CN111727041A - 用于治疗非酒精性脂肪性肝病和非酒精性脂肪性肝炎的组合物 - Google Patents
用于治疗非酒精性脂肪性肝病和非酒精性脂肪性肝炎的组合物 Download PDFInfo
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Abstract
本申请描述了一种单独使用促生长激素分泌素或将其与选自二肽基肽酶‑4拮抗剂、胰高血糖素样肽受体激动剂、噻唑烷二酮、葡萄糖钠转运蛋白2拮抗剂和二甲双胍的药物联用用于治疗诸如非酒精性脂肪性肝病和非酒精性脂肪性肝炎的疾病的新方法。还提供了与此相关的组合物。
Description
发明领域
本发明涉及一种使用促生长激素分泌素或将促生长激素分泌素与选自二肽基肽酶-4拮抗剂、胰高血糖素样肽受体激动剂、噻唑烷二酮、葡萄糖钠转运蛋白2拮抗剂、二甲双胍和维生素E的药物联用用于治疗非酒精性脂肪性肝病和非酒精性脂肪性肝炎的新方法。
本申请中引用的所有出版物、专利、专利申请和其他参考文献出于所有目的通过引用整体并入本文,其程度就如同每个单独的出版物、专利、专利申请或其他参考文献均被明确地和单独地指明为出于所有目的通过引用整体并入。本申请参考文献的引用不应被解释为承认这是本发明的现有技术。
背景技术
非酒精性脂肪性肝病(NAFLD)是世界上最常见的肝病。这是肝脏中储存过多脂肪的病况。这种病况不是由大量饮酒(大量饮酒将是酒精性肝病)引起的。NAFLD导致肝部炎症、纤维化和肝细胞癌,其已成为一个主要的健康问题,并与肥胖、胰岛素抵抗、2型糖尿病和代谢性疾病的患病率增加有关。据估计,其在美国人口中的发病率为25-30%,并且还在增加。另据估计,大约20%患有NAFLD的人也患有非酒精性脂肪性肝炎(NASH),这会导致诸如肝硬化和肝癌的并发症。将NAFLD和/或NASH的治疗视为治疗肥胖、胰岛素抵抗、2型糖尿病和代谢性疾病的另一种方法。
目前,对于NAFLD或NASH都没有有效的治疗方法。因此,期望开发治疗这些疾病的方法。
发明内容
在一方面中,本发明提供了一种使用促生长激素分泌素(GHS)治疗非酒精性脂肪性肝病的新方法。
在一方面中,本发明提供了一种使用GSH与选自下述的药物的组合治疗NAFLD的新方法:二肽基肽酶-4(DPP4)拮抗剂、胰高血糖素样肽(GLP-1)受体激动剂、噻唑烷二酮、葡萄糖钠转运蛋白2(SGLT2)拮抗剂、二甲双胍和维生素E。
在另一个方面中,本发明提供了一种使用促生长激素分泌素治疗非酒精性脂肪型肝炎的新方法。
在一方面中,本发明提供了一种使用GSH与选自下述的药物的组合治疗NASH的新方法:二肽基肽酶-4拮抗剂、胰高血糖素样肽受体激动剂、噻唑烷二酮、葡萄糖钠转运蛋白2拮抗剂、二甲双胍和维生素E。
具体实施方式
发明人发现单独使用促生长激素分泌素(例如,伊布莫仑(ibutamoren))或将其与选自下述的药物联用有望治疗诸如NAFLD和NASH的疾病:二肽基肽酶-4拮抗剂、胰高血糖素样肽受体激动剂、噻唑烷二酮、葡萄糖钠转运蛋白2拮抗剂、二甲双胍和维生素E。
例如,发明人发现使用将促生长激素分泌素伊布莫仑与DPP4拮抗剂捷诺维TM联用的新治疗方法的伊布莫仑可用于治疗NAFLD和NASH。伊布莫仑和捷诺维TM均具有口服活性,并且安全性良好。发明人相信,例如作为单个药丸配制的组合物利用了伊布莫仑的性质来使GH正常化,而捷诺维TM增强了葡萄糖刺激的胰岛素释放。基于其不同的作用机制,发明人相信将证明两者的组合对于治疗/预防NAFLD是协同的或者至少是叠加的。
伊布莫仑(在本申请中也称为伊布莫仑甲磺酸盐)的结构如下所示:
伊布莫仑可以从例如Sigma Aldrich和Caymen Chemical的供应商处购得。
NAFLD和生长激素(GH)
NAFLD导致肝部炎症、纤维化和肝细胞癌,其已成为一个主要的健康问题,并与肥胖、胰岛素抵抗、2型糖尿病和代谢性疾病的患病率增加有关。一项针对7,146名个体的横断面研究表明,NAFLD与循环中生长激素(GH)水平较低相关(Xu,Xu等,2012)。GH缺乏的成人中胰岛素样生长因子(IGF-1)和IGF结合蛋白-3BP3(IGFBP3)的水平较低,并且具有胰岛素抵抗。GH对IGF-1和IGFBP3均具有正向调控作用。
在垂体切除大鼠中进行的研究表明,GH对于调控LDL受体表达和循环脂蛋白水平至关重要(Rudling,Norstedt等,1992)。除增加IGF-1和IGFBP3以外,GH治疗还控制参与胆固醇和胆汁酸生物合成关键酶的活性。此外,GH控制增强甘油三酸酯(TG)水解、降低TG储存以及增加二酰基甘油合成的基因的表达(Zhao,Cowley等,2011)。
GH与肝脏中GH受体(GHR)的结合可激活转录因子STAT5。小鼠中GHR或STAT5的肝选择性消融导致肝脂肪变性、胰岛素抵抗、葡萄糖耐受不良、甘油三酸酯合成增加和外排减少(Fan,Menon等,2009,Baik,Yu等,2011,Liu,Cordoba-Chacon等,2016)。GH-STAT5还调控胆汁酸合成和代谢。这些性质导致得出结论,将GH恢复至正常水平是NAFLD的潜在治疗方法。
