CN1413107A - 降血糖剂用于治疗葡萄糖代谢障碍 - Google Patents
降血糖剂用于治疗葡萄糖代谢障碍 Download PDFInfo
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Abstract
本发明涉及降血糖剂或其可药用盐在生产药物中的用途,所述药物可用于预防或延缓向显性糖尿病、特别是II型糖尿病的进展、预防或减少微血管并发症(例如视网膜病、神经病、肾病)、预防或减少过高的心血管发病率(例如心肌梗塞、动脉闭塞疾病、动脉粥样硬化和中风)和心血管死亡率、预防癌症和减少癌症死亡。此外,本发明还涉及治疗与IGM、IGT或IFG有关的疾病和病症的方法。
Description
葡萄糖代谢障碍(IGM)是指高于正常范围但又不足以达到II型糖尿病的诊断标准的血糖水平。不同国家的IGM发病率不同,但通常要比显性糖尿病高2-3倍。直到最近,存在IGM的个体还被认为是前驱糖尿病的患者,但许多流行病学研究的数据表明,存在IGM的个体在其患糖尿病的危险性及其心血管的发病率和死亡率方面是各不相同的。数据表明,存在IGM、特别是IGT的个体并不总是出现糖尿病,然而,无论他们是否有糖尿病,他们都存在心血管的发病率和死亡率的高度危险性。
在存在IGM的个体中,约58%存在葡萄糖耐量障碍(IGT),另外29%存在空腹葡萄糖障碍(IFG),13%同时存在两种异常(IFG/IGT)。IGT的特征在于升高的饭后(餐后)高血糖,而IFG由ADA根据空腹的血糖值确定(参见下表)。
ADA于1997年确定的正常葡萄糖耐量(NGT)、IGM和II型糖尿病的分类如下:
*)这些标准是根据WHO推荐的口服葡萄糖耐量试验(OGTT)制定的,即将75g无水葡萄糖溶解于水中,口服给此负荷量葡萄糖2小时后取血,分析餐后血糖。其它OGTT试验也已证实IGT和IFG的相关危险,包括:1)用50g葡萄糖代替75g葡萄糖,2)用随机(非空腹)血糖样品进行分析和3)分析负荷葡萄糖后1小时而不是2小时的餐后血糖。在所有这些情况下,以上定义的血糖过多的类型与下述的危险增加相关,但是优选标准化的OGTT以便减少试验结果的差异。
NGT | IGM | II型糖尿病 | |
IFG | |||
FPG水平 | <6.1mmol/L(<110mg/dl) | 6.1-7mmol/L(110-126mg/dl) | >7mmol/L(>126mg/dl) |
和 和/或 或IGT | |||
饭后2小时的葡萄糖水平(75g OGTT*)) | <7.8mmol/l(<140mg/dl) | 7.8-11.1mmol/L(140-220mg/dl) | >11.1mmol/L(>200mg/dl) |
已知存在IGM的个体、特别是存在IFG者进展为糖尿病的几率显著高于无高血糖个体,而且有较高的心血管危险,尤其是当其定展为糖尿病时。令人感兴趣的是,存在IGM的个体、特别是存在IGT者,即使并未发展为糖尿病,其癌症发病率、心血管疾病发病率和死亡率也高。因此,IGM、尤其是其亚组IFG显示有高度心血管危险,特别是当病人变为显性糖尿病后。另一方面,IGT在非糖尿病和糖尿病患者中均与癌症、心血管疾病和死亡率高危相关。与IGT相关的危险增加不依赖于所有其它的已知心血管危险因子,如年龄、性别、高血压、低HDL和高LDL胆固醇水平[Lancet 1999;354:617-621]。
IGM、尤其是IGT,在没有糖尿病特征性的异常FPG的微血管和大血管并发症中的一个机制是餐后高血糖。已证实即使在非糖尿病个体中,单独的餐后高血糖也可以降低血清中存在的天然自由基捕获剂(TRAP)。在试验条件下,显示TRAP水平的降低与自由基形成的增加和氧化应激的增加有关。这些自由基牵涉于与动脉粥样硬化、心血管发病率和死亡率及癌症有关的微血管和大血管病理变化。[Ceriello,A,Diabetic Medicine 15:188-193,1998]。在餐后高血糖过程中天然抗氧化剂如TRAP的减少,可以解释不发展为糖尿病的存在IGM、尤其是IGT的个体的心血管危险的增加。IGT在非糖尿病和糖尿病中是独立危险因子的事实,证明其是不同于糖尿病的一个心血管发病率和死亡率以及癌症的预防和治疗的新指证。
IGM与以下的可能的疾病或病症有关:1.)进展为II型显性糖尿病(第9版糖尿病国际分类的代码250.2=ICD-9代码250.2)[Diabetes Researchand Clinical Practice 1998;40:S1-S2];2.)增加的糖尿病微血管并发症,特别是视网膜病变和糖尿病的其它眼部并发症(ICD-9代码250.5)、肾病(ICD-9代码250.4)、神经病变(ICD-9代码250.6)[Diabetes Care2000;23:1113-1118]和外周血管病或坏疸(ICD-9代码2250.7);3.)增加的心血管发病率(ICD-9代码410-414),特别是心肌梗塞(ICD-9代码410)、冠心病或动脉粥样硬化(ICD-9代码414)和其它急性和亚急性的冠脉缺血形式(ICD-9代码411);4.)增加的脑血管疾病如中风(ICD-9代码430-438)[Circulation 1998;98:2513-2519]);5.)增加的心血管死亡率(ICD-9代码390-459)[Lancet 1999;354:617-621]和猝死(ICD-9代码798.1);6.)恶性肿瘤的高发生率和死亡率(ICD-9代码140-208)[AmJ Epidemiol.1990;131:254-262,Diabetologia 1999;42:1050-1054]。与IGM相关的其它代谢紊乱包括血脂异常(ICD-9代码272)、高尿酸血症(ICD-9代码790.6)以及高血压(ICD-9代码401-404)和心绞痛(ICD-9代码413.9)[Ann Int Med 1998;128:524-533]。
