CN101208345A - (s)-n-甲基纳曲酮、其合成方法以及其药物用途 - Google Patents
(s)-n-甲基纳曲酮、其合成方法以及其药物用途 Download PDFInfo
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- CN101208345A CN101208345A CNA200680022964XA CN200680022964A CN101208345A CN 101208345 A CN101208345 A CN 101208345A CN A200680022964X A CNA200680022964X A CN A200680022964XA CN 200680022964 A CN200680022964 A CN 200680022964A CN 101208345 A CN101208345 A CN 101208345A
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Abstract
本发明涉及S-MNTX、制备S-MNTX的方法、含有S-MNTX的药物制剂和它们的使用方法。
Description
技术领域
本发明涉及(S)-N-甲基纳曲酮(S-MNTX)、用于制备S-MNTX的立体选择性合成方法、含有S-MNTX的药物制剂和它们的使用方法。
背景技术
甲基纳曲酮(MNTX)是纯阿片样物质拮抗剂纳曲酮的季衍生物。其作为盐存在。文献中用于MNTX溴化物盐的名称包括:甲基纳曲酮溴化物、N-甲基纳曲酮溴化物、甲溴纳曲酮、纳曲酮甲基溴化物、MRZ2663BR。如美国专利4,176,186中所述,在70年代中期由Goldberg等首次报道了MNTX。认为将甲基基团加到环氮中形成带电化合物,所述带电化合物与纳曲酮相比具有更大的极性和更小的脂可溶性。MNTX的这种特征防止其穿过人的血-脑屏障。因此,MNTX在外周而不是中枢神经体系发挥其作用,具有不与阿片样物质对中枢神经体系的镇痛作用发生对抗的优点。
MNTX是手性分子,并且季氮可以是R或S构型(见图1)。不知道不同的MNTX立体异构体是否表现出不同的生物学和化学特性。文献中描述的MNTX的所有报道的功能显示MNTX是外周阿片样物质拮抗剂。一些这样的拮抗剂功能记载于美国专利4,176,186、4,719,215、4,861,781、5,102,887、5,972,954、6,274,591、6,559,158和6,608,075,以及美国专利申请10/163,482(2003/0022909A1)、10/821,811(20040266806)、10/821,813(20040259899)和10/821,809(20050004155)中。这些用途包括降低阿片样物质的副作用而不降低阿片样物质的镇痛作用。这样的副作用包括恶心、呕吐、烦躁不安、瘙痒、尿潴留、肠蠕动缓慢、便秘、胃蠕动缓慢、延迟的胃排空和免疫抑制。文献中公开了MNTX不但降低源自阿片样物质镇痛治疗的副作用,而且降低由内源性阿片样物质单独或与外源性阿片样物质联合治疗所介导的副作用。这样的副作用包括抑制胃肠蠕动、手术后胃肠功能紊乱、特发性便秘和其它包括但不限于上述那些病症的这样的病症。然而,从文献中不清楚这些研究中所用的MNTX是否是R和S立体异构体的混合物或单一的立体异构体。
文献表明化合物分离的立体异构体有时可能具有相对的物理和功能特性,尽管在任何特定情况下这是否是事实是不可预期的。右甲吗喃是咳嗽抑制剂,而其对映体左甲吗喃是强效的麻醉剂。R,R-哌甲酯是治疗注意缺陷多动障碍(ADHD)的药物,而其对映体S,S-哌甲酯是抗抑郁剂。S-氟西汀能有效抗偏头痛,而其对映体R-氟西汀用于治疗抑郁。西酞普兰的S对映体是用于治疗抑郁的治疗活性异构体。R对映体是无活性的。奥美拉唑的S对映体比R对映体更有效用于治疗胃灼热。