GH通过调节11β-羟类固醇脱氢酶1型(HSD1)来控制皮质醇的局部生成,该酶负责将可的松局部转化为活性糖皮质激素皮质醇;皮质醇调控糖异生和脂肪沉积。HSD1在肝脏、脂肪组织和脑中表达。肝脏中HSD1的过量生产通过增加限速的糖异生酶磷酸烯醇丙酮酸羧激酶的表达来增加皮质醇诱导的糖异生。此外,HSD1在大网膜脂肪中过表达会刺激脂肪形成,从而可能导致向心性肥胖。由此可见,抑制HSD1活性以减少局部皮质醇的产生是预防和治疗2型糖尿病、肥胖、与年龄相关的认知功能障碍和NAFLD的潜在方法。HSD1抑制剂可改善db/db小鼠的胰岛素敏感性并改善肝脂肪变性(Yuan,Li等,2016)。Gh生成受损会增加HSD1表达,并且GH缺乏的患者表现出皮质醇/可的松比例升高,其可以通过给予低剂量GH来逆转。
遗传研究表明,NAFLD与编码包含patatin样磷脂酶结构域的蛋白3(PNPLA3)的基因多态性相关。尽管机制仍不清楚,但变体PNPLA3-148M与NAFLD病变的各方面均相关(Boursier和Diehl 2015)。对表达这种基因变体的肥胖西班牙裔儿童和表达人PNPLA3-148M的小鼠进行的研究表明,NAFLD的发展依赖于高碳水化合物而不是高脂肪饮食的摄入(Davis,Le等,2010,Boursier和Diehl 2015,Smagris,BasuRay等,2015)。最近的证据表明PNPLA3是通过涉及泛素化的机制清除的,但是PNPLA3-148M具有抗性,导致变体蛋白积聚在脂质小滴上(BasuRay,Smagris等,2017)。根据小鼠研究(Smagris,BasuRay等,2015),在具有两个WT等位基因的对象中增加或减少PNPLA3对脂肪变性的影响不大,而增加PNPLA3-148M则会加剧脂肪变性。由于GH增加了野生型PNPLA3-WT的表达(Zhao,Cowley等,2011),因而GH治疗应被证明可有效治疗PNPLA3-148M杂合子。
胰岛素和生长激素在肝脂肪变性中的作用
肥胖和2型糖尿病与胰岛素抵抗相关。该抵抗主要在骨骼肌和胰岛素抑制肝脏糖异生的能力中介导。肝脏糖异生的抑制取决于脂肪组织中游离脂肪酸的减少(Bergman和Iyer2017)。因此,抵抗在骨骼肌和脂肪组织中纯粹是肝外的,而肝脏保留了其对胰岛素的敏感性以刺激脂肪生成——将其称为“选择性胰岛素抵抗”,参见(Titchenell,Quinn等,2016)。
糖尿病的治疗是一种平衡,一方面是调控和控制高血糖,同时又不增加肝脂肪生成。因此,通过外源性胰岛素或磺酰脲类药物增加胰岛素水平在治疗NAFLD中不起作用。然而,延长内源性GLP-1活性的GLP-1激动剂或DPP4拮抗剂是优选的,因为其增强了响应于葡萄糖的胰岛素释放并降低了血糖,这降低了增强肝脏中脂肪生成的能力。由于现已确定胰岛素对脂肪细胞的抑制脂解的作用会抑制肝脏糖异生,并且其是由胰岛素的第一时相分泌来调节,因此DPP4抑制剂是抑制该过程的理想疗法(Mest和Mentlein 2005)。
肥胖和2型糖尿病与GH分泌受抑制有关。胰岛素和GH以脉冲方式分泌,并且两者均受到严格调控。例如,当胰岛素分泌增加时,IGFBP-1迅速被抑制,然后导致游离IGF-1的增加,而IGF-1反馈以抑制GH分泌。进餐后,胰岛素水平增加,以促进葡萄糖向细胞内的转运并增强脂肪形式的能量存储。肝脏对于代谢的整合至关重要,其储存糖原和脂肪,以在能量利用增强(例如,运动或饥饿)时使用(Cahill 1971)。饥饿12至14小时后,肝脏中的糖原储存被耗尽,然后身体转向从脂肪获取能量。除了将脂肪存储在肝脏中之外,其还存储在白色脂肪组织(主要是皮下脂肪)中,可根据需要进行动员。胰岛素和GH是主要用于调控肝脏和脂肪组织中脂肪的沉积以及随后的动员的两种激素。因此,随着进餐后时间的增加,胰岛素水平下降,GH水平上升。进食时,胰岛素升高,GH被抑制。胰岛素和GH的调控是复杂的,但是这两种激素都受到胃肠道中产生的另外两种激素的调节(GLP-1针对胰岛素而生长激素释放肽针对GH)。GLP-1和生长激素释放肽均以类似方式起作用,分别增强胰岛素和GH脉冲的正常幅度。至关重要的是,胰岛素和GH在适当的时间通常以一种彼此相反的方式分泌,即当胰岛素水平较高时,GH水平被抑制。
每日口服伊布莫仑可恢复内源性GH的正常状态
由于内源性GH整天由垂体腺前叶脉冲释放,因而仅注射重组GH(rhGH)无法恢复GH释放的生理特性。在GH缺乏的对象中,低剂量GH可改善胰岛素敏感性,但是高水平GH会产生胰岛素抵抗;因此,选择适合的治疗剂量具有挑战性。内源性GH的释放受调控反馈机制的影响,但施用外源性rhGH绕过了GH负反馈途径。而相比之下,施用GH促分泌素伊布莫仑增强了内源性GH脉冲释放的幅度并使GH正常化,因为伊布莫仑对GH脉冲的刺激作用受到IGF-1介导的自然抑制性反馈的作用;因此,避免了GH/IGF-1轴的过度刺激(Smith,Van der Ploeg等,1997)。因此,通过重复正常的GH生理作用,伊布莫仑对于在NAFLD的治疗/预防中提高胰岛素敏感性是理想的。
使用GLP-1类似物或DPP4抑制剂治疗NAFLD的局限性