显然,与IGM、特别是IGT相关的各种疾病和状态提示有非常大的治疗需要。许多相同的疾病和病症同时与IGM和糖尿病相关,但是,直到最近才认识到有IGM、特别是IGT的非糖尿病人群应是预防和治疗的一个指证。因此,在存在IGM、特别是IGT和/或IFG的个体中,早期胰岛素分泌的恢复和/或餐时高血糖的降低可以帮助预防或延迟向显性糖尿病的进展并通过预防发展为显性糖尿病预防或减少与糖尿病相关的微血管并发症。此外,在存在IGM、特别是IGT和/或IFG的个体中,早期胰岛素分泌的恢复和/或餐后高血糖的降低也可以预防或减少过多的心血管发病率和死亡率和预防癌症或降低其死亡率。
因此,在血糖量正常和II型糖尿病之间的阶段、特别是血糖过多期,正在成为主要关注所在,并非常需要一种方法来抑制或延迟进展为II型糖尿病,以及与IGM、特别是IFG和/或IGT相关的各种心血管和微血管疾病和病症及癌症。
现已出人意料地发现,降血糖剂例如胰岛素分泌促进剂可用于预防或延迟显性糖尿病的进展、减少糖尿病的微血管并发症、减少血管、特别是心血管的发病率和死亡率、特别是心血管的发病率和死亡率,并可在存在IGT和/或IFG的个体中降低与癌症有关的死亡率升高。
降血糖剂包括,例如胰岛素分泌促进剂或胰岛素灵敏度增强剂(胰岛素抗性解封闭剂)或胰岛素以及,如果适当的话,它们的可药用盐。
胰岛素分泌促进剂是具有促进胰腺β-细胞分泌胰岛素的特性的活性成分。
胰岛素分泌促进剂(也称为胰岛素促分泌素和促胰岛素药物)是,例如短效或长效降血糖剂。
短效降血糖剂是,例如苯乙酸衍生物以及格列喹酮。
相应的苯基丙氨酸衍生物是,例如,下式的纳格列奈(纳格列奈)[N-(反-4-异丙基环己基羰基)-D-苯基丙氨酸](参见EP 196222和EP526171)和瑞格列奈[(S)-2-乙氧基-4-{2-[[3-甲基-1-[2-(1-哌啶基)苯基]丁基]氨基]-2-氧代乙基}苯甲酸];其游离的形式或者,如果适当的话,它们的可药用盐。
术语纳格列奈还包括结晶改性形式,例如EP 0526171 B1或US5,488,510中所公开的那些,这些专利的主题、特别是关于结晶改性形式的鉴定、生产和特征描述的内容引入本申请作为参考,特别是所述美国专利的权利要求8至10的主题(涉及H-型结晶改性形式)以及EP 196222 B1中关于B-型结晶改性形式的相应内容,特别是关于B-型结晶改性形式的鉴定、生产和特征描述的内容。本发明优选使用B-或H-型,更优选H-型。
长效降血糖剂是,例如双胍衍生物或磺酰脲衍生物。
适宜的双胍是,例如甲福明或者,如果适当的话,其可药用盐、特别是其盐酸盐。
磺酰脲衍生物(SU)的例子是,可以通过细胞膜上的SU受体传递胰岛素分泌信号来促进胰腺β-细胞分泌胰岛素的物质,包括(但不仅限于)甲苯磺丁脲;氯磺丙脲;妥拉磺脲;醋磺己脲;4-氯-N-[(1-吡咯烷基氨基)羰基]-苯磺酰胺(glycopyramide);格列本脲;格列齐特;1-丁基-3-间氨基苯磺酰脲;氨磺丁脲;格列波脲;格列吡嗪;格列喹酮;格列派特;格列噻唑;glibuzole;格列己脲;格列嘧啶;格列平脲;苯磺丁脲和tolylcyclamide,或者,如果适当的话,它们的可药用盐。
胰岛素分泌促进剂还包括新一代SU的代表性药物,例如(2S)-2-苄基-3-(顺-六氢-2-二氢异吲哚基羰基)-丙酸钙二水合物(KAD-1229)和格列美脲(Hoe 490);其游离的形式或其可药用盐的形式。
胰岛素分泌促进剂还包括DPP-IV抑制剂、GLP1和GLP1激动剂。
DPP-IV是一种丝氨酸蛋白酶,它催化N-末端Xaa-Pro或XaaAla二肽残基、包括高血糖素类蛋白-1(GLP-1)的裂解。相应的DPP-IV抑制剂可以增加GLP-1的循环浓度,从而增加胰岛素的分泌。
代表性的DPP-IV抑制剂记载于WO98/19998和WO00/34241中。优选1-{2-[(5-氰基吡啶-2-基)氨基]乙基氨基}乙酰基-2(S)-氰基-吡咯烷二盐酸盐(参见WO98/19998的实施例3)和(S)-1-[(3-羟基-1-金刚烷基)氨基]-乙酰基-2-氰基-吡咯烷(参见WO00/34241的实施例1)。
GLP-1和GLP-1激动剂也可以促进胰岛素分泌。
优选的胰岛素分泌促进剂是瑞格列奈和甲福明,首选纳格列奈。
胰岛素灵敏度增强剂可以恢复受损的胰岛素受体功能,降低胰岛素抗性,从而增强胰岛素的灵敏度。
适宜的胰岛素灵敏度增强剂是,例如,适宜的降血糖剂噻唑烷二酮衍生物(格列酮)。
