CN117357517A - 含有恩格列净的药物组合物及其用途 - Google Patents
含有恩格列净的药物组合物及其用途 Download PDFInfo
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- CN117357517A CN117357517A CN202210769663.4A CN202210769663A CN117357517A CN 117357517 A CN117357517 A CN 117357517A CN 202210769663 A CN202210769663 A CN 202210769663A CN 117357517 A CN117357517 A CN 117357517A
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Abstract
本发明提供一种药物组合物,由治疗有效量的艾沙利酮、恩格列净和药学上可接受的载体组成。其中,艾沙利酮含量为0.5~10mg,恩格列净含量为1~50mg。本发明的优点是,该药物组合物具有显著的协同治疗慢性心力衰竭的作用,尤其适用于射血分数降低的心衰,可降低患者心血管死亡和心衰恶化的发生风险;此外,该药物组合物还具有降低血压和血糖的作用,故适合用于治疗合并糖尿病或高血压的心衰。通过本发明的实施,提供给患者这种特定用途的药物组合物,还可以增加患者服药依从性,提高疗效。
Description
技术领域
本发明涉及一种含有艾沙利酮和恩格列净的药物组合物及其用途,属于药学领域。
背景技术
心力衰竭是指心脏结构或功能异常导致心室充盈或射血能力受损的一组临床综合征,是心血管疾病发展的严重和终末阶段。引发心力衰竭的主要危险因素有各种心脏病、高血压等,根据心衰发生的时间、速度、严重程度可分为慢性心衰和急性心衰,在原有慢性心脏疾病基础上逐渐出现心衰症状和体征的为慢性心衰。根据指南,心力衰竭可分为射血分数降低的心力衰竭(HFrEF)、射血分数中间值的心力衰竭(HFmrEF)和射血分数保留的心力衰竭(HFpEF)三种类型。HFrEF定义为射血分数小于40%的心力衰竭。
一般地,临床常用于治疗心衰的药物包括强心药(正性肌力药物)、利尿剂、肾素-血管紧张素-醛固酮系统(RAS)抑制剂(包括血管紧张素转换酶抑制剂、血管紧张素II受体拮抗剂、醛固酮受体拮抗剂)、β受体阻滞药,近年来还发展了血管紧张素受体-脑啡肽酶抑制药(ARNI)、钠-葡萄糖协同转运蛋白2(SGLT2)抑制药等。这些药物可以单独使用,也可以联合用药,后者搭配的原则一般是强心药基础上与利尿或扩血管药物的联合,以改善短期血流动力学作用为主要目标,比较倚重强心和扩血管治疗,忽视对心力衰竭复杂因素(如神经内分泌因素)的干预,故长期临床疗效并不理想。
盐皮质激素是由肾上腺皮质球状带细胞分泌的类固醇激素,其主要作用是促进肾小管重吸收钠离子和保留水,并排泄钾离子。早期研究发现具有甾体结构的盐皮质激素受体拮抗剂可用于高血压和心力衰竭的治疗,例如螺内酯和依普利酮。近年国外研发出新一代选择性的非甾体结构的盐皮质激素受体阻断剂艾沙利酮(Esaxerenone),它同样可用于治疗高血压和充血性心力衰竭,还用于糖尿病肾病患者,可控制蛋白尿和延缓慢性肾脏病发展。
恩格列净是一种高选择性的口服钠-葡萄糖共转运体2(SGLT2)抑制剂,拥有独特的不依赖胰岛素的降糖途径,即通过减少葡萄糖在肾脏的重吸收从尿中直接排糖,但容易导致低血糖。除具有明确的降糖效果外,恩格列净在心血管方面的益处也获得了循证医学研究的证实。
随着人们对慢性心衰发病机理的认识水平不断提高,心衰的药物治疗从最初的强心、利尿、扩血管等以改善短期血流动力学和缓解临床症状为主要目标,逐渐转变为抑制神经内分泌系统以延缓心室重构、降低住院率和病死率的长期策略。因此,选择具有协同作用的药物组合,多靶点干预心衰的复杂病理机制,有利于提高临床疗效,从而降低再住院率以及病死率,提高患者的生活质量。
