CN104053441B - 用于预防或治疗高脂血症的药物组合物 - Google Patents

用于预防或治疗高脂血症的药物组合物 Download PDF

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CN104053441B
CN104053441B CN201280058939.2A CN201280058939A CN104053441B CN 104053441 B CN104053441 B CN 104053441B CN 201280058939 A CN201280058939 A CN 201280058939A CN 104053441 B CN104053441 B CN 104053441B
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hyperlipemia
salt
angiotensin
hypertriglyceridemia
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李钟郁
李相昊
林泽周
高银志
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Daewoong Pharmaceutical Co Ltd
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Abstract

本发明提供用于预防或治疗高脂血症的药物组合物，其包含作为活性成分的(4S,5R)-5-[3,5-双(三氟甲基)苯基]-3-({2-[4-氟-2-甲氧基-5-(丙烷-2-基)苯基]-5-(三氟甲基)苯基}甲基)-4-甲基-1,3-噁唑烷-2-酮或其药学上可接受的盐；以及血管紧张素II受体阻断剂。

Description

用于预防或治疗高脂血症的药物组合物
技术领域
本发明涉及用于预防或治疗高脂血症的药物组合物。更具体而言，本发明涉及用于预防或治疗高脂血症的药物组合物，其包含作为活性成分的(4S,5R)-5-[3,5-双(三氟甲基)苯基]-3-({2-[4-氟-2-甲氧基-5-(丙烷-2-基)苯基]-5-(三氟甲基)苯基}甲基)-4-甲基-1,3-噁唑烷-2-酮或其药学上可接受的盐，以及血管紧张素II受体阻断剂。
背景技术
高脂血症涉及血液中异常高水平的任意或所有脂类和/或脂蛋白类。根据升高的脂类的类型，高脂血症可以划分为高胆固醇血症、高甘油三酯血症或两者皆有的混合型高脂血症。已知甘油三酯是动脉粥样硬化的独立危险因素之一。虽然高甘油三酯血症和心血管疾病如动脉粥样硬化之间的关联性尚不清楚，但是已知高甘油三酯血症增加动脉粥样硬化的风险(CullenP.Evidencethattriglyceridesareanindependentcoronaryheartdiseaseriskfactor(甘油三酯是独立的冠心病危险因素的证据).AmJCardiol2000；86:943-9；LeNA,WalterMF.Theroleofhypertriglyceridemiainatherosclerosis(高甘油三酯血症在动脉粥样硬化中的作用).CurrAtherosclerRep2007；9:110-5；StalenhoefAF,deGraafJ.Associationoffastingandnonfastingserumtriglycerideswithcardiovasculardiseaseandtheroleofremnant-likelipoproteinsandsmalldenseLDL(空腹和非空腹血清甘油三酯与心血管疾病的关系以及残粒样脂蛋白和小而密LDL的作用).CurrOpinLipidol2008；19:355-61)。并且，已报道胰腺炎发生于甘油三酯水平高于1000mg/dl或12mmol/l的人中。
同时，下列式1的化合物的化学名称为(4S,5R)-5-[3,5-双(三氟甲基)苯基]-3-({2-[4-氟-2-甲氧基-5-(丙烷-2-基)苯基]-5-(三氟甲基)苯基}甲基)-4-甲基-1,3-噁唑烷-2-酮，其具有选择性胆固醇酯转运蛋白(CETP)抑制活性。该化合物作为用于预防或治疗动脉粥样硬化的药物而研发(国际专利公开号WO2006/014357)。
<式1>
发明内容
技术问题
为了研发能够提供有效治疗效果的抗高脂血症的药物或药物组合，本发明人进行了各种研究。令人惊讶的是，本发明人发现，与仅施用式1的化合物相比，将式1的化合物和血管紧张素II受体阻断剂共同施用，能够明显抑制血液中甘油三酯的浓度；并增加血液中的HDL胆固醇。
因此，本发明的目的是提供用于预防或治疗高脂血症的药物组合物,其包含作为活性成分的式1的化合物和血管紧张素II受体阻断剂。
技术方案
根据本发明的一个方面，提供了用于预防或治疗高脂血症的药物组合物，其包含作为活性成分的式1的化合物或其药学上可接受的盐；和血管紧张素II受体阻断剂：
<式1>
在本发明的药物组合物中，血管紧张素II受体阻断剂可以选自：奥美沙坦或其盐、奥美沙坦酯或其盐、替米沙坦或其盐、洛沙坦或其盐，以及缬沙坦或其盐。优选的是，血管紧张素II受体阻断剂可以是奥美沙坦酯或其盐。
