CN112569356A - 一种含有利尿剂的药物组合物 - Google Patents
一种含有利尿剂的药物组合物 Download PDFInfo
- Publication number
- CN112569356A CN112569356A CN201910942300.4A CN201910942300A CN112569356A CN 112569356 A CN112569356 A CN 112569356A CN 201910942300 A CN201910942300 A CN 201910942300A CN 112569356 A CN112569356 A CN 112569356A
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- Prior art keywords
- pharmaceutical composition
- indapamide
- macitentan
- folic acid
- composition
- Prior art date
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Classifications
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K31/33—Heterocyclic compounds
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
本发明提供一种治疗肺动脉高压的药物组合物，由治疗有效量的双重内皮素受体拮抗剂、叶酸类物质、吲达帕胺及药剂学上可接受的载体组成。本发明提供的药物组合物可以有效降低肺动脉高压，并且能减少单一活性成份的副作用；另外，本药物组合物还可以使患者服药方便，提高依从性。
Description
技术领域
本发明提供一种治疗肺动脉高压的药物组合物，由双重内皮素受体拮抗剂、叶酸类物质、吲达帕胺及药剂学上可接受的载体组成。本发明属于药学领域。
背景技术
肺动脉高压(pulmonaryarterialhypertension，PAH)是指在静息状态下，平均肺动脉压≥25mmHg(1mmHg＝0.133kPa)，且肺毛细血管楔压≤15mmHg的疾病状态。PAH通常为进展性，严重危害人体健康。PAH的病因有特发性、遗传性、药物或毒物诱导、结缔组织病、人类免疫缺陷病毒(HIV)感染、门脉高压、体循环－肺循环分流等原因。肺动脉高压的基本病理改变是进展性血管内皮、平滑肌增生与肥厚、纤维化、血管收缩与原位血栓形成。病理生理机制涉及炎症、血管内皮与血小板功能异常、平滑肌、纤维组织、胶原基质在多种分子机制作用下异常增生等。特发性PAH(idiopathicPAH，IPAH)的发病率约(7～8)/100万，结缔组织病相关性PAH(PAH－CTD)约为(5～6)/100万，结缔组织病患者中患病率最高达40％。如得不到有效治疗，PAH的中位生存时间为2.8年。
内皮素在PAH发生和发展中起重要作用。正常情况下，机体通过内皮素与其受体的平衡作用控制血管收缩、增生和肥大。内皮素两种类型受体ETA和ETB均表达于血管平滑肌细胞，且ETA受体显著性多于ETB；血管内皮有与平滑肌等量的ETB表达。内皮素与ETA结合导致血管收缩、增生、肥大和纤维化。内皮素与内皮细胞和平滑肌上的ETB结合可加速内皮素降解，血管扩张(一氧化氮、前列环素I2浓度升高)、抗纤维增生和促进动脉增生(一氧化氮浓度升高)，但与血管平滑肌上的ETB结合则导致纤维增生和血管收缩。应用内皮素受体拮抗剂阻断PAH病理生理环节，是靶向治疗方法之一。内皮素受体拮抗剂分为两大类：一类是选择性内皮素受体拮抗剂，如安利生坦(ambrisentan)、西他生坦(sitaxentan，已撤市)，另一类是双重内皮素受体拮抗剂，如波生坦(bosentan，全可利)、马西替坦(macitentan)。研究表明，从干预PAH病理生理环节角度看，双重阻断内皮素受体的效果更好。