Bianchetti等(1983Life Science 33(Sup I):415-418)研究了三对季麻醉拮抗剂非对映异构体及其母体叔胺、左洛啡烷、纳洛芬和纳洛酮,以了解有关手性氮的构型是怎样影响体外和体内活性的。已经发现活性相当大地根据季衍生物是如何制备的而变化。在每个系列中,仅通过N-烯丙基-取代的叔胺的甲基化得到的非对映异构体(称为“N-甲基非对映异构体”)在替代来自大鼠脑膜的3H-纳曲酮中是有效的,并在豚鼠回肠中用作吗啡拮抗剂。相反地,通过N-甲基取代的叔胺与烯丙基卤反应得到的非对映异构体(称为“N-烯丙基非对映异构体”)不替代3H-纳曲酮,并且在豚鼠回肠中具有可忽略的拮抗剂活性和轻微的激动剂作用。体内结果通常与体外的那些一致。因此仅仅是“N-甲基”而不是“N-烯丙基非对映异构体”抑制吗啡诱导的大鼠便秘并起到拮抗剂的作用。作者声明通过1H和13C核磁共振(NMR)分析,制备的材料表现为是纯的,但是这些方法是不精确的。作者引用了文献参考用于纳洛芬的“N-甲基非对映异构体”的R构型的归属,没有提出左洛啡烷和纳洛酮非对映异构体的归属。推断这些非对映异构体的构型将是有风险的(RJ.Kobylecki等,J.Med.Chem.25,1278-1280,1982)。
Goldberg等人的美国专利4,176,186和更最近的Cantrell等人的WO2004/043964 A2描述了MNTX合成的方案。二者都描述了通过用甲基化剂季铵化叔N-取代的吗啡喃生物碱来合成MNTX。关于由合成产生的立体异构体,Goldberg等人和Cantrell等人都未提及。因为基于现有技术不能确定立体化学,所以作者谨慎地未提及立体化学。如其它反应参数例如温度和压力一样,纳曲酮中的环丙基甲基侧链不同于现有技术的侧链并且可能影响了MNTX合成中的立体化学产物。基于各自中所述的合成方法,不知道由此产生的MNTX是否是R、S构型或两种构型的混合物。
文献中没有描述纯形式的S-MNTX以及制备纯S-MNTX的方法。在不存在纯S-MNTX作为标准的情况下,研究者将不能确定性地表征和区分Goldberg等人或Cantrell等人合成得到的立体异构体。
发明内容
现在已经制备出高纯度的S-MNTX,所述S-MNTX允许在色谱中相对于(R)-N-甲基纳曲酮(R-MNTX)来表征其相对保留时间。发现纯S-MNTX具有不同于文献中所报道的MNTX活性的活性。
本发明提供高纯度的S-MNTX、高纯度的S-MNTX晶体及其中间体、用于制备高纯度的S-MNTX的新方法、分析R-MNTX和S-MNTX混合物中的S-MNTX的方法、区分S-MNTX与R-MNTX的方法、定量S-MNTX的方法、含有其的药物产品和这些物质的相关用途。
本发明提供S-MNTX及其盐。得到S-MNTX的方案是现有技术不可预期的。此外,已令人惊讶地发现S-MNTX具有阿片样物质激动剂活性。
根据本发明的一个方面,提供组合物。所述组合物是下式I的关于氮为S构型的分离的化合物:
其中X是反离子。
S-MNTX是盐。因此对于本发明的应用,将具有反离子,包括两性离子。更通常,所述反离子是卤离子、硫酸根、磷酸根、硝酸根或带电阴离子有机物质。卤离子包括氟离子、氯离子、碘离子和溴离子。在某些重要的实施方案中,所述卤离子是碘离子,在另外一些重要的实施方案中,所述卤离子是溴离子。在某些实施方案中,所述带电阴离子物质是磺酸根或羧酸根。磺酸根的实例包括甲磺酸根、苯磺酸根(besylate)、甲苯磺酸根、和三氟甲磺酸根。羧酸根的实例包括甲酸根、乙酸根、柠檬酸根和富马酸根。
根据本发明,以分离的形式提供S-MNTX。通过分离,这意味着至少50%纯。在重要的实施方案中,提供75%纯度、90%纯度、95%纯度、98%纯度和甚至99%纯度或以上的S-MNTX。在一个重要的实施方案中,所述S-MNTX是晶体形式。
根据本发明的另一个方面,提供组合物。所述组合物是MNTX,其中存在于组合物中的MNTX大于10%关于氮为S构型。更优选地,存在于组合物中的MNTX大于30%、40%、50%、60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、98.5%、99%、99.5%、99.6%、99.7%、99.8%、以及甚至99.9%关于氮为S构型。在一些实施方案中,没有如通过高效液相色谱(HPLC)测量可检测的R-MNTX。
