数研究者认为,葛根素注射液是以50%丙二醇为溶媒配制而成,不可避免因提取工艺、技术等方面的差异产生纯度不够,引入杂质而导致各种反应(见徐向辉撰写的《对临床使用葛根素注射液出现不良反应的分析》,上海中医药杂志,2006,40(8):71-72;和徐世国撰写的《葛根素的临床应用及不良反应》,时珍国医国药,2005,16(12):1307-1308)。在对2000-2004年国内主要医药期刊报道的63例葛根素不良反应进行分析后发现,男40例,女23例;年龄34~81(57.5±23.5)岁。所有病例均为静脉滴注给药。给药剂量为0.4~0.6 g,药品稀释液均为5%葡萄糖液、生理盐水、5%葡萄糖盐水等。反应发生时间最快者为3 min,最慢者为13 d ,均发生在给药过程中。首次给药出现反应者47例,重复给药出现反应者16例。统计显示,常见不良反应有***反应(发热、颤抖等,24例)、过敏性休克(4例)、溶血性贫血(13例)、肝损害、肾损害(7例)、药物热(10例)、死亡(5例)。所有病例均无过敏史,反应发生后停药经对症处理均恢复(死亡病例除外)。用药剂量及所用稀释液在药品说明书提示范围内,所有反应均肯定为葛根素所致。不良反应的发生与所患疾病无关,与年龄、性别无关,与药物稀释液无多大联系。与患者体质差异有关,特别是年老体弱者易发生。反应发生时间的长短与中药制剂起效缓慢程度有关(见全心荣撰写的《葛根素不良反应63例文献分析》,现代中西医结合杂志,2005,14(1):140)。一患者静滴葛根素约10min,即出现为急性肾功能不全,溶血性贫血(见关铭华撰写的《葛根素致溶血性贫血》,药物不良反应杂志,2003,5:291)。因此,葛根素引起的溶血性贫血是葛根素本身所致。
发明内容
本发明的目的在于提供谷胱甘肽的医药新用途,即谷胱甘肽在葛根素注射剂中的应用,谷胱甘肽可有效防治葛根素诱发的血管内溶血不良反应。
实际上,本发明涉及谷胱甘肽在制备葛根素注射用复方制剂时的应用,也可以和葛根素注射剂以注射和输液的方式临时配合应用,或者在以注射和输液的方式应用谷胱甘肽后再接着应用葛根素注射剂。
为达到上述目的,本发明采用的技术方案是:谷胱甘肽在制备葛根素注射剂的新用途。谷胱甘肽和葛根素注射剂以注射和输液的方式临时配合应用。在以注射和输液的方式应用谷胱甘肽后再接着应用葛根素注射剂。
上述技术方案中的有关内容解释如下:
1、上述方案中,所述的注射剂,含有以下重量份药物:谷胱甘肽l~50份,葛根素l~50000份。
2、上述方案中,所述的注射剂,还含有辅料1~50重量份,注射用水l~10000重量份。所述的辅料为碳酸氢钠溶液、葡萄糖液、丙二醇液、葡萄糖盐水、氯化钠注射液或生理盐水。
3、上述方案中,所述的注射剂可以是临床上可接受的注射液、粉针或输液。
4、上述方案中,所述的注射剂的制备方法如下所述:
所述的粉针,由谷胱甘肽和葛根素混合、灭菌制得;或者由谷胱甘肽、葛根素和氯化钠混合,加注射用水溶解,再用盐酸或碳酸氢钠溶液调整pH值至5.0-8.5,过滤,滤液灭菌后灌封在粉状安瓿中再次灭菌制得;
所述的注射液。由谷胱甘肽、葛根素和氯化钠混合,加注射用水溶解,再用盐酸或碳酸氢钠溶液调整pH值5.0-8.5,过滤,滤液灌封在安瓿中灭菌制得。或谷胱甘肽由5%葡萄糖液,5%葡萄糖盐水,丙二醇液(由丙二醇与生理盐水按体积比(1:1)配置而成,内含丙二醇0.5ml/ml),氯化钠注射液或生理盐水溶解,再与葛根素注射剂混合,过滤,滤液灌封在安瓿中灭菌制得。
所述的输液,由谷胱甘肽、葛根素和氯化钠混合,加注射用水溶解,再用盐酸或碳酸氢钠溶液调整pH值5.0-8.5,溶解,过滤,滤液灌封在盐水玻璃瓶中灭菌制得。或谷胱甘肽由5%葡萄糖液,5%葡萄糖盐水,丙二醇液(由丙二醇与生理盐水按体积比(1:1)配置而成,内含丙二醇0.5ml/ml),氯化钠注射液或生理盐水溶解,再与葛根素注射剂混合,过滤,滤液灌封在安瓿中灭菌制得。
