CN106102734B - 肝内胆汁淤积性疾病的治疗 - Google Patents
肝内胆汁淤积性疾病的治疗 Download PDFInfo
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Abstract
通过用MBX‑8025或MBX‑8025盐的疗法治疗肝内胆汁淤积性疾病。
Description
技术领域
本发明涉及肝内胆汁淤积性疾病的治疗。
背景技术
肝内胆汁淤积性疾病
胆汁淤积症是胆汁从肝脏向十二指肠的流动减缓或阻塞的病症。胆汁淤积症可以方便地分为两种类型：肝内胆汁淤积症，在肝脏中，胆汁形成受到诸如各种疾病、延长的静脉营养或作为某些药物(如某些抗生素)的副作用的病症干扰；和肝外胆汁淤积症，发生于肝脏之外，通常情况下，胆汁的流动受到胆管机械性部分或完全封闭而阻碍，如受到胆管肿瘤、囊肿、胆管结石、狭窄或对胆管的压力；但是原发性硬化性胆管炎(PSC)可能是肝内或肝外。胆汁淤积的常见症状包括疲劳、瘙痒症(发痒)、黄疸病和黄色瘤(皮肤下富胆固醇物质的沉积)。胆汁淤积症的影响是深远的而普遍的，导致肝疾病与全身性疾病、肝功能衰竭恶化以及需要肝移植。
肝内胆汁淤积性疾病，按照频率递减顺序，包括原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、进行性家族性肝内胆汁淤积症(PFIC)和Alagille综合征(AS)。
PBC是一种通过肝脏小胆管的缓慢进行性破坏标记的肝脏自身免疫性疾病，而在疾病的早期会影响小叶内管。当这些导管受损坏时，胆汁在肝脏内累积(胆汁淤积症)并随着时间的推移而损害组织，这可能会导致疤痕形成、纤维化和肝硬化。最近的研究表明，这可能在3000-4000人中会影响到1人，其中性别比为女性:男性至少为9:1。对于PBC还不曾治愈过，而肝移植往往就成为必要；但药物如降低胆汁淤积症并改善肝功能的熊去氧胆酸(ursodeoxycholic acid，UDCA，熊二醇(ursodiol))、吸收胆汁酸的考来烯胺、针对疲劳的莫达非尼、脂溶性维生素(维生素A、D、E和K，由于胆汁流量减少使得难以吸收这些维生素)可能会减慢进展，而允许正常的寿命和生活质量。UDCA是在美国批准用于治疗PBC的唯一药物。据日本研究人员报道，向UDCA中加入苯扎贝特、过氧化物酶体增殖物激活的受体α(PPARα)和孕烷X受体激动剂有益于治疗UDCA单一治疗难治的患者，改善血清胆酶、胆固醇(C)和甘油三酯(TG)。
PSC是一种慢性胆汁淤积性肝病疾病，特征在于肝内或肝外胆管炎症和纤维化，最终导致肝硬化。据信炎症的根本原因是自身免疫性；而患有PSC的患者约四分之三患有炎性肠道疾病(通常是溃疡性结肠炎)，但这对于流行性(一般报道为10,000人中约1人)和性别比(一般报道为以男性为主)依据国家而报道不一。标准治疗包括UDCA，这已证明降低患有PSC的人中升高的肝酶数字，但并没有改善肝脏存活率或整体存活率；并且还包括止痒剂、消胆胺、脂溶性维生素和抗生素来治疗感染(细菌性胆管炎)。在2009年报道的一份研究中，长期大剂量UDCA疗法与PSC中血清肝功能的改善有关，但并不能提高存活率，并与严重不良事件发生率较高有关。肝移植是唯一行之有效的长期治疗。
PFIC是指与肝内胆汁淤积症相关的一组三种类型的常染色体隐性遗传性疾病：家族性肝内胆汁淤积症1(PFIC-1)，胆汁盐输出泵缺乏(PFIC-2)和多药耐药性蛋白3缺乏(PFIC-3)。它们具有1/50,000-1/100,000的组合发病率。疾病的发病通常在2岁前，其中PFIC-3通常最早出现，但已确诊患有PFIC的患者甚至进入青春期。患者通常表现出胆汁淤积症、黄疸以及未能茁壮成长；并且以强烈的瘙痒为特征。可能会出现脂肪吸收不良和脂溶性维生素缺乏。生化标志物包括在PFIC-1和-2中正常的γ-谷氨酰转肽酶(GGT)，但是在PFIC-3中GGT明显升高；而同时血清胆汁酸水平大大升高；但是血清胆固醇水平通常不升高，正如通常在胆汁淤积症中所见，因为这种疾病是由于相对于与胆细胞相关的解剖问题的转运子所致。该疾病在无肝移植情况下通常是进行性的，导致肝功能衰竭和童年死亡；并且可能在PFIC-2中于非常早的年龄发展肝细胞癌。具有UDCA的药物是常见的；在PFIC-1中补充脂溶性维生素、消胆胺和胰酶。