在一些实施方案中,所述组合物是溶液,在另外一些实施方案中,所述组合物是油,在另外一些实施方案中,所述组合物是霜剂,并且在仍另外的实施方案中,所述组合物是固体或半固体。在一个重要实施方案中,所述组合物是晶体。
根据本发明的另一方面,提供药物制剂。所述药物制剂包含在药学上可接受载体中的上述S-MNTX组合物的任一种。所述药物制剂包含有效量的S-MNTX。在一些实施方案中,组合物中含有很少或不含有可检测的R-MNTX。如果存在,R-MNTX处于使得向对象施用有效量S-MNTX的水平。在一些实施方案中,药物制剂进一步包含除了MNTX以外的治疗剂。在一个实施方案中,所述治疗剂是阿片样物质或阿片样物质激动剂。阿片样物质或阿片样物质激动剂的实例是阿芬他尼、阿尼利定、阿西马朵林(asimadoline)、布马佐辛、burprenorphine、布托啡诺、可待因、地佐辛、二乙酰吗啡(海洛因)、二氢可待因、地芬诺酯、非多托嗪、芬太尼、funaltrexamine、氢可酮、氢吗啡酮、左洛啡烷、左旋乙酰美沙酮、羟甲左吗喃、洛哌丁胺、美吡利啶(哌替啶)、美沙酮、吗啡、吗啡-6-葡糖苷酸、纳布啡、烯丙吗啡、阿片、羟可待酮、羟吗啡酮、镇痛新、哌丙吡胺、丙氧芬、瑞芬太尼、舒芬太尼、替利定、曲美布丁(trimebutine)、曲马多或其组合。在一些实施方案中,所述阿片样物质或阿片样物质激动剂不容易穿过血脑屏障,因此,当全身性施用药剂时,基本上不具有中枢神经体系(CNS)活性(即其属于称为“外周作用”的药剂类)。在另外的实施方案中,所述治疗剂是阿片样物质拮抗剂。阿片样物质拮抗剂包括外周μ阿片样物质拮抗剂。外周μ阿片样物质拮抗剂的实例包括去甲羟基吗啡酮(noroxymorphone)的季衍生物(见Goldberg等人,美国专利4,176,186和Cantrell等人WO2004/043964),比如描述于美国专利5,250,542、5,434,171、5,159,081、5,270,328、和6,469,030中的哌啶N-烷基羧酸酯/盐,比如描述于美国专利4,730,048、4,806,556、和6,469,030中的阿片生物碱衍生物,比如描述于美国专利3,723,440和6,469,030中的季苯并吗吩烷化合物。
在一个实施方案中,所述外周阿片样物质拮抗剂是R-MNTX。R-MNTX是根据现有技术记载的制备方法的MNTX主导形式,虽然相信这样的制备物污染有S-MNTX。利用下述方案可合成纯的R-MNTX。简要地,如下进行R-MNTX的立体选择性合成:将羟基保护基加到纳曲酮以得到3-O-保护的纳曲酮、将所述3-O-保护的纳曲酮甲基化以得到3-O-保护的-R-MNTX盐、以及除去羟基保护基以得到R-MNTX。可在有机溶剂(例如四氢呋喃)和/或不是纳曲酮的叔胺(例如三乙胺)的任一种或两者都存在下,加入羟基保护基。通过3-O-保护的纳曲酮与甲基碘的反应甲基化纳曲酮,以制备3-O-保护的-R-MNTX碘化物盐。可通过羟基保护基例如异丁酰基保护纳曲酮。采用氢溴酸处理3-O-保护的-R-MNTX碘化物盐以除去保护基并产生R-MNTX溴化物盐/碘化物盐,并可将所述溴化物盐/碘化物盐通过阴离子交换树脂柱(溴离子形式)以得到R-MNTX溴化物。
在另外一些实施方案中,所述治疗剂不是阿片样物质、阿片样物质激动剂、或阿片样物质拮抗剂。例如,所述治疗剂可以是抗病毒剂、抗生素、抗真菌剂、抗细菌剂、杀菌剂、抗原生动物剂、抗寄生虫剂、抗炎剂、血管收缩剂、局部麻醉剂、抗腹泻剂、抗痛觉过敏剂或其组合。