发明内容
为克服传统的心衰治疗存在的不足,本发明提供一种治疗慢性心力衰竭的药物组合物,尤其适用于治疗射血分数降低的慢性心力衰竭以及合并糖尿病和/或高血压的心衰。
为实现上述目的,本发明采用以下技术方案:
一种药物组合物,包括
(1)治疗有效量的艾沙利酮及其药用前体、活性代谢产物、或盐类中的一种;
(2)治疗有效量的恩格列净及其药用前体、活性代谢产物、或盐类中的一种;
其中,艾沙利酮与恩格列净的质量比为0.5~10:1~50。
在本发明中,艾沙利酮与恩格列净的质量比优选为1.25~5:10~25。
在本发明中,艾沙利酮的治疗有效量范围为0.5~10mg,恩格列净的治疗有效量范围为1~50mg。
在本发明中,艾沙利酮的优选治疗有效量范围为1.25~5mg,恩格列净的优选治疗有效量范围为10~25mg。
作为一种优选,本发明提供的组合物含有2.5mg艾沙利酮和10mg恩格列净。
作为一种优选,本发明提供的组合物含有2.5mg艾沙利酮和25mg恩格列净。
作为一种优选,本发明提供的组合物含有5mg艾沙利酮和10mg恩格列净。
作为一种优选,本发明提供的组合物含有5mg艾沙利酮和25mg恩格列净。
作为一种优选,本发明提供的组合物含有0.5mg艾沙利酮和1mg恩格列净。
作为一种优选,本发明提供的组合物含有1.25mg艾沙利酮和10mg恩格列净。
作为一种优选,本发明提供的组合物含有10mg艾沙利酮和50mg恩格列净。
在本发明中,药物组合物的制药剂型为口服制剂,包括但不限于普通片剂、双层片剂、多层片剂、缓释片剂、单室控释片剂、双室控释片剂、微孔型控释片剂、舌下含片、口腔速崩片、分散片、肠溶片、颗粒剂、丸剂、肠溶胶囊、延迟释放片、定时/位释放片、普通胶囊、缓释胶囊、控释胶囊、含有微丸或小片的胶囊、含有微丸或小片的pH依赖型胶囊、颗粒剂、口服液、膜剂或贴剂等剂型,其中优选片剂、胶囊或颗粒剂。
在本发明中药物组合物在制备用于治疗慢性心力衰竭的药物中的用途。
在本发明中药物组合物在制备用于治疗射血分数降低的慢性心力衰竭的药物中的用途。
在本发明中药物组合物在制备用于治疗高血压合并慢性心力衰竭的药物中的用途。
在本发明中药物组合物在制备用于治疗糖尿病合并慢性心力衰竭的药物中的用途。
在本发明中药物组合物在制备用于治疗高血压合并糖尿病以及慢性心力衰竭的药物中的用途。
术语“治疗有效量”是指为达到有效控制或治疗疾病的目的,临床医生根据患病个体病情严重程度对患病个体施与药物的剂量。应当理解本发明提供的药物治疗有效量不是对本发明的限制,而是对本发明的优选,通常情况下,在该剂量优选范围内,该药物能够对患病个体产生有效的治疗效果。患病个体是指患有疾病的独立存在的生命体,在本发明中,生命体尤指人类。
本发明提供的药物组合物中的化合物在相同的制剂中可以同时施与患病个体,也可分别地相继施与患病个体。若是相继施与患病个体,则第二个(或附加的)活性成分施与的延迟不应当导致活性成分联合带来的有益效果的损失。若是同时施与患病个体,组合物中的化合物可以混合存在于同一个药物制剂形式中,也可以以同样的制剂形式分别独立存在。若是以同样的制剂形式分别独立存在,则药物组合物可以变通的以“组合药盒”形式存在。“组合药盒”是一种盒状容器,内置一种或多种剂量形式的药物组合及其使用说明书,在本发明中优选艾沙利酮及其药用前体、活性代谢产物、或盐类中的一种和恩格列净及其药用前体、活性代谢产物、或盐类中的一种。
本发明的另一个目的是提供含有药用剂量的艾沙利酮及其药用前体、活性代谢产物中的一种、药用剂量的恩格列净及其药用前体、活性代谢产物、或盐类的一种和可药用载体的药物组合物在制备治疗慢性心力衰竭的药物的用途,本发明提供的药物组合物可协同治疗慢性心力衰竭,还可改善血压和血糖水平,因而成为更适宜的治疗慢性心力衰竭药物。
