CN1474690A - 用于治疗心血管疾病的含有肾素抑制剂的协同性药物联合形式 - Google Patents
用于治疗心血管疾病的含有肾素抑制剂的协同性药物联合形式 Download PDFInfo
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- CN1474690A CN1474690A CNA018190685A CN01819068A CN1474690A CN 1474690 A CN1474690 A CN 1474690A CN A018190685 A CNA018190685 A CN A018190685A CN 01819068 A CN01819068 A CN 01819068A CN 1474690 A CN1474690 A CN 1474690A
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Abstract
本发明涉及一种含有式(I)的肾素抑制剂或其可药用盐的联合形式。
Description
本发明涉及一种药物联合形式,例如,含有式(I)的肾素抑制剂或其可药用盐的联合的制剂或药物组合物。
本发明特别涉及一种药物联合形式,例如,含有式(I)的肾素抑制剂或其可药用盐以及至少一种选自下列的治疗剂的联合的制剂或药物组合物:(i)AT1-受体拮抗剂或其可药用盐,(ii)HMG-Co-A还原酶抑制剂或其可药用盐,(iii)血管紧张素转化酶(ACE)抑制剂或其可药用盐,(iv)钙通道阻断剂或其可药用盐,(v)醛固酮合酶抑制剂或其可药用盐,(vi)醛固酮拮抗剂或其可药用盐,(vii)双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂或其可药用
盐,(viii)内皮素拮抗剂或其可药用盐,及(ix)利尿剂或其可药用盐。
术语“至少一种治疗剂”是指除式(I)化合物之外,可联合一种或多种、例如两种甚至三种本发明所指定的活性成分。
肾素抑制剂可以抑制天然的酶肾素的作用。后者经过肾脏进入到血液中,并在血液中影响血管紧张素原的裂解,释放出十肽血管紧张素I,随后,血管紧张素I在肺部、肾脏和其它器官中裂解形成八肽血管紧张素原II。所述八肽可以通过动脉血管收缩直接升高血压,并且还可以通过从肾上腺中释放出钠离子保留激素醛固酮间接地引起血压升高,并同时增加细胞外液的容积。因此血压的升高可归因于血管紧张素II的作用。肾素酶活性的抑制剂将导致血管紧张素I形成的减少。其结果导致产生的血管紧张素II的量减少。活性肽类激素浓度的降低是肾素抑制剂产生例如降血压效果的直接原因。
化学名称为2(S),4(S),5(S),7(S)-N-(3-氨基-2,2-二甲基-3-氧代丙基)-2,7-二(1-甲基乙基)-4-羟基-5-氨基-8-[4-甲氧基-3-(3-甲氧基-丙氧基)苯基]-辛酰胺的式(I)的肾素抑制剂具体公开在EP 678503 A中。特别优选的是其半富马酸盐。
AT1-受体拮抗剂(也称作血管紧张素II受体拮抗剂)可理解为是指那些可与血管紧张素II受体的AT1-受体亚型相结合,但不能导致该受体激活的活性成分。AT1受体受到抑制的结果是,这些拮抗剂可例如用作抗高血压药物或用于治疗充血性心力衰竭。
AT1受体拮抗剂类物质包括那些具有不同结构特征的化合物,基本优选那些非肽类的化合物。例如,可以提到的是选自下列的化合物:缬沙坦(参见EP 443983)、洛沙坦(参见EP 253310)、坎地沙坦(candesartan,参见EP 459136))、依普沙坦(eprosartan,参见EP 403159)、伊贝沙坦(irbesartan,参见EP 454511)、奥美沙坦(olmesartan,参见EP 503785)、他索沙坦(tasosartan,参见EP 539086)、替米沙坦(参见EP 522314)、命名为E-1477的下式化合物命名为SC-52458的下式化合物以及命名为ZD-8731的下式化合物或者,上述每一化合物的可药用盐。
优选的AT1-受体拮抗剂是那些已经上市的试剂,最优选的是缬沙坦或其可药用盐。
HMG-Co-A还原酶抑制剂(也称为β-羟基-β-甲基戊二酰-辅酶-A还原酶抑制剂)可理解为是指那些可用于降低脂类水平、包括血液胆固醇水平的活性剂。
HMG-Co-A还原酶抑制剂类物质包括那些具有不同结构特征的化合物。例如,可提及的是选自下列的化合物:阿托伐他汀、西立伐他汀(cerivastatin)、密实菌素(compactin)、达伐他汀、二氢密实菌素、氟吲他汀(fluindostatin)、氟伐他汀、洛伐他汀、匹伐他汀(pitavastatin)、美伐他汀、帕伐他汀、利伐他汀(rivastatin)、辛伐他汀和维洛他汀(velostatin),或者,每一化合物的可药用盐。
优选的HMG-Co-A还原酶抑制剂是已经上市的那些,最优选氟伐他汀、匹伐他汀以及阿托伐他汀,或者,每一化合物的可药用盐。
使用ACE-抑制剂(也称为血管紧张素转化酶抑制剂)阻断血管紧张素I向血管紧张素II的酶降解转化是一种调节血压的成功方法,并可获得有效治疗充血性心力衰竭的疗法。
ACE抑制剂类物质包括具有不同结构特征的化合物。例如,可提及的实例是选自下列的化合物:阿拉普利、贝那普利、贝那普利拉、卡托普利、西洛普利、西拉普利、地拉普利、依那普利、依那普利拉(enaprilat)、福辛普利、咪哒普利、赖诺普利、莫替普利、哌道普利、喹那普利、雷米普利、斯哌普利、替莫普利和群多普利,或者,每一化合物的可药用盐。
优选的ACE抑制剂是已经上市的那些,最优选贝那普利和依那普利。
CCB类物质主要包括二氢吡啶类(DHP类)和非-DHP类,如地尔硫卓型和维拉帕米型CCB类。
用于所述联合形式的CCB优选是选自下列的DHP类代表性药物:氨氯地平、非洛地平、ryosidine、伊拉地平、拉西地平、尼卡地平、硝苯地平、尼古地平、尼鲁地平、尼莫地平、尼索地平、尼群地平和尼伐地平;并且优选选自下列的非-DHP类代表性药物:氟桂利嗪、普尼拉明、地尔硫卓、芬地林、加罗帕米、米贝地尔(mibefradil)、阿尼帕米、噻烷丙胺和维拉帕米,以及,每一种化合物的可药用盐。所有这些CCB类都可治疗性地用作例如抗高血压、抗心绞痛或抗心律失常药物。
