CN117241798A - 包括gpr40促进剂以及sglt-2抑制物的医药组成物 - Google Patents
包括gpr40促进剂以及sglt-2抑制物的医药组成物 Download PDFInfo
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- CN117241798A CN117241798A CN202280031057.0A CN202280031057A CN117241798A CN 117241798 A CN117241798 A CN 117241798A CN 202280031057 A CN202280031057 A CN 202280031057A CN 117241798 A CN117241798 A CN 117241798A
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Abstract
本文公开了用于预防、缓解或治疗选自二型糖尿病、高胰岛素血症、萄糖耐量受损障碍及胰岛素抵抗障碍病症的任何疾病的医药组成物、其制备方法以及使用其治疗二型糖尿病等的方法，其中所述医药组成物包含GPR40激动剂和SGLT2抑制物，所述GPR40激动剂为式1所示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或者所述化合物、所述外消旋物、所述镜像异构物或所述非镜像异构物的药学上可接受的盐。
Description
技术领域
本揭示的实施例涉及一种包括GPR40促进剂以及SGLT-2抑制物的医药组成物、其制备方法以及使用其治疗二型糖尿病等的方法。
背景技术
糖尿病是一种由胰岛素分泌受损或不足引起的代谢性疾病，且其特征在于高血糖症(即，血液中葡萄糖过量)，并且是一种导致各种微血管及大血管并发症及发病率的进行性、衰弱性疾病(progressive debilitating disorder)。二型糖尿病作为最常见的糖尿病类型，其特征在于在一段时间的代偿性高胰岛素血症后，与胰岛素分泌不足相关的胰岛素抵抗增加。
已经证明游离脂肪酸(Free fatty acid，FFA)通过主要增强葡萄糖刺激的胰岛素分泌(glucose-stimulated insulin secretion，GSIS)来影响β细胞的胰岛素分泌。已知在β细胞中表达的G蛋白偶联受体(G-protein-coupled receptor，GPCR)因应于血浆葡萄糖水准的变化来调节胰岛素的释放。
亦被称为脂肪酸受体1(FFAR1)的GPR40是一种膜结合的FFA受体(membrane-boundFFA receptor)，其优先在胰岛、尤其是其β细胞中进行表达，并介导中长链脂肪酸诱导的胰岛素分泌。GPR40亦在肠内分泌细胞中进行表达。肠内分泌细胞中GPR40的激活促进肠的肠促胰岛素激素(例如，GLP-1、GIP、CCK及PYY)的分泌。GPR40调节剂不仅可通过肠促胰岛素作用促进GSIS，而且有望与多种抗糖尿病药物联合使用。因此，此种GPR40调节剂可通过增强血糖控制而有助于减轻二型糖尿病患者的医疗负担。
鉴于该等优势，许多制药公司在过去几年中一直致力于研发GPR40促进剂。然而，仍无市售的GPR40促进剂。几个切实成果的实例为由日本武田制药有限公司(TakedaPharmaceutical Co.,Ltd.of Japan)研发的法西格利姆(fasiglifam)。法西格利姆是第一种进入临床试验的GPR40促进剂化合物，并已证明其对二型糖尿病患者具有降血糖功效。然而，在3期临床试验期间，由于担心药物诱导的肝毒性或药物诱导的肝损伤(drug-inducedliver injury，DILI)，法西格利姆的研发被中断。