GLP-1受体激动剂或降解GLP-1的DPP4酶抑制剂可增强胰腺β-细胞的葡萄糖敏感性。尽管增加了对葡萄糖产生应答的脉冲胰岛素释放的幅度,但是对胰岛素敏感性是否改善的认识并不普遍一致(Tominaga,Ikezawa等,1996,Ahren,Larsson等,1997)。由于NAFLD的一个重要方面是其与胰岛素抵抗的关系,因此仅靶向GLP-1途径不太可能具有足够的治疗获益;的确,这得到了临床研究报告的支持。例如,使用二甲双胍和/或磺酰脲类药物的2型糖尿病患者被分配接受GLP-1受体激动剂利拉鲁肽和/或DPP4抑制剂西格列汀(捷诺维TM)治疗12周;两种治疗均不能减轻肝脂肪变性或纤维化(Smits,Tonneijck等,2016)。在一项针对50名NAFLD患者的24周研究中,得出结论西格列汀在降低肝脏脂肪方面并不比安慰剂好(Cui,Philo等,2016)。另一项针对12名接受西格列汀治疗24周的受试者的研究表明,纤维化没有得到改善(Joy,McKenzie等,2017)。发明人提出,仅靶向GLP-1途径治疗NAFLD的局限性在于其不能充分缓解与NAFLD相关的胰岛素抵抗。
使用伊布莫仑和捷诺维的组合对NAFLD的拟定治疗
NAFLD的理想治疗方法是恢复缺乏的GH分泌,然后恢复胆汁酸分泌和肝脂质代谢,并适当增加定时胰岛素的分泌。发明人相信这可以通过例如伊布莫仑和捷诺维TM的组合实现,使用伊布莫仑模拟生长激素释放肽,以及使用捷诺维TM通过阻断通常会破坏GLP-1的DPP4而增加内源性GLP-1。伊布莫仑与生长激素释放肽相比具有明显的优势,因为除了不具有口服活性,生长激素释放肽还抑制胰岛素从胰腺β-细胞释放。通过直接比较发现,伊布莫仑不抑制葡萄糖刺激的胰岛素分泌;因此,伊布莫仑并不会使GLP-1对胰岛素释放的刺激作用失效。因此,含有伊布莫仑和DPP4抑制剂如捷诺维TM的组合的药丸将具有治疗/预防NAFLD所必需的性质。
动物研究表明GH是肝脏脂肪代谢的重要调节剂。内脏脂肪和肝脏中的脂肪积累随年龄的增长而增加,这与GH分泌从青春期中期开始每7-10年逐渐减少50%有关,因此老年人的GH水平与GH缺乏的年轻人相似。GH缺乏的成人酒精性脂肪性肝病(NAFLD)和脂肪性肝炎的发病率增加。GH替代疗法逆转了这一过程。提出以下假设,诸如伊布莫仑之类的GH促分泌素将恢复脉冲性GH分泌并降低内脏脂肪;这是基于以下观察结果:内源性GH分泌与内脏脂肪量和肝脂肪蓄积(NAFLD)负相关,而低剂量GH逆转了这一过程。HIV脂肪代谢障碍与内脏脂肪蓄积增加和脂肪性肝炎有关。已通过超生理学rhGH注射和替沙莫林(长效GHRH类似物)对其进行了治疗。由于已证明伊布莫仑可增强肥胖个体的GH分泌,增加其血清IGF-1并增加瘦体重,因而该假设得到了支持。拟定将伊布莫仑作为NAFLD和由NAFLD引起的脂肪性肝炎的治疗药物。提出与改善胰岛素敏感性的各种药物组合,以减轻伊布莫仑诱导的GH分泌增加导致的轻度致糖尿病作用。
维生素E
氧化应激在NASH的进展中具有重要作用。维生素E是一种众所周知的自由基清除剂,已将其处方用于治疗NASH。在饮食干预难以治疗的成人NASH患者中,使用维生素E治疗1年,降低了血清转氨酶活性以及TGF-β1。在吡格列酮对比维生素E对比安慰剂治疗患有非酒精性脂肪性肝炎的非糖尿病患者的(PIVENS)试验中,在无糖尿病和肝硬化的成人NASH中,维生素E(800mg/天)在改善NASH的组织学方面优于安慰剂。
根据五项研究的随机效应模型分析,与对照组相比,维生素E显著降低了血清肝胆酶、肝脂肪变性、炎症和肝细胞膨胀(ballooning)。然而,在那些研究中,未证实纤维化得到改善。
在日本,长期服用维生素E(300mg/天)超过2年可改善NASH患者的肝纤维化,尤其是那些血清转氨酶活性和胰岛素抵抗得以改善的患者。该结果表明,即使服用维生素E,也应控制代谢因素。
尽管根据PIVENS试验,维生素E现在仅建议用于经活检证实的无糖尿病NASH患者,但无论糖尿病状态如何,维生素E均与组织学改善相关。然而,用于NASH治疗的维生素E的主要问题是长期或大剂量使用可能会产生毒性。维生素E治疗可能会增加全因死亡率、前列腺癌(SELECT试验)和出血性中风,尽管存在一些相互矛盾的结果。当将维生素E用于NASH时,应考虑使用较低剂量(300–400mg/天而非800mg)的药物治疗。
本发明的某些实施方式
在一方面中,本发明提供了一种治疗非酒精性脂肪性肝病(NAFLD)或非酒精性脂肪性肝炎(NASH)的新方法,所述方法包括:向需要其的患者施用治疗有效量的促生长激素分泌素(GHS)。
在另一个方面中,该新方法还包括:施用选自下述的治疗有效量的第二种药物:二肽基肽酶-4(DPP4)拮抗剂、胰高血糖素样肽(GLP-1)受体激动剂、噻唑烷二酮、葡萄糖钠转运蛋白2(SGLT2)拮抗剂、二甲双胍和维生素E。
患者指人类患者,无论是儿童还是成人。
在另一个方面中,疾病是NAFLD。
在另一个方面中,疾病是NASH。
在另一个方面中,GHS是伊布莫仑(伊布莫仑甲磺酸盐)。
在另一个方面中,例如,每日一次施用10-50mg伊布莫仑。在一个实施方式中,每日一次施用25-50mg伊布莫仑。伊布莫仑施用量的其他实例包括10、15、20、25、30、35、40、45和50mg。在另一个方面中,伊布莫仑是口服施用的。
在另一个方面中,第二种药物是DPP4拮抗剂。
在另一个方面中,DPP4拮抗剂选自:
在另一个方面中,第二种药物是GLP-1受体激动剂。