优选的CCB类包括氨氯地平、地尔硫卓、伊拉地平、尼卡地平、硝苯地平、尼莫地平、尼索地平、尼群地平和维拉帕米,或其可药用盐(这取决于具体的CCB)。特别优选的DHP是氨氯地平或其可药用盐,尤其是其苯磺酸盐。特别优选的代表性非-DHP类是维拉帕米或其可药用盐、尤其是其盐酸盐。
醛固酮合酶是通过将皮质酮羟基化以形成18-OH-皮质酮并将18-OH-皮质酮转化成醛固酮来将皮质酮转化成醛固酮的酶。已知醛固酮合酶抑制剂类物质可用于治疗高血压和原发性醛固酮增多症,其包括甾类和非甾类醛固酮合酶抑制剂,后者是最优选的。
市售的醛固酮合酶抑制剂或已经得到卫生部门批准的醛固酮合酶抑制剂是优选的。
醛固酮合酶抑制剂包括具有不同结构特征的化合物。例如,可提及的实例是选自下列的化合物:非甾类芳香酶抑制剂阿那曲唑(anastrozole)、法倔唑(包括其(+)-对映体),以及甾类芳香酶抑制剂依西美坦,或者如果适用的话,其可药用盐。
对血管紧张素转化酶和中性内肽酶都具有抑制作用的化合物,即所谓的双重ACE/NEP抑制剂可用于治疗心血管病变。
优选的双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂是例如奥美曲羟(omapatrilate,参见EP 629627)、fasidotril或fasidotrilate,或Z13752A(参见WO 97/24342),或者如果适当的话,其可药用盐。
内皮素(ET)是由血管内皮合成并释放的具有很强血管收缩能力的肽类。内皮素存在着三种同种型(ET-1、ET-2和ET-3)。(ET表示ET的任一种或所有的同种型)。据报道,在例如原发性高血压患者的血浆中具有升高的ET水平。内皮素受体拮抗剂可用于抑制由ET引起的血管收缩。
优选的内皮素拮抗剂是,例如,波生坦(参见EP 526708 A)、恩拉生坦(enrasentan,参见WO 94/25013)、阿曲生坦(参见WO 96/06095),尤其是盐酸阿曲生坦、达鲁生坦(darusentan,参见EP 785926 A)、BMS 193884(参见EP 702012 A)、西他生坦(sitaxsentan,参见US 5594021),特别是西他生坦钠、YM 598(参见EP 882719 A)、S 0139(参见WO 97/27314)、J 104132(参见EP 714897 A或WO 97/37665),以及tezosentan(参见WO96/19459),或者,每一化合物的可药用盐。
利尿剂是例如选自下列的噻嗪衍生物:氯噻嗪、氢氯噻嗪、甲基氯噻嗪(methylclothiazide)和氯噻酮。氢氯噻嗪是最优选的。
优选含有式(I)的肾素抑制剂或其可药用盐,以及作为第二种活性成分的选自缬沙坦、氟伐他汀、阿托伐他汀、匹伐他汀、苯扎普利、依那普利、氨氯地平,特别是其苯磺酸盐、法倔唑的(+)对映体、依普利酮、奥美曲羟、Z 13752A、西他生坦,特别是西他生坦钠、达鲁生坦和氢氯噻嗪的活性成分的药物联合形式,例如联合的制剂或药物组合物。
进一步优选含有式(I)的肾素抑制剂或其可药用盐和一种选自缬沙坦、氟伐他汀、阿托伐他汀、匹伐他汀、苯扎普利、依那普利、氨氯地平,特别是其苯磺酸盐、法倔唑的(+)对映体、依普利酮、奥美曲羟、Z 13752A、西他生坦,特别是西他生坦钠和达鲁生坦的活性成分,并且还包含氢氯噻嗪作为第三种活性成分的药物联合形式,例如联合的制剂或药物组合物。
用通用名或商标名表示的活性成分的结构可从正版的概要“默克索引(The Merck Index)”或从例如国际专利数据库(如,IMS世界出版物)中得到。相应的内容在此处引入作为参考。任何本领域的技术人员完全有能力鉴定所述活性化合物,并且,根据这些参考文献,他们也有能力制备这些化合物并用标准实验模型测定其体外和体内的药学适应症和性质。
相应的活性成分或其可药用盐也可以以溶剂化物例如水合物或者包含结晶时使用的其它溶剂的溶剂化物的形式使用。
联合使用的化合物可以以其可药用盐的形式存在。如果这些化合物具有例如至少一个碱性中心,则它们可形成酸加成盐。如需要,还可形成具有另外的碱性中心的相应酸加成盐。具有酸性基团(例如COOH)的化合物还可与碱形成盐。
最令人惊讶的是,在实验中发现式(I)的肾素抑制剂或其盐与选自(i)至(ix)的治疗剂联合给药不仅能产生有益的、特别是协同的治疗效果,而且还能产生由联合治疗引起的附加的有益效果,以及与仅使用此处公开的药物联合形式中的一种药物活性化合物的单一疗法相比,其它令人惊讶的有益效果。
具体地讲,最令人惊讶的是,在实验中发现本发明的药物联合形式不仅能产生有益的、特别是协同的治疗效果;还能产生由联合治疗引起的附加的有益效果,诸如效力出人意料地延长、治疗的范围更广以及对下文中所具体描述的疾病和病况的出人意料的有益效果。
通过已建立的试验模型、尤其是文中所描述的那些实验模型,可以看出式(I)的肾素抑制剂与选自(i)至(ix)的治疗剂的药物联合形式可对下文所述的疾病产生更为有效的预防或治疗效果。具体地讲,通过已建立的试验模型、尤其是文中所描述的试验模型,可以看出本发明的药物联合形式可对下文所述的疾病产生更为有效的预防或更为优选的治疗效果。
对于许多本文所述的药物联合形式而言,如果同时给药,将不仅可以产生进一步增强的有益的、特别是协同的治疗效果;还将产生由同时治疗所引起的附加的有益效果,诸如效力出人意料地延长、治疗的范围更广以及其它出人意料的有益效果,例如,在与糖尿病有关的疾病和病况中不会使体重增加得很多。而且,对于人类患者、特别是年老的病人来说,相对于按照一种较为复杂的疗程表在时间上交错给药而言,在同一时间例如在餐前服用两种片剂更为方便且更容易记住。更优选的是,在本文所描述的所有情况下,将两种活性成分以固定的联合形式、即,以单个片剂的形式给药。服用一种药片要比在同一时间内服用两种药片更为容易。此外,包装也更为容易。
本文所用的术语“协同性”是指,使用本发明的方法和组合物所达到的效果要大于包括本发明各活性成分的方法和组合物所分别产生的效果的总和。
相关领域的技术人员完全有能力选择相关的标准动物实验模型以证实本文中所提出的治疗适应症和有益效果。
通过分别给药AT1-受体拮抗剂类物质或ACE抑制剂或者本发明所用的活性剂的联合形式所产生的药物活性可以通过例如相关领域已知的相应的药理学模型来证实。相关领域的技术人员完全有能力选择适宜的动物实验模型以证实上下文所指出的治疗适应症和有益效果。