本发明的有益效果是:本发明提供了含有药用剂量的艾沙利酮及其药用前体、活性代谢产物、或盐类中的一种、药用剂量的恩格列净及其药用前体、活性代谢产物、或盐类中的一种和可药用载体的药物组合物。本发明创造性地将降压药物(艾沙利酮)和降糖药物(恩格列净)联合使用,不仅具有降压和降糖的效果,还取得了预料不到的协同治疗慢性心力衰竭的效果,为高血压、糖尿病合并慢性心力衰竭的治疗提供了新的方法和组合药物。
下面结合具体实施方式对本发明做进一步说明,并非对本发明的限定,凡依照本发明内容进行的任何本领域的等同替换,均属于本发明的保护范围。
具体实施方式
实施例1:组合物对糖尿病合并慢性心力衰竭大鼠的心脏保护作用和神经内分泌系统功能改善作用
阿霉素为蒽环类抗肿瘤药物,作用于心肌组织,促进细胞的凋亡、坏死,从而发展为慢性心力衰竭。本实施例通过向高糖高脂饲料喂养的大鼠体内注射阿霉素和链脲佐菌素(STZ)制作糖尿病合并慢性心衰的模型,观察本发明组合物对糖尿病合并慢性心力衰竭大鼠血流动力学指标及神经内分泌系统功能指标的影响。
一、方法
选择SPF级雄性SD大鼠210只,8周龄(购自北京维通利华),随机挑选10只SD大鼠,给予生理盐水灌胃和正常饲料喂食,作为正常对照组。其余大鼠给以高糖和高脂饲料喂养4周,在4周末将30mg/kg的STZ与0.1mmol/L的柠檬酸缓冲液相溶,pH为4.4,在左侧下腹部一次性注射到大鼠体内。在整个模型建立过程中禁止应用各种影响血糖的药物,并充分给予水和食物。在建立糖尿病大鼠模型的同时应用盐酸阿霉素配制大鼠慢性心力衰竭模型:在大鼠尾部进行静脉注射,1mg(kg·次),1次/周,注射6周。制模期间严格掌握给药量和给药时间,注意观察动物活动、全身状态和摄食情况。在确定糖尿病合并心力衰竭大鼠模型建立成功后,随机分组,每组7-8只,按表1的给药剂量分别进行灌胃给药,正常对照组和模型对照组灌胃等容积的生理盐水,连续灌胃12周。
用药12周后,禁食、禁水12h,予戊巴比妥(50mg/kg)腹腔注射麻醉,检测下列指标:(1)左室舒张末压(LVEDP)、左室收缩末压(LVSP):应用超声心动图,检测血流动力学参数LVEDP和LVSP。(2)血清的心房利钠肽(ANP)和脑钠肽(BNP):腹腔静脉取血,3000r·min-1离心15min,分离血清后﹣80℃保存。放射免疫法测定血清中ANP及BNP含量。
为证实本发明提供的药物组合物的科学性,说明药物组合物的组分配伍合理,相互结合可以发挥协同增效作用,而不是简单的药理作用叠加,引入金正均Q值法分析。金正均Q值法又称概率相加法,根据在量效曲线区内,两种药物联用的药理作用及两种药物单用的药理作用,用如下计算公式计算:Q=EA+B/(EA+EB-EA*EB),式中分子代表“实测合并效应”,分母代表“期望合并效应”,(为满足组分及组合物药理作用关系的分析,将它们的药理作用转化为可以直观体现药理作用强弱的效应,计算公式:Ei=1-Pi/P模型组,Pi为各组分的药理指标,P模型组为模型组的药理指标),Q为两者之比:Q小于0.85时认为两种药物联用为拮抗作用;小于1.15大于0.85时,认为是相加作用;大于1.15时认为是协同作用。
二、结果
如表1和表2所示,与正常对照组比较,模型对照组的左室舒张末压(LVEDP)、血清的心房利钠肽(ANP)和脑钠肽(BNP)明显升高(P<0.01),左室收缩末压(LVSP)均明显降低(P<0.01),并且在造模过程中大鼠陆续出现精神萎靡、进食减少、活动量下降、呼吸困难、口唇及足趾发绀等心衰表现,以及出现多饮、多尿、多食、消瘦的典型“三多一少”、烂尾等糖尿病表现,提示糖尿病合并慢性心衰模型成功构建。与模型对照组比较,所有药物组的LVEDP、ANP和BNP均明显降低(P<0.05或P<0.01),LVSP明显升高(P<0.05)。