在本发明的一个方面,S-MNTX与抗腹泻剂组合,所述抗腹泻剂为洛哌丁胺、洛哌丁胺类似物,洛哌丁胺的N-氧化物及其类似物、代谢物以及前药,地芬诺酯,西沙比利,抗酸剂,氢氧化铝,硅酸镁铝,碳酸镁,氢氧化镁,碳酸钙,聚卡波菲(Polycarbophil),聚二甲基硅氧烷,莨菪碱,阿托品,呋喃唑酮,地芬诺新,善得定,兰索拉唑,高岭土,果胶,活性炭,磺胺脒,琥珀酰磺胺噻唑,邻苯二甲酰基磺胺噻唑(phthalylsulphathiazole),铝酸铋,碱式碳酸铋,碱式柠檬酸铋,柠檬酸铋,三钾二枸橼酸铋,酒石酸铋,碱式水杨酸铋,碱式硝酸铋和碱式没食子酸铋,阿片酊剂(止痛剂)、草药、植物衍生的抗腹泻剂或其组合。
在本发明的一个方面,S-MNTX与抗炎剂组合,所述抗炎剂为非甾体抗炎剂(NSAID)、肿瘤坏死因子抑制剂、巴利昔单抗(basiliximab)、达克珠单抗(daclizumab)、英夫单抗、霉酚酸酯、mofetil、硫唑嘌呤、他克莫司、类固醇、柳氮磺吡啶、奥沙拉嗪、美沙拉秦、或其组合。
本发明的药物制剂可具有多种形式,包括但不限于肠溶包衣的组合物、为控制释放或持续释放制剂的组合物、为溶液的组合物、为局部制剂的组合物、为栓剂的组合物、冻干的组合物、吸入剂中的组合物、鼻喷雾装置中的组合物等。所述组合物可用于口服施用、胃肠外施用、粘膜施用、鼻部施用、局部(topical)施用、眼部施用、局部(local)施用等。如果胃肠外施用,所述施用可以是皮下、静脉内、皮内、腹膜内、鞘内施用等。
根据本发明的另外一个方面,提供合成S-MNTX的方法。所述方法包括在第一溶剂中化合(碘甲基)环丙烷与羟吗啡酮,以制备S-MNTX的碘盐。然后可任选地通过以下步骤取代为碘离子的反离子:将所述S-MNTX碘盐转移到第二溶剂中并将碘离子交换成除了碘离子以外的反离子。在一个重要的实施方案中,将所述S-MNTX碘盐从第一溶剂中转移到第二溶剂中,并且所述碘离子在第二溶剂中被交换成溴离子来制备S-MNTX溴盐。优选的第一溶剂是偶极非质子溶剂。最优选的是N-甲基吡咯烷酮(NMP)。优选的第二溶剂是至少乙酸异丙酯或二烷。本发明的方法还包括通过色谱、重结晶或其组合纯化S-MNTX盐。在一个实施方案中,所述纯化是通过多次重结晶进行。可在宽的温度范围和在大气条件下进行反应。在重要的实施方案中,在65至75℃的控制反应温度下进行第一溶剂中的反应,优选在约70℃进行,并且在室温下进行第二溶剂中的反应。
更广泛地,所述方法包括通过以下步骤合成附加反离子的S-MNTX:在第一溶剂中化合环丙基甲基衍生物与羟吗啡酮,以制备附加反离子的S-MNTX。所述环丙基甲基衍生物包含离去基团。优选地,所述离去基团是卤化物或磺酸盐。优选地,所述离去基团是碘化物。所述第一溶剂可以是偶极非质子溶剂。这样溶剂的实例是N-甲基吡咯烷酮、二甲基甲酰胺、甲基磷酰胺(methylphosphoramide)、丙酮、1,4-二烷、乙腈、和其组合。优选N-甲基吡咯烷酮。所述第一溶剂可以是偶极质子溶剂。实例是2-丙醇、1-丙醇、乙醇、甲醇。所述方法可进一步包括将S-MNTX的反离子与其它反离子交换。反离子的实例是溴离子、氯离子、氟离子、硝酸根、磺酸根或羧酸根。所述磺酸根可以是甲磺酸根、苯磺酸根、甲苯磺酸根、或三氟甲磺酸根。所述羧酸根可以是甲酸根、乙酸根、柠檬酸根和富马酸根。所述方法可包括在用其它反离交换S-MNTX的反离子之前,将S-MNTX反离子转移到第二溶剂中。所述方法可进一步包括纯化附加反离子的S-MNTX,例如通过重结晶、通过色谱或通过重结晶和色谱。
根据本发明的另外一个方面,通过以有效治疗或预防腹泻的量向需要这种治疗的对象施用含有S-MNTX的药物组合物,而提供抑制对象腹泻的方法。所述药物制剂可以是上述类型。所述腹泻可以是急性或慢性的。所述腹泻可由任何种类的情形单独或组合引起,比如由感染剂、食物不耐受、食物过敏、吸收不良综合征、对药物或非特异性病因学的反应引起。在一些实施方案中,所述腹泻与肠易激疾病或炎性肠疾病相关。在一个实施方案中,所述炎性肠疾病是乳糜泻。在另一个实施方案中,所述炎性肠疾病是克罗恩(Crohn′s)病。在又一另外的实施方案中,所述炎性肠疾病是溃疡性结肠炎。在另外实施方案中,所述腹泻源于胃或肠切除术,胆囊切除、或器官损害。在另外的实施方案中,所述腹泻与良性肿瘤或分泌血管活性肠肽的肿瘤有关。在进一步另外的实施方案中,所述腹泻是慢性功能性(特发性)腹泻。
