CN110234317A - 具有治疗与非酒精性脂肪性肝炎(nash)和高甘油三酯血症相关的肥胖的双重作用的依拉贝特二甲双胍盐 - Google Patents
具有治疗与非酒精性脂肪性肝炎(nash)和高甘油三酯血症相关的肥胖的双重作用的依拉贝特二甲双胍盐 Download PDFInfo
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Abstract
本发明涉及来源于依拉贝特(elafibranor)的药物。更具体地,本发明涉及包含至少一种活性成分的组合物,其特征在于至少一种活性成分包含依拉贝特二甲双胍盐。本发明还涉及具有双重作用的依拉贝特衍生物,用于治疗与非酒精性脂肪性肝炎(NASH)和高甘油三酯血症相关的肥胖。
Description
技术领域
本发明涉及衍生于依拉贝特(elafibranor)的药物。
本发明更具体地涉及一种具有双重作用的依拉贝特衍生物,用于治疗与非酒精性脂肪性肝炎和高甘油三酯血症相关的肥胖。这涉及一种新产品——依拉贝特二甲双胍盐(GFT505)、制备所述新产品的方法、以及含有所述新产品作为活性成分的药物组合物。
本发明还涉及通过肠内或胃肠外途径以各种形式给药的药物制剂,用于治疗或预防由代谢综合征引起的疾病,如肥胖、超重、糖尿病、胰岛素抵抗、血脂异常、肝脏疾病,其中肝脏疾病包括脂肪变性、肝纤维化或肝硬化,以及由此引起的心血管疾病。更确切地,本发明涉及用于治疗或预防与非酒精性脂肪性肝炎(NASH)相关的肥胖的药物组合物。
现有技术
肥胖和体重问题是西方国家的主要问题。2012年,法国有2460万人超重,即三分之一的法国人口。一半人有体重问题。在欧洲13%的死亡原因似乎是由肥胖引起的。因此,寻找更有效的活性分子对治疗这些疾病至关重要。
本发明中所描述的依拉贝特(elafibranor)是指基因健康(Genfit)公司开发的的实验模块,其可以其代号GFT505或GFT-505引用而出现,最初开发用于治疗包括糖尿病、胰岛素抵抗和血脂异常的代谢类疾病。它目前的治疗目标是肝脏疾病,特别是非酒精性脂肪性肝炎(NASH)。
依拉贝特的化学名为2-[2,6二甲基-4-[3-[4-(甲硫基)苯基]-3-氧代-1(戊基)苯氧基]-2-甲基丙酸,化学式为C22H24O4S,分子量为384.489g/mol。其式I的化学结构见图1。
基因健康公司专利EP 1525177 B1描述了1,3-二苯基丙-2-烯-1-酮家族分子的使用和制备。在该文件中提到的化合物29的依拉贝特通过核磁共振光谱(1H DMSO)鉴定,其具有以下特征(δppm):1.39(s,6H),2.22(s,6H),2.57(s,3H),7.40(d,J=8.55Hz,2H),7.57(s,2H),7.62(d,J=15.5Hz,1H),7.83(d,J=15.5Hz,1H),8.10(d,J=8.55Hz,2H),12.97(s,1H)SM(ES-MS):383.3(M-1)。
没有公开的文献给出关于该分子的物理和化学鉴定的更多信息,该分子包含与贝特族(fibrate family)分子相同的苯氧基化丙酸基团(图2)。
属于贝特族的分子以其在水中的低溶解度、可降低甘油三酯的血浆浓度,以及可降低极低密度脂蛋白的胆固醇的血浆浓度而著称。
贝特类物质以能激活核受体而著称,核受体即PPAR(过氧化物酶体增殖物激活受体),特别是α亚型,调节富含甘油三酯和高密度脂蛋白(良好胆固醇)的脂蛋白代谢相关基因的转录。
关于依拉贝特分子的其它信息主要涉及该分子的临床前、临床和毒理学特性。如贝特类药物一样,依拉贝特被认为是核受体PPARα/δ的辅激活子。临床试验显示对该分子很好的耐药性,特别是通过动物体内高剂量毒理学研究(包括致癌性研究)得到了巩固。