在另一个方面中,GLP-1受体激动剂选自:
在另一个方面中,第二种药物是噻唑烷二酮(TZD)。噻唑烷二酮(也称为格列酮类)是一类具有降血糖作用的药物(例如,抗高血糖药和/或抗糖尿病药)。
在另一个方面中,TZD选自:
在另一个方面中,第二种药物是葡萄糖钠转运蛋白2(SGLT2)拮抗剂。
在另一个方面中,SGLT2拮抗剂选自:
在另一个方面中,第二种药物是二甲双胍。二甲双胍有多种剂量可供选择,包括500、850和1000mg的速释片和500、750和1000mg的缓释片。二甲双胍通常以1500、2000、2500至2550mg/天的剂量施用,口服。
在另一个方面中,在治疗方法中,GHS是伊布莫仑且第二种药物选自:
(i.)西格列汀;
(ii.)维达列汀;
(iii.)沙格列汀;
(iv.)利格列汀;
(v.)阿格列汀;
(vi.)吡格列酮;
(vii.)罗格列酮;
(viii.)恩格列净;
(ix.)达格列净;和,
(x.)二甲双胍。
在另一个方面中,在治疗方法中,GHS是伊布莫仑其第二种药物是西格列汀。
在另一个方面中,在治疗方法中,GHS是伊布莫仑其第二种药物是吡格列酮。
在另一个方面中,在治疗方法中,GHS是伊布莫仑其第二种药物是二甲双胍。
在另一个方面中,本发明提供了一种治疗非酒精性脂肪性肝病(NAFLD)或非酒精性脂肪性肝炎(NASH)的新方法,所述方法包括:向需要其的患者施用:
(i.)治疗有效量的促生长激素分泌素(GHS);
(ii.)治疗有效量的选自下述的第二种药物:二肽基肽酶-4(DPP4)拮抗剂、胰高血糖素样肽(GLP-1)受体激动剂、噻唑烷二酮和葡萄糖钠转运蛋白2(SGLT2)拮抗剂;和,
(iii.)治疗有效量的第三种药物,其是二甲双胍。
在另一个方面中,第二种药物选自二肽基肽酶-4(DPP4)拮抗剂、噻唑烷二酮和葡萄糖钠转运蛋白2(SGLT2)拮抗剂。
在另一个方面中,第二种药物是二肽基肽酶-4(DPP4)拮抗剂。
在另一个方面中,第二种药物是噻唑烷二酮。
在另一个方面中,第二种药物是葡萄糖钠转运蛋白2(SGLT2)拮抗剂。
在另一个方面中,在治疗方法中,GHS是伊布莫仑、第二种药物是西格列汀和第三种药物是二甲双胍。
在另一个方面中,在治疗方法中,GHS是伊布莫仑、第二种药物是吡格列酮和第三种药物是二甲双胍。
第一种(即,GSH)和第二种药物(或第一、第二和第三种药物)的给药时机取决于其独立给药方案。给药时机的实例包括:
(i.)同时给药,单一制剂。这可以通过将药物(两种或三种)共同配制为单一制剂(例如,口服制剂),然后再施用单一制剂来实现。
(ii.)同时给药,不同制剂。这可以通过在大约相同的时间独立施用(例如,不同的口服制剂、口服/注射制剂或注射制剂)来实现。
(iii.)同时给药+另外给药。对于以重叠的时机(例如,早上,但晚上仅给予一种)施用的药物,可以使用方案(i.)或(ii.)中的一种,然后再另外给药。
(iv.)非同时给药。对于以不同时机(例如,每日口服制剂对比每周注射)施用的药物,可以根据其各自的方案施用药物。
本发明的潜在获益之一是可能同时施用第一种和第二种(或第一种、第二种和第三种)药物。例如,如果第二种(或第二种和第三种)药物能够口服施用,则可以将第一种和第二种(或第二种和第三种)药物配制成单一的口服制剂(例如,丸剂、片剂、胶囊、粉剂、液体混悬剂等)。
在另一个方面中,本发明提供了一种新型药物组合物,所述药物组合物包含:
(i.)治疗有效量的促生长激素分泌素(GHS);
(ii.)治疗有效量的第二种药物选自:二肽基肽酶-4(DPP4)拮抗剂、噻唑烷二酮、葡萄糖钠转运蛋白2(SGLT2)拮抗剂和二甲双胍;和,
(iii.)药学上可接受的运载体;
其中所述组合物用于治疗NAFLD和/或NASH。
在另一个方面中,组合物可以口服或胃肠外施用。
在另一个方面中,第二种药物是DPP4拮抗剂。
在另一个方面中,GHS是伊布莫仑且第二种药物是西格列汀。
在另一个方面中,第二种药物是噻唑烷二酮。
在另一个方面中,GHS是伊布莫仑且第二种药物是吡格列酮。
在另一个方面中,第二种药物是SGLT2拮抗剂。
在另一个方面中,第二种药物是二甲双胍。
在另一个方面中,GHS是伊布莫仑且第二种药物是二甲双胍。
在另一个方面中,本发明提供了一种新型三药组合物,所述组合物包含:
(i.)治疗有效量的促生长激素分泌素(GHS);和,
(ii.)治疗有效量的选自下述的第二种药物:二肽基肽酶-4(DPP4)拮抗剂、噻唑烷二酮和葡萄糖钠转运蛋白2(SGLT2)拮抗剂;
(iii.)治疗有效量的第三种药物,其是二甲双胍;
(iv.)药学上可接受的运载体;
其中所述组合物用于治疗NAFLD和/或NASH。
在另一个方面中,三药组合物是口服或胃肠外施用。
在另一个方面中,在三重组合中,第二种药物是DPP4拮抗剂。
在另一个方面中,在三重组合中,GHS是伊布莫仑且第二种药物是西格列汀。
在另一个方面中,在三重组合中,第二种药物是噻唑烷二酮。
在另一个方面中,在三重组合中,GHS是伊布莫仑且第二种药物是吡格列酮。
在另一个方面中,在三重组合中,第二种药物是SGLT2拮抗剂。
在另一个方面中,本发明提供了一种新型包装试剂盒,所述试剂盒包含:
(i.)至少一个第一隔室,其包含:治疗有效量的促生长激素分泌素(GHS)和药学上可接受的运载体;
(ii.)至少一个第二隔室,其包含:治疗有效量的选自下述的第二种药物:二肽基肽酶-4(DPP4)拮抗剂、噻唑烷二酮、葡萄糖钠转运蛋白2(SGLT2)拮抗剂和二甲双胍以及药学上可接受的运载体。
在另一个方面中,本发明提供了一种新型包装试剂盒,所述试剂盒包含:
(i.)至少一个第一隔室,其包含:治疗有效量的促生长激素分泌素(GHS)和药学上可接受的运载体;
(ii.)至少一个第二隔室,其包含:治疗有效量的选自下述的第二种药物:二肽基肽酶-4(DPP4)拮抗剂、噻唑烷二酮和葡萄糖钠转运蛋白2(SGLT2)拮抗剂以及药学上可接受的运载体;
(iii.)至少一个第三隔室,其包含:治疗有效量的第三种药物,其是二甲双胍,以及药学上可接受的运载体。
在另一个方面中,本发明提供了第一种药物和第二种药物在制备用于治疗本文所述适应证的药物中的用途。
在另一个方面中,本发明提供了第一种药物、第二种药物和第三种药物在制备用于治疗本文所述适应证的药物中的用途。
在另一个方面中,本发明提供了一种包含第一药物和第二药物的新型组合物在制备用于治疗本文所述适应证的药物中的用途。
在另一个方面中,本发明提供了一种包含第一药物、第二药物和第三药物的新型组合物在制备用于治疗本文所述适应证的药物中的用途。
本申请引用的大多数已获批的药物均具有特定的药用盐(例如,伊布莫仑是甲磺酸盐,伊布莫仑甲磺酸盐)。虽然已获批的盐是上文引用的盐,但其他药学上可接受的盐也被认为是当前要求保护的发明的一部分。
在不脱离本发明的精神或实质属性的情况下,本发明可以以其他特定形式来体现。本发明包括本文所述方面的所有组合。应当理解的是,本发明的任何和所有实施方式可以与任何其他一个或多个实施方式结合起来描述另外的实施方式。还应理解的是,实施方式的每个单独的要素旨在被单独地视为其自己的独立实施方式。此外,实施方式的任何要素旨在与来自任何实施方式的任何和所有其他要素组合以描述另外的实施方式。
定义
“治疗(treating)”或“治疗(treatment)”涵盖哺乳动物疾病状态的治疗,并且包括:(a)防止在哺乳动物中发生疾病状态,特别是当这种哺乳动物易患疾病状态但尚未被诊断为患有该疾病时;(b)抑制疾病状态,例如阻止其发展;和/或(c)缓解疾病状态,例如使疾病状态消退,直至达到所需的终点。治疗还包括改善疾病的症状(例如,减轻疼痛或不适),其中这种改善可以直接影响或可以不直接影响疾病(例如,原因、传播、表达等)。
“药学上可接受的盐”是指所公开化合物的衍生物,其中母体化合物通过制备其酸式或碱式盐而被修饰。药学上可接受的盐的实例包括但不限于碱性残基(如胺)的无机或有机酸的盐;酸性残基(如羧酸)的碱金属或有机盐;等等。药学上可接受的盐包括例如由无毒的无机或有机酸形成的母体化合物的常规无毒盐或季铵盐。例如,此类常规的无毒盐包括但不限于衍生自选自下述的无机和有机酸的那些:1,2-乙二磺酸、2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢盐、碳酸、柠檬酸、乙二胺、乙二磺酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、乙二醇酰水杨酸(glycollyaranilic)、己基间苯二酚、海巴明酸(hydrabamic)、氢溴酸、盐酸、氢碘酸、羟基马来酸、羟基萘甲酸、羟乙磺酸、乳酸、乳糖酸、月桂基磺酸、马来酸、苹果酸、扁桃酸、甲磺酸、萘磺酸(napsylic)、硝酸、草酸、亚甲基双羟萘酸(pamoic)、泛酸、苯乙酸、磷酸、聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、碱式乙酸(subacetic)、琥珀酸、氨基磺酸(sulfamic)、磺胺酸(sulfanilic)、硫酸、鞣酸、酒石酸以及甲苯磺酸。
本发明的药学上可接受的盐可以通过常规化学方法由含有碱性或酸性部分的母体化合物合成。通常,可以通过使这些化合物的游离酸或碱形式与化学计算量的合适的碱或酸在水中或在有机溶剂中或在两者的混合物中反应来制备这些盐;通常可以使用非水介质,如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。适宜的盐的列表可以参见Remington'sPharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA,1990,p 1445,其全部内容通过引用在此并入。
“治疗有效量”包括当单独或组合施用以治疗肥胖、糖尿病、血脂异常、心血管疾病、炎性疾病、肝病、癌症及其组合或合并症或本申请中列出的其他适应证时是有效的本发明化合物的量。“治疗有效量”还包括有效治疗所需适应证的所要求保护的化合物的组合的量。化合物的组合可以是协同组合。例如,Chou和Talalay,Adv.Enzyme Regul.1984,22:27-55所描述的,当化合物联合施用时的效果大于化合物作为单一药剂施用时的叠加作用时,出现协同作用。通常,在次最佳剂量或更低剂量的化合物中最明显地显示出协同作用。与单一组分相比,协同作用可以降低细胞毒性、增强作用或产生一些联用的其他有益作用。