根据本发明,S-MNTX可与不是S-MNTX的抗腹泻剂联合施用。通过联合,这意味着同时或在时间上足够接近,从而两种药剂同时治疗所述病症。在一个实施方案中,所述药剂是阿片样物质或阿片样物质激动剂。在另外一个实施方案中,所述药剂不是阿片样物质或阿片样物质激动剂。
根据本发明的另外一个方面,提供用于降低对象中由回肠造口术或结肠造口术(cholostomy)引起的流出物体积的方法。所述方法包括以有效降低由回肠造口术或结肠造口术引起的流出物体积的量向需要这种降低的对象施用含有S-MNTX的药物组合物。所述药物制剂可以是上述类型的。
根据本发明的另外一个方面,提供用于降低对象中由回肠造口术或结肠造口术引起的流出速率的方法。所述方法包括以有效降低由回肠造口术或结肠造口术引起的流出速率的量向需要这种降低的对象施用含有S-MNTX的药物组合物。所述药物制剂可以是上述类型的。
根据本发明的另外一个方面,提供用于抑制对象中胃肠蠕动的方法。所述方法包括以有效抑制对象中胃肠蠕动的量向需要这种抑制的对象施用含有S-MNTX的药物组合物。所述药物制剂可以是上述类型的。根据本发明,S-MNTX可以与另外一种不是S-MNTX的蠕动抑制剂联合施用。在一个实施方案中,所述药剂是阿片样物质或阿片样物质激动剂。阿片样物质和阿片样物质激动剂如上所述。在另外一个实施方案中,所述药剂不是阿片样物质或阿片样物质激动剂。这种胃肠道蠕动抑制剂的实例如上所述,每一种如同在该发明内容中具体引用的一样。
根据本发明的另外一个方面,提供用于治疗肠易激综合征的方法。所述方法包括以有效改善肠易激综合征的至少一种症状的量向需要这种治疗的患者施用含有S-MNTX的药物组合物。所述药物制剂可以是上述类型的。在一个实施方案中,所述症状是腹泻。在另一个实施方案中,所述症状是交替性便秘和腹泻。在另一个实施方案中,所述症状是腹部疼痛、腹部膨胀、异常的大便频率、异常的大便稠度、或其组合。
根据本发明的另外一个方面,提供用于抑制对象疼痛的方法。所述方法包括以有效抑制疼痛的量向需要这种治疗的患者施用含有S-MNTX的药物组合物。所述药物制剂可以是上述类型。该方法可进一步包括向所述对象施用除了S-MNTX以外的治疗剂。在一个实施方案中,所述除了S-MNTX以外的药剂是阿片样物质。在另一个实施方案中,所述除了S-MNTX以外的药剂是非阿片样物质疼痛减轻剂。非阿片样物质疼痛减轻剂包括皮质甾类和非甾体抗炎药物。下面将更详细描述疼痛减轻剂,如同引入本文发明内容中一样。在另一个实施方案中,所述除了S-MNTX以外的药剂是抗病毒剂、抗生素、抗真菌剂、抗细菌剂、杀菌剂、抗原生动物剂、抗寄生虫剂、抗炎剂、血管收缩剂、局部麻醉剂、抗腹泻剂、或抗痛觉过敏剂。如果所述疼痛是外周痛觉过敏,例如,其可源于咬伤、刺痛、烧伤、病毒或细菌感染、口腔手术、拔牙、对皮肤和肉体的损伤、伤口、擦伤、挫伤、手术切口、晒伤、皮疹、皮肤溃疡、粘膜炎、齿龈炎、支气管炎、喉炎、喉咙痛、带状疱疹、真菌疼痛、发热性疱疹、疖子、脚底疣、阴道损伤、肛门损伤、角膜磨蚀、后-放射状角膜切除术、或炎症。其还可与手术后恢复有关。所述手术可例如是放射状角膜切除术、拔牙、乳房肿瘤切除术、会阴切开术、腹腔镜检查和关节镜检查。
在一些实施方案中,将药物组合物局部施用于疼痛部位。在一些实施方案中,所述施用是关节内施用。在一些实施方案中,所述施用是全身性施用。在一些实施方案中,所述施用是局部施用。在一些实施方案中,所述组合物被施用于眼睛。
根据本发明的另外一个方面,提供用于抑制对象中炎症的方法。所述方法包括以有效抑制炎症的量向需要这种治疗的患者施用含有S-MNTX的药物组合物。所述药物制剂可以是上述类型。该方法还可包括向所述对象施用除了S-MNTX以外的治疗剂。所述除了S-MNTX以外的治疗剂可以是抗炎剂。所述施用可以是例如在炎症部位的局部施用、全身施用、或局部施用。