因此，在患有包括糖尿病在内的代谢症候群的患者数量迅速增加的现代社会中，越来越需要使用具有增强葡萄糖依赖性胰岛素分泌此种功能的GPR40促进剂来为二型糖尿病患者提供有效的治疗。
作为GPR40促进剂，在韩国专利特开公报第10-2018-0069718号中揭示了由式I表示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或所述化合物、所述外消旋物、所述镜像异构物或所述非镜像异构物的药学上可接受的盐，所述韩国专利特开公报的揭示内容全文并入本案供参考。
[式I]
血浆葡萄糖通常经由肾小球进行过滤，并被近端小管主动重吸收。钠-葡萄糖协同转运蛋白2(Sodium-glucose cotransporter 2，SGLT-2)被认为是参与近端小管中的葡萄糖再摄取的主要转运蛋白。作为肾脏中钠依赖性葡萄糖转运蛋白的SGLT-2的选择性抑制物预期能够通过提高胰岛素敏感性及通过增加尿中葡萄糖的排泄来延迟糖尿病并发症的发作而使血浆葡萄糖水准正常化。
<相关文献>
<专利文件>
韩国专利特开公报第10-2018-0069718号
<非专利文件>
发明内容
技术问题
本揭示的实施例提供一种医药组成物，所述医药组成物可安全使用而不会引起例如低血糖症等副作用，同时通过有效降低糖尿病患者的血糖水准来达成胰岛素分泌的增加及胰岛素抵抗障碍的改善。
本揭示的实施例提供一种医药组成物，所述医药组成物可通过具有降血糖效果的两种药物的组合来达成协同效应。
技术解决方案
根据本揭示的一个实施例，提供了一种医药组成物，所述医药组成物用于预防、缓解或治疗选自由二型糖尿病、高胰岛素血症、葡萄糖耐量受损障碍及胰岛素抵抗障碍组成的群组中的任何疾病，其中所述医药组成物包含GPR40促进剂及SGLT2抑制物，所述GPR40促进剂为由式1表示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或所述化合物、所述外消旋物、所述镜像异构物或所述非镜像异构物的药学上可接受的盐。
[式1]
根据本揭示的另一实施例，提供了一种预防、缓解或治疗选自由以下组成的群组中的任何疾病的方法：二型糖尿病、高胰岛素血症、葡萄糖耐量受损及胰岛素抵抗，其中所述方法包括向有此需求的患者提供GPR40促进剂及SGLT2抑制物，所述GPR40促进剂是由式1表示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或所述化合物、所述外消旋物、所述镜像异构物或所述非镜像异构物的药学上可接受的盐。
根据本揭示的又一实施例，提供了一种制备医药组成物的方法，所述医药组成物用于预防、缓解或治疗选自由二型糖尿病、高胰岛素血症、葡萄糖耐量受损及胰岛素抵抗组成的群组中的任何疾病，其中所述方法包括将GPR40促进剂及SGLT2抑制物配制成单一剂型或分开的剂型，所述GPR40促进剂是由式1表示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或所述化合物、所述外消旋物、所述镜像异构物或所述非镜像异构物的药学上可接受的盐。
有益效果
通过联合使用GPR40促进剂及SGLT2抑制物，可安全地使用根据本揭示的医药组成物，而不会引起例如低血糖症等副作用，由此产生较单独使用GPR40促进剂及SGLT2抑制物更佳的效果，并因此使得能够减少剂量，同时通过有效降低糖尿病患者的血糖水准来达成胰岛素分泌的增加及胰岛素抵抗障碍的改善。
此外，根据本揭示的医药组成物可通过GPR40促进剂及SGLT2抑制物的协同降血糖效果而有效降低糖尿病患者的血糖水准。
附图说明
图1的A示出在联合施用由式1表示的化合物及达格列净之后自0至120分钟血糖水准的变化的测量结果，图1的B示出在联合施用之后自0至60分钟血糖曲线下面积(areaunder the blood glucose curve，AUC)的测量结果，且图1的C示出在联合施用之后自0至120分钟AUC的测量结果。