对血压的有益效果可以,例如,用R.L.Webb等人在J.Hypertension,16:843-852,1998中所公开的试验模型证明。方法:
本发明含有式(I)化合物或其可药用盐的联合形式可以通过各种给药途径给药,但在该实施例中利用连续输注的方式通过皮下植入的微型渗透泵进行给药。每一试剂都可以在宽的剂量范围内测试以确定联合形式中每一试剂的最佳药物水平,从而可推导出最大响应值。对于这些研究,优选使用由每组至少6只动物组成的治疗组。每一项研究最好在评估单个组分的同时测定联合治疗组的效果。尽管可以通过急性给药(例如1天)来观察药物的效果,但优选在以下描述的慢性条件(其中的实验在2-3周的观察期内进行)下观察响应效果。长时间的研究可使得代偿响应具有足够的时间来发展得很完全,因此,观察到的结果可以最为接近地描述代表持久或稳定效果的试验系统的实际响应情况。以下描述的对血压的影响显示了当两种试剂联合使用时的协同抗高血压效果。统计分析:
通过测定每一治疗组中的血压最大变化值或血压变化-时间曲线的曲线下面积(AUC)对联合治疗与单一疗法进行比较。所有的值均以组平均值±SEM的形式表示。当p<0.05时,具有统计学意义。每一治疗组的AUC值可使用单因素ANOVA进行统计学比较,然后进行适当的分析,例如,进行Tukey′s测试。结论:
在以联合形式给药时,血压降低到相同程度时所需的每一组分的剂量要小于各单一疗法时所需的剂量。另一出人意料的发现是:与单独给予高剂量的式(I)化合物或其可药用盐相比,联合给药可使血压降低到更低的程度。
这些有益效果可通过例如G.Jeremic等人在J.Cardovasc.Pharmacol.27:347-354,1996中描述的试验模型来证实。
例如,可通过以下试验模型来证实本发明的联合形式在预防和治疗心肌梗塞(包括心肌梗塞后的指征,以延缓充血性心力衰竭的进展)中的有价值的潜力。实验设计
在欲进行的实验中,使用在大鼠中的持久性冠状动脉闭塞(CAO)作为极性心肌梗塞模型。实验是用5个治疗组进行的,其特征如下:·假手术动物组·CAO+载体·CAO+式(I)化合物或其可药用盐,特别是半富马酸盐,·CAO+醛固酮合酶抑制剂·CAO+式(I)化合物或其可药用盐、特别是半富马酸盐+醛固酮合酶抑制剂。
采用以下给药剂量和途径:对于盐酸倔唑的(+)-对映体Alza微型渗透0.4mg/kg/天。
在实验期间测定下列变量:·梗塞尺寸·LV室体积·备用LV心肌中的间隙和血管周围胶原密度·通过Western印迹法测定的备用LV心肌中的COL-I和COL-III蛋白含量·LV心肌切片中的心肌细胞横截面积和长度·肾素和醛固酮的血浆浓度·钠、钾和醛固酮的尿浓度·清醒动物的血压·麻醉动物的LV和颈动脉血压方法学梗塞尺寸:用氮蓝四唑将6μm厚的左心室横向组织切片染色,并通过B/WXC-77CE CCD摄像机(Sony)拍摄。使用专门开发的软件(Porzio等人,1995)在KS 300图像分析系统(Carl Zeiss Vision)上处理所得图像。由一个对治疗毫不知情的操作者确定室间隔膜的边界,并以半自动方式用未染色的心室组织面积确定每一切片上的梗塞面积。该软件自动计算确定为室、隔膜、梗塞区域、梗塞的LV壁以及有活力的LV壁的心室切片各组成部分的一组几何参数(Porzio等人,1995)。组织学:通过静脉内注射0.5M KCl使心脏舒张停止,之后通过用缓冲的4%甲醛逆行灌注将心脏原位固定。固定后,分别称重左心室(LV)和右心室的游离壁;用测径规测定LV较长方向上的直径。用苏木精&曙红将LV组织切片染色以进行定性检测,并用半自动图像分析系统定量测定心肌细胞横截面积。用半自动图像分析系统在Sirius红染色的切片上评价LV中的间隙胶原沉积(Masson等人,1998)。LV备用心肌中的胶原含量:将备用心肌中的LV组织匀浆化,进行PAGE-SDS电泳并电印迹到硝酸纤维素膜上。将印迹暴露于初级抗体,即兔抗大鼠胶原I型或III型抗血清(Chemicon)。通过缀合到碱性磷酸酶(对于I型胶原)或过氧化物酶(对于III型胶原)上的次级抗体识别初级抗体。左心室室体积:在等于测定的LV终端舒张压的流体静力压下,在心跳停止于舒张期(KCl)且在福尔马林中固定的心脏中测定LV室体积。将测量棒插到LV中以测定LV内长度。在接近心室底部和顶部的两个1mm厚的横向切片中测定LV室的横向直径(Jeremic等人,1996)。由积分横向直径和内长度的方程计算室体积。全身和左心室血流动力学:将连接在记录仪(Windograf,Gould Electronics)上的微尖压力传感器(Millar SPC-320)插到右颈动脉中以记录收缩和舒张压。将压力传感器伸到LV中以测定LV收缩压(LVSP)和舒张末压(LVEDP),LV压力随时间的一阶导数(+dP/dt)和心率。非侵害性血压:通过尾套法(Letica LE 5002)测定清醒大鼠的收缩压和心率。尿电解质、激素:将大鼠在代谢笼中单独饲养,并将24小时的尿液收集于1ml 6N HCl中。测定水摄取量。将尿儿茶酚胺提取到Bondelut C18柱(Varian)上,通过HPLC(Apex-II C18,3μm,50×4.5mm分析柱,JonesChromatography)分离,并用电化学检测器(Coulochem II,ESA)(Goldstein等人,1981)定量测定。用特异性放射免疫分析法(Aldoctk-2,DiaSorin和血管紧张素II,Nichols Diagnostics)测定血浆和尿中的醛固酮以及血浆中的血管紧张素II。通过火焰光度法测定尿中钠和钾的量。样本大小
在每一治疗组中有10只可供分析的动物便足以检测出生物学显著性差异。只有梗塞面积至少为LV切片面积的10%的大鼠才包括在最后的分析中。
内皮机能障碍是公认的血管疾病中的关键因素。内皮作为各种激素或具有相反作用的副产物的来源起着双重作用:血管舒张和血管收缩,抑制或促进生长,纤维蛋白溶解或血栓形成,产生抗氧化剂或氧化剂。伴有内皮机能障碍的遗传倾向性高血压动物构成了评价心血管治疗效果的有效模型。