适宜的格列酮是,例如(S)-((3,4-二氢-2-(苯基-甲基)-2H-1-苯并吡喃-6-基)甲基-噻唑烷-2,4-二酮(恩格列酮)、5-{[4-(3-(5-甲基-2-苯基-4-噁唑基)-1-氧代丙基)-苯基]-甲基}-噻唑烷-2,4-二酮(达格列酮)、5-{[4-(1-甲基-环己基)甲氧基)-苯基]甲基}-噻唑烷-2,4-二酮(环格列酮)、5-{[4-(2-(1-吲哚基)乙氧基)苯基]甲基}-噻唑烷-2,4-二酮(DRF2189)、5-{4-[2-(5-甲基-2-苯基-4-噁唑基)-乙氧基)]苄基}-噻唑烷-2,4-二酮(BM-13.1246)、5-(2-萘基磺酰基)-噻唑烷-2,4-二酮(AY-31637)、二{4-[(2,4-二氧代-5-噻唑烷基)甲基]苯基}甲烷(YM268)、5-{4-[2-(5-甲基-2-苯基-4-噁唑基)-2-羟基乙氧基]苄基}-噻唑烷-2,4-二酮(AD-5075)、5-[4-(1-苯基-1-环丙烷羰基氨基)-苄基]-噻唑烷-2,4-二酮(DN-108)、5-{[4-(2-(2,3-二氢吲哚-1-基)乙氧基)苯基]甲基}-噻唑烷-2,4-二酮、5-[3-(4-氯-苯基)]-2-丙炔基]-5-苯基磺酰基)噻唑烷-2,4-二酮、5-[3-(4-氯苯基)]-2-丙炔基]-5-(4-氟苯基-磺酰基)噻唑烷-2,4-二酮、5-{[4-(2-(甲基-2-吡啶基-氨基)-乙氧基)苯基]甲基}-噻唑烷-2,4-二酮(罗格列酮(罗格列酮))、5-{[4-(2-(5-乙基-2-吡啶基)乙氧基)苯基]-甲基}噻唑烷-2,4-二酮(吡格列酮(吡格列酮))、5-{[4-((3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基)-苯基]-甲基}-噻唑烷-2,4-二酮(曲格列酮)、5-[6-(2-氟-苄氧基)萘-2-基甲基]-噻唑烷-2,4-二酮(MCC555)、5-{[2-(2-萘基)-苯并噁唑-5-基]-甲基}噻唑烷-2,4-二酮(T-174)和5-(2,4-二氧代噻唑烷-5-基甲基)-2-甲氧基-N-(4-三氟甲基-苄基)苯甲酰胺(KRP297)。优选吡格列酮、罗格列酮和曲格列酮。
用通用名或商标名确定的活性成分的结构可以从正版的标准纲要“TheMerck Index”或数据库例如Patents International(例如IMS WorldPublications)得到。其相应的内容引入本文作为参考。本领域技术人员完全可以确定活性成分,并根据这些参考文献生产并在常规的试验模型中、包括体外和体内,测试药物的适应症和特性。
可以对有益效果进行验证,以证实降血糖剂例如胰岛素增敏剂可以在存在IGM的个体中恢复早期的胰岛素分泌并降低餐后葡萄糖水平。可以在存在IGM的个体中进行多中心、双盲、平行组的随机研究,以在8周的治疗时间内评估在每次正餐前施用纳格列奈30mg、60mg或120mg或安慰剂所引起的确定的低血糖的发生率以及对进餐葡萄糖的影响。个体挑选是基于75g口服葡萄糖耐量试验(OGTT)2小时血糖值,基本满足以下附加标准的病人进入研究:
OGTT后2小时的血糖在7.8-11.1mmol/L之间(一次OGTT在进入研究前的年内进行,第二次在进入研究前两周内进行)
-FPG<7mmol/L;
-病人体重指数(BMI)在20-32kg/m2之间;
-病人在整个研究过程中保持先前的饮食:
-男性、非孕期女性、孕期女性使用医学上证实的避孕方法者可以进入研究:
-试验期不准使用其它抗糖尿病药。
相应剂量的药物例如纳格列奈根据每日正餐的次数(早餐、中餐、餐点、晚餐)给药2次(BID)、3次(TID)或4次(QID),用1大杯水服下。第一剂在第一次正餐时给药(标准餐,即55%碳水化合物,25%脂肪和20%蛋白质)。在0、2、4和8周随访,随访时至少禁食7小时。所有送实验室检测的血样均在7.00和10.00a.m抽取。HbA1c在基线和治疗8周后测定(空腹葡萄糖和果糖胺)。给药(时间0点)后10、20、20、60、120和180分钟取血样测定葡萄糖和胰岛素水平。在0和8周随访时,病人完成含有大约500kcal的标准餐并进行胰岛素和葡萄糖水平的测定。
该研究中所获得的所有数据的分析结果清晰地显示2小时餐后血糖水平、HBA1c和果糖胺水平令人惊讶和显著地降低,早期胰岛素分泌恢复,因此纳格列奈能够预防或延迟进展为II型糖尿病。通过较长时间的治疗和随访,可以预防或降低与IGM相关的疾病和病症。
这种在存在IGM、尤其是IFG和IGT的个体中的研究不同于糖尿病患者,因为个体的FPG正常,并且没有糖尿病或前驱糖尿病。
令人惊奇的是,降血糖剂以及降血糖剂的联合形式可用于在存在IGM、特别是IFG和/或IGT的个体中预防或延缓向II型显性糖尿病的进展;预防、减少或延缓选自如下的病症发作:增加的微血管并发症;增加的心血管发病率;脑血管疾病增加;心血管死亡率和猝死的增加;恶性肿瘤的高发生率和死亡率;以及与IGM有关的其它代谢紊乱。
此外,降血糖剂以及降血糖剂的联合形式还可用于在存在IGM、特别是IFG和/或IGT的个体中预防、减少或延缓选自如下的病症的发作:视网膜病、糖尿病的其它眼部并发症、肾病、神经病、外周血管病、外周血管病、坏疸、心肌梗塞、冠心病、动脉粥样硬化、冠脉缺血的其它急性和亚急性形式、中风、血脂异常、血尿酸过多、高血压、心绞痛、导致截肢的微血管病变、癌症、癌症死亡、肥胖、尿酸血症、胰岛素抗性、动脉闭塞疾病和动脉粥样硬化。