在本发明的实施方案中，高脂血症可以是高甘油三酯血症或高甘油三酯血症相关疾病。高甘油三酯血症相关疾病包括动脉粥样硬化或胰腺炎。在本发明的另一实施方案中，高脂血症可以是高胆固醇血症。在本发明的又一实施方案中，高脂血症可以是混合型高脂血症。
本发明的药物组合物可以配制成口服剂型。口服剂型可包含适于以10-300mg/日的剂量施用的量的式1的化合物或其药学上可接受的盐；和/或适于以5-320mg/日的剂量施用的量的血管紧张素II受体阻断剂。
有益效果
本发明最新发现，与仅施用式1的化合物相比，共同施用式1的化合物和血管紧张素II受体阻断剂如奥美沙坦、奥美沙坦酯、替米沙坦、洛沙坦、缬沙坦等，能够明显抑制血液中甘油三酯的浓度；并增加血液中的HDL胆固醇。因此，本发明的药物组合物能够有利地应用于预防或治疗高脂血症，包括高甘油三酯血症(包括高甘油三酯血症相关疾病在内)、高胆固醇血症，以及混合型高脂血症。
本发明的最佳实施方式
本发明提供了用于预防或治疗高脂血症的药物组合物，其包含作为活性成分的式1的化合物或其药学上可接受的盐；和血管紧张素II受体阻断剂：
<式1>
可根据国际公开号WO2006/014357的公开来制备式1的化合物或其药学上可接受的盐。将国际公开号WO2006/014357作为参考并入本说明书中。
血管紧张素II受体阻断剂(ARB)包括奥美沙坦或其盐、奥美沙坦酯或其盐、替米沙坦或其盐(例如钠盐等)、洛沙坦或其盐(例如钾盐等)，以及缬沙坦或其盐(例如钠盐、钙盐等)。血管紧张素II受体阻断剂可优选是奥美沙坦酯或其盐。
在实施方案中，本发明的药物组合物可以是用于预防或治疗高甘油三酯血症或高甘油三酯血症相关疾病的药物组合物。高甘油三酯血症相关疾病是指由血液中水平异常升高的甘油三酯引起的疾病。高甘油三酯血症相关疾病包括动脉粥样硬化和胰腺炎，但并不限于此。高甘油三酯血症相关疾病的优选实例包括动脉粥样硬化。
在另一实施方案中，本发明的药物组合物可以是用于预防或治疗高胆固醇血症的药物组合物。
在又一实施方案中，本发明的药物组合物可以是用于预防或治疗混合型高脂血症的药物组合物。
本发明的药物组合物可以配制成口服剂型或肠胃外剂型，优选配制成口服剂型。并且，本发明的药物组合物可以具有通过将式1的化合物和血管紧张素II受体阻断剂配制成单一单位剂型而获得的形式。或者，本发明的药物组合物可以具有通过将式1的化合物和血管紧张素II受体阻断剂配制成单独剂型，然后将所得剂型包装于单个包装单元中而获得的形式。
具有一个或两个单元剂型的用于口服的药物组合物，可以包括药学上可接受的载体，例如稀释剂、崩解剂、甜味剂、润滑剂和/或调味剂，并且可以根据常规方法配制成片剂、胶囊、粉剂、颗粒剂、悬浮剂、乳剂、糖浆剂等。在口服片剂的情况下，载体如乳糖、玉米淀粉，和润滑剂如硬脂酸镁是常用的。在口服胶囊的情况下，乳糖和/或干玉米淀粉可以用作稀释剂。当需要水性悬浮剂用于口服时，活性成分可以与乳化剂和/或悬浮剂结合。视需要，可以使用某些甜味剂和/或调味剂。对于具有一个或两个单元剂型的肠胃外给药(例如肌内给药、腹腔内给药、皮下给药和静脉给药)的药物组合物而言，通常制备活性成分的无菌溶液，应适当调节溶液的pH，并用等渗剂和/或缓冲剂进行缓冲。
可以以每日约10mg至每日约300mg的治疗有效量将本发明的药物组合物所含的式1的化合物或其药学上可接受的盐施用于个体患者。并且，可以以每日约5mg至每日约320mg的治疗有效量将血管紧张素II受体阻断剂施用于个体患者。当然，可以根据患者的年龄、体重、敏感性、症状等改变剂量。在一个实施方案中，本发明的药物组合物可以配制成口服剂型。口服剂型可包含适于以10-300mg/日的剂量施用的量的式1的化合物或其药学上可接受的盐；和/或适于以5-320mg/日的剂量施用的量的血管紧张素II受体阻断剂。当然，血管紧张素II受体阻断剂的日剂量取决于其类型。
本发明还提供了包含式1的化合物即：(4S,5R)-5-[3,5-双(三氟甲基)苯基]-3-({2-[4-氟-2-甲氧基-5-(丙烷-2-基)苯基]-5-(三氟甲基)苯基}甲基)-4-甲基-1,3-噁唑烷-2-酮或其药学上可接受的盐以及血管紧张素II受体阻断剂的活性成分在制备预防或治疗高脂血症的药物中的用途。在本发明的用途中，高脂血症可以是高甘油三酯血症或高甘油三酯血症相关疾病。高甘油三酯血症相关疾病包括动脉粥样硬化和胰腺炎，但并不限于此。高甘油三酯血症相关疾病的优选实例包括动脉粥样硬化。并且，在本发明的用途中，高脂血症可以是高胆固醇血症或混合型高脂血症。
本发明在其范围内包括用于治疗患者的高脂血症的方法，其包括对有需要的患者施用治疗有效量的式1的化合物即：(4S,5R)-5-[3,5-双(三氟甲基)苯基]-3-({2-[4-氟-2-甲氧基-5-(丙烷-2-基)苯基]-5-(三氟甲基)苯基}甲基)-4-甲基-1,3-噁唑烷-2-酮或其药学上可接受的盐以及治疗有效量的血管紧张素II受体阻断剂。在本发明的治疗高脂血症的方法中，高脂血症可以是高甘油三酯血症或高甘油三酯血症相关疾病。高甘油三酯血症相关疾病包括动脉粥样硬化和胰腺炎，但并不限于此。高甘油三酯血症相关疾病的优选实例包括动脉粥样硬化。并且，在本发明的治疗高脂血症的方法中，高脂血症可以是高胆固醇血症或混合型高脂血症。