内皮机能障碍的特征是例如引起一氧化氮下降的氧化应激增加,与凝血或纤维蛋白溶解有关的因子例如血纤维蛋白溶酶原激活抑制剂-1(PAI-1)、组织因子(TF)、组织型纤维蛋白溶酶原激活物(tPA)增加,粘附分子例如ICAM和VCAM增加,生长因子例如bFGF、TGFb、PDGF、VEGF和引起细胞生长炎症和纤维化的所有因子增加。
可在下述药理学实验中证实对例如内皮机能障碍的治疗效果:材料和方法
将购自RCC Ldt(Fullingsdorf,瑞士)的20-24周龄的SHR放在温度和光控制室中,让它们能自由摄取大鼠食物(Nafag 9331,Gossau,瑞士)和自来水。该实验是依据NIH指南进行的,并得到了Canton兽医局(Bew 161,Kantonales Veterinramt,Liestal,瑞士)的批准。将NO合成抑制剂L-NAME(Sigma Chemicals)投入饮用水中(50mg/l),所有大鼠均如此处置12周。根据消耗的水量计算出的L-NAME的平均日剂量为2.5mg/kg/天(范围是2.1-2.7)。
可将大鼠分成5组:组1,对照(n=40);组2,半富马酸盐形式的式(I)化合物(ren1;n=40);组3,依那普利(ena1;n=30);组4,依那普利和半富马酸盐形式的式(I)化合物的联合形式(ena1ren1;n=30);组5,半富马酸盐形式的式(I)化合物(ren2-高剂量;n=30)。药物投入饮用水中给药。依那普利的剂量选自Sweet等人(1987)的工作,显示心肌梗塞治愈的大鼠的存活情况显著增加。1mg/kg的AngII在对照组的正常血压大鼠上产生的加压效果在给予半富马酸盐形式的式(I)化合物后有所降低(Gervais等人1999)。
每周测定一次体重。在研究开始之前3周和前2周以及给药后2周通过尾套体积描记法测定收缩期血压和心率。在开始治疗前的那周以及在第4和12周,收集各个(代谢)笼内的大鼠尿液24小时以测定尿量并采用标准的实验室方法测定蛋白、肌酐、钠和钾。在相同的时间点,从眼眶后血管丛采集血样(最多1ml)以测定肌酐、Na+和K+。
在第4周从每组中取出10只大鼠处死,采集肾和心脏以进行形态学分析。在第12周将余下的大鼠处死。记录心脏和肾的重量。在第4周(形态学研究)和第12周(研究结束)在5% EDTA中进行末端取血,用DPCcoat-a-count醛固酮-RIA试剂盒(Bühlmann,瑞士)通过放射免疫测定法测定醛固酮。统计学分析:
所有数据都用平均值±SEM表示。统计学分析用单因素ANOVA进行,随后进行Duncan’s多范围检验和Newman-Keuls检验,以在不同组之间进行比较。概率值小于0.05的结果可视为有统计学意义。结果:
即便没有达到降血压的剂量,半富马酸盐形式的式(I)化合物和依那普利的治疗都能使存活率产生显著改善。
令人惊讶的观察结果是,在该模型中,用低剂量式(I)的肾素抑制剂和例如依那普利阻断RAS可以改善存活率,尽管肾脏功能障碍和高血压并没有得到改善。蛋白尿和肾脏损伤并没有减轻。肾脏和心脏切片中显示肾小球硬化、纤维蛋白样坏死和纤维化。这些结果清楚地表明,有内皮机能障碍的SHR的存活与治疗的降血压效果没有关系,而是可能与对内皮的直接影响有关。
在不影响血清脂质水平的情况下,对于动脉粥样硬化消退的促进作用可以通过例如使用H.Kano等人在Biochemical and Biophysical ResearchCommunications 259,414-419(1999)中描述的动物模型来验证。
本发明的化合物或药物联合形式可用于消退胆固醇饮食导致的动脉粥样硬化,这可以用例如C.Jiang等人在Br.J.Pharmacol.(1991),104,1033-1037中所描述的试验模型来证实。
本发明的化合物或药物联合形式可用于治疗肾衰竭、特别是慢性肾衰竭,这可以用例如D.Cohen等人在Journal of CardiovascularPharmacology,32:87-95(1998)中描述的试验模型来证实。
使用本发明组合物的其它益处是,可以降低按照本发明联合使用的各药物的剂量,从而减少服药量,例如,不仅可以减少剂量,而且可以减少服用频率;或者可用于减少副作用的发生率。这与接受治疗的患者的需要和要求是一致的。
优选地,本发明的药物联合形式中的活性试剂的联合治疗有效量可以分别或以固定的联合形式、同时或以任何顺序依次给药。
本文所述的本发明的药物组合物可用于同时使用或以任何顺序依次使用,也可以分开使用或以固定的联合形式使用。
相应地,本发明还涉及一种用于预防、延缓其进展、治疗以下疾病或病况的方法(a)高血压、充血性心力衰竭、肾衰竭,特别是慢性肾衰竭、经皮腔内血管成形术后再狭窄、冠状动脉旁路术后再狭窄;(b)动脉粥样硬化、胰岛素抗性和X综合征、2型糖尿病、肥胖、肾病、肾衰竭,如慢性肾衰竭、甲状腺功能减退、心肌梗塞(MI)后存活、冠心病、老年高血压、家族性异常血脂症性高血压、胶原形成增加、纤维变性和高血压后的重构(联合形式的抗增殖作用)、与高血压有关或无关的所有这些疾病或病况;(c)伴有或不伴有高血压的内皮机能障碍;(d)高脂血症、高脂蛋白血症、动脉粥样硬化以及高胆固醇血症,(e)青光眼;(f)单纯性收缩期高血压(ISH),(g)糖尿病性视网膜病,以及(h)外周血管疾病;该方法包括,向有此需要的恒温动物,包括人类,给予联合有效量的含有式(I)的肾素抑制剂或其可药用盐和至少一种选自下列的治疗剂的联合形式:(i)AT1-受体拮抗剂或其可药用盐,(ii)HMG-Co-A还原酶抑制剂或其可药用盐,(iii)血管紧张素转化酶(ACE)抑制剂或其可药用盐,(iv)钙通道阻断剂或其可药用盐,(v)醛固酮合酶抑制剂或其可药用盐,(vi)醛固酮拮抗剂或其可药用盐,(vii)双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂或其可药用盐,(viii)内皮素拮抗剂或其可药用盐,和(ix)利尿剂或其可药用盐。