在本发明中,本发明的一种或多种化合物可以以任何常规方式(例如,肠内或胃肠外)施用。施用方法的实例包括口服和透皮。本领域技术人员知晓,本发明化合物的施用途径可以有很大变化。除其他口服施用以外,缓释和/或改良释放的组合物也可能是有利的。其他可接受的途径可以包括注射(例如,静脉内、肌内、皮下和腹腔内);皮下植入物;和,颊部、舌下、局部、直肠、阴道和鼻内施用。还可以使用生物蚀解性、非生物蚀解性、生物降解性和非生物降解性的施用系统。口服制剂的实例包括片剂、包衣片剂、硬明胶胶囊和软明胶胶囊、溶液剂、乳剂、粉剂、颗粒剂和混悬剂。
如果制备片剂形式的固体组合物,则可以将一种或多种活性成分与药物载剂混合,其实例包括二氧化硅、淀粉、乳糖、硬脂酸镁和滑石粉。片剂可以任选地用蔗糖或其他合适的物质包衣,或者可以进行处理以使其具有持续或延迟的活性,以及以使其连续释放预定量的活性成分。例如,可以通过将一种或多种活性成分与稀释剂混合,然后将所得的混合物掺入软胶囊或两片硬胶囊中来获得胶囊剂。举例来说,糖浆剂或酏剂可以含有一种或多种活性成分以及甜味剂(通常是零卡路里的)、防腐剂(例如,对羟基苯甲酸甲酯和/或对羟基苯甲酸丙酯)、调味剂和适当的颜色。例如,水分散性粉剂或颗粒剂可以包含与分散剂或湿润剂或与混悬剂(如聚乙烯吡咯烷酮)混合的一种或多种活性成分,以及甜味剂或矫味剂。直肠施用可以使用栓剂、凝胶或泡沫,栓剂是用在直肠温度下熔化的粘合剂(例如,可可豆脂和/或聚乙二醇)制备的。胃肠外施用可以使用水性混悬剂、等渗盐溶液或注射用无菌溶液进行,其中含有药理学上相容的分散剂或润湿剂(例如,丙二醇和/或聚乙二醇)。还可以任选地与一种或多种运载体或添加剂一起,将一种或多种活性成分配制成微囊或微球。一种或多种活性成分还可以以环糊精(例如α-、β-或γ-环糊精,2-羟丙基-β-环糊精和/或甲基-β-环糊精)的复合物的形式存在。
每天施用的本发明化合物的剂量将因人而异,并且在某种程度上可以取决于所治疗疾病(例如,NAFLD或NASH)的严重程度。本发明化合物的剂量也将根据所施用的一种或多种药物而变化。上文已经提供了本发明化合物剂量的实例,但是其可以基于两种或三种药物的组合的协同作用而变化。
化合物可以在一段时间内以单一剂量或多个较小剂量施用。施用化合物的时间长度因人而异,并且可以持续直至达到所需的结果(即,减少体内脂肪或防止体内脂肪增加)。
通过以下实施例进一步说明本公开内容,这些实施例不应被解释为将本公开内容在范围或精神上限制于本文所述的具体程序。应当理解的是,提供这些实施例是为了说明某些实施方式,因此并不意图限制本公开内容的范围。还应当理解的是,在不脱离本公开内容的精神和/或所附权利要求的范围的前提下,可以向本领域技术人员提出其各种其他实施方式、修改及其等同物。
实施例
实施例1
在本表中提供了本发明口服组合物的实例(仅显示了活性成分)。
实施例2
在本表中提供了本发明口服组合物进一步的实例(仅显示了活性成分):
实施例3
生长激素是一种在垂体腺中产生的激素,有助于调控代谢和生长。一般而言,与不肥胖的个体相比,肥胖个体分泌的生长激素较少。有数据表明,生长激素可能有助于减少肝脏中的脂肪量,也可以减少肝脏中的炎症,这两者都对患有NAFLD的个体有帮助。该拟定研究的目的是研究使用伊布莫仑(也称为伊布莫仑甲磺酸盐,是一种促生长激素分泌素)进行治疗是否将在患有NAFLD的肥胖个体中减少肝脏脂肪以及改善肝脏炎症和瘢痕形成。
研究类型:干预(临床试验)
预计入组:76名参与者
分配:随机
干预模型:平行分配
干预模型说明:前12个月为随机、双盲安慰剂对照阶段,随后为6个月的开放标签阶段,在该6个月期间所有参与者均接受活性药物(伊布莫仑)
设盲:四重(参与者、护理提供者、研究者、结局评估者)
主要目的:治疗
官方标题:促生长激素分泌素改善非酒精性脂肪性肝病和相关的心血管风险分组和干预
结局指标
主要结局指标:
-肝脏脂肪含量[时间范围:从基线到12个月的变化]
-通过氢-核磁共振光谱法测量的肝脏脂肪含量
次要结局指标:
-NAFLD活性评分[时间范围:从基线到12个月的变化]
-来自肝脏活检的NAFLD活性评分(NAS,评分在0-8之间)
-餐后肝脏脂肪从头合成[时间范围:从基线到12个月的变化]
-通过稳定同位素法测量的肝脏脂肪从头合成
-冠状动脉斑块体积[时间范围:从基线到12个月的变化]
通过冠状动脉计算机断层血管造影(CCTA)确定的钙化和非钙化斑块的体积
-非高密度脂蛋白(非-HDL)胆固醇[时间范围:从基线到12个月的变化]
-C-反应蛋白[时间范围:从基线到12个月的变化]
-纤维化评分[时间范围:从基线到12个月的变化]
-来自肝脏活检的纤维化评分
资格标准
参与研究的年龄:18岁至70岁(成人,老年人)
参与研究的性别:全部
接受健康志愿者:否
标准
纳入标准:
-18-70岁的男性和女性
-体重指数(BMI)≥30kg/m2
-肝脂肪变性,通过以下方式确定:a)在基线访视12个月内进行的肝活检为1+级脂肪变性,且体重未降低>10%或未添加治疗脂肪肝的药物,或b)氢-核磁共振光谱法(1H-MRS)测得肝脂肪分数≥5%
-丙型肝炎抗体和乙型肝炎表面抗原为阴性
-对于年龄≥50岁的女性,在基线1年内乳房X光检查为阴性