AS，也称为Alagille-Watson综合征，综合征性胆管缺乏和肝动脉(动脉-肝，arteriohepatic)发育不良，是一种与肝脏、心脏、眼睛和骨骼异常以及特征性面部特征相关的常染色体显性遗传疾病；发病率为约1/100,000。肝脏异常是肝脏内变窄并且畸形的胆管；而这些会导致胆汁流的梗阻，引起肝硬化(疤痕形成)。AS主要是由位于20号染色体上的Jagged1基因的变化所致。在3％-5％的病例中，整个基因从20号染色体的一个拷贝中缺失(丢失)；在其余的病例中，在Jagged1DNA序列中存在变化或突变。在极少数的病例中，不到1％，在另一个基因Notch2中的变化导致AS。在约三分之一的病例中，突变是遗传的；在约三分之二的病例中，突变在这种病例中是新发的。对于AS还没有治愈的，尽管肝脏疾病的严重程度通常在3-5岁龄时达到峰值而7-8岁龄时通常缓解。在一些人中，肝脏疾病会进展至终末期肝脏疾病，并可能需要肝移植(AS患者约15％需要肝移植)。许多不同的药物(例如，熊去氧胆酸(UDCA，熊二醇))已被用于改善胆汁流动和减少瘙痒，并且许多患者被给予了高剂量的脂溶性维生素。
碱性磷酸酶(ALP)和GGT是胆汁淤积症的关键标志物。尽管他们中的一个单独的升高并不指示胆汁淤积症，并且对于确认会需要其他参数，但是ALP和GGT都升高是胆汁淤积症的指征；并且这两者的降低指示胆汁淤积症的改善。因此ALP和GGT水平起到肝内胆汁淤积性疾病中存在的胆道病理生理学存在的生物化学标志物的作用，而ALP水平已用作肝内疾病如PBC的临床研究中的原发性结果标志物。
肝内胆汁淤积性疾病的治疗
如上所提及的，UDCA因为在降低胆汁淤积症和改善肝功能方面的功效而是肝内胆汁淤积性疾病的一种常见治疗。然而，2012年UDCA在PBC中的Cochrane综述发现，虽然UDCA证明能够降低肝脏病理学、黄疸和腹水的生物标志物，但在医学文献中没有UDCA对死亡率或肝移植的任何益处的证据，而同时其使用却与体重增加和成本相关。
奥贝胆酸(6α-乙基鹅去氧胆酸)，一种半合成胆汁酸类似物，是一种高度有效的法尼酯X受体激动剂，已经完成了与熊去氧胆酸组合用于PBC的2期研究，并且正处于关于PBC中脂蛋白代谢的单独第二个2期研究和PBC中的3期安慰剂对照研究中的研究之下。然而，对于许多肝内胆汁淤积性疾病患者唯一的长期治疗是肝移植。
合乎需要的是开发出针对肝内胆汁淤积性疾病的药物治疗。
MBX-8025
MBX-8025是下式的化合物
MBX-8025具有的化学名为(R)-2-(4-((2-乙氧基-3-(4-(三氟甲基)苯氧基)丙基)硫基)-2-甲基苯氧基)乙酸[IUPAC名由CHEMDRAW ULTRA 12.0生成]。MBX-8025及其合成、制剂和用途公开于，例如，美国专利No.7301050(表1中的化合物15，实施例M，权利要求49)，美国专利No.7635718(表1中的化合物15，实施例M)和美国专利No.8106095(表1中的化合物15，实施例M，权利要求14)中。MBX-8025的赖氨酸(L-赖氨酸)盐及其相关化合物公开于美国专利No.7709682(整个实施例中的MBX-8025L-赖氨酸盐，要求授权保护的晶体形式)中。
MBX-8025是过氧化物酶体增殖物激活受体-δ(PPARδ)的一种口服活性的强效(2nM)激动剂，它是特异性的(相比于PPARα和过氧化物酶体增殖物激活受体-γ受体>600倍和>2500倍)。PPARδ激活刺激脂肪酸的氧化和利用，改善血脂和脂蛋白代谢、葡萄糖的利用以及线粒体呼吸，并保留干细胞的动态平衡。根据美国专利No.7301050，PPARδ激动剂，如MBX-8025，被建议用于治疗PPARδ介导的病症，包括“糖尿病、心血管疾病、代谢性X综合征、高胆固醇血症、低高密度脂蛋白(HDL)-胆固醇血症、高低密度蛋白(LDL)-胆固醇血症、血脂异常、动脉粥样硬化和肥胖症”，血脂异常据说包括高甘油三酯血症和混合性高脂血症。