此外,本发明还涉及式(I)的肾素抑制剂或其可药用盐和至少一种选自下列的治疗剂的联合形式(i)AT1-受体拮抗剂或其可药用盐,(ii)HMG-Co-A还原酶抑制剂或其可药用盐,(iii)血管紧张素转化酶(ACE)抑制剂或其可药用盐,(iv)钙通道阻断剂或其可药用盐,(v)醛固酮合酶抑制剂或其可药用盐,(vi)醛固酮拮抗剂或其可药用盐,(vii)双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂或其可药用盐,(viii)内皮素拮抗剂或其可药用盐,以及(ix)利尿剂或其可药用盐;在制备用于预防、延缓其进展或治疗选自下列的疾病或病况的药物中的用途(a)高血压、充血性心力衰竭、肾衰竭,特别是慢性肾衰竭、经皮腔内血管成形术后再狭窄、冠状动脉旁路术后再狭窄;(b)动脉粥样硬化、胰岛素抗性和X综合征、2型糖尿病、肥胖、肾病、肾衰竭,如慢性肾衰竭、甲状腺功能减退、心肌梗塞(MI)后存活、冠心病、老年高血压、家族性异常血脂症性高血压、胶原形成增加、纤维变性和高血压后的重构(联合形式的抗增殖作用)、与高血压有关或无关的所有这些疾病或病况;(c)伴有或不伴有高血压的内皮机能障碍;(d)高脂血症、高脂蛋白血症、动脉粥样硬化和高胆固醇血症;(e)青光眼;(f)单纯性收缩期高血压(ISH),(g)糖尿病性视网膜病,以及(h)外周血管疾病。
此外,本发明还涉及用于预防、延缓其进展、治疗选自下列的疾病或病况的药物组合物(a)高血压、充血性心力衰竭、肾衰竭,特别是慢性肾衰竭、经皮腔内血管成形术后再狭窄、冠状动脉旁路术后再狭窄;(b)动脉粥样硬化、胰岛素抗性和X综合征、2型糖尿病、肥胖、肾病、肾衰竭,如慢性肾衰竭、甲状腺功能减退、心肌梗塞(MI)后存活、冠心病、老年高血压、家族性异常血脂症性高血压、胶原形成增加、纤维变性和高血压后的重构(联合形式的抗增殖作用)、与高血压有关或无关的所有这些疾病或病况;(c)伴有或不伴有高血压的内皮机能障碍;(d)高脂血症、高脂蛋白血症、动脉粥样硬化和高胆固醇血症;(e)青光眼;(f)单纯性收缩期高血压(ISH),(g)糖尿病性视网膜病,以及(h)外周血管疾病;其含有式(I)的肾素抑制剂或其可药用盐和至少一种选自下列的治疗剂的联合形式(i)AT1-受体拮抗剂或其可药用盐,(ii)HMG-Co-A还原酶抑制剂或其可药用盐,(iii)血管紧张素转化酶(ACE)抑制剂或其可药用盐,(iv)钙通道阻断剂或其可药用盐,(v)醛固酮合酶抑制剂或其可药用盐,(vi)醛固酮拮抗剂或其可药用盐,(vii)双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂或其可药用盐,(viii)内皮素拮抗剂或其可药用盐,以及(ix)利尿剂或其可药用盐;以及可药用的载体。
使用本发明组合物的其它益处是,可以降低按照本发明联合使用的各药物的剂量,从而减少服药量,例如,不仅可以减少剂量,而且可以减少服用频率;或者可用于减少副作用的发生率。这与接受治疗的患者的需要和要求是一致的。
优选地,本发明的药物联合形式中的活性试剂的联合治疗有效量可以分别或以固定的联合形式、同时或以任何顺序依次给药。
本文所述的本发明的药物组合物可用于同时使用或以任何顺序依次使用,也可以分开使用或以固定的联合形式使用。
另一方面,本发明还涉及用于预防、延缓其进展、治疗本发明所述的疾病或病况的药盒,该药盒含有(a)一定量的在第一单位剂量形式中的式(I)的肾素抑制剂或其可药用盐;(b)一定量的在第二单位剂量形式等中的至少一种选自组分(i)至(ix)的治疗剂,或者,在每一适宜的情况下,它们的可药用盐;以及(c)用于包含所述第一、第二等单位形式的容器。
在其一种改变形式中,本发明还涉及“成套的药盒(kit-of-parts)”,它的意思是指例如,依据本发明联合使用的各组分可独立地给药,或者通过使用具有不同量的组分的不同固定联合形式来给药,即同时或在不同的时间点给药。成套药盒的各部分可例如同时施用或按时间顺序交错施用,也就是说在不同时间点以相同或不同的时间间隔施用成套药盒的任何部分。优选对时间间隔进行选择,使得通过联合使用各部分所获得的治疗疾病或病况的效果好于通过仅使用任何一种组分所获得的效果。
本发明还涉及商业包装,其中包含本发明的联合形式,以及指导同时、单独或顺序使用的说明书。
这些药物制剂可用于向恒温动物经肠、如口服给药,也可用于直肠或胃肠外给药,制剂中可以仅含药理学活性化合物,或者还含有常用的药学辅料。例如,药物制剂可由约0.1%至90%,优选约1%至约80%的活性化合物组成。用于经肠或胃肠外以及眼部给药的药物制剂可以制成例如单位剂型,如包衣片、片剂、胶囊或栓剂,或者也可以是安瓿的形式。这些制剂可以以熟知的方式,例如使用传统的混合、制粒、包衣、溶解或冷冻干燥方法制备。因此,用于口服的药物制剂可通过如下方法制得:将活性化合物与固体赋型剂混合,如需要,可将所得的混合物制粒,并且,如果需要或必需,在加入适宜的辅料后,将混合物或颗粒制成片剂或包衣片芯。
活性化合物的剂量取决于各种因素,诸如给药方式、恒温动物的种类、年龄和/或个体的情况。
本发明药物联合形式中的活性成分的优选剂量为治疗有效剂量,特别是那些可通过商业途径获得的剂量。
通常,在口服给药时,对于体重约为75kg的患者,预期可以使用约1mg至约360mg的每日剂量。
活性化合物的剂量取决于各种因素,诸如给药方式、恒温动物的种类、年龄和/或个体的情况。
药物制剂可以以适宜的剂量单位形式提供,例如,胶囊或片剂,并可同时含有一定量的其它联合有效的组分。
给予恒温动物,例如人类,例如体重约为70kg的人类的式(I)的肾素抑制剂的剂量、特别是可有效抑制肾素,例如,降低血压和/或改善青光眼症状的剂量是每人每天约3mg至约3g,优选约10mg至约1g,例如,约20mg至200mg;可分成1至4个可以是例如相同大小的单个剂量。通常,儿童的剂量为成人的一半。每一个体所需的剂量可以通过例如测定活性成分的血清浓度来监控,从而调节至最佳水平。单个剂量包括,例如,每个成人患者10、40或100mg。
缬沙坦,作为AT1-受体拮抗剂的代表性化合物,可以以适宜的剂量单位形式使用,例如,胶囊或片剂,其中含有治疗有效量的,例如约20至约320mg可以向患者给药的缬沙坦。活性成分可每日给药三次,从例如20mg或40mg缬沙坦的每日剂量开始,增加至每日80mg,然后进一步增加至每日160mg到最高每日320mg。优选将缬沙坦分别以80mg或160mg的剂量每日服用两次。相应的剂量可在例如早晨、中午或晚间服用。优选每日服用两次。
对于HMG-Co-A还原酶抑制剂,优选的剂量单位形式是,例如,片剂或胶囊,其中含有例如约5mg至约120mg的化合物,当使用的是氟伐他汀时,优选含有例如20mg、40mg或80mg(相当于游离酸)氟伐他汀,可每日服用例如一次。