依拉贝特(GFT05)对非酒精性脂肪性肝炎NASH也有有益的作用,改善了肝功能异常的生化指标,如肝酶:ALAT、ASAT、γGT和ALP7。
目前还没有对依拉贝特的物理和化学数据全面的描述,无论是单独的化学分子还是作为药物组合物中的活性分子。在专利或科学出版物中没有对其生理可接受的盐的描述。
自2003年以来,基因健康公司的几项专利中描述了依拉贝特(GFT505),这些专利涵盖了任何治疗应用,并且自2009年以来,还涉及一种新的特定治疗应用,特别是用于治疗非酒精性脂肪性肝炎NASH。
专利EP1525177和US7943661涉及查尔酮衍生物的新家族。这些专利描述了制备和使用下式II(图4)所述的1,3-二苯基丙-2-烯-1-酮的取代衍生物的方法,其中依拉贝特分子构成任何治疗应用的一部分(说明书中描述的化合物29,权利要求25),而不限于某一特定疾病。
第二组专利EP2504005、US8772342和US9221751涉及用于肝纤维化或肝脂肪变性的肝脏疾病治疗方法中的化合物。
特别地,权利要求7涉及用于治疗肝纤维化或肝脂肪变性的依拉贝特分子。权利要求9和10涉及包含下式III(图5)所示化合物的药物组合物,其用于治疗肝纤维化或肝脂肪变性的肝脏疾病。
专利EP2504005B1是关于专利EP2504005B1中要求保护的化合物的分案申请EP2641596A1的主题,但这里仅用于疾病的特定背景:肝硬化、酒精相关疾病和免疫介导的肝脏疾病。
应注意与依拉贝特有关的其它专利。专利US7566737B涉及一种药物组合物,其包含式II的1,3-二苯基丙-2-烯-1-酮的取代衍生物(包含依拉贝特分子)和另一种具有治疗活性的成分之间的组合。
专利US8895619 B涉及通过施用依拉贝特分子治疗肝纤维化的方法(权利要求1-7、10-11),特别是用于治疗肝硬化的方法(权利要求8-9)。
申请US2016/0051501涉及通过式化合物治疗病毒性或酒精相关或免疫性肝脏疾病的方法。
其它专利中没有引用依拉贝特。只有研究结果出现在几篇文章中,其中第一篇发表于2007年(Fruchart,Am J Cardiol(美国心脏病学杂志)2007;100[suppl(增补)]:41N-46N;2013:Fruchart Cardiovascular Diabetology(心血管糖尿病学)2013,12:82)。
由SanyalAJ等人发表的《由GFT-505(依拉贝特)引起的脂肪性肝炎消退的肝脏和肝外特征》提出了一项2b期研究结果(Golden505),该研究提出了给予270名NASH患者(3组,包括糖尿病患者和非糖尿病患者)每日施用80或120mg剂量的依拉贝特。但文章中没有关于用于本研究的40mg剂量的药物组合物的信息,或关于依拉贝特的物理和化学特征或关于早餐前给药的基本原理的信息。
尽管已经进行了1期的研究,但包括代谢在内的依拉贝特的药代动力学参数并未公开。2012年,在剂量研究《GFT505研究:比较生物利用度——性别影响——单次和多次上升剂量安全性和药代动力学》中,基因健康公司对依拉贝特的制剂进行了更改。对新旧制剂之间的相对生物利用度进行了研究,剂量范围可达300mg。没有公布结果或信息来证明并支持这一制定工作的原因。
二甲双胍的化学名称为3-(二氨基亚甲基)-1,1-二甲基胍,结构如图3(式I)所示,化学式为C4H11N5。该物质被认为是具有抗高血糖作用的抗糖尿病双胍类药物(等)中的活性成分。二甲双胍与乳酸的低产生率有关。它有助于降低低密度脂蛋白胆固醇和甘油三酯的水平,但不引起体重增加,并防止糖尿病的心血管并发症。二甲双胍不被代谢,能通过肾脏不变地排泄。