双重内皮素受体拮抗剂虽然是目前治疗PAH的一线药物，但在使用过程中会产生一定的副作用，给患者带来风险。例如，波生坦常见的不良反应为转氨酶升高，即肝功能损害，西他生坦可引起严重的外周水肿或体液潴留。服用西他生坦100mg引起的水肿发生率约为9％，体液潴留还会导致咳嗽、呼吸困难、心力衰竭风险增加等。因此，需要对双重内皮素受体拮抗剂进行产品改进，为PAH患者提供一种更加有效和/或副作用更少的治疗手段，满足重要临床需求。
发明内容
本发明的目的是针对双内皮素受体拮抗剂治疗PAH存在的不足，提供一种疗效显著、毒副作用更小的药物组合物。
为了实现上述目的，本发明采用以下技术方案：
一种治疗肺动脉高压的药物组合物，由以下成分组成：
(1)治疗有效量的双重内皮素受体拮抗剂；
(2)治疗有效量的叶酸类物质；
(3)治疗有效量的吲达帕胺；
(4)药剂学上可接受的载体。
本发明中，所述的双重内皮素受体拮抗剂为马西替坦。
在本发明提供的药物组合物中，马西替坦可以盐类、酯类、活性代谢产物或药用前体等形式存在。本发明提供的马西替坦作为药物成分，马西替坦的盐类、酯类、活性代谢产物或药用前体等存在形式也在本申请包含的范围内。在本发明中，马西替坦的治疗有效量为2.5～10mg，优选5～10mg。马西替坦的盐类、酯类、活性代谢产物或药用前体等的治疗有效量可以进行相应换算。
在本发明提供的药物组合物中，叶酸类物质包括叶酸、5-甲基四氢叶酸、甲酰四氢叶酸钙、L-甲基叶酸、叶酸盐、叶酸或叶酸盐的活性代谢物和可在体内释放/生成叶酸的物质，即包括人工合成及植物提取物来源的各种叶酸形式。叶酸类物质的治疗有效量选自0.2～1.2mg，优选0.4～0.8mg。
在本发明提供的药物组合物中，吲达帕胺可以盐类、酯类、活性代谢产物或药用前体等形式存在。本发明提供的吲达帕胺作为药物成分，吲达帕胺的盐类、酯类、活性代谢产物或药用前体等存在形式也在本申请包含的范围内。在本发明中，吲达帕胺的治疗有效量选自1.25～5mg，优选1.25～2.5mg。吲达帕胺的盐类、酯类、活性代谢产物或药用前体等的治疗有效量可以进行相应换算。
在本发明中，组合物有效成分的治疗有效量是指该药药效成分在该组合物中与其他药效成分组合后使组合物发挥药效的剂量范围。优选剂量是组合物有效成分的治疗有效量的优选，优选剂量的药效比治疗有效量的药效效果好。通常组合物有效成分的药用剂量包括使组合物产生最大药效的最佳剂量或最佳剂量范围，此最佳剂量或最佳剂量范围将使患者更多获益。
作为一种优选，本发明提供的药物组合物的组成是5mg马西替坦、0.4mg叶酸和1.25mg吲达帕胺。
作为另一种优选，本发明提供的药物组合物的组成是5mg马西替坦、0.8mg叶酸和2.5mg吲达帕胺。
作为另一种优选，本发明提供的药物组合物的组成是5mg马西替坦、0.4mg叶酸和2.5mg吲达帕胺。
作为另一种优选，本发明提供的药物组合物的组成是5mg马西替坦、0.8mg叶酸和1.25mg吲达帕胺。
作为另一种优选，本发明提供的药物组合物的组成是10mg马西替坦、0.4mg叶酸和2.5mg吲达帕胺。
作为另一种优选，本发明提供的药物组合物的组成是10mg马西替坦、0.8mg叶酸和2.5mg吲达帕胺。
该药物组合物中还含有药剂学可接受的载体，可制成普通口服制剂，包括普通片剂、普通胶囊、颗粒剂等，制成片剂时所述可药用载体包括有助于将活性化合物配制成药用制剂的赋形剂和辅药，如微晶纤维素、无机盐类、乳糖、氯化钠、柠檬酸和亚硫酸钠等的一种或几种物质的组合物，属于本领域常识。
本发明所述药物组合物亦可以变通的以"组合药盒"形式使用。上述"组合药盒"是一种盒状容器，内置多种剂量形式的药物组合，及其服用说明书。"组合药盒"更适用于个体化用药。