已由Bays等“A Novel Peroxisome Proliferator Receptor-δAgonist:Lipidand Other Metabolic Effects in Dyslipidemic Overweight Patients Treated withand without Atorvastatin”，J.Clin.Endocrin.Metab.，96(9)，2889-2897(2011)和Choi等“Effects of the PPAR-δagonist MBX-8025on atherogenic dyslipidemia”，Atherosclerosis，220，470-476(2012)报道了MBX-8025L-赖氨酸二水合物盐在混合性血脂异常中的2期研究(6组，30受试者/组：每日一次安慰剂，阿托伐他汀(ATV)20mg，或MBX-8025L-赖氨酸二水合物盐50或100mg(以游离酸计算)单独胶囊剂或与ATV 20mg组合，持续8周)。与安慰剂相比，单独MBX-8025和与ATV组合显著(P<0.05)降低20％-38％的载脂蛋白B-100、18％-43％的LDL、26％-30％的甘油三酯(TG)、18％-41％的非HDL-C、16％-28％的游离脂肪酸、43％-72％的高敏C反应性蛋白；它提高了1％-12％的HDL并还降低了代谢综合征患者的数目和小LDL粒子的数量优势。相比于ATV的25％降低，MBX-8025降低了40％-48％的小/非常小LDL粒子；并且相比于ATV的30％降低，MBX-8025提高了34％-44％的大LDL颗粒。相比于对照组中仅仅4％和ATV组中的6％，MBX-8025显著降低了32％-43％的ALP；并且相比于对照组中仅仅3％和ATV组中的2％的降低，MBX-8025显著降低了24％-28％的GGT。因此MBX-8025校正了混合性血脂异常中的所有三个血脂异常-降低了TG和LDL并升高了HDL，选择性地耗尽了小的致密的LDL粒子(92％)、减少了心血管炎症并改善了其他代谢参数，包括降低血清转氨酶、增加胰岛素敏感性(降低稳态模型评价-胰岛素抵抗性、空腹血糖以及胰岛素)、降低了GGT和ALP，显著(>2倍)降低了满足代谢综合征标准的受试者百分比，并趋向于降低腰围和增加瘦体重。MBX-8025是安全的并通常耐受性良好，而且也降低肝酶水平。正如美国专利申请公开No.2010-0152295中解释说明的，MBX-8025将LDL粒径模式I(25.75nm-26.34nm的优势LDL粒径)转换至模式A(大于26.34nm的优势LDL粒径)；并从模式B(小于25.75nm的优势LDL粒径)转换至模式I或A，其中LDL粒径是通过梯度凝胶电泳测定的。
发明内容
本发明是肝内胆汁淤积性疾病的治疗方法，包括采用MBX-8025或MBX-8025盐的疗法。
因为MBX-8025降低肝内胆汁淤积性疾病中升高的碱性磷酸酶和γ谷氨酰转肽酶，则其使用会导致胆汁淤积降低并为提供针对这些疾病的有效治疗(其他药物，如氯贝特(也降低高脂血症患者中的ALP和GGT)已知能够降低肝内胆汁淤积性疾病中的胆汁淤积)。
在各个方面中，本发明是：
适用于治疗肝内胆汁淤积性疾病的MBX-8025或MBX-8025盐；
MBX-8025或MBX-8025盐用于治疗肝内胆汁淤积性疾病的用途，或在制备用于治疗肝内胆汁淤积性疾病的药物中的用途；
包含MBX-8025或MBX-8025盐用于治疗肝内胆汁淤积性疾病的药物组合物；
包含含有MBX-8025或MBX-8025盐用于治疗肝内胆汁淤积性疾病的组合物的试剂盒；和
通过给予MBX-8025或MBX-8025盐治疗肝内胆汁淤积性疾病的方法。
本发明的优选实施方式的特征在于所提交的本申请的本说明书和权利要求1-14的特征。
具体实施方式
定义
“肝内胆汁淤积性疾病”及其治疗描述于段落[0002]-[0012]中。
MBX-8025或MBX-8025盐的“治疗有效量”是指当给予于人用于治疗肝内胆汁淤积性疾病时足以对肝内胆汁淤积性疾病发挥治疗作用的用量。人的肝内胆汁淤积性疾病的“治疗”或“处置”包括以下一种或多种：
(1)预防或降低发展肝内胆汁淤积性疾病的风险，即，在可能易感于肝内胆汁淤积性疾病但还未经历或表现出肝内胆汁淤积性疾病的症状的受试者中，不会发展肝内胆汁淤积性疾病的临床症状(即，预防)；
(2)抑制肝内胆汁淤积性疾病，即，遏阻或降低肝内胆汁淤积性疾病或其临床症状的发展；和