在一些实施方案中,所述炎症是牙周炎、正牙炎症、炎性结膜炎、痔疮和生殖器炎症。在另外的实施方案中,所述炎症是皮肤炎性病症。实例包括与选自以下病症相关的炎症:刺激性接触性皮炎、牛皮癣、湿疹、搔痒症、脂溢性皮炎、货币状皮肤炎、扁平苔藓、寻常痤疮、粉刺、多形、nodulokystic痤疮、集簇性痤疮(conglobata)、老年性痤疮、二级痤疮、药物性痤疮、角质化病症、和水疱样真皮(blistery derma)、异位性皮炎、以及UV引起的炎症。所述皮肤炎性病症还可与使用导致皮肤敏化或刺激的化妆品或护肤品引起的皮肤敏化作用或刺激有关,或所述皮肤炎性病症可以是非过敏性炎性皮肤病症。其还可以由全反式视黄酸引起。在另外的实施方案中,所述炎症可以是全身炎性病症。实例包括选自以下的病症:炎性肠疾病、类风湿性关节炎、恶病质、哮喘、克罗恩病、内毒素休克、成人呼吸窘迫综合征、缺血/再灌注损伤、移植物抗宿主反应、骨重吸收、移植和狼疮。另外的实施方案可包括与选自以下病症相关的炎症:多发性硬化、糖尿病、以及与获得性免疫缺陷综合征(AIDS)或癌症相关的消瘦。
根据本发明的另外一个方面,提供用于抑制对象中肿瘤坏死因子产生的方法。所述方法包括以有效抑制肿瘤坏死因子产生的量向需要这种治疗的患者施用含有S-MNTX的药物组合物。所述药物制剂可以是上述类型的。该方法还可包括向所述对象施用除了S-MNTX以外的治疗剂。
根据本发明的另外一个方面,提供用于调节对象胃肠功能的方法。所述方法包括均以调节胃肠功能的量向需要这种治疗的患者施用含有S-MNTX的药物组合物、以及向所述对象施用外周μ阿片样物质拮抗剂。在一个实施方案中,所述外周μ阿片样物质拮抗剂是R-MNTX。
根据本发明的另外一个方面,提供一种方法。所述方法包括通过以有效预防或治疗心理性进食或消化障碍的量向患者施用上述组合物来预防或治疗心理性进食或消化障碍。
根据本发明的另外一个方面,提供一种药盒。所述药盒包括包装,所述包装含有药物组合物的密封容器,所述药物组合物含有S-MNTX。所述药盒可进一步包括除了S-MNTX以外的治疗剂。在一个实施方案中,所述除了S-MNTX以外的治疗剂是阿片样物质或阿片样物质激动剂。在一个方面,当全身施用时,所述阿片样物质或阿片样物质激动剂基本上不具有CNS活性(即是“外周作用”)。在另外的实施方案中,所述除了S-MNTX以外的治疗剂是阿片样物质拮抗剂。阿片样物质拮抗剂包括外周μ阿片样物质拮抗剂。在一个实施方案中,所述外周阿片样物质拮抗剂是R-MNTX。在另外实施方案中,除了S-MNTX以外的药剂是抗病毒剂、抗生素、抗真菌剂、抗细菌剂、杀菌剂、抗原生动物剂、抗寄生虫剂、抗炎剂、血管收缩剂、局部麻醉剂、抗腹泻剂、或抗痛觉过敏剂或其组合。
根据本发明的另外一个方面,提供分析R-MNTX和S-MNTX混合物中的S-MNTX的方法。该方法包括进行高效液相色谱(HPLC)并且将S-MNTX应用于色谱柱作为标准。该方法优选地包括施用S-MNTX和R-MNTX作为标准,以测定相对保留时间/洗脱时间。R-MNTX和S-MNTX的相对保留时间如本文所述。在本发明的一个方面,使用两种溶剂(溶剂A和溶剂B)进行色谱法,其中溶剂A是含水溶剂并且溶剂B是含甲醇溶剂,其中A和B都含有三氟乙酸(TFA)。优选地,A是0.1%的水TFA和B是0.1%的甲醇TFA。在重要的实施方案中,柱包含结合的、封端的二氧化硅。在重要的实施方案中,柱凝胶的孔径是5微米。在最优选的实施方案中,柱、流速和梯度程序如下:
柱:Luna C18(2),150×4.6mm,5μ
流速:1mL/分钟
梯度程序:
时间(分钟) | %A | %B |
0:00 | 95 | 5 |
8:00 | 65 | 35 |
12:00 | 35 | 65 |
15:00 | 0 | 100 |
16:00 | 95 | 5 |
18:00 | 95 | 5 |
通过230nm波长的紫外可便利地进行检测。
前述的HPLC也可通过检测产生的色谱中的各自R和S曲线下的面积,用于检测S-MNTX和R-MNTX的相对量。