本发明的有益效果是：本发明提供的药物组合物的药用有效成分为双重内皮素受体拮抗剂、叶酸类物质和吲达帕胺，其中双重内皮素受体拮抗剂单用时有水肿、肝功能损害、心力衰竭风险增加等副作用，通过与吲达帕胺及叶酸类物质联合应用，可以达到更低的使用剂量增加疗效、减轻副作用的协同效果，此外可以使患者服药方便、提高治疗依从性。
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1-6制备马西替坦、叶酸和吲达帕胺(1000片)
制备工艺：
将马西替坦、叶酸和吲达帕胺混合，加入羧甲淀粉钠、十二烷基硫酸钠混合，再加入微晶纤维素、预胶化淀粉混合均匀，用适量的10％聚维酮乙醇溶液制成软材，制粒、干燥、整粒，将含水量为3％左右的颗粒与适量的硬脂酸镁混合均匀，压片制成1000片即得。
实施例7-10制备马西替坦、叶酸和吲达帕胺(1000片)
制备工艺：
将马西替坦、叶酸和吲达帕胺混合，加入羧甲淀粉钠、十二烷基硫酸钠混合，再加入微晶纤维素、预胶化淀粉混合均匀，用适量的10％聚维酮乙醇溶液制成软材，制粒、干燥、整粒，将含水量为3％左右的颗粒与适量的硬脂酸镁混合均匀，压片制成1000片即得。
实施例11：马西替坦/叶酸/吲达帕胺治疗肺动脉高压大鼠的疗效和安全性评价
(一)方法
实验造模：雄性SD大鼠70只适应性饲养一周后，将10只大鼠不经过任何处理，作为正常对照组。其余将大鼠予以一次腹腔内注射0.5ml野百合碱(MCT)60mg/kg，两周后形成肺动脉高压大鼠，然后随机分组。
实验分组及给药方案：正常对照组(n＝10)，造模后的大鼠随机分成模型组和给药组，具体分组及给药剂量见表1，灌胃给药4周后各组禁食过夜，各组停药48小时后进行血流动力学测定，包括右心房压以及肺动脉平均压。
统计分析：
1.试验数据数据结果均以
表示。组间比较采用t检验，P<0.05有显著性统计学差异，P<0.01具有非常显著统计学差异，P>0.05无统计学差异。
2.为证实本发明提供的药物组合物的科学性，说明药物组合物的三种组分配伍合理，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，对组间实验结果采用金正均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，三种药物联用的药理作用及三种药物单用的药理作用，用如下计算公式计算：Q＝EA+B+C/(EA+EB+EC-EA*EB-EA*EC-EB*EC-EA*EB*EC)，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：
表1.本发明组合物对大鼠血流动力学指标的影响(
n＝10-12)
与正常对照组比较，#P<0.05，##P<0.01；与模型组比较，*P<0.05，**P<0.01；与马西替坦组比较，□P<0.05，□□P<0.01。
表2.本发明组合物对大鼠肺动脉高压患者血流动力学指标的效应分析
表1结果显示，模型组与正常对照组相比，肺动脉平均压和右心房压水平显著升高，表明造模成功。马西替坦组、马西替坦+叶酸+吲达帕胺组肺动脉平均压和右心房压水平与模型组相比显著下降，具有统计学差异(P<0.01)，叶酸或者吲达帕胺单用对肺动脉平均压和右心房压无明显作用。与马西替坦单药组比较，马西替坦+叶酸+吲达帕胺组肺动脉平均压和右心房压进一步显著降低(P<0.05)。金正均Q值分析组合物肺动脉平均压、右心房压Q值分别为1.34和1.30，均大于1.15，说明马西替坦+叶酸+吲达帕胺联合用药表现出意想不到的协同增效作用。
实施例12：马西替坦/叶酸/吲达帕胺治疗肺动脉高压的临床试验
(一)方法
患者来源：某医院心血管内科于2015年1月～2017年1月收治的43例肺动脉高压患者作为研究对象，所有患者经右心导管行肺动脉压力检测，均符合2009年美国心脏病学院基金会(ACCF)与美国心脏病协会(AHA)联合颁布的肺动脉高压诊断标准。