对于ACE抑制剂,优选的剂量单位形式是,例如,片剂或胶囊,其中含有例如约5mg至约20mg,优选5mg、10mg、20mg或40mg的贝那普利;约6.5mg至100mg,优选6.25mg、12.5mg、25mg、50mg、75mg或100mg的卡托普利;约2.5mg至约20mg,优选2.5mg、5mg、10mg或20mg的依那普利;约10mg至约20mg,优选10mg或20mg的福辛普利;约2.5mg至约4mg,优选2mg至4mg的哌道普利;约5mg至约20mg,优选5mg、10mg或20mg的喹那普利;或约1.25mg至约5mg,优选1.25mg、2.5mg或5mg的雷米普利。优选每日服用三次。
特别优选的是低剂量的药物联合形式。
以下实施例举例说明了上述的发明;但是,它们并不以任何方式限制本发明的范围。制剂实施例1.薄膜包衣片剂:
*)在操作中除去薄膜包衣片按照例如以下方法制备:
成分 | 每单位的组成(mg) | 标准 |
制粒 | ||
缬沙坦[=活性成分] | 80.00 | |
微晶纤维素/Avicel PH 102 | 54.00 | NF,Ph.Eur |
交联聚维酮 | 20.00 | NF,Ph.Eur |
胶态无水二氧化硅/胶态二氧化硅/Aerosil 200 | 0.75 | Ph.Eur/NF |
硬脂酸镁 | 2.5 | NF,Ph.Eur |
混合 | ||
胶态无水二氧化硅/胶态二氧化硅/Aerosil 200 | 0.75 | Ph.Eur/NF |
硬脂酸镁 | 2.00 | NF,Ph.Eur |
包衣 | ||
纯净水*) | - | |
DIOLACK浅红00F34899 | 7.00 | |
总片重 | 167.00 |
将缬沙坦、微晶纤维素、交联聚维酮、部分胶态无水二氧化硅/胶态二氧化硅/Aerosile 200、二氧化硅和硬脂酸镁的混合物在扩散混合器中预混合,之后在筛磨上过筛。将所得混合物再次在扩散混合器中预混合,用滚压机压实,然后用筛磨过筛。向所得混合物加入剩余的胶态无水二氧化硅/胶态二氧化硅/Aerosile 200,并在扩散混合器中制备最终的混合物。将整个混合物在旋转压片机中压片,然后在多孔包衣锅中用Diolack浅红对片剂进行薄膜包衣。制剂实施例2:薄膜包衣片剂:
成分 | 每单位的组成(mg) | 标准 |
制粒 | ||
缬沙坦[=活性成分] | 160.00 | |
微晶纤维素/Avicel PH 102 | 108.00 | NF,Ph.Eur |
交联聚维酮 | 40.00 | NF,Ph.Eur |
胶态无水二氧化硅/胶态二氧化硅/Aerosil 200 | 1.50 | Ph.Eur/NF |
硬脂酸镁 | 5.00 | NF,Ph.Eur |
混合 | ||
胶态无水二氧化硅/胶态二氧化硅/Aerosil 200 | 1.50 | Ph.Eur/NF |
硬脂酸镁 | 4.00 | NF,Ph.Eur |
包衣 | ||
Opadry浅棕00F33172 | 10.00 | |
总片重 | 330.00 |
薄膜包衣片剂按照例如制剂实施例1中的描述制备。制剂实施例3:薄膜包衣片剂:
*)Opadry棕OOF16711着色剂的组成示于下表中。**)在操作中除去Opadry的组成:
成分 | 每单位的组成(mg) | 标准 |
片芯:内相 | ||
缬沙坦[=活性成分] | 40.00 | |
二氧化硅,胶态无水的(胶态二氧化硅)[=助流剂] | 1.00 | Ph.Eur,USP/NF |
硬脂酸镁[=润滑剂] | 2.00 | USP/NF |
交联聚维酮[=崩解剂] | 20.00 | Ph.Eur |
微晶纤维素[=粘合剂] | 124.00 | USP/NF |
外相 | ||
二氧化硅,胶态无水的,(胶态二氧化硅)[=助流剂] | 1.00 | Ph.Eur,USP/NF |
硬脂酸镁[=润滑剂] | 2.00 | USP/NF |
薄膜包衣 | ||
Opadry棕OOF 16711*) | 9.40 | |
纯净水**) | - | |
总片重 | 199.44 |
成分 | 组成的近似% |
氧化铁,黑色(C.I.N0.77499,E 172) | 0.50 |
氧化铁,棕色(C.I.No.77499,E 172) | 0.50 |
氧化铁,红色(C.I.No.77491,E 172) | 0.50 |
氧化铁,黄色(C.I.No.77492,E 172) | 0.50 |
Macrogolum(Ph.Eur) | 4.00 |
二氧化钛(C.I.No.77891,E 171) | 14.00 |
羟丙甲基纤维素(Ph.Eur) | 80.00 |
薄膜包衣片剂按照例如制剂实施例1中的描述制备。制剂实施例4:胶囊:
成分 | 每单位的组成(mg) |
缬沙坦[=活性成分] | 80.00 |
微晶纤维素 | 25.10 |
交联聚维酮 | 13.00 |
聚维酮 | 12.50 |
硬脂酸镁 | 1.30 |
十二烷基硫酸钠 | 0.60 |
外壳 | |
氧化铁,红色(C.I.No.77491,EC No.E 172) | 0.123 |
氧化铁,黄色(C.I.No.77492,EC No.E 172) | 0.123 |
氧化铁,黑色(C.I.No.77499,EC No.E 172) | 0.245 |
二氧化钛 | 1.540 |
明胶 | 74.969 |
总片重 | 209.50 |
片剂可按照例如以下方法制备:制粒/干燥
将缬沙坦和微晶纤维素在流化床制粒机中喷雾制粒,所使用的制粒溶液由溶于纯净水的聚维酮和十二烷基硫酸钠组成。将所得颗粒在流化床干燥器中干燥。研磨/混合
将干燥的颗粒和交联聚维酮及硬脂酸镁一起研磨。将所得物质在锥形螺杆混合机中混合约10分钟。填充胶囊
将混合后的全部颗粒在控制的温度和湿度下填充到空的硬明胶胶囊中。将填充后的胶囊除尘、目检、重量检验、检疫,最后由质量评价部门进行评估。制剂实施例5:胶囊:
成分 | 每单位的组成(mg) |
缬沙坦[=活性成分] | 160.00 |
微晶纤维素 | 50.20 |
交联聚维酮 | 26.00 |
聚维酮 | 25.00 |
硬脂酸镁 | 2.60 |
十二烷基硫酸钠 | 1.20 |
外壳 | |