根据本发明,降血糖剂可用于在存在IGM、特别是IFG和/或IGT的个体中预防或延缓向显性糖尿病的进展、减少糖尿病的微血管并发症、减少血管、特别是心血管的死亡率和发病率、特别是心血管的发病率和死亡率,并在存在IGT的个体中减少与癌症有关的死亡率。
因此,本发明涉及在存在IGM、特别是IFG和/或IGT的个体中预防或延缓向II型显性糖尿病的进展的方法;预防、减少或延缓选自如下的病症发作的方法:增加的微血管并发症;增加的心血管发病率;脑血管疾病增加;心血管死亡率和猝死的增加;恶性肿瘤的高发生率和死亡率;以及与IGM有关的其它代谢紊乱。
本发明尤其涉及在存在IGM、特别是IFG和/或IGT的个体中预防、减少或延缓选自如下的病症发作的方法:视网膜病、糖尿病的其它眼部并发症、肾病、神经病、外周血管病、外周血管病坏疸、心肌梗塞、冠心病、动脉粥样硬化、冠脉缺血的其它急性和亚急性形式、中风、血脂异常、血尿酸过多、高血压、心绞痛、导致截肢的微血管病变、癌症、癌症死亡、肥胖、尿酸血症、胰岛素抗性、动脉闭塞疾病和动脉粥样硬化。
因此,本发明涉及在存在IGM、特别是IFG和IGT的个体中预防或延缓向显性糖尿病、特别是II型糖尿病的进展(ICD-9代码250.2)的方法、预防或减少微血管并发症例如视网膜病(ICD-9代码250.5)、神经病(ICD-9代码250.6)、肾病(ICD-9代码250.4)和外周血管病或坏疸(ICD-9代码250.7)、后来命名的“微血管并发症”的方法。此外,本发明还涉及在存在IGM、特别是IFG和IGT的个体中预防或减少过高的心血管发病率(ICD-9代码410-414),例如心肌梗塞(ICD-9代码410)、动脉闭塞疾病、动脉粥样硬化和冠脉缺血的其它急性和亚急性形式(ICD-9代码411-414)、后来命名的“心血管发病率”的方法;预防、减少或延缓脑血管疾病例如中风(ICD-9代码430-438)的发作增加的方法;减少增加的心血管死亡率(ICD-9代码390-459)和猝死(ICD-9代码798.1)的方法;预防癌症(ICD-9代码140-208)的发展和减少癌症死亡的方法。本发明还涉及在存在IGM、特别是IFG和IGT的个体中预防或减少与IGM有关的其它代谢紊乱,包括高血糖(包括单独的餐后高血糖)、血脂异常(ICD-9代码272)、血尿酸过多(ICD-9代码790.6)以及高血压(ICD-9代码401-404)和心绞痛(ICD-9代码413.9)的方法。
以上及下文中根据第9版疾病国际分类确定的代码以及赋予该代码的相应定义引入本文作为参考并构成了本发明的一部分。
由降血糖剂引起的早期分泌的减少是迅速可逆的,并且餐后葡萄糖水平的降低有利于该适应症的预防或治疗。
该方法包括向有此需要的个体施用有效量的降血糖剂例如胰岛素分泌促进剂或其可药用盐。需要该方法的个体是温血动物、包括人。
本发明还涉及用于在存在IGM、特别是IFG和/或IGT以及相关的疾病和病症例如单独的餐后高血糖的个体中预防或延缓向显性糖尿病、特别是II型糖尿病的进展,预防、减少或延缓微血管并发症的发作,预防或减少坏疸或导致截肢的微血管病变,预防或减少过高的心血管发病率和心血管死亡率,预防癌症和减少癌症死亡的方法。
本发明还涉及治疗与IGM、特别是IFG和/或IGT(包括单独的餐后高血糖)有关的疾病和病症、包括肥胖、衰老、孕期糖尿病、血脂异常、高血压、尿酸血症、胰岛素抗性、动脉闭塞疾病、动脉粥样硬化、视网膜病、肾病、心绞痛、心肌梗塞和中风的方法。
优选所述的预防可以对葡萄糖水平处于经大量流行病学研究证实可以引起增加的心血管、微血管和癌症危险的范围内的个体产生效果。这些水平包括OGTT后的血浆葡萄糖水平≥7.8mmol/L或随机葡萄糖评估和/或空腹血浆葡萄糖在IFG范围内(空腹血浆葡萄糖在6.1和7mmol/l之间)。当可以用新的流行病学数据来降低与上述危险确切相关的血糖水平时,或者当定义IGT和IFG危险组的国际标准改变时,本发明的用途仍可用于治疗处于危险的组。
本发明还涉及用于在存在IFG的个体中应用的方法,该方法包括,向有需要的个体施用治疗有效量的DPP-IV抑制剂。
本发明涉及降血糖剂或其可药用盐在生产药物中的用途,所述药物用于在存在IGM、特别是IFG和/或IGT的个体中预防或延缓向II型显性糖尿病的进展;预防、减少或延缓选自如下的病症发作:增加的微血管并发症;增加的心血管发病率;脑血管疾病增加;心血管死亡率和猝死的增加;恶性肿瘤的高发生率和死亡率;以及与IGM有关的其它代谢紊乱。
本发明涉及胰岛素分泌促进剂或其可药用盐在生产用于预防或延缓向显性糖尿病、特别是II型糖尿病的进展、预防或减少微血管并发症、预防或减少过高的心血管发病率和心血管死亡率、预防癌症和减少癌症死亡的药物中的用途。
本发明涉及胰岛素分泌促进剂或其可药用盐在生产药物中的用途,所述药物在存在IGM、特别是IFG和/或IGT以及相关疾病和病症例如单独的餐后高血糖的个体中用于:预防或延缓向显性糖尿病、特别是II型糖尿病的进展、预防或减少微血管并发症、预防或减少过高的心血管发病率和心血管死亡率、预防癌症和减少癌症死亡。