(3)缓解肝内胆汁淤积性疾病，即，引起肝内胆汁淤积性疾病的复原、反转或改善，或降低其临床症状的数量、频率、持续时间或严重程度。
特定受试者的治疗有效量根据要治疗的受试者的年龄、健康和身体状况，肝内胆汁淤积性疾病及其程度，医学状况的评价和其他相关因素而变化。预期的是治疗有效量将落入通过常规试验能够确定的相对较宽的范围内。
“MBX-8025”描述于段落[0014]-[0017]中。
MBX-8025的盐(例如，药学上可接受的盐)包括于本发明中并适用于本申请中描述的组合物、方法和用途中。优选用药学上可接受的酸形成这些盐。参见，例如，Stahl和Wermuth合编“药用盐手册(Handbook of Pharmaceutically Acceptable Salts)”，VerlagHelvetica Chimica Acta，Zürich，Switzerland，关于药用盐、其选择、制备和用途的广泛讨论。除非上下文另有要求，提及MBX-8025既指化合物也指其盐。
因为MBX-8025包含羧基基团，当存在的酸性质子与无机或有机碱反应时，它可以形成盐。通常情况下，用过量的碱性试剂，如含有合适阳离子的氢氧化物、碳酸盐或醇盐处理MBX-8025。阳离子如Na+、K+、Ca2+、Mg2+和NH4 +是存在于药用盐中的阳离子的实例。因此，合适的无机碱包括氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。还可以使用有机碱制备盐，如伯胺、仲胺和叔胺的盐，取代胺包括天然存在的取代胺和环胺，包括异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二甲氨基乙醇、氨丁三醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、乙二胺、葡糖胺、N-烷基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶等。正如段落[0017]中指出，MBX-8025目前配制为其L-赖氨酸二水合物盐；并且MBX-8025也在临床试验中以其钙盐进行了研究。
“包括”或“含有”及其语法变体是包含性而非限制的词语并意味着表示所记载的组分、基团、步骤等的存在，但不排除存在或添加其他组分、基团、步骤等。因此，“包括”并不意味着“由...组成”，“基本上由…组成”，或“仅由…组成”；并且，例如，“包括”化合物的制剂必须包含该化合物，但也可含有其他活性成分和/或赋形剂。
制剂和给予
可以通过适合于所治疗的受试者和受试者病症的性质的任何途径给予MBX-8025。给予途径包括注射给予，包括静脉内、腹膜内、肌内和皮下注射，经粘膜或透皮递送给予，通过局部施用，鼻喷雾剂，栓剂等或可以口服给予。制剂可以可选地是脂质体制剂，乳剂，经设计跨粘膜给予药物的制剂或经皮制剂。对于这些给予方法中的每一种的合适制剂可以，例如，查阅“雷明顿：药学的科学和实践(Remington:The Science and Practice ofPharmacy)”，第20版，Gennaro编辑，Lippincott Williams&Wilkins，Philadelphia，Pa.，U.S.A。因为MBX-8025可以口服利用，典型的制剂将是口服的，并且典型的剂型将是口服给予的片剂或胶囊剂。正如段落[0017]中，MBX-8025已经配制成胶囊用于临床试验。
取决于预期的给予模式，药物组合物可以以固体、半固体或液体剂型的形式，优选以适于精确剂量的单次给予的单位剂量形式。除了有效量的MBX-8025之外，组合物可以含有合适的药用赋形剂，包括有助于将活性化合物加工成可药用的制剂的助剂。“药用赋形剂”是指赋形剂或赋形剂的混合物，其不干扰活性化合物生物活性的有效性并且没有毒性或要不然不会有害于其给予的受试者的赋形剂或赋形剂混合物。
对于固体组合物，常规的赋形剂包括，例如，药用级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖、碳酸镁等。例如，可以通过将本文中的活性化合物和可选的药用助剂溶解、分散等于水或水性赋形剂，如例如水、盐水、葡萄糖水溶液等中以形成溶液或悬浮液而制备液体药理学可给予的组合物。如果需要，要给予的药物组合物也可以包含少量无毒的辅助赋形剂如润湿剂或乳化剂、pH缓冲剂等，例如，乙酸钠、脱水山梨醇单月桂酸酯、三乙醇胺乙酸钠、油酸三乙醇胺等。