图2的A示出在联合施用由式1表示的化合物及恩格列净之后自0至120分钟血糖水准的变化的测量结果，图2的B示出在联合施用之后自0至60分钟血糖曲线下面积(AUC)的测量结果，且图2的C示出在联合施用之后自0至120分钟AUC的测量结果。
具体实施方式
本揭示的一个实施例是有关于一种医药组成物，所述医药组成物用于预防、缓解或治疗选自由二型糖尿病、空腹血糖受损、高血糖症、葡萄糖耐量受损障碍及胰岛素抵抗障碍组成的群组中的任何疾病，其中所述医药组成物包含：由式1表示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或所述化合物、所述外消旋物、所述镜像异构物、所述非镜像异构物的药学上可接受的盐；及SGLT2抑制物。
[式1]
所述由式1表示的化合物是在韩国专利特开公报第10-2018-0069718号中作为实例5揭示的化合物，其通式为(S)-3-(4-(((R)-7-氟-4-(6-(((R)-四氢呋喃-3-基)氧基)吡啶-3-基)-2,3-二氢-1H-茚-1-基)氧基)苯基)己-4-炔酸((S)-3-(4-(((R)-7-fluoro-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-ynoic acid)。
所述化合物具有激活GPR40的能力，可口服施用，并具有诱导葡萄糖依赖性胰岛素分泌的机制。因此，所述化合物极为有效地将血糖降低至正常水准，而不会引起例如低血糖症等副作用。
所述由式1表示的化合物可以外消旋物、镜像异构物、非镜像异构物或其药学上可接受的盐的形式使用。具体而言，就溶解度或稳定性而言，较佳的是使所述化合物以其S-异构物的游离酸形式使用。
此外，所述化合物通过其中基于GPR40的降血糖作用而包含GPR40的直接或间接机制而对肥胖症及高血压具有预防和/或治疗效果。因此，本揭示的另一实施例是有关于所述医药组成物用于预防、改善或治疗选自由高脂血症、高甘油三酯血症、高胆固醇血症及血脂异常组成的群组中的任何代谢疾病的新颖药物用途。
本揭示的发明人发现，由式1表示的化合物与钠-葡萄糖协同转运蛋白2(SGLT2)抑制物的联合使用可表现出远远超过该两种药物独立作用时的降血糖效果的简单总和的协同降血糖作用，且因此相较于所述两种药物单独使用以具有相同水准的降血糖效果时，可显著减少副作用。
可与由式1表示的化合物一起施用的SGLT2抑制物的实例可包括卡格列净(canagliflozin)、达格列净(dapagliflozin)、恩格列净(empagliflozin)、贝沙格列净(bexagliflozin)、埃格列净(ertugliflozin)、瑞格列净(remogliflozin)、托格列净(tofogliflozin)、鲁格列净(luseogliflozin)、伊格列净(ipragliflozin)及索格列净(sotagliflozin)。具体而言，SGLT2抑制物可为达格列净、卡格列净、埃格列净或恩格列净。更具体而言，SGLT2抑制物可为达格列净或恩格列净。SGLT2抑制物可为其游离酸的形式或其药学上可接受的盐、酯或溶剂化物的形式。
尽管构成所述组成物的由式1表示的化合物及SGLT2抑制物可一起包含在一种制剂中，但应理解，本揭示并非仅限于此，并且由式1表示的化合物与SGLT2抑制物可分开或依序施用。亦即，由式1表示的化合物与SGLT2抑制物可以分开的剂型存在，以分开或依序施用至患者。然而，就用药方便性及依从性而言，较佳的是将由式1表示的化合物与SGLT2抑制物一起包含在一种制剂中。