下面将参考以下实施例，进一步详细描述本发明。这些实施例仅用于说明的目的，并非意图限制本发明的范围。
实施例1对诱发高胆固醇血症的动物中甘油三酯抑制活性的评价
(1)试验方法
使用雄性新西兰白兔作为试验动物。对除了G1组动物(阴性对照组，n＝4)外的所有动物喂食辐照灭菌的高胆固醇餐，即DYET#620007(Purina#5321食物，含1％胆固醇,Dyets,Inc.,伯利恒,PA18017)，其购自中央实验室动物公司(CentralLab.AnimalInc)。为了诱发高胆固醇血症，为动物提供超过8周的进餐。从动物采集血液样品后，对其进行血清生化分析。选择总胆固醇水平约为870mg/dL的动物，作为诱发高胆固醇血症的动物。将试验材料溶于含0.5％羧甲基纤维素钠和1％Tween80的盐水中，然后使用配有乳胶导管的口腔注射器将其直接施用于胃，每日一次，持续4周。试验组列于下表1中。
<表1>
在开始供应高胆固醇餐的那天从动物(即在喂食前)和在开始施用试验材料后的2周和4周时，经颈静脉从动物(其在采集血液前禁食12-16小时)中采集血液样品。
(2)结果
如上所述的诱发高胆固醇血症的动物中甘油三酯的浓度列于下表2中。表2中的值代表各组的甘油三酯的评价浓度(mg/dL)。
<表2>
组 0周 2周 4周
G1 66.3 99.5 52.5
G2 192.6 315.1 544.1
G3 167.4 255.8 356.7
G4 122.0 156.6 145.6
G5 188.7 123.7 111.2
G6 86.2 112.8 114.3
G7 131.4 138.4 135.0
如表2所示，在反复口服式1的化合物和/或血管紧张素II受体阻断剂四周时，相比仅施用式1的化合物的组(G3，在开始给药后的4周时，356.7mg/dL)，共同施用组(G4-G7)显示出明显高的甘油三酯抑制活性。特别是，式1的化合物与替米沙坦的共同施用组(G5)显示出最有效的甘油三酯抑制活性。因此，预期式1的化合物与血管紧张素II受体阻断剂如奥美沙坦、奥美沙坦酯、替米沙坦、洛沙坦或缬沙坦，能够有利地应用于预防或治疗高甘油三酯血症或高甘油三酯血症相关疾病。
实施例2对诱发高甘油三酯血症和高胆固醇血症的动物中活性的评价
(1)试验方法
使用雄性新西兰白兔作为试验动物。对除了G1组动物(阴性对照组)外的所有动物喂食辐照灭菌的高甘油三酯血症和高胆固醇餐，即DYET#621082(Purina#5321食物，含0.5％胆固醇、14％椰子油和2％麦芽糖糊精，Dyets公司,伯利恒,PA18017)，其购自Saeronbio公司(SaeronbioInc.)。为了诱发高甘油三酯血症和高胆固醇血症，为动物提供超过4周的进餐。从动物采集血液样品后，对其进行血清生化分析。选择相比未经处理的对照组总胆固醇水平和甘油三酯水平显示明显变化的动物。根据总胆固醇水平和甘油三酯水平，将所选择的动物分为4组，由此，所有的组在总胆固醇水平和甘油三酯水平方面具有基本相等的平均值。将试验材料溶于含0.5％羧甲基纤维素钠和1％Tween80的盐水中，然后使用配有乳胶导管的口腔注射器将其直接施用于胃，每日一次，持续4周。试验组列于下表3中。
<表3>
在开始施用试验材料的那天(即分组的时间，0周)和在开始施用试验材料后的4周时，经颈静脉从动物(其采集血液前禁食12-16小时)(n＝4-7)中采集血液样品。
(2)结果
如上所述的诱发高甘油三酯血症和高胆固醇血症的动物中甘油三酯的浓度列于下表4中。表4中的值代表各组的甘油三酯的平均浓度(mg/dL)。
<表4>
组 4周 血液中甘油三酯的抑制百分比(％)
G1 35.7 -
G2 326.5 -
G3 293.1 10.2
G4 217.4 33.4
G5 139.4 57.3
如表4所示，在反复口服式1的化合物和/或奥美沙坦酯4周时，相比G2组，仅施用式1的化合物的组(G3)或仅施用奥美沙坦酯的组(G4)分别显示对甘油三酯水10.2％和33.4％的抑制。然而，相比G2组，共同施用组(G5)显示对甘油三酯水平57.3％的抑制。G5的甘油三酯抑制活性(即57.3％抑制)相比G3和G4的甘油三酯抑制活性的总和(即43.6％的抑制)更强。因此，可以得出式1的化合物与血管紧张素II受体阻断剂如奥美沙坦酯的组合提供了抑制甘油三酯水平的强有力的协同作用。
血液样品中的HDL胆固醇浓度显示于下表5中。表5中的值代表从各组血液样品测得的HDL胆固醇浓度(mg/dL)。
<表5>
组 4周 HDL胆固醇水平增加的百分比(％)
G1 8.1 -
G2 122.2 -
G3 168.5 37.9
G4 125.3 2.6
G5 193.9 58.7
如表5所示，在反复口服式1的化合物和/或奥美沙坦酯4周时，相比G2组，仅施用式1的化合物的组(G3)或仅施用奥美沙坦酯的组(G4)显示血液HDL胆固醇水平分别增加37.9％和2.6％。然而，相比G2组，共同施用组(G5)显示血液HDL胆固醇水平增加58.7％；且分别与G3和G4相比，共同施用组(G5)显示强有力的协同作用。因此，预期式1的化合物与血管紧张素II受体阻断剂如奥美沙坦酯能够有利地应用于预防或治疗高胆固醇血症和混合型高脂血症，以及高甘油三酯血症(包括高甘油三酯血症相关疾病)。