活性分子的分子量为129.16g/mol,熔点为223-226℃。二甲双胍盐酸盐常作为活性成分用于市场上的药物(如),因为它在水中的溶解度非常好(Log P为-0.5和pKa为12.4),即使在高温和高湿条件下(40℃/75%相对湿度,ICH标准),也能建立化学稳定。
申请人希望提高依拉贝特的疗效。
令人惊讶的是,发现二甲双胍盐形式的依拉贝特具有不同于单独服用依拉贝特和二甲双胍的有益效果。这是因为二甲双胍盐提供了活性成分的协同作用,特别是影响其生物利用度。
附图简要说明
本发明的目的、对象、特征和优点将从以下附图所示的实施方式的详细描述中更加清楚地显现,其中:
图1为依拉贝特的化学式;
图2为贝特类药物和依拉贝特的共同化学基团;
图3为二甲双胍的化学式;
图4为取代的1,3-二苯基丙-2-烯-1-酮的衍生化学式,其包含依拉贝特;
图5为专利申请EP2504005的化合物的通式,该化合物包含依拉贝特;
图6为依拉贝特(GFT505)的合成图;
图7A为依拉贝特(GFT505)的1H核磁共振波谱;
图7B为依拉贝特(GFT505)的高效液相色谱质谱;
图7C为依拉贝特(GFT505)的紫外光谱;
图8A为依拉贝特(GFT505)二甲双胍盐的1H NMR;
图8B为依拉贝特(GFT505)二甲双胍盐的高效液相色谱质谱/紫外光谱;
图9为依拉贝特(GFT505)二甲双胍盐粉末的高效液相色谱质谱,(第1组暴露于光下14天,第2组避光保护14天)。
发明内容
在开始详细阅读本发明的实施方案之前,可选地联合使用或可替代地使用的可选特征将示于下文。
首先声明,本发明涉及一种组合物,其包含作为活性成分的药物可接受的依拉贝特(GFT505)二甲双胍盐。
有利地,本发明涉及包含至少一种活性成分的组合物,其特征在于,所述至少一种活性成分包含依拉贝特二甲双胍盐。
有利地,该组合物旨在治疗和/或预防由代谢综合征引起的疾病,包括糖尿病、肥胖、肝脏和心血管疾病以及血脂异常。
有利地,该组合物旨在治疗和/或预防包括非酒精性肝脂肪变性病征(non-alcoholic hepatic steatoses)、非酒精性脂肪性肝炎、肝纤维化、肝硬化和癌症的肝脏疾病。
有利地,该组合物旨在治疗和/或预防肝脏疾病,其特征在于该肝脏疾病包括非酒精性肝脂肪变性(NAFLD)。
有利地,该组合物旨在治疗或预防肝脏疾病,其特征在于肝脏疾病包括非酒精性脂肪性肝炎(NASH)。
有利地,该组合物旨在治疗或预防肥胖。
有利地,该组合物为适于口服给药的形式。
有利地,该组合物为适于肠胃外给药的形式。
有利地,该组合物最多包含500mg依拉贝特二甲双胍盐。
口服给药方法可简单快速地服用药物组合物。
有利地,该组合物为适于静脉给药的形式。
有利地,该组合物为适于皮下给药的形式。
有利地,该组合物包含至少一种辅料,其选自粘合剂、崩解剂、稀释剂、润滑剂、表面活性剂、缓冲剂、助流剂、染料、调味剂、甜味剂、溶剂或防腐剂。
本发明还涉及一种药物可接受的依拉贝特二甲双胍盐,其化学式为C22H23O4S·C4H11N5。
有利地,该组合物的药物形式由用于注射液的粉末组成。
有利地,该药物形式由用于口服混悬液的粉末组成。
与碱性形式的依拉贝特盐相比,依拉贝特药物可接受的盐具有在水中溶解性更好的优点。
有利地,该药物形式包括注射液、片剂、分散片、口腔分散片、胶囊、可溶性片剂、冻干品、泡腾片、嚼片剂、缓释片剂或袋剂。
有利地,在模拟进餐的酸性环境、水中、FaSSIF和FeSSIF介质中的溶解曲线,在30min后,药物可接受的依拉贝特二甲双胍盐的溶解百分比大于90%。