而LVEDP和LVSP是反映心脏血流动力学的指标;ANP和BNP是心脏的神经内分泌激素,是反映心功能和神经内分泌激活程度的指标。ANP主要由心房合成,BNP由心室合成。心衰时,由于心房和心室容量负荷增加,心房和心室牵张刺激增强而使得ANP和BNP神经内分泌激素过度激活,合成分泌增多。因此上述结果可说明单药组(艾沙利酮、非奈利酮、依普利酮、螺内酯、恩格列净、达格列净)、二联组(艾沙利酮+恩格列净、非奈利酮+恩格列净、非奈利酮+达格列净、依普利酮+达格列净、螺内酯+达格列净)药物均对糖尿病合并慢性心力衰竭大鼠有显著的心功能保护作用,以及有明显改善心脏的神经内分泌系统异常和延缓心衰进程的作用。
同时,与单药组相比,二联组大鼠的LVEDP、ANP和BNP降低更为明显,LVSP升高更为明显。这说明二联组的用药合用后,对糖尿病合并慢性心力衰竭大鼠的心功能各项指标改善更明显,病理改变减轻更明显,具有显著的协同改善糖尿病合并慢性心力衰竭大鼠的血流动力学状况以及改善心脏的神经内分泌系统(利钠肽系统)的效果。艾沙利酮+恩格列净组降低LVEDP、血清ANP和BNP以及升高LVSP作用效果Q值分别为1.23、1.34、1.30、1.26,均大于1.15,其他组别的Q值均为小于1.15大于0.85的范围,为简单的相加作用。
结合实验数据,可知相对于其他GLP-1受体拮抗剂联合SGLT2抑制剂来说,艾沙利酮与恩格列净合用在改善糖尿病合并慢性心力衰竭大鼠心功能和抑制心脏的神经内分泌系统方面具有更佳的协同增效作用,协同改善左心室收缩和舒张功能,降低心房利钠肽和脑钠肽,阻断神经内分泌系统的过度激活,延缓心室重构,对心脏产生了保护,起到协同改善糖尿病合并心力衰竭患者预后、加强心脏保护和抑制神经内分泌系统以延缓心室重构的作用,适用于慢性心力衰竭患者,尤其适用于糖尿病合并慢性心力衰竭患者。
表1组合物对各组大鼠LVEDP、LVSP的影响(n=5~8)
注:与正常对照组比较,**P<0.01;与模型对照组比较,#P<0.05,##P<0.01。
表2组合物对各组大鼠血清ANP和BNP影响(n=5~8)
注:与正常对照组比较,**P<0.01;与模型对照组比较,#P<0.05,##P<0.01。
Claims (10)
1.一种药物组合物,包括:
(1)治疗有效量的艾沙利酮及其药用前体、活性代谢产物、或盐类中的一种;
(2)治疗有效量的恩格列净及其药用前体、活性代谢产物、或盐类中的一种;
其中,艾沙利酮与恩格列净的质量比为0.5~10:1~50。
2.根据权利要求1所述的药物组合物,其特征在于,所述艾沙利酮与恩格列净的质量比为1.25~5:10~25。
3.根据权利要求1所述的药物组合物,其特征在于,所述艾沙利酮的治疗有效量为0.5~10mg,恩格列净的治疗有效量为1~50mg。
4.根据权利要求2所述的药物组合物,其特征在于,所述艾沙利酮的治疗有效量为1.25~5mg,恩格列净的治疗有效量为10~25mg。
5.根据权利要求1~4中任一项所述的药物组合物,其特征在于:药物组合物的制药剂型为口服制剂,包括片剂、胶囊、颗粒剂或其他医药学上可接受的剂型。
6.根据权利要求1~4中任一项所述的药物组合物在制备用于治疗慢性心力衰竭的药物中的用途。
7.根据权利要求1~4中任一项所述的药物组合物在制备用于治疗射血分数降低的慢性心力衰竭的药物中的用途。
8.根据权利要求1~4中任一项所述的药物组合物在制备用于治疗高血压合并慢性心力衰竭的药物中的用途。
9.根据权利要求1~4中任一项所述的药物组合物在制备用于治疗糖尿病合并慢性心力衰竭的药物中的用途。
10.根据权利要求1~4中任一项所述的药物组合物在制备用于治疗高血压合并糖尿病以及慢性心力衰竭的药物中的用途。
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