5、上述方案中,所述的临时配合应用是指在医院,在应用葛根素注射剂的同时与谷胱甘肽混合一同输液或注射。
6、上述方案中,所述的在以注射和输液的方式应用谷胱甘肽后再接着应用葛根素注射剂,是指在医院,以注射和输液的方式应用谷胱甘肽后,再接着以注射和输液的方式应用葛根素注射剂。
葛根素具有有扩张冠状动脉和脑血管、降低心肌耗氧量,改善微循环和抗血小板聚集的作用。临床上用于辅助治疗冠心病、心绞痛、心肌梗塞、视网膜动静脉阻塞、突发性耳聋及缺血性脑血管病、小儿病毒性心肌炎、糖尿病等。葛根素可以与谷胱甘肽配伍制成复方葛根素注射剂用于防治多种疾病,如用于防治糖尿病周围神经病变、高血压合并糖尿病、糖尿病肾病、急性脑梗死、稳定型心绞痛、下肢深部静脉血栓形成以及椎基底动脉供血不足性眩晕等。但是,含葛根素注射剂中的葛根素极易引起血管内溶血。谷胱甘肽不仅具有保肝、健脑等多种生理活性,本发明者经过研究证实谷胱甘肽还具有拮抗由葛根素诱发的血管内溶血不良反应,提高葛根素注射给药的安全性。
下面结合一些试验进一步来说明本发明的目的和所能达到的效果。
本实验参考《中药、天然药物刺激性和溶血性研究的技术指导原则》对溶血试验进行预试验,发现4-6mM葛根素能够引起1%的兔红细胞溶血10%,体外溶血试验发生概率为100%,溶血试验结果均得到重现,说明方法可重复。该方法可用于发现注射剂的潜在的偶发溶血现象,是进行注射剂新药开发判断是否存在偶发性溶血的可行试验方法,有利于减少不良反应的发生,提高注射剂的安全性。本发明以家兔为实验动物模型,研究谷胱甘肽对葛根素溶液溶血不良反应的作用及效果。
一、谷胱甘肽拮抗含有葛根素的溶液溶血不良反应的作用及效果
(一)葛根素注射剂溶血试验
研究谷胱甘肽与葛根素合用对家兔红细胞的影响。家兔给药方法, 葛根素处理组及给药(葛根素注射剂+谷胱甘肽)家兔分为 2组,每组 5 只。给葛根素注射剂(15 mg•kg-1)+谷胱甘肽(0.16g•kg-1)组经耳缘静脉,每日根据体质量分别按照 0.16g/kg•kg-1剂量给药。葛根素处理组家兔给予葛根素,每日根据体质量按照 15 mg•kg-1剂量给药。1 个给药周期,每周期 10 d。给药前及每周期第6天给药后 24 h 采血。
取葛根素注射剂组家兔的红细胞,分别加入一定剂量的谷胱甘肽与葛根素,10min后,观察红细胞的状态和溶血发生率,用X2检验统计分析实验结果,探寻谷胱甘肽对葛根素注射剂偶发性溶血的对抗作用。现将结果报告如下:
1实验材料
1.1受试药物
谷胱甘肽注射剂①,谷胱甘肽购自重庆药友制药有限责任公司,用电子天平准确称取谷胱甘肽12.29mg,溶于生理盐水溶液,用10mL容量瓶将谷胱甘肽溶液定容至10mL,此为注射剂①,浓度为4mmol•L-1。用微孔滤膜(0.22μm)过滤除菌,4℃保存备用。
注射剂②:用灭菌生理盐水将注射剂①稀释至2mmol•L-1,10mL, 4℃保存备用。
注射剂③:用灭菌生理盐水将注射剂①稀释至1mmol•L-1,10mL, 4℃保存备用。
葛根素注射剂④:由浙江康恩贝制药股份有限公司提供,2mL,产品批号090501,每mL注射剂含葛根素50mg。
葛根素注射剂(250mM)⑤:用电子天平精确称取葛根素粉末(购自江苏天晟药品有限公司)1.041g,用40%二甲基亚砜(DMSO,DZ0231,AMRESCO)溶解,超声助溶,生理盐水溶液稀释至9mL,容量瓶定容至10mL,溶液颜色呈无色(配置环境:超净工作台中进行)。溶剂为40%DMSO溶液。用微孔滤膜(0.22μm)过滤除菌,4℃保存。
复方葛根素注射剂⑥:取注射剂①0.04mL,注射剂④0.20 mL,混匀,共0.24mL,组成注射剂⑥。每mL注射剂含葛根素41.67mg、谷胱甘肽204.8μg。
复方葛根素注射剂⑦:取注射剂②0.04mL,注射剂④0.20 mL,混匀,共0.24mL,组成注射剂⑦。每mL注射剂含葛根素41.67mg、谷胱甘肽102.4μg。