所述组成物可一次或多次施用至有此需求的受试者，并且可以能够利用最少用药获得最大效果而无副作用的剂量进行施用。具体而言，根据本揭示的医药组成物的有效剂量可依据患者的年龄、性别、身体状况、体重、对活性成分的吸收性、疾病类型及其他药物而改变。
由式1表示的化合物对SGLT2抑制物的重量比可在0.2:9.8至9:1、具体而言1:9至8:2、且更具体而言2:8至7:3的范围内。在此范围内，每种药物可通过其特定的药理学机制发挥降血糖效果，并且可通过两种药物的不同药理学机制产生血糖控制的协同效应。
以所述医药组成物的总重量计，由式1表示的化合物的含量可为0.5重量％(wt％)至20重量％，具体而言为0.5重量％至10重量％，并且以所述医药组成物的总重量计，SGLT2抑制物的含量可为0.5重量％至20重量％，具体而言为0.5重量％至10重量％。
所述组成物的日剂量可在约0.0001毫克/千克至100毫克/千克、具体而言0.1毫克/千克至50毫克/千克的范围内，并且可以单剂量或分剂量施用，但并非仅限于此。当所述医药组成物的日剂量在0.1毫克/千克至50毫克/千克的范围内时，可确保所述医药组成物的正确及安全使用，而无例如低血糖症等副作用，同时通过有效降低血糖水准而在糖尿病患者中达成胰岛素分泌的增加及胰岛素抵抗障碍的改善。由式1表示的化合物的剂量可在0.01毫克/天至100毫克/天、具体而言0.1毫克/天至50毫克/天的范围内，并且SGLT2抑制物的剂量可在0.01毫克/天至100毫克/天、具体而言0.1毫克/天至50毫克/天的范围内。
除了由式1表示的化合物及SGLT2抑制物之外，所述医药组成物还可包含药学上可接受的载体、赋形剂或稀释剂。
所述药学上可接受的载体、赋形剂或稀释剂可包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、磷酸钙、藻酸盐、明胶、硅酸钙、甲基纤维素、纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油，但并非仅限于此。以所述医药组成物的总固体重量计，所述药学上可接受的载体、赋形剂或稀释剂的含量可为1重量％至85重量％、或5重量％至75重量％。
在所述医药组成物的制剂中，可使用此项技术中常用的稀释剂或赋形剂，例如填充剂、黏合剂、体积膨胀剂、湿润剂、崩解剂及界面活性剂。
根据本揭示的所述医药组成物可通过各种途径施用至受试者。所述医药组成物可通过此项技术中已知的任何合适的途径施用。举例而言，所述医药组成物可口服、鼻内、经支气管、动脉内、静脉内、皮下、肌内或腹膜内施用。具体而言，所述医药组成物可以固体口服剂型(例如，片剂或胶囊)施用。更具体而言，所述医药组成物可被制备成单层片剂、双层片剂或核-壳型双层片剂的形式。
根据本揭示的医药组成物可在不影响本揭示的两种药物(即，由式1表示的化合物及SGLT2抑制物)的协同效应的情况下还包括另一种抗糖尿病药剂或降血糖药剂。
举例而言，所述抗糖尿病药剂或降血糖药剂可包括：选自由二甲双胍(metformin)、丁双胍(buformin)及苯乙双胍(phenformin)组成的群组中的双胍类药物；选自由曲格列酮(troglitazone)、环格列酮(ciglitazone)、罗格列酮(rosiglitazone)、吡格列酮(pioglitazone)及恩格列酮(englitazone)组成的群组中的胰岛素增敏剂；选自由西他列汀(sitagliptin)、利格列汀(linagliptin)、维达列汀(vildagliptin)、吉格列汀(gemigliptin)、沙格列汀(saxagliptin)、阿格列汀(alogliptin)、特利列汀(teneligliptin)、阿拉格列汀(anagliptin)及依格列汀(evogliptin)组成的群组中的DPP4抑制物；选自由艾塞那肽(exenatide)、利西那肽(lixisenatide)、利拉鲁肽(liraglutide)、阿必鲁肽(albiglutide)及度拉糖肽(dulaglutide)组成的群组中的胰高血糖素样肽(GLP)1促进剂；选自由甘胺酰胺(glycylamide)、格列生脲(glisentide)、格列戊脲(glypentide)、格列吡嗪(glipizide)、格列本脲(glibenclamide)、格列齐特(gliclazide)、格列美脲(glimepiride)、妥拉磺脲(tolazamide)、甲苯磺丁脲(tolbutamide)、醋酸己脲(acetohexamide)、胺磺丁脲(carbutamide)、氯磺丙脲(chlorpropamide)、格列波脲(glibornuride)、格列喹酮(gliquidone)、羟乙酰胺(glycoamide)、格列派特(glisoxepide)及格列吡脲(glyclopiamide)组成的群组中的胰岛素促分泌剂；以及选自由阿卡波糖(acarbose)、伏格列波糖(voglibose)、乙格列酯(emiglitate)及米格列醇(miglitol)组成的群组中的α-葡萄糖苷酶抑制物。
本揭示的又一实施例是有关于一种预防、缓解或治疗选自由以下组成的群组中的任何疾病的方法：二型糖尿病、高胰岛素血症、葡萄糖耐量受损障碍及胰岛素抵抗障碍，其中所述方法包括向有此需求的患者提供GPR40促进剂及SGLT2抑制物，所述GPR40促进剂是由式1表示的化合物、或其外消旋物、镜像异构物、非镜像异构物、或药学上可接受的盐。在所述方法中，由式1表示的化合物与SGLT2抑制物可在一种制剂中施用，或者可分开或依序施用以增强其治疗效果。因此，在所述方法中，由式1表示的化合物与SGLT2抑制物亦可以分开的剂型存在，以依序或分开施用至患者。
关于所述治疗方法中的药物中的每一者的剂量、施用方法及施用途径的细节，参见本揭示的前述实施例。
本揭示的再一实施例是有关于一种制备医药组成物的方法，所述医药组成物用于预防、缓解或治疗选自由二型糖尿病、高胰岛素血症、葡萄糖耐量受损障碍及胰岛素抵抗障碍组成的群组中的任何疾病，其中所述方法包括将GPR40促进剂及SGLT2抑制物与药学上可接受的赋形剂、载体或稀释剂一起或分开配制，所述GPR40促进剂是由式1表示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或所述化合物、所述外消旋物、所述镜像异构物或所述非镜像异构物的药学上可接受的盐。
关于在所述制备方法中的药物中的每一者的剂量、施用方法及施用的细节，参见本揭示的前述实施例。
接下来，将参照一些实例更详细地描述本揭示。然而，应注意，提供该等实例仅用于例示目的，而不应将该等实例以任何方式解释为限制本揭示。
[实例]
实例1：联合使用由式1表示的化合物及达格列净对降低血糖水准的协同效应。
在此实验中，通过在韩国专利特开公报第10-2018-0069718号的实例5中描述的方法制备了由式1表示的化合物，并且使用达格列净(HY-10450，医药科技股份有限公司(MedChemExpress Co.,Ltd.))。作为对照组，使用载剂(0.5％羧甲基纤维素(carboxymethyl cellulose，CMC))。
在8至10周龄的雄性斯普拉格-杜勒(Sprague-Dawley，SD)大鼠适应环境至少1周后，使用健康大鼠进行口服葡萄糖耐量试验(oral glucose tolerance test，OGTT)。
在禁食16小时后，将大鼠随机分组，每组有5只体重及血糖水准相似的大鼠，随后施用载剂(0.5％羧甲基纤维素(CMC))、单独的0.3毫克/千克的由式1表示的化合物、单独的0.1毫克/千克的达格列净、或0.3毫克/千克的由式1表示的化合物与0.1毫克/千克的达格列净的组合。在施用所述药物中的每一者1小时后，以10毫升/千克的剂量腹膜内注射葡萄糖(2克/千克)。在注射葡萄糖前60分钟及注射葡萄糖后0分钟、15分钟、30分钟、60分钟及120分钟，使用血糖仪(格鲁克DR艾尔麦迪克斯股份有限公司(GlucoDR.Almedicus.Co.Ltd.))通过尾静脉穿刺测量了血糖水准。结果由相对于施用载剂的血糖曲线下面积(AUC)的减少率(％)表示。