根据本发明的另外一个方面,提供保证制备不含有R-MNTX(阿片样物质拮抗剂)的S-MNTX(阿片样物质激动剂)的方法。该方法首次能确保意欲用于激动剂活性的S-MNTX药物制剂不被对抗S-MNTX活性的化合物所污染。在本发明的此方面,提供制备S-MNTX的方法。所述方法包括:(a)得到含有S-MNTX的第一组合物,(b)通过色谱、重结晶或其组合纯化所述第一组合物,(c)利用R-MNTX作为标准,在纯化的第一组合物样品上进行HPLC,和(d)测定样品中存在或不存在R-MNTX。在重要的实施方案中,R-MNTX和S-MNTX都用作标准,以测定例如R-MNTX和S-MNTX的相对保留时间。在一个实施方案中,纯化是多次重结晶步骤或多次色谱步骤。在另一个实施方案中,进行纯化直到如HPLC测定的样品中不含有R-MNTX。然而,应当理解,在本发明的一些方面中,“纯化的第一组合物”不是必须不含有可检测的R-MNTX。例如,这样的R-MNTX的存在可能指示如果需要纯的S-MNTX,应当进行进一步的纯化。该方法可进一步包括包装不含有HPLC可检测的R-MNTX的纯化的第一组合物。该方法可进一步包括在包装的、纯化的第一组合物上或之内提供标记,标识所述包装的、纯化的第一组合物不含有HPLC可检测的R-MNTX。该方法可进一步包括包装药学上有效的量用于治疗本文所述的任何一种病症。可通过本文所述的方法得到含有S-MNTX的第一组合物。可通过本文所述的方法得到纯R-MNTX。
根据本发明的另外一个方面,提供包装的产品。所述包装包含含有S-MNTX的组合物和标记,其中所述组合物不含有HPLC可检测的R-MNTX,所述标记在包装之上或被包含在包装之内以标识组合物不含有可检测的R-MNTX。组合物可具有多种形式,包括但不限于实验室试验中使用的标准,制造规程中使用的标准、或药物组合物。如果组合物是药物组合物,那么标记的一个重要的形式是书写在标签或说明书之上以描述药物制剂的特征。所述标记可直接标识组合物不含有R-MNTX,或其可例如通过声明组合物是纯的或100%S-MNTX同样间接地进行标识。药物组合物可用于治疗本文所述的任何病症。药物组合物可包含有效量的纯S-MNTX并且可具有下面所述的任何形式,如同在该发明内容中具体引用的,包括但不限于溶液、固体、半固体、肠溶包衣材料等。
下面更详细地描述本发明的这些和其它方面。
附图说明
图1提供R-MNTX和S-MNTX的溴化物盐的化学结构;
图2举例说明本发明的代表性反应方案;
图3提供S-MNTX的质子NMR谱图;
图4提供S-MNTX的红外谱图;
图5提供S-MNTX的HPLC谱图;和
图6提供S-MNTX的质谱图。
图7举例说明根据本发明的药盒。
具体实施方式
本发明提供化合物S-MNTX、立体选择性合成S-MNTX的合成路线、基本上纯的S-MNTX、基本上纯的S-MNTX的晶体、S-MNTX的分析方法、含有基本上纯的S-MNTX的药物制剂、以及其使用方法。
S-MNTX(也称为(S)-N-(环丙基甲基)-去甲羟基吗啡酮甲基盐)具有下式I的结构:
其中X是反离子。反离子可以是任何反离子,包括两性离子。优选的反离子是药学上可接受的。反离子包括卤离子、硫酸根、磷酸根、硝酸根或带电阴离子有机物质。卤离子可以是碘离子、溴离子、氯离子、氟离子或其组合。在一个实施方案中,所述卤离子是碘离子。在一个优选实施方案中,所述卤离子是溴离子。所述带电阴离子有机物质可以是磺酸根或羧酸根。
相信S-MNTX的制备方法和S-MNTX的激动剂特性同样地适用于除了所述衍生物是环丙基甲基以外的去甲羟基吗啡酮的S-季衍生物。因此,本发明意欲包括当环丙基甲基被R部分取代时的去甲羟基吗啡酮的S-季衍生物,其中R是仅由碳和氢组成的1至20个碳的烃基,包括被烃或一个或多个原子比如氮、氧、硅、磷、硼、硫或卤素取代或未取代的烷基、烯基、炔基、和芳基(记载于PCT公开物WO2004/043964中)。在重要的实施方案中,R是烯丙基、氯代烯丙基、或炔丙基。在重要的实施方案中,所述烃基含有4至10个碳。