本发明涉及药物组合物,该药物组合物用于在存在IGM、特别是IFG和/或IGT的个体中预防或延缓向II型显性糖尿病的进展;预防、减少或延缓选自如下的病症发作:增加的微血管并发症;增加的心血管发病率;脑血管疾病增加;心血管死亡率和猝死的增加;恶性肿瘤的高发生率和死亡率;以及与IGM有关的其它代谢紊乱;该药物组合物含有降血糖剂或其可药用盐和可药用载体。
本发明涉及药物组合物,该药物组合物用于预防或延缓向显性糖尿病、特别是II型糖尿病的进展、预防或减少微血管并发症、预防或减少过高的心血管发病率和心血管死亡率、预防癌症和减少癌症死亡,该药物组合物含有胰岛素分泌促进剂或其可药用盐和可药用载体。
本发明涉及药物组合物,该组合物在存在IGM、特别是IFG和/或IGT以及相关疾病和病症例如单独的餐后高血糖的个体中用于:预防或延缓向显性糖尿病、特别是II型糖尿病的进展、预防或减少微血管并发症、预防或减少过高的心血管发病率和心血管死亡率、预防癌症和减少癌症死亡。
相应的活性成分或其可药用盐还可以以水合物或含有结晶用的其它溶剂的形式使用。
此外,本发明还涉及药物联合形式,例如复方制剂或药物组合物,其含有至少一种胰岛素分泌促进剂和至少一种胰岛素敏化剂;或至少两种胰岛素分泌促进剂;或至少两种胰岛素敏化剂;该药物联合形式可在存在IGM、特别是IFG和/或IGT的个体中用于预防或延缓向II型显性糖尿病的进展;预防、减少或延缓选自如下的病症发作:增加的微血管并发症;增加的心血管发病率;脑血管疾病增加;心血管死亡率和猝死的增加;恶性肿瘤的高发生率和死亡率;以及与IGM有关的其它代谢紊乱。
使用本发明的药物联合形式的其它优点是,可以采用较低的联合应用的各药物的剂量以降低剂量,例如,所需的剂量不仅可以更小,而且应用频率可以更低,或者可以用来减少副反应的发生率。这与所治疗的患者的要求和需要是相符的。
优选地,本发明联合形式的各活性成分的联合治疗有效量可以同时或以任何顺序依次给药、分别给药或以固定的复方给药。
术语“治疗有效量”是指可以在温血动物、包括人中产生达到本发明所指出的治疗效果所需的生物学或医学响应的药物或药物联合形式的量。当施用单一的降血糖剂以及固定或不固定的降血糖剂的联合形式时,可以施用“治疗有效量”。本发明的联合形式中的“联合有效量”还可以包括非有效量的至少一种准备联用的物质,如果可以通过施用(固定或不固定的)联合形式达到总的效果的话。
以上及下文中描述的本发明的药物组合物可以同时使用或以任何顺序依次使用,可以分别使用或作为固定的联合形式使用。
本发明的联合形式的优选成分优选是指定为优选的降血糖剂的那些,首选纳格列奈、瑞格列奈、甲福明、吡格列酮、罗格列酮、曲格列酮、1-{2-[(5-氰基吡啶-2-基)氨基]乙基氨基}乙酰基-2(S)-氰基-吡咯烷和(S)-1-[(3-羟基-1-金刚烷基)氨基]-乙酰基-2-氰基-吡咯烷,或者,如果适当的话,以上各物质的可药用盐。
在它的一种改变形式中,本发明还涉及“成套的药盒”,例如,按照本发明联用的各成分可以彼此独立地给药或者通过使用不同的含有特定量成分的固定的联合形式进行给药,即同时给药或在不同的时间点给药。因此,药盒中的各部分可以同时给药,或者按照时间顺序交错给药,也就是说将药盒中的各部分在不同的时间点以相同或不同的时间间隔给药。优选对时间间隔进行选择,从而使各部分的联合使用能够在治疗疾病或情况时产生大于单独使用任何一种成分所能达到的效果。
此外,本发明还涉及商业包装,其含有本发明的联合形式以及用于同时、分别或依次使用的说明书。
联合使用的化合物可以以可药用盐的形式存在。如果这些化合物含有例如至少一种碱性中心,则它们可以形成酸加成盐。还可以形成存在另一个碱性中心的相应的酸加成盐。含有酸性基团(例如COOH)的化合物还可以与碱形成盐。
例如,纳格列奈的可药用盐是,例如与碱形成的盐,即阳离子盐,例如碱金属和碱土金属盐以及铵盐。
本发明的药物组合物可以通过已知的方式制备,并且可以是适于向哺乳动物(温血动物)、包括人肠道(例如口服或直肠)和胃肠外给药的形式,它们含有治疗有效量的药理学活性化合物本身或其与一种或多种可药用载体、特别是适于肠道或胃肠外应用的载体的组合。
新的药物制剂含有例如约10%至约100%、优选80%,优选约20%至约60%的活性成分。用于肠道或胃肠外给药的本发明的药物制剂是例如单位剂量形式的药物制剂,例如糖包衣片剂、片剂、胶囊或栓剂以及安瓿。这些药物制剂可以通过已知的方式制备,例如,通过常规的混合、制粒、糖包衣、溶解或冷冻干燥的方法制备。因此,口服应用的药物制剂可以通过将活性成分与固体载体混合,如需要,将得到的混合物制粒,然后,如果需要的话,加入适宜的赋形剂,然后将该混合物或颗粒加工成片剂或糖包衣片的片芯。
本发明所用的降血糖剂的剂量可以是已经上市的药物所采用的剂量。例如,可以服用剂量为0.5mg、1mg或2mg活性成分的瑞格列奈片剂或剂量为500mg或850mg活性成分的甲福明片剂。同样,这些剂量也可用于在本发明的联合形式中联用的物质。本领域技术人员完全可以根据他的知识来确定具体的降血糖剂在单独或联合使用时的具体剂量。