本发明涉及一种包含作为活性成分的药物可接受的依拉贝特(GFT505)二甲双胍盐的组合物在用于治疗或预防由代谢综合征引起的疾病的药物中的用途,特别是具有治疗与非酒精性脂肪性肝炎(NASH)和与高甘油三酯血症相关的肥胖的双重作用。
另一方面,本发明涉及药物可接受的依拉贝特(GFT505)二甲双胍盐的制备,该盐具有比游离碱形式的依拉贝特更有利的物理和化学性质,特别是在溶解性和/或稳定性方面。
发明详述
本发明涉及一种药物可接受的晶型(任选为多晶型或无定形)的依拉贝特二甲双胍盐及其在制备用于治疗或预防疾病的药物中的用途,所述疾病尤其是与代谢综合征相关的疾病,并且具有对肥胖和肝脂肪变性病征(hepatic steatoses)具有双重作用。
本发明还涉及化学式为C26H34O4N5S的2-[2,6二甲基-4-[3-[4-(甲硫基)苯基]-3-氧代-1(E)-丙烯基]苯氧基]-2-甲基丙酸的药物可接受的盐的用途,其能够用于预防或治疗特别是由代谢综合征引起的疾病,例如肥胖、胰岛素抵抗和包括非酒精性脂肪性肝炎NASH在内的肝脏疾病。
依拉贝特二甲双胍盐(elafibranor metformin salt)也称为依拉贝特二甲双胍盐(elafibranorate metformin salt)。
本发明的药物组合物可以肠道、肠胃外、局部或皮下给药。根据一种给药方式,组合物通过肠道给药,例如片剂、胶囊、软胶囊、冻干品、分散片、口分散片、泡腾片或可溶性片剂、口服液或口服混悬液用粉末。
根据优选的给药形式,组合物以片剂或胶囊的形式口服给药。
根据优选的给药形式,组合物以例如可注射液或可注射液粉末的形式静脉内或皮下给药。
用于静脉或口服给药的制剂含有结晶或无定形结构的依拉贝特二甲双胍盐,以在适用时优化制造该特效药的方法。
本发明的药物优选组合物之一是用于口服混悬液或注射制剂的粉末,其在正常温度和湿度条件下是可溶和稳定的。
因此,作为新产品,本发明涉及二甲双胍盐和2-[2,6二甲基-4-[3-[4-(甲硫基)苯基]-3-氧代-1(E)-丙烯基]苯氧基]-2-甲基丙酸盐,并且还涉及二甲双胍盐和2-[2,6二甲基-4-[3-[4-(甲硫基)苯基]-3-氧代-1(E)-丙烯基]苯氧基]-2-甲基丙酸盐的制备。
该制备可以通过二甲基双胍使2-[2,6二甲基-4-[3-[4-(甲硫基)苯基]-3-氧代-1(E)-丙烯基]苯氧基]-2-甲基丙酸成盐的方法进行。制备方法在以下实施例中给出。
实施例
实施例1:依拉贝特(GFT505)的合成和表征
申请人决定制备依拉贝特的样品,以评估合成该分子的步骤的可行性,并表征所得产品的物理和化学性质。操作方法来源于专利EP 1525177 B1中描述的用于合成化合物29的信息。这些步骤是相同的。
实验方案
该化合物由1-[4-甲基噻吩基]-3-[3,5-二甲基叔丁氧羰基二甲基甲基氧苯基]丙-2-烯-1-酮合成。
步骤1:1-[4-甲基噻吩基]-(戊)-3-[3,5-二甲基-4-羟基苯基]丙-2-烯-1-酮(中间体1)。
将4-甲基苯乙酮(20g,0.12mol,1eq)和3,5-二甲基-4-羟基苯甲醛(18g,0.12mol,1eq)溶解在300ml的4N盐酸的二恶烷溶液中。搅拌反应介质30小时,然后蒸发溶剂。通过在70ml异丙醇和12ml水中热重结晶进行纯化,得到30g产物(黄色固体,收率:92%)。
原料配方:C18H18O2S
ESI-MS m/z=299.18[M+H]+
1H NMR DMSO-d6δppm:2.18(s,6H),2.53(s,3H),7.36(d,J=8.5Hz,2H),7.47(s,2H),7.57(d,J=15.5Hz,1H),7.69(d,J=15.5Hz,1H),8.05(d,J=8.5Hz,2H),8.93(s,1H)。