复方葛根素注射剂⑧:取注射剂③0.04mL,注射剂④0.20 mL,混匀,共0.24mL,组成注射剂⑧。每mL注射剂含葛根素41.67mg、谷胱甘肽51.2μg。
复方葛根素注射剂⑨:取注射剂①0.04mL,注射剂⑤0.099 mL,混匀,共0.14mL,组成注射剂⑨。每mL注射剂含葛根素73.61mg、谷胱甘肽351.1μg。
复方葛根素注射剂⑩:取注射剂②0.04mL,注射剂⑤0.099 mL,混匀,共0.14mL,组成注射剂⑩。每mL注射剂含葛根素73.61mg、谷胱甘肽175.5μg。
复方葛根素注射剂○11:取注射剂③0.04mL,注射剂⑤0.099 mL,混匀,共0.14mL,组成注射剂○11。每mL注射剂含葛根素73.61mg、谷胱甘肽87.8μg。
1.2实验动物
家兔10只(2.5Kg左右),由西北农林科技大学动物实验中心提供。在室温15~25℃,相对湿度50%条件下饲养。
1.3试剂、仪器
氯化钠注射剂,石药银湖制药有限公司生产;注射用水,自制;TGL-16B高速离心机,湖南星科科学仪器有限公司;HPY-01B生化培养箱,黄石恒丰医疗器械有限公司;BIO-RAD680酶标仪;酶标条购由江苏海门三和兴亚医疗器械厂生产,购自陕西省杨凌宝鑫器材有限公司。
2方法
2.1红细胞悬浮液的制备
家兔10只,分成葛根素注射剂组和葛根素注射剂+谷胱甘肽处理组,在耳缘静脉注射第6天后,24 h 采血。分别进行溶血实验。每只家兔心脏采血10mL,肝素钠(江苏万邦生化医药股份有限公司)160IU抗凝后,置于刻度离心管内,以2000转/分钟离心10分钟,弃去血浆,加入适量的氯化钠注射剂洗涤,离心弃去上清液及白细胞层。再加适量生理盐水摇匀、离心,如此反复洗涤3次,至离心后上清液呈无色透明为止。将所得压积红细胞用生理盐水稀释成11%(体积比)的红细胞悬液。至此,红细胞悬液准备完毕。
2.2葛根素溶液体外溶血实验设计
设葛根素溶液作用于红细胞的浓度为6mM(0.00259g•mL-1 )。设阴性对照组,溶剂对照组(用DMSO代替葛根素溶液作用于红细胞),药物处理组及阳性对照组。用METTLER TOLEDO台式pH计测定葛根素溶液的pH值为7.16。
按照下表1中所示,分别往试管里加入相应成分,注意加样顺序。每加完一种成分后,都轻轻摇匀。等体系中所有成分都加入体系中后,轻轻震荡混匀,放置37℃的生化培养箱温育。10min后观察溶血和凝聚反应。凝聚反应判定方法:若溶液中有红棕色或棕红色絮状沉淀,振摇后不分散,表明有红细胞凝集发生,若凝聚物振摇后又能均匀分散,则为假凝集,若凝聚物不被摇散者则为真凝集。接着各管按照5000rpm/min 条件离心,肉眼观察上清液颜色。取上清液,于540nm波长处检测光吸收值(OD值)。根据2005年《中药、天然药物刺激性和溶血性研究的技术指导原则》,按公式计算各组各管的溶血率(%):
溶血率(%)=(药物处理组OD值-阴性对照组OD值)/(阳性对照管组OD值-阴性对照组OD值)
参考评价标准:溶血率>5% 表明有溶血现象发生,并进行统计学处理。
表1 葛根素溶液与谷胱甘肽体外溶血实验分组设计
3 结果
葛根素每日根据体质量按照 15 mg•kg-1剂量处理时,同时给予0.16g•kg-1剂量的谷胱甘肽,没有发现实验家兔溶血。本试验又考察了在葛根素6mM浓度时,40μM、20μM、10μM谷胱甘肽对5只葛根素注射的家兔红细胞的影响,同时进行葛根素注射剂④、⑤的偶发性溶血实验研究,实验结果均有详细记录。用X2检验统计分析,结果见表2。
注:与生理盐水阴性组比较,a P<0.01;与葛根素注射剂组比较,b P<0.01
结果显示:生理盐水组未出现溶血,注射用水组全部溶血:与生理盐水组比较,葛根素
注射剂④、⑤组全部出现溶血,溶血发生率与生理盐水组存在极显著差异(P<0.01);溶血试
验结果均得到重现,说明本溶血实验方法稳定可靠,试验结果可重复。与葛根素注射剂④、
⑤组比较,复方葛根素注射剂⑥、⑦、⑧、⑨、⑩、各组均未出现溶血,复方葛根素注射剂