当温血动物是体重约为70kg的人类时,纳格列奈(I)优选以约5至1200、更优选25至800mg/天的剂量向温血动物给药。优选的剂量含有30mg、60mg或120mg待给药的纳格列奈,优选在正餐前给药。根据正餐的次数,给药方案可以是每天两次(BID)或每天三次(TID)或每天四次(QID)。
以下实施例举例说明了以上描述的发明;但是,它们并不以任何方式限定本发明的范围。实施例1:纳格列奈(I)的片剂
按照如下描述制备216,000片每片含有120mg纳格列奈(I)的片剂:组成:
纳格列奈(I) 12.960kg
乳糖,NF 30.564kg
微晶纤维素,NF 15.336kg
聚维酮,USP 2.592kg
交联羧甲基纤维素钠,NF 3.974kg
胶态二氧化硅,NF 1.382kg
硬脂酸镁,NF 1.231kg
包衣:opadry黄 1.944kg
纯净水,USP* Q.S。*:在加工过程中除去制备方法:将微晶纤维素、聚维酮、一部分交联羧甲基纤维素钠、纳格列奈(I)和乳糖在高剪切混合机中混合,然后用纯净水制粒。将湿的颗粒在流化床干燥器中干燥然后过筛。将胶态二氧化硅和剩余的交联羧甲基纤维素钠混合,过筛然后与干燥的颗粒在V型掺合机中混合。将硬脂酸镁过筛,与V型掺合机中的混合物混合,然后将整个混合物压制成片剂。将opadry黄悬浮在纯净水中并将片剂用该包衣悬浮液包衣。实施例2:纳格列奈(I)的盖伦制剂No.1颗粒内层:纳格列奈(I) 120mg乳糖-水合物 283mg微晶纤维素 142mg聚维酮 24mg交联羧甲基纤维素钠 24mg颗粒外层:硬脂酸镁 7mgopadry白 20mg实施例3:纳格列奈(I)的盖伦制剂No.2颗粒内层:纳格列奈(I) 120mg乳糖一水合物 283mg微晶纤维素 142mg聚维酮 24mg交联羧甲基纤维素钠 24mg颗粒外层:交联羧甲基纤维素钠 12.8mg硬脂酸镁 11.4mgopadry黄 18.0mg胶态二氧化硅 12.8mg实施例4:纳格列奈的片剂
按照如下描述制备108,000片每片含有120mg纳格列奈的片剂:组成:纳格列奈 12.960kg乳糖,NF 30.564kg微晶纤维素,NF 15.336kg聚维酮,USP 2.592kg交联羧甲基纤维素钠,NF 3.974kg胶态二氧化硅,NF 1.382kg硬脂酸镁,NF 1.231kg包衣:opadry黄 1.944kg纯净水,USP* Q.S。*:在加工过程中除去制备方法:将微晶纤维素、聚维酮、一部分交联羧甲基纤维素钠、纳格列奈和乳糖在collette gral制粒机中制粒并加入纯净水。将湿的颗粒在流化床干燥器中干燥然后过筛。将胶态二氧化硅和剩余的交联羧甲基纤维素钠混合,过筛然后与干燥的颗粒在V型掺合机中混合。将硬脂酸镁过筛,与V型掺合机中的混合物混合,然后将整个混合物压制成片剂。将opadry黄悬浮在纯净水中并将片剂用该包衣悬浮液包衣。该方法的另一种实施方式包括将胶态二氧化硅和剩余的交联羧甲基纤维素钠在干燥后加入到第二个制粒机中,然后一起过筛;然后以每批三种颗粒/干燥器装料混合。实施例5:纳格列奈的药物组合物(120mg)纳格列奈 120mg乳糖一水合物 283mg微晶纤维素 142mg聚维酮 24mg交联羧甲基纤维素钠 36.8mg硬脂酸镁 11.4mgopadry黄 18.0mg胶态二氧化硅 12.8mg
Claims (10)
1.降血糖剂或其可药用盐在生产药物中的用途,所述药物用于在存在IGM、特别是IFG和/或IGT的个体中预防或延缓向II型显性糖尿病的进展;预防、减少或延缓选自如下的病症发作:增加的微血管并发症;增加的心血管发病率;脑血管疾病增加;心血管死亡率和猝死的增加;恶性肿瘤的高发生率和死亡率;以及与IGM有关的其它代谢紊乱。
2.权利要求1所述的生产药物的用途,所述药物用于在存在IGM和相关的疾病和病症例如单独的餐后高血糖的个体中预防或延缓向显性糖尿病、特别是II型糖尿病的进展、预防或减少微血管并发症、预防或减少心血管发病率、降低心血管死亡率、预防癌症和减少癌症死亡。
3.权利要求1或2所述的生产药物的用途,所述药物用于治疗或预防分别与IGT或IFG有关的疾病和病症。
4.权利要求1至3中任意一项所述的生产药物的用途,所述药物用于在存在IGM、特别是IFG和/或IGT的个体中预防、减少或延缓选自如下的病症发作:视网膜病、糖尿病的其它眼部并发症、肾病、神经病、外周血管病、外周血管病或坏疸、心肌梗塞、冠心病、动脉粥样硬化、冠脉缺血的其它急性和亚急性形式、中风、血脂异常、血尿酸过多、高血压、心绞痛、导致截肢的微血管病变、癌症、癌症死亡、肥胖、尿酸血症、胰岛素抗性、动脉闭塞疾病和动脉粥样硬化。
5.权利要求1至3中任意一项所述的生产药物的用途,所述药物用于治疗与单独的餐后高血糖和/或IFG有关的疾病和病症,包括肥胖、衰老、家族性糖尿病、孕期糖尿病、血脂异常、高血压、尿酸血症、胰岛素抗性、动脉闭塞疾病、动脉粥样硬化、视网膜病、肾病、心绞痛、心肌梗塞和中风。
6.权利要求1至5中任意一项所述的生产药物的用途,所述药物用于在餐后葡萄糖偏离到了异常范围内(OGTT后2小时或随机葡萄糖试验的血浆葡萄糖值在7.8至11.1mmol/L之间)的个体中预防性使用。