步骤2:1-[4-甲基噻吩基]-(戊)-3-[3,5-二甲基-4-叔丁基羰基二甲基甲基氧基苯基]丙-2-烯-1-酮(中间体2)
将碳酸铯(87g,0.134mol,4eq)和碘化四丁基铵(12g,0.033mol,0.5eq)加入中间溶液1(20g,0.067mol,1eq)的50ml DMSO/水(3/2)混合溶液中。将反应介质在80℃下搅拌30min,并加入溴异丁酸叔丁酯(30g,0.134mol,2eq)。然后每隔1小时加入2eq溴异丁酸叔丁酯,在DMSO中稀释至50%。将反应介质在80℃下搅拌2天。将反应介质冷却至环境温度,然后加入1.5升水,用二氯甲烷萃取产物(4次)。有机相在相分离柱上干燥然后蒸发干燥。通过硅胶纯化(环己烷/乙酸乙酯:95/5至80/20):得到18g产物(橙色固体,收率:61%)。
原料配方:C26H32O4S
ESI-MS m/z=441.33[M+H]+
1H NMR DMSO-d6δppm:1.36(s,6H),2.19(s,6H),2.48(宽峰,H2O+9H),2.54(s,3H),7.38(d,J=8.4Hz,2H),7.55(s,2H),7.59(d,J=15.6Hz,1H),7.80(d,J=15.6Hz,1H),8.07(d,J=8.4Hz,2H)。
步骤3:1-[4-甲基噻吩基]-(戊)-3-[3,5-二甲基-4-羧二甲基甲基氧基苯基]丙-2-烯-1-酮
中间体2(25g,0.057mol,1eq)溶解在50ml二氯甲烷中,并轻轻加入22ml三氟乙酸(5eq,0.284mol)。将反应介质在环境温度下搅拌3.5小时,然后将溶剂蒸发干燥。通过硅胶纯化(二氯甲烷/甲醇:100/0->95/5);得到13g产物(黄色固体,产率60%)。
原料配方:C22H24O4S
ESI-MS m/z=385.25[M+H]+
1H NMR DMSO-d6δppm:1.36(s,6H),2.19(s,6H),2.54(s,3H),7.37(d,J=8.6Hz,2H),7.55(s,2H),7.59(d,J=15.6Hz,1H),7.80(d,J=15.6Hz,1H),8.07(d,J=8.6Hz,2H),12.94(s,1H)。
反应图如图6所示。
结果:
获得的10.1g批号EM0274L2产品,其分析数据总结如下:
分子量:384.5(精确分子量:384.1);
1H NMR:符合结构,参见下图6A的波谱。
LCMS:TR=1.42mn,m/z:385.00=[M+H]+;
纯度:>98%(1H核磁共振和LCMS);
熔点:144-145℃
产品外观为无定形黄色固体粉末。该产品在近可见光区显示出显著的吸收,其顶点约为347nm。
信息详见下图7。
所获得的产品在化学纯度方面是一致的,并且在近可见光下显示出吸收,因此需要检查在光和光毒性下的化学稳定性。
实施例2:依拉贝特溶解度的测量
在对本发明进行的实验中,显示依拉贝特(GFT505)具有类似于贝特族的化学结构(图2)。依拉贝特是一种羧酸,申请人选择检查该分子在水中的溶解度,以便根据患者的期望来决定药物组合物开发的可行性,并且该药物组合物对患者更有效且更能耐受。
实验方案
在有或无表面活性剂的情况下,在24小时和72小时内,研究了碱性依拉贝特在各种水性缓冲液中的热力学溶解度。此工作使用批号EM0274L2。产品溶解在表1所示的溶剂中。在环境温度(22-24℃)下培养24小时和72小时后,对溶液取样,然后在烧瓶中用0.2μM聚碳酸酯过滤器过滤以进行LCMS分析,并在DMSO中稀释一次,然后搅拌2min(涡流或超声波)。
结果:
热力学溶解度结果见下表1:
表1:依拉贝特在水性介质中的热力学溶解度
依拉贝特在水性介质中的溶解度低。随pH的变化而增加,pH从4.6到8.5,溶解度从114变化到4419μM。助溶剂如丙二醇或聚乙二醇400的加入显著提高了分子的溶解度。
实施例3:依拉贝特二甲双胍盐的制备
申请人制备了依拉贝特二甲双胍盐,用于测定其特性,并将其与游离碱形式的依拉贝特进行比较,以生产药物组合物。
实验方案
该批依拉贝特二甲双胍盐由一批游离的碱性依拉贝特生产。
将1g的GFT505(2.6mmol)和104mg的NaOH(1eq,2.6mmol)悬浮在8ml异丙醇和10ml甲醇中,并加热至65℃。将431mg氯化二甲双胍(1eq,2.6mmol)的2ml异丙醇溶液加入到加入黄色反应介质中,并在65℃下搅拌30min。冷却到环境温度后,快速过滤细悬浮液,用2×1ml异丙醇洗涤。约30min后,淡黄色固体开始沉淀。在环境温度下静置24小时后,过滤固体,用2×1ml异丙醇洗涤,并在45℃真空下干燥24小时。黄色残留物在65℃下溶解在10ml异丙醇和6ml甲醇中。停止加热,使透明反应介质在搅拌下冷却。固体在约47℃使开始沉淀。24小时后,过滤固体,用2×1ml异丙醇洗涤,并在45℃真空下干燥72小时(批号CP0685L1,见2016年8月30日报告1)。在45℃和高真空(<10-2mbar)下再干燥10天后,前一批中检测到的溶剂痕迹消失(批号CP0685L2)。
然后将产品在惰性气体下冷却(2-8℃)保存,以防止任何分解。对产品进行分析,包括鉴定和化学纯度(见图8)。
结果
结果如下:
分子量:513
外观:无定形黄色固体。
熔点:178/180℃
TR=1.46mn,m/z:385=[M+H]+
结构:
图8所示的其它数据。
实施例4:依拉贝特(GFT505)二甲双胍盐溶解度的测试
为了肠胃外给药或在快速释放肠内组合物的情况下使用依拉贝特盐,该实施例给出了多种形式的依拉贝特盐的溶解度特征。
在环境温度和水性介质(水和药典示出的缓冲液)中,测定溶解动力学。结果总结如下。
表2:依拉贝特二甲双胍盐的溶解度
依拉贝诺二甲双胍盐的溶解度大约是游离碱形式依拉贝诺的20倍。
实施例5:依拉贝特及其某一形式的盐的稳定性
申请人决定在暴露于光和温度后检查依拉贝特及其二甲双胍盐的稳定性。
实验方案
样品以粉末和水溶液的形式单独制备并用于以下样品:依拉贝特、依拉贝特二甲双胍。
稳定性由UPLC MS在7至14天的时间内测量,计算依拉贝特峰相对于初始值的还原程度并测量其纯度指数。产品暴露在日光和环境温度下。
对于参考样品,将它们冷藏(2-8℃),用铝纸避光,在惰性气体下保护固体产品。
结果
结果表明,无论是粉末形式还是溶液形式,游离碱性依拉贝特比依拉贝特盐对光更敏感(光敏性)。二甲双胍盐的黄色粉末在颜色上有明显的变化,变为深黄色,这与游离碱形式的产品具有相同的趋势。然而,储存14天后的收率在100±5%的标准范围内:检测到分解产物(<5%)。图9为LCMS(第1组暴露在光下,第2组用铝箔保护粉末样品)。
温度对其稳定性没有影响。未发现光照下有分解产物产生。
Claims (12)
1.包含至少一种活性成分的组合物,其特征在于,所述至少一种活性成分包含依拉贝特二甲双胍盐。
2.根据前述权利要求所述的组合物,其用于治疗或预防由代谢综合征引起的疾病,所述疾病包括糖尿病、肥胖、肝脏和心血管疾病和血脂异常。
3.根据前述权利要求任一项所述的组合物,其用于治疗或预防肝脏疾病,所述肝脏疾病包括非酒精性肝脂肪变性病征、非酒精性脂肪性肝病、纤维变性、肝硬化和癌症。
4.根据前述权利要求所述的组合物,其用于治疗或预防肝脏疾病,其特征在于所述肝脏疾病包括非酒精性肝脂肪变性(NAFLD)。
5.根据权利要求3所述的用于治疗或预防肝脏疾病的组合物,其特征在于,所述肝脏疾病包括非酒精性脂肪性肝炎(NASH)。
6.根据权利要求2所述的组合物,其特征在于,所述组合物用于治疗或预防肥胖。
7.根据前述权利要求任一项所述的组合物,其特征在于所述组合物为适于口服给药的形式。
8.根据权利要求1至6中任一项所述的组合物,其特征在于所述组合物为适于肠胃外给药的形式。
9.根据权利要求1至6中任一项所述的组合物,其特征在于所述组合物为适于静脉给药的形式。
10.根据权利要求1至6中任一项所述的组合物,其特征在于所述组合物为适于皮下给药的形式。
11.根据前述权利要求任一项所述的组合物,其特征在于所述组合物包含至少一种辅料,所述辅料选自粘合剂、崩解剂、稀释剂、润滑剂、表面活性剂、缓冲剂、助流剂、染料、调味剂、甜味剂、溶剂或防腐剂。
12.药物可接受的依拉贝特二甲双胍盐,具有式C22H23O4S·C4H11N5:
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PCT/EP2017/074703 WO2018060373A1 (fr) | 2016-09-30 | 2017-09-28 | Sel de metformine d'elafibranor presentant une activite duale pour le traitement de l'obesite associee a la steato-hepatite non alcoolique (nash) et a l'hypertriglyceridemie |
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WO2012148252A2 (es) * | 2011-04-29 | 2012-11-01 | Instituto De Investigación En Química Aplicada, S.A. De C.V. | Cocristales ionicos con base en metformina |
CN104434891A (zh) * | 2009-11-26 | 2015-03-25 | 基恩菲特公司 | 使用1,3-二苯基丙-2-烯-1-酮衍生物治疗肝脏疾患 |
WO2016044433A2 (en) * | 2014-09-16 | 2016-03-24 | Biopharma Works | Metformin derivatives |
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CN104434891A (zh) * | 2009-11-26 | 2015-03-25 | 基恩菲特公司 | 使用1,3-二苯基丙-2-烯-1-酮衍生物治疗肝脏疾患 |
WO2012148252A2 (es) * | 2011-04-29 | 2012-11-01 | Instituto De Investigación En Química Aplicada, S.A. De C.V. | Cocristales ionicos con base en metformina |
WO2016044433A2 (en) * | 2014-09-16 | 2016-03-24 | Biopharma Works | Metformin derivatives |
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