-如果每天使用维生素E≥400国际单位,则稳定剂量持续≥6个月
排除标准:
-使用终生饮酒史问卷评估为大量饮酒,其定义为:在过去5年中,至少连续3个月,女性每天饮酒>20克,男性每天饮酒>30克
-已知诊断为糖尿病,使用任何抗糖尿病药物(包括噻唑烷二酮或二甲双胍),空腹血糖>126mg/dL,或血红蛋白A1c(HbA1c)≥7%
-对NAFLD/非酒精性脂肪性肝炎进行任何特定的药理学治疗,维生素E除外
-已知肝硬化,Child-Pugh评分≥7,活检时为4期纤维化,或在影像学或检查中发现肝硬化或门脉高压的临床证据。如果在筛选时不知道受试者为肝硬化,但是根据基线肝脏活检结果发现其为肝硬化,则应将该受试者转诊至肝病医生处进行临床护理,并将其排除在进一步的研究之外。
-在基线访视前≤6个月长期全身性使用皮质类固醇
-长期使用熊去氧胆酸(Actigall)()、甲氨蝶呤、胺碘酮或他莫昔芬
-已知诊断为α-1抗胰蛋白酶缺乏症、威尔逊氏病、血色素沉着症或自身免疫性肝炎
-在过去1年内使用过生长激素或生长激素释放激素或GH促分泌素
-在筛选后的2个月内改变降脂或抗高血压方案
-血红蛋白<10.0g/dL或肌酐>1.5mg/dL
-活跃性恶性肿瘤
-对于男性,有前列腺癌病史或前列腺特异性抗原(PSA)>5ng/mL的前列腺恶性肿瘤证据
-经研究者判定为存在属于参与研究禁忌证的严重慢性疾病
-有垂体功能减退、头部辐照或已知影响GH轴的任何其他病史
-使用生理性睾丸激素(男性)或者雌激素或孕激素(女性),除非在进入研究之前已稳定使用一年或更长时间
-常规磁共振成像(MRI)排除标准,如是否存在起搏器或脑动脉瘤夹
-基线前2年内进行减肥手术。允许在基线访视前2年以上进行过减肥手术,只要没有主动减肥(过去6个月内体重减轻<10%)即可
-对于女性,尿妊娠试验(hCG)为阳性,试图妊娠或母乳喂养
-已知对伊布莫仑过敏
-禁用β受体阻滞剂或硝酸甘油(这是冠状动脉造影的一部分)的禁忌证
-大量辐射暴露,包括任何放疗史,或在随机分组前12个月内有以下任何:a)两次以上经皮冠状动脉介入治疗;b)两项以上的心肌灌注研究;3)两次以上计算机断层血管造影
-在随机分组后12个月内积极考虑涉及上述大量放射暴露的程序或治疗
-不愿意或不能遵守给药方案和方案规定的程序
-由于上面未详述的其他原因,研究者认为不适于参与该研究。
实施例4
该拟定研究的目的是研究使用伊布莫仑(也称为伊布莫仑甲磺酸盐,是一种促生长激素分泌素)联合第二种活性成分进行治疗是否将在患有NAFLD的肥胖个体中减少肝脏脂肪以及改善肝脏炎症和瘢痕形成。
分组和干预
结局指标
主要结局指标:
-肝脏脂肪含量[时间范围:从基线到12个月的变化]
-通过氢-核磁共振光谱法测量的肝脏脂肪含量
次要结局指标:
-NAFLD活性评分[时间范围:从基线到12个月的变化]
-来自肝脏活检的NAFLD活性评分(NAS,评分在0-8之间)
-餐后肝脏脂肪从头合成[时间范围:从基线到12个月的变化]
-通过稳定同位素法测量的肝脏脂肪从头合成
-冠状动脉斑块体积[时间范围:从基线到12个月的变化]
通过冠状动脉计算机断层血管造影(CCTA)确定的钙化和非钙化斑块的体积
-非高密度脂蛋白(非-HDL)胆固醇[时间范围:从基线到12个月的变化]
-C-反应蛋白[时间范围:从基线到12个月的变化]
-纤维化评分[时间范围:从基线到12个月的变化]
-来自肝脏活检的纤维化评分
资格标准
参与研究的年龄:18岁至70岁(成人,老年人)
参与研究的性别:全部
接受健康志愿者:否
标准
纳入标准:
-18-70岁的男性和女性
-体重指数(BMI)≥30kg/m2
-肝脂肪变性,通过以下方式确定:a)在基线访视12个月内进行的肝活检为1+级脂肪变性,且体重未降低>10%或未添加治疗脂肪肝的药物,或b)氢-核磁共振光谱法(1H-MRS)测得肝脂肪分数≥5%
-丙型肝炎抗体和乙型肝炎表面抗原为阴性
-对于年龄≥50岁的女性,在基线1年内乳房X光检查为阴性
-如果每天使用维生素E≥400国际单位,则稳定剂量持续≥6个月
排除标准:
-使用终生饮酒史问卷评估为大量饮酒,其定义为:在过去5年中,至少连续3个月,女性每天饮酒>20克,男性每天饮酒>30克
-已知诊断为糖尿病,使用任何抗糖尿病药物(包括噻唑烷二酮或二甲双胍),空腹血糖>126mg/dL,或血红蛋白A1c(HbA1c)≥7%
-对NAFLD/非酒精性脂肪性肝炎进行任何特定的药理学治疗,维生素E除外
-已知肝硬化,Child-Pugh评分≥7,活检时为4期纤维化,或在影像学或检查中发现肝硬化或门脉高压的临床证据。如果在筛选时不知道受试者为肝硬化,但是根据基线肝脏活检结果发现其为肝硬化,则应将该受试者转诊至肝病医生处进行临床护理,并将其排除在进一步的研究之外。
-在基线访视前≤6个月长期全身性使用皮质类固醇
-长期使用熊去氧胆酸(Actigall)、甲氨蝶呤、胺碘酮或他莫昔芬
-已知诊断为α-1抗胰蛋白酶缺乏症、威尔逊氏病、血色素沉着症或自身免疫性肝炎
-在过去1年内使用过生长激素或生长激素释放激素或GH促分泌素
-在筛选后的2个月内改变降脂或抗高血压方案
-血红蛋白<10.0g/dL或肌酐>1.5mg/dL
-活跃性恶性肿瘤
-对于男性,有前列腺癌病史或前列腺特异性抗原(PSA)>5ng/mL的前列腺恶性肿瘤证据