对于口服给予，组合物将通常采取片剂或胶囊的形式；或者，特别是适用于儿科用途，它可以是水性或非水性溶液，悬浮液或糖浆。片剂和胶囊是优选的口服给予形式。口服使用的片剂和胶囊剂通常将包括一种或更常用的赋形剂如乳糖和玉米淀粉。也通常添加润滑剂，如硬脂酸镁。当使用液体悬浮液时，活性剂可以与乳化和悬浮赋形剂组合。如果需要，调味剂、着色剂和/或甜味剂也可以加入。引入口服制剂中的其他可选的赋形剂包括防腐剂、悬浮剂、增稠剂等。
通常情况下，MBX-8025的药物组合物，或包含MBX-8025的组合物的试剂盒，包装于具有标签或说明书或这二者的容器内，标签或说明书指示药物组合物或试剂盒在肝内胆汁淤积性疾病的治疗中的用法。
对于患有肝内胆汁淤积性疾病的成年受试者，用于口服剂量的MBX-8025(以游离酸计算)的合适用量会是20-200mg/天，优选50-100mg/天，这取决于疾病和疾病的阶段以及各种因素如肝和肾功能。即，对于疾病如PSC和PBC中的成人口服给药，MBX-8025的合适用量将类似于临床试验中使用的量。对于疾病如AS和PFIC中的儿童受试者将会作出剂量向上述外范围下端的适当降低，这取决于这些其他因素如年龄和体重。
治疗肝内胆汁淤积性疾病的领域中的普通技术人员无需过度实验并根据个人的知识及本申请的公开内容将能够确定MBX-8025或MBX-8025盐用于具体疾病、疾病阶段以及患者的治疗有效量以达到治疗有效量。
实施例
用剂量为50、100、150或200mg/天的MBX-8025治疗患有肝内胆汁淤积性疾病如PBC的成人受试者。允许受试者其通常的其他药物，包括UDCA。在研究之前，并且在研究期间以一定间隔，如在研究期间每4周和MBX-8025疗法的最后剂量之后4周，针对安全性和药效动力学评价评估受试者。每次访视时，在12小时的禁食之后，抽血和采集尿液；并实施标准代谢组、全血细胞计数和标准尿检。针对TC、HDL-C、TG、VLDL-C、LDL-C和载脂蛋白B，针对肝功能标志物如总碱性磷酸酶和骨特异性碱性磷酸酶，针对γ-谷氨酰转肽酶以及针对总的和结合的胆红素分析血液。受试者还保持健康日志，这在每次访问时进行审查。受试者在其疾病方面表现出剂量相关的改善，正如由例如ALP和GGT的下降所示出的。
Claims (11)
1.一种化合物在制备用于治疗肝内胆汁淤积性疾病的药物中的应用，所述化合物是(R)-2-(4-((2-乙氧基-3-(4-(三氟甲基)苯氧基)丙基)硫基)-2-甲基苯氧基)乙酸或其盐。
2.根据权利要求1所述的应用，其中，所述化合物是(R)-2-(4-((2-乙氧基-3-(4-(三氟甲基)苯氧基)丙基)硫基)-2-甲基苯氧基)乙酸L-赖氨酸二水合物。
3.根据权利要求1所述的应用，其中，口服给予所述化合物。
4.根据权利要求1所述的应用，其中，当所述化合物的剂量被计算为(R)-2-(4-((2-乙氧基-3-(4-(三氟甲基)苯氧基)丙基)硫基)-2-甲基苯氧基)乙酸时，所述化合物的所述剂量为20-200mg/天。
5.根据权利要求4所述的应用，其中，当所述化合物的剂量被计算为(R)-2-(4-((2-乙氧基-3-(4-(三氟甲基)苯氧基)丙基)硫基)-2-甲基苯氧基)乙酸时，所述化合物的所述剂量为50-100mg/天。
6.根据权利要求1所述的应用，其中，按照1次/天给予所述化合物。
7.根据权利要求1所述的应用，其中所述肝内胆汁淤积性疾病是原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性家族性肝内胆汁淤积症或Alagille综合征。
8.根据权利要求7所述的应用，其中所述肝内胆汁淤积性疾病是原发性胆汁性肝硬化。
9.根据权利要求7所述的应用，其中所述肝内胆汁淤积性疾病是原发性硬化性胆管炎。
10.根据权利要求7所述的应用，其中所述肝内胆汁淤积性疾病是进行性家族性肝内胆汁淤积症。
11.根据权利要求7所述的应用，其中所述肝内胆汁淤积性疾病是Alagille综合征。
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