7.权利要求1至6中任意一项所述的用途,其中的降血糖剂是(i)胰岛素分泌促进剂,其选自适宜的苯基乙酸衍生物、格列喹酮、适宜的双胍、磺酰基脲衍生物、DPP-IV抑制剂、GLP1和GLP1激动剂,或者,如果适当的话,以上各物质的可药用盐;和(ii)胰岛素敏化剂,其选自格列酮,例如吡格列酮、罗格列酮和曲格列酮,或者,如果适当的话,以上各物质的可药用盐。
8.权利要求7的用途,其中的胰岛素分泌促进剂选自磺酰基脲、瑞格列奈、纳格列奈、DPP-IV抑制剂、GLP1和GLP1激动剂,或者,如果适当的话,以上各物质的可药用盐。
9.权利要求8的用途,其中的胰岛素分泌促进剂是纳格列奈或其可药用盐。
10.药物组合物,该药物组合物用于在存在IGM、特别是IFG和/或IGT的个体中预防或延缓向II型显性糖尿病的进展;预防、减少或延缓选自如下的病症发作:增加的微血管并发症;增加的心血管发病率;脑血管疾病增加;心血管死亡率和猝死的增加;恶性肿瘤的高发生率和死亡率;以及与IGM有关的其它代谢紊乱;该药物组合物含有降血糖剂或其可药用盐和可药用载体。
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CNA2006101159985A Pending CN1911221A (zh) | 1999-12-23 | 2000-12-04 | 降血糖剂用于治疗葡萄糖代谢障碍 |
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US (6) | US6949555B2 (zh) |
EP (1) | EP1239854A1 (zh) |
JP (3) | JP2003518496A (zh) |
KR (3) | KR20100028131A (zh) |
CN (2) | CN1413107A (zh) |
AU (2) | AU777776B2 (zh) |
BR (1) | BR0016631A (zh) |
CA (1) | CA2393083C (zh) |
HU (1) | HUP0600522A2 (zh) |
IL (3) | IL150204A0 (zh) |
NO (1) | NO20022979L (zh) |
NZ (2) | NZ531929A (zh) |
PL (1) | PL355761A1 (zh) |
RU (1) | RU2264811C2 (zh) |
SG (1) | SG149676A1 (zh) |
SK (1) | SK8902002A3 (zh) |
WO (1) | WO2001047514A1 (zh) |
ZA (1) | ZA200204959B (zh) |
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DE19616486C5 (de) * | 1996-04-25 | 2016-06-30 | Royalty Pharma Collection Trust | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
TW492957B (en) * | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
ES2159184T3 (es) * | 1997-06-13 | 2001-09-16 | Novo Nordisk As | Nueva posologia para la dmni. |
KR20010075698A (ko) * | 1998-11-11 | 2001-08-09 | 피터 기딩스 | 베타 아고니스트 및 추가의 항당뇨병제를 포함하는 병용제 |
CA2351058A1 (en) * | 1998-11-12 | 2000-05-25 | Smithkline Beecham P.L.C. | Pharmaceutical composition for modified release of an insulin sensitiser and another antidiabetic agent |
CO5150173A1 (es) * | 1998-12-10 | 2002-04-29 | Novartis Ag | Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv |
US6559188B1 (en) * | 1999-09-17 | 2003-05-06 | Novartis Ag | Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes |
US6878749B2 (en) * | 1999-09-17 | 2005-04-12 | Novartis Ag | Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes |
IL150204A0 (en) * | 1999-12-23 | 2002-12-01 | Novartis Ag | Use of hypoglycemic agent for treating impaired glucose metabolism |