根据上述方法在注射葡萄糖后0至60分钟及0至120分钟测量AUC的结果示出于表1及图1中。
表1
实例2：联合使用由式1表示的化合物与恩格列净对降低血糖水准的协同效应。
除了使用0.3毫克/千克的恩格列净(HY-15409，医药科技股份有限公司)代替0.1毫克/千克的达格列净之外，以与实例1中相同的方式进行了实验。结果示出于表2及图2中。
表2
结果表明，相较于单独施用由式1表示的化合物或单独施用达格列净或恩格列净，联合施用由式1表示的化合物与SGLT2抑制物(达格列净或恩格列净)可产生降低血糖水准的协同效应。
Claims (10)
1.一种医药组成物，用于治疗选自由二型糖尿病、高胰岛素血症、葡萄糖耐量受损障碍及胰岛素抵抗障碍组成的群组中的任何疾病，所述医药组成物包含由式1表示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或所述化合物、所述外消旋物、所述镜像异构物或所述非镜像异构物的药学上可接受的盐、及SGLT2抑制物：
[式1]
2.根据权利要求1所述的医药组成物，其中所述SGLT2抑制物选自由卡格列净、达格列净、恩格列净、贝沙格列净、埃格列净、瑞格列净、托格列净、鲁格列净、伊格列净及索格列净组成的群组。
3.根据权利要求2所述的医药组成物，其中所述SGLT2抑制物是达格列净或恩格列净。
4.根据权利要求1所述的医药组成物，其中所述医药组成物以固体口服剂型施用。
5.根据权利要求4所述的医药组成物，其中所述固体口服剂型为片剂或胶囊。
6.根据权利要求1所述的医药组成物，还包含药学上可接受的载体、赋形剂或稀释剂。
7.根据权利要求1至6中任一项所述的医药组成物，其中由式1表示的所述化合物对所述SGLT2抑制物的重量比介于0.2:9.8至9:1的范围内。
8.根据权利要求1至6中任一项所述的医药组成物，其中由式1表示的所述化合物为其游离酸的形式。
9.根据权利要求1至6中任一项所述的医药组成物，还包含：
选自由二甲双胍、丁双胍及苯乙双胍组成的群组中的双胍类药物；
选自由曲格列酮、环格列酮、罗格列酮、吡格列酮及恩格列酮组成的群组中的胰岛素增敏剂；
选自由西他列汀、利格列汀、维达列汀、吉格列汀、沙格列汀、阿格列汀、特利列汀、阿拉格列汀及依格列汀组成的群组中的DPP4抑制物；
选自由艾塞那肽、利西那肽、利拉鲁肽、阿必鲁肽及度拉糖肽组成的群组中的胰高血糖素样肽(GLP)1促进剂；
选自由甘胺酰胺、格列生脲、格列戊脲、格列吡嗪、格列本脲、格列齐特、格列美脲、妥拉磺脲、甲苯磺丁脲、醋酸己脲、胺磺丁脲、氯磺丙脲、格列波脲、格列喹酮、羟乙酰胺、格列派特及格列吡脲组成的群组中的胰岛素促分泌剂；以及
选自由阿卡波糖、伏格列波糖、乙格列酯及米格列醇组成的群组中的α-葡萄糖苷酶抑制物。
10.一种制备医药组成物的方法，所述医药组成物用于预防、缓解或治疗选自由二型糖尿病、高胰岛素血症、葡萄糖耐量受损障碍及胰岛素抵抗障碍组成的群组中的任何疾病，所述制备医药组成物的方法包括将GPR40促进剂及SGLT2抑制物与药学上可接受的赋形剂、载体或稀释剂一起或分开配制，所述GPR40促进剂是由式1表示的化合物、所述化合物的外消旋物、所述化合物的镜像异构物、所述化合物的非镜像异构物、或所述化合物、所述外消旋物、所述镜像异构物或所述非镜像异构物的药学上可接受的盐：
[式1]
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