一般而言,“烷基”指可以是链中具有1至约10个碳原子的直链、支链或环状的脂肪族烃基,以及该范围内的所有组合和亚组合。“支链”指其中低级烷基基团(例如甲基、乙基或丙基)连接到直链烷基链的烷基基团。在某些优选实施方案中,烷基基团是C1-C5烷基基团,即具有1至约5个碳的支链或直链烷基基团。在另外的优选实施方案中,烷基基团是C1-C3烷基基团,即具有1至约3个碳的支链或直链烷基基团。示例性的烷基基团包括甲基、乙基、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基、壬基和癸基。“低级烷基”指具有1至约6个碳原子的烷基基团。优选的烷基基团包括1至约3个碳的低级烷基基团。
“烷基化剂”是可以与原料反应以将烷基基团结合(通常共价地)到原料的化合物。所述烷基化剂通常包括当结合到原料时从烷基基团中分离的离去基团。离去基团可以是例如卤素、卤代磺酸酯或卤代乙酸酯。烷基化剂的一个实例是环丙基甲基碘。
“有机溶剂”具有相对于本领域一般技术人员而言的常规普通意义。用于本发明的示例性的有机溶剂包括但不限于四氢呋喃、丙酮、己烷、醚、氯仿、乙酸、乙腈、氯仿、环己烷、甲醇、和甲苯。还包括无水有机溶剂。
“偶极非质子”溶剂是不能提供不稳定的氢原子并表现出永久性偶极矩的亲质子溶剂。实例包括丙酮、乙酸乙酯、二甲基亚砜(DMSO)、二甲基甲酰胺(DMF)和N-甲基吡咯烷酮。
“偶极质子”溶剂是能提供不稳定的氢原子并表现出永久性偶极矩的那些溶剂。实例包括水,醇例如2-丙醇、乙醇、甲醇,羧酸例如甲酸、乙酸和丙酸。
S-MNTX表现出不同于R-MNTX的特性和不同于S-MNTX和R-MNTX混合物的特性。这些特性包括在色谱柱上的流动性、生物活性和功能活性、以及晶体结构。相信体内清除率、副作用特性等也可不同于R-MNTX或R-MNTX和S-MNTX的混合物。如本文公开并要求专利保护的,纯S-MNTX起到外周阿片样物质受体激动剂的作用,如通过抑制胃肠传输所证明的。结果,S-MNTX活性可被含有R-MNTX和S-MNTX的混合物中的R-MNTX干扰或对抗。因此,非常希望使得S-MNTX处于分离的并且基本上纯的形式。
在本发明的一个方面,提供合成S-MNTX的方法。可制备基于色谱技术纯度大于或等于10%、20%、30%、40%、50%、60%、70%、75%、80%、85%、90%、95%、97%、98%、98.5%、99%和99.5%的曲线下面积(AUC)的S-MNTX。在一个优选实施方案中,S-MNTX的纯度是98%或更高。纯化的S-MNTX中的R-MNTX的量可以小于或等于约90%、80%、70%、60%、50%、40%、30%、20%、10%、5%、3%、2%、1%、0.5%、0.3%、0.2%、0.1%(AUC)或是通过本文所述色谱技术不可检测的。技术人员应当理解,方法的检测将取决于所用技术的检测限和定量限。定量限是不管实验室、分析者、仪器或试剂批号的变化,可始终如一地测量并报告的R-MNTX的最低量。检测限是可检测但是不必要定量为准确值的样品中R-MNTX的最低量。在本发明的一个实施方案中,所述检测限是0.1%,所述定量限是0.2%。在又一另外的实施方案中,所述检测限是0.02%,所述定量限是0.05%。
尝试了多种合成方案来合成S-MNTX。许多合成未能成功制备S-MNTX或未能成功制备可接受纯度水平或产率的S-MNTX。在本发明的成功方法中,通过使得羟吗啡酮的酚OH基未保护,直接烷基化羟吗啡酮来合成S-MNTX(图2)。羟吗啡酮与甲基环丙烷物质碘甲基环丙烷反应。所得S-MNTX盐包括反离子(比如碘离子),所述反离子然后可交换成优选的反离子比如溴离子。通过羟可待酮例如与三溴化硼的去甲基化反应可得到约95%产率的S-MNTX合成中的原料羟吗啡酮。作为替代,可通过商业来源得到所述羟吗啡酮。
烷基化反应可在可以是无水的溶剂或溶剂体系中进行。所述溶剂体系可以是单一的溶剂或可以包括两种或多种溶剂的组合。适当的溶剂体系可包括偶极非质子溶剂比如N-甲基吡咯烷酮(NMP)、二