氧化铁,红(C.I.No.77491,EC No.E 172) | 0.123 |
氧化铁,黄(C.I.No.77492,EC No.E 172) | 0.123 |
氧化铁,黑(C.I.No.77499,EC No.E 172) | 0.245 |
二氧化钛 | 1.540 |
明胶 | 74.969 |
总片重 | 342.00 |
该制剂按照制剂实施例4的描述制备。制剂实施例6:硬明胶胶囊:
实施例7至11:
实施例12:硬明胶胶囊:
1)由于存在水分而包含2%的过量2)20mg的游离酸等价于21.06mg Na盐3)部分的在操作中除去实施例13:硬明胶胶囊
1)由于存在水分而包含2%的过量2)20mg的游离酸等价于21.06mg Na盐3)部分的在操作中除去实施例14:圆形、向两面微凸的、边缘成倾斜角的薄膜包衣片剂:
1)84.24mg的氟伐他汀钠盐等价于80mg氟伐他汀游离酸2)需根据其中的水分进行调整(LOD)3)在操作中除去实施例15:圆形、向两面微凸的、边缘成倾斜角的薄膜包衣片剂
实施例16: 薄膜包衣片剂
成分 | 每单位的组成(mg) |
缬沙坦[=活性成分] | 80.00 |
十二烷基硫酸钠 | 0.60 |
硬脂酸镁 | 1.30 |
聚维酮 | 12.50 |
交联聚维酮 | 13.00 |
微晶纤维素 | 21.10 |
总片重 | 130.00 |
实施例 | 7 | 8 | 9 | 10 | 11 |
成分 | 每单位中的含量(mg) | 每单位中的含量(mg) | 每单位中的含量(mg) | 每单位中的含量(mg) | 每单位中的含量(mg) |
制粒 | |||||
缬沙坦[=药物] | 80.000 | 160.000 | 40.000 | 320.000 | 320.000 |
微晶纤维素(NF,Ph.Eur.)/Avicel PH 102 | 54.000 | 108.000 | 27.000 | 216.000 | 216.000 |
交联聚维酮(NF,Ph.Eur.) | 15.000 | 30.000 | 7.500 | 80.000 | 60.000 |
胶态无水二氧化硅(Ph.Eur.)/胶态二氧化硅(NF)/Aerosil 200 | 1.500 | 3.000 | 0.750 | 3.000 | 6.000 |
硬脂酸镁(NF,Ph.Eur.) | 3.000 | 6.000 | 1.500 | 10.000 | 12.000 |
混合 | |||||
胶态无水二氧化硅(Ph.Eur.)/胶态二氧化硅(NF)/Aerosil 200 | --- | --- | --- | 3.000 | - |
硬脂酸镁,NF,Ph.Eur. | 1.500 | 3.000 | 0.750 | 8.000 | 6.000 |
片芯重量/mg | 155.000 | 310.000 | 77.500 | 640.000 | 620.000 |
包衣 | - | - | 3.800 | 15.000 | 16.000 |
成分 | 每单位中的含量[mg] |
胶囊 | |
氟伐他汀钠1) | 21.481 2) |
碳酸钙 | 62.840 |
碳酸氢钠 | 2.000 |
微晶纤维素 | 57.220 |
预胶化淀粉 | 41.900 |
纯净水3) | 适量 |
硬脂酸镁 | 1.050 |
滑石 | 9.430 |
目标胶囊填充重量 | 195.92 |
胶囊外壳 | |
硬明胶胶囊外壳 | 48.500 |
打印用油墨(预先印刷的) | |
白墨水 | 痕量 |
红墨水 | 痕量 |
目标胶囊重量 | 244.42 |
成分 | 每单位中的含量[mg] |
氟伐他汀钠 | 42.9621)2) |
碳酸钙 | 125.680 |
碳酸氢钠 | 4.000 |
微晶纤维素 | 114.440 |
预胶化淀粉 | 83.800 |
纯净水3) | 适量 |
硬脂酸镁 | 2.100 |
滑石 | 18.860 |
目标胶囊填充重量 | 391.840 |
胶囊外壳 | |
硬明胶胶囊外壳 | 76.500 |
打印用油墨(预先印刷的) | |
白墨水 | 痕量 |
红墨水 | 痕量 |
目标胶囊重量 | 468.34 |
成分 | 每单位中的含量[mg] |
片芯 | |
氟伐他汀钠1) | 84.242) |
微晶纤维素/微晶纤维素细粉 | 111.27 |
Hypromellose/羟丙甲基纤维素(Methocel K100LVP CR;HPMC100 cps) | 97.50 |
羟丙基纤维素(Klucel HXF) | 16.25 |
碳酸氢钾 | 8.42 |
聚维酮 | 4.88 |
硬脂酸镁 | 2.44 |
片芯片剂重量 | 325.00 |
包衣 | |
包衣预混合物-Opadry黄(00F22737) | 9.75 |
总重量 | 334.75 |
纯净水3) | 适量 |
成分 | 单位重量/体积[mg] | 单位重量/体积[mg] | 单位重量/体积[mg] | 单位重量/体积[mg] |
盐酸贝那普利 | 5.00 | 10.00 | 20.00 | 40.00 |
乳糖一水合物,NF | 142.00 | 132.00 | 117.00 | 97.00 |
预胶化淀粉,NF | 8.00 | 8.00 | 8.00 | 8.00 |
胶态二氧化硅,NF(Cab-O-Sil,M-5) | 1.00 | 1.00 | 1.00 | 1.00 |
交联聚维酮,NF | 3.00 | 3.00 | 3.00 | 3.00 |
微晶纤维素,NF | 18.00 | 18.00 | 18.00 | 24.25 |
氢化蓖麻油,NF硬脂酸镁,NF | 8.00 | 8.00 | 8.00 | 1.75 |
色素:黄色-棕色(混悬液)红色-棕色(混悬液) | - | 2.00 | 0.50 | 0.50 |
纯净水,USP | 痕量 | 痕量 | 痕量 | 痕量 |
Opadry色素:黄色粉红色 | 8.38 | 8.38 | 8.38 | 8.38 |
总计 | 193.38 | 190.38 | 183.88 | 183.88 |