⑥、⑦、⑧、⑨、⑩、各组溶血发生率均与葛根素注射剂④、⑤组存在极显著差异(P<0.01);
与生理盐水组比较,复方葛根素注射剂⑥、⑦、⑧、⑨、⑩、各组溶血发生率均与生理盐水
组无差异(P>0.05);复方葛根素注射剂⑥、⑦、⑧、⑨、⑩、各组与葛根素注射剂④、⑤组葛
根素浓度相同,均为6mM,但复方葛根素注射剂⑥和⑨、⑦和⑩、⑧和分别含40μM、20μM、10
μM谷胱甘肽,而葛根素注射剂④、⑤各组不含谷胱甘肽。
以上结果提示:不同浓度的谷胱甘肽与葛根素配伍应用,均可拮抗由葛根素诱发的溶血不良反应,并可使发生率降低至生理盐水水平。
以上实验结果显示:葛根素能引发溶血,含有葛根素的注射剂均有可能引发溶血,在加入谷胱甘肽后,均可消除含葛根素的溶血不良反应。
上述试验结果提示:葛根素注射液以及葛根素与谷胱甘肽配伍制成的注射剂未见溶血反应的发生。
因此,在制备含葛根素的注射液时或应用葛根素注射液时,加入谷胱甘肽,可消除葛根素引起的溶血不良反应,提高了葛根素注射给药的安全性。
本发明的优点是:在制备含葛根素的注射液时或应用葛根素注射液时,加入谷胱甘肽,具有较好的拮抗由葛根素诱发的血管内溶血不良反应,价廉,无毒副作用,安全。
下面结合实施例对本发明作进一步描述:
具体实施方式:
实施例l:(复方葛根素注射液的制备)
取谷胱甘肽15mg,葛根素10 g,加入氯化钠9 g,加水至1000mL,用1mol/l盐酸或碳酸氢钠溶液调整pH至5.0—8.5,过滤,滤液灌封在2、5或10mL的安瓿中,100℃灭菌30 min,得到注射液。本品可用于辅助治疗冠心病、心绞痛、心肌梗死、视网膜动、静脉阻塞、突发性耳聋及缺血性脑血管病、小儿病毒性心肌炎、糖尿病等。本品可静脉注射或肌肉注射,每次l~500 mL,一日1~3次,l0~20天为一疗程,可连续使用2~3个疗程。
实施例2:(复方葛根素粉针的制备)
取谷胱甘肽30mg,葛根素1 g,灌封在10mL的粉针安瓿中,100℃灭菌30min,得到粉针。本品可用于辅助治疗冠心病、心绞痛、心肌梗死、视网膜动、静脉阻塞、突发性耳聋及缺血性脑血管病、小儿病毒性心肌炎、糖尿病等。应用时将制得粉针l~5000mg与氯化钠注射液或生理盐水注射液混匀,即可进行静脉注射或肌肉注射,每次l~500mL,一日l~3次,10~20天为一疗程,可连续使用2~3个疗程。
实施例3:(复方葛根素输液的制备)
取谷胱甘肽7.5mg,葛根素2g,氯化钠9g,加水至1000mL,用lmol/l盐酸或碳酸氢钠溶液调整pH至5.0—8.5,过滤,滤液灌封在250ml的盐水玻璃瓶中,100℃灭菌30min,得到输液。本品可用于辅助治疗冠心病、心绞痛、心肌梗死、视网膜动、静脉阻塞、突发性耳聋及缺血性脑血管病、小儿病毒性心肌炎、糖尿病等。应用时可直接进行静脉注射或肌肉注射,每次l~500 mL,一日1~3次,l0~20天为一疗程,可连续使用2~3个疗程。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (7)
1.谷胱甘肽在制备防治葛根素注射剂诱发的血管内溶血的药物上的应用。
2.根据权利要求1所述的应用,其特征在于:以输液的方式应用谷胱甘肽后,再接着使用葛根素注射剂。
3.根据权利要求1所述的应用,其特征在于:葛根素注射剂和谷胱甘肽注射剂在使用前混匀,再以输液的方式应用。
4.根据权利要求2所述的应用,其特征在于:先应用谷胱甘肽输液后,再接着应用葛根素注射剂。
5.根据权利要求1所述的应用,其特征在于:含有以下重量份药物:谷胱甘肽1~50份,葛根素1~50000份。
6.根据权利要求1、2、3、4所述的应用,其特征在于:含有辅料1~50重量份。
7.根据权利要求6所述的辅料,其特征在于:所述的辅料为碳酸氢钠溶液、葡萄糖液、丙二醇液或氯化钠注射液。
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