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2000
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- 2000-12-04 KR KR1020107003831A patent/KR20100028131A/ko not_active Application Discontinuation
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- 2000-12-04 CA CA2393083A patent/CA2393083C/en not_active Expired - Fee Related
- 2000-12-04 SG SG200403826-1A patent/SG149676A1/en unknown
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- 2000-12-04 KR KR1020107026905A patent/KR20100130651A/ko not_active Application Discontinuation
- 2000-12-04 BR BR0016631-6A patent/BR0016631A/pt not_active Application Discontinuation
- 2000-12-04 AU AU30059/01A patent/AU777776B2/en not_active Ceased
- 2000-12-04 WO PCT/EP2000/012174 patent/WO2001047514A1/en active Application Filing
- 2000-12-04 CN CNA2006101159985A patent/CN1911221A/zh active Pending
- 2000-12-04 EP EP00990641A patent/EP1239854A1/en not_active Ceased
- 2000-12-06 US US09/731,139 patent/US6949555B2/en not_active Expired - Fee Related
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- 2002-06-12 IL IL150204A patent/IL150204A/en not_active IP Right Cessation
- 2002-06-20 ZA ZA200204959A patent/ZA200204959B/en unknown
- 2002-06-20 NO NO20022979A patent/NO20022979L/no not_active Application Discontinuation
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2004
- 2004-07-06 US US10/885,057 patent/US20040242647A1/en not_active Abandoned
- 2004-09-10 US US10/939,002 patent/US20050043362A1/en not_active Abandoned
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- 2005-01-21 AU AU2005200398A patent/AU2005200398B2/en not_active Ceased
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- 2006-01-25 US US11/339,188 patent/US20060122244A1/en not_active Abandoned
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- 2006-10-17 US US11/581,891 patent/US20070032538A1/en not_active Abandoned
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101548972B (zh) * | 2008-04-03 | 2012-10-17 | 万特制药(海南)有限公司 | 一种含有瑞格列奈的固体药物组合物 |
CN104127424A (zh) * | 2014-07-30 | 2014-11-05 | 沈阳药科大学 | 格列本脲衍生物及其制备方法和应用 |
CN104127423A (zh) * | 2014-07-30 | 2014-11-05 | 沈阳药科大学 | 格列喹酮衍生物及其制备方法和应用 |
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