用以下组分制备10000片片剂,每一片含有100mg活性成分:式(I)化合物的半富马酸盐 1000g玉米淀粉 680g胶态硅酸 200g硬脂酸镁 20g硬脂酸 50g羧甲基淀粉钠 250g水 适量
将前述实施例中提到的作为活性成分的式I化合物之一、50g玉米淀粉和胶态硅酸的混合物用由250g玉米淀粉和2.2kg去矿物质水制成的淀粉糊处理而制成湿的物质块。将该物质块压过孔径为3mm的筛网并在45℃下在流化床干燥机中干燥30分钟。将干燥的颗粒压过孔径为1mm的筛网,与预先过筛(1mm筛网)的330g玉米淀粉、硬脂酸镁、硬脂酸和羧甲基淀粉钠的混合物混合,然后压制成向两面微凸的片剂。
Claims (10)
2.权利要求1的组合物,其中的肾素抑制剂以半富马酸盐的形式存在。
3.权利要求1或2的组合物,其中,各自独立的,-所述AT1-受体拮抗剂是缬沙坦或其可药用盐;-所述HMG-Co-A还原酶抑制剂是氟伐他汀和匹伐他汀,或其可药用盐;-所述血管紧张素转化酶(ACE)抑制剂是贝那普利或依那普利,或其可药用盐;-所述钙通道阻断剂是氨氯地平或其可药用盐;-所述醛固酮合酶抑制剂是法倔唑(包括其(+)-对映体)或其可药用盐;-所述醛固酮拮抗剂是依普利酮;-所述双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂是奥美曲羟或其可药用盐;-所述内皮素拮抗剂是波生坦或其可药用盐;并且-所述利尿剂是氢氯噻嗪。
4.用于预防、延缓其进展、治疗选自以下疾`或病况的权利要求1至3中任一项所述的组合物:(a)高血压、充血性心力衰竭、肾衰竭,特别是慢性肾衰竭、经皮腔内血管成形术后再狭窄、冠状动脉旁路术后再狭窄;(b)动脉粥样硬化、胰岛素抗性和X综合征、2型糖尿病、肥胖、肾病、肾衰竭,如慢性肾衰竭、甲状腺功能减退、心肌梗塞(MI)后存活、冠心病、老年高血压、家族性异常血脂症性高血压、胶原形成增加、纤维变性和高血压后的重构(联合形式的抗增殖作用)、与高血压有关或无关的所有这些疾病或病况;(c)伴有或不伴有高血压的内皮机能障碍;(d)高脂血症、高脂蛋白血症、动脉粥样硬化和高胆固醇血症;以及(e)青光眼。
5.用于预防、延缓其进展、治疗选自以下疾病或病况的权利要求1至3中任一项所述的组合物:(f)单纯性收缩期高血压(ISH),(g)糖尿病性视网膜病,以及(h)外周血管疾病。
6.用于同时、分别或顺序使用的权利要求1至5中任一项所述的组合物。
7.用于预防、延缓其进展或治疗权利要求4中所述疾病或病况的药盒,其含有(a)一定量的在第一单位剂量形式中的式(I)的肾素抑制剂或其可药用盐;(b)一定量的在第二单位剂量形式等中的至少一种选自组分(i)至(ix)的治疗剂,或者,在每一适宜的情况下,它们的可药用盐;以及(c)用于包含所述第一、第二等单位形式的容器。
8.式(I)的肾素抑制剂或其可药用盐和至少一种选自下列的治疗剂的联合形式(i)AT1-受体拮抗剂或其可药用盐,(ii)HMG-Co-A还原酶抑制剂或其可药用盐,(iii)血管紧张素转化酶(ACE)抑制剂或其可药用盐,(iv)钙通道阻断剂或其可药用盐,(v)醛固酮合酶抑制剂或其可药用盐,(vi)醛固酮拮抗剂或其可药用盐,(vii)双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂或其可药用盐,(viii)内皮素拮抗剂或其可药用盐,以及(ix)利尿剂或其可药用盐;在制备用于预防、延缓其进展或治疗选自下列的疾病或病况的药物中的用途(a)高血压、充血性心力衰竭、肾衰竭,特别是慢性肾衰竭、经皮腔内血管成形术后再狭窄、冠状动脉旁路术后再狭窄;(b)动脉粥样硬化、胰岛素抗性和X综合征、2型糖尿病、肥胖、肾病、肾衰竭,如慢性肾衰竭、甲状腺功能减退、心肌梗塞(MI)后存活、冠心病、老年高血压、家族性异常血脂症性高血压、胶原形成增加、纤维变性和高血压后的重构(联合形式的抗增殖作用)、与高血压有关或无关的所有这些疾病或病况;(c)伴有或不伴有高血压的内皮机能障碍;(d)高脂血症、高脂蛋白血症、动脉粥样硬化和高胆固醇血症;以及(e)青光眼。
9.式(I)的肾素抑制剂或其可药用盐和至少一种选自下列的治疗剂的联合形式(i)AT1-受体拮抗剂或其可药用盐,(ii)HMG-Co-A还原酶抑制剂或其可药用盐,(iii)血管紧张素转化酶(ACE)抑制剂或其可药用盐,(iv)钙通道阻断剂或其可药用盐,(v)醛固酮合酶抑制剂或其可药用盐,(vi)醛固酮拮抗剂或其可药用盐,(vii)双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂或其可药用盐,(viii)内皮素拮抗剂或其可药用盐,以及(ix)利尿剂或其可药用盐;在制备用于预防、延缓其进展或治疗选自下列的疾病或病况的药物中的用途(f)单纯性收缩期高血压(ISH),(g)糖尿病性视网膜病,以及(h)外周血管疾病。
10.预防、延缓其进展、治疗选自下列的疾病或病况的方法:(a)高血压、充血性心力衰竭、肾衰竭,特别是慢性肾衰竭、经皮腔内血管成形术后再狭窄、冠状动脉旁路术后再狭窄;(b)动脉粥样硬化、胰岛素抗性和X综合征、2型糖尿病、肥胖、肾病、肾衰竭,如慢性肾衰竭、甲状腺功能减退、心肌梗塞(MI)后存活、冠心病、老年高血压、家族性异常血脂症性高血压、胶原形成增加、纤维变性和高血压后的重构(联合形式的抗增殖作用)、与高血压有关或无关的所有这些疾病或病况;(c)伴有或不伴有高血压的内皮机能障碍;(d)高脂血症、高脂蛋白血症、动脉粥样硬化以及高胆固醇血症,(e)青光眼;(f)单纯性收缩期高血压(ISH),(g)糖尿病性视网膜病,以及(h)外周血管疾病;该方法包括,向有此需要的恒温动物,包括人类,给予联合有效量的含有式(I)的肾素抑制剂或其可药用盐和至少一种选自下列的治疗剂的联合形式:(i)AT1-受体拮抗剂或其可药用盐,(ii)HMG-Co-A还原酶抑制剂或其可药用盐,(iii)血管紧张素转化酶(ACE)抑制剂或其可药用盐,(iv)钙通道阻断剂或其可药用盐,(v)醛固酮合酶抑制剂或其可药用盐,(vi)醛固酮拮抗剂或其可药用盐,(vii)双重血管紧张素转化酶/中性内肽酶(ACE/NEP)抑制剂或其可药用盐,(viii)内皮素拮抗剂或其可药用盐,和(ix)利尿剂或其可药用盐。
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