Claims (11)

1.用于预防或治疗高脂血症的药物组合物，其包含作为活性成分的式1的化合物或其药学上可接受的盐和血管紧张素II受体阻断剂：
2.根据权利要求1所述的药物组合物，其中，所述血管紧张素II受体阻断剂选自奥美沙坦或其盐、奥美沙坦酯或其盐、替米沙坦或其盐、洛沙坦或其盐，以及缬沙坦或其盐。
3.根据权利要求1所述的药物组合物，其中，所述血管紧张素II受体阻断剂是奥美沙坦酯或其盐。
4.根据权利要求1-3中任一项所述的药物组合物，其中所述高脂血症是高甘油三酯血症或高甘油三酯血症相关疾病。
5.根据权利要求4所述的药物组合物，其中，所述高甘油三酯血症相关疾病是动脉粥样硬化或胰腺炎。
6.根据权利要求1-3中任一项所述的药物组合物，其中所述高脂血症是高胆固醇血症。
7.根据权利要求1-3中任一项所述的药物组合物，其中所述高脂血症是混合型高脂血症。
8.根据权利要求1-3中任一项所述的药物组合物，其中将所述组合物配制成口服剂型。
9.根据权利要求8所述的药物，其中所述口服剂型包含适于以10-300mg/日的剂量施用的量的式1的化合物或其药学上可接受的盐。
10.根据权利要求8所述的药物，其中所述口服剂型包含适于以5-320mg/日的剂量施用的量的血管紧张素II受体阻断剂。
11.包含式1的化合物或其药学上可接受的盐以及血管紧张素II受体阻断剂的活性成分，在用于制备预防或治疗高脂血症的药物中的用途：
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