-经研究者判定为存在属于参与研究禁忌证的严重慢性疾病
-有垂体功能减退、头部辐照或已知影响GH轴的任何其他病史
-使用生理性睾丸激素(男性)或者雌激素或孕激素(女性),除非在进入研究之前已稳定使用一年或更长时间
-常规磁共振成像(MRI)排除标准,如是否存在起搏器或脑动脉瘤夹
-基线前2年内进行减肥手术。允许在基线访视前2年以上进行过减肥手术,只要没有主动减肥(过去6个月内体重减轻<10%)即可
-对于女性,尿妊娠试验(hCG)为阳性,试图妊娠或母乳喂养
-服用任何强CYP3A4抑制剂,例如,酮康唑,一些蛋白酶抑制剂(例如,利托那韦(Ritonavir))
-禁用β受体阻滞剂或硝酸甘油(这是冠状动脉造影的一部分)的禁忌证
-大量辐射暴露,包括任何放疗史,或在随机分组前12个月内有以下任何:a)两次以上经皮冠状动脉介入治疗;b)两项以上的心肌灌注研究;3)两次以上计算机断层血管造影
-在随机分组后12个月内积极考虑涉及上述大量放射暴露的程序或治疗
-不愿意或不能遵守给药方案和方案规定的程序
-由于FDA有警告,总体而言,数据表明,使用吡格列酮可能与膀胱癌风险增加有关。因而,在该试验中,有膀胱癌病史或目前患有膀胱癌的患者将不包括在本研究中
-由于上面未详述的其他原因,研究者认为不适于参与该研究。
根据上述指导,本发明的许多修改和变化是可能的。因此,应该理解,在所附权利要求的范围内,本发明可以以如本文具体描述以外的其他方式实施。
Claims (28)
1.一种治疗非酒精性脂肪性肝病(NAFLD)或非酒精性脂肪性肝炎(NASH)的方法,所述方法包括:向需要其的患者施用治疗有效量的促生长激素分泌素(GHS)。
2.根据权利要求1所述的方法,其中所述疾病是NAFLD。
3.根据权利要求1所述的方法,其中所述疾病是NASH。
4.根据权利要求1所述的方法,其中所述GSH是伊布莫仑。
5.根据权利要求4所述的方法,其中治疗有效量的伊布莫仑是25-50mg/天。
6.一种治疗非酒精性脂肪性肝病(NAFLD)或非酒精性脂肪性肝炎(NASH)的方法,所述方法包括向需要其的患者施用下述的步骤:
治疗有效量的促生长激素分泌素(GHS);和
治疗有效量的选自下述的第二种药物:二肽基肽酶-4(DPP4)拮抗剂、胰高血糖素样肽(GLP-1)受体激动剂、噻唑烷二酮、葡萄糖钠转运蛋白2(SGLT2)拮抗剂、二甲双胍和维生素E。
7.根据权利要求6所述的方法,其中所述GHS是伊布莫仑。
8.根据权利要求6所述的方法,其中治疗有效量的伊布莫仑是25-50mg/天。
9.根据权利要求6所述的方法,其中所述第二种药物是DPP4拮抗剂。
10.根据权利要求6所述的方法,其中所述DPP4拮抗剂是西格列汀。
11.根据权利要求6所述的方法,其中所述GHS是伊布莫仑和所述第二种药物西格列汀。
12.根据权利要求6所述的方法,其中所述第二种药物是GLP-1受体激动剂。
13.根据权利要求6所述的方法,其中所述第二种药物是噻唑烷二酮。
14.根据权利要求6所述的方法,其中所述第二种药物是吡格列酮。
15.根据权利要求6所述的方法,其中所述GHS是伊布莫仑和所述第二种药物是吡格列酮。
16.根据权利要求6所述的方法,其中所述第二种药物是SGLT2拮抗剂。
17.根据权利要求6所述的方法,其中所述第二种药物是二甲双胍。
18.根据权利要求6所述的方法,其中所述GHS是伊布莫仑和所述第二种药物是二甲双胍。
19.一种治疗NAFLD或NASH的方法,所述方法包括向需要其的患者施用:
a治疗有效量的促生长激素分泌素(GHS);
b治疗有效量的选自下述的第二种药物:二肽基肽酶-4(DPP4)拮抗剂、胰高血糖素样肽(GLP-1)受体激动剂、噻唑烷二酮和葡萄糖钠转运蛋白2(SGLT2)拮抗剂;和
c治疗有效量的第三种药物,其是二甲双胍。
20.根据权利要求19所述的方法,其中治疗有效量的伊布莫仑是25-50mg/天。
21.根据权利要求19所述的方法,其中所述GHS是伊布莫仑和所述第二种药物是西格列汀。
22.根据权利要求19所述的方法,其中所述GHS是伊布莫仑和所述第二种药物是吡格列酮。
23.一种药物组合物,所述药物组合物包含:
a治疗有效量的GHS;
b治疗有效量的选自下述的第二种药物:DPP4拮抗剂、噻唑烷二酮、SGLT2拮抗剂、二甲双胍和维生素E;和,
c药学上可接受的运载体;
其中所述组合物用于治疗NAFLD和/或NASH。
24.根据权利要求23所述的药物组合物,其中所述GHS是伊布莫仑。
25.根据权利要求23所述的药物组合物,其中治疗有效量的伊布莫仑是25-50mg/天。
26.一种药物组合物,所述药物组合物包含:
a治疗有效量的GHS;
b治疗有效量的选自下述的第二种药物:DPP4拮抗剂、噻唑烷二酮和SGLT2拮抗剂;
c治疗有效量的第三种药物,其是二甲双胍;和,
d药学上可接受的运载体;
其中所述组合物用于治疗NAFLD和/或NASH。
27.根据权利要求26所述的药物组合物,其中所述GHS是伊布莫仑。
28.根据权利要求26所述的药物组合物,其中治疗有效量的伊布莫仑是25-50mg/天。
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