患者排除标准：排除符合以下任何一项者：
①各类型先天性心脏畸形者；②先心病以外的其他因素如遗传或HIV等所密切关联的PAH患者；③被证实有肺动脉栓塞性疾病或肺实质性疾病者；④合并肿瘤、肾脏疾病、内分泌系统疾病以及代谢性全身疾病者；⑤具出血史或近6个月内有发生过消化道出血与颅内出血者；⑥血压＜90/50mmHg或＞170/110mmHg，肝酶＞3倍正常值上限，肌酐＞450值上限，肌酐，具以上三项中任意一项或多项者；⑦近3月内有接受过钙离子拮抗剂相关药物治疗者；⑧孕育期妇女。
治疗方案：
A组(22人)：马西替坦片+吲达帕胺片+叶酸片(5/2.5mg/0.8mg)，每日一次，口服，治疗20周；
B组(21人)：马西替坦片(10mg)，每日一次，口服，治疗20周
(二)检测及统计方法：
各组停药后，进行血流动力学测定，包括右心房压以及肺动脉平均压。
统计分析：同上。
(三)结果：
治疗20周以后，在改善肺动脉高压患者的肺动脉平均压和右心房压方面，低剂量(5mg)马西替坦与2.5mg吲达帕胺及0.8mg叶酸联用与1mg马西替坦的治疗作用相当，两组肺动脉平均压和右心房压均较使用前显著降低，见表3。
表3.本发明组合物对肺动脉高压患者血流动力学指标的影响(
n＝21-22)
治疗20周后，检查两组患者血常规和生化指标发现，单药马西替坦10mg/日组，有1例患者出现贫血，2例转氨酶升高至治疗前的2-3倍，2例出现水肿，三联药物组患者均未出现上述不良反应，可能的原因是在三联药物组合中马西替坦剂量低，相应的副作用也较小，另一方面配伍的吲达帕胺和叶酸在利水肿和保肝方面存在一定的协同减毒作用。
从以上研究发现较低剂量的马西替坦于吲达帕胺、叶酸组方具有协同增效减毒的作用，并有利于提高服药依从性。
Claims (12)
1.一种用于肺动脉高压的药物组合物，组成成分为：
(1)治疗有效量的双重内皮素受体拮抗剂；
(2)治疗有效量的叶酸类物质；
(3)治疗有效量的吲达帕胺；
(4)药剂学上可接受的载体。
2.根据权利要求1所述的药物组合物，其特征在于：所述双重内皮素受体拮抗剂为马西替坦，治疗有效量为2.5～10mg，优选5-10mg。
3.根据权利要求1所述的药物组合物，其特征在于：所述的叶酸类物质包括叶酸、5-甲基四氢叶酸、甲酰四氢叶酸、亚叶酸、左亚叶酸钙，治疗有效量为0.2～1.2mg，优选0.4～0.8mg。
4.根据权利要求1所述的药物组合物，其特征在于：所述的吲达帕胺治疗有效量为1.25～5mg，优选1.25～2.5mg。
5.根据权利要求1所述的药物组合物，其特征在于：药物组合物的组成是5mg马西替坦、0.4mg叶酸和1.25mg吲达帕胺。
6.根据权利要求1所述的药物组合物，其特征在于：药物组合物的组成是5mg马西替坦、0.8mg叶酸和2.5mg吲达帕胺。
7.根据权利要求1所述的药物组合物，其特征在于：药物组合物的组成是5mg马西替坦、0.4mg叶酸和2.5mg吲达帕胺。
8.根据权利要求1所述的药物组合物，其特征在于：药物组合物的组成是5mg马西替坦、0.8mg叶酸和1.25mg吲达帕胺。
9.根据权利要求1所述的药物组合物，其特征在于药物组合物的组成是10mg马西替坦、0.4mg叶酸和2.5mg吲达帕胺。
10.根据权利要求1所述的药物组合物，其特征在于药物组合物的组成是10mg马西替坦、0.8mg叶酸和2.5mg吲达帕胺。
11.权利要求1～10任一所述的药物组合物，其特征在于：所述的药物组合物可制成普通片剂、软胶囊剂、硬胶囊剂等口服剂型。
12.权利要求1～10任一所述的药物组合物在制备用于治疗肺动脉高压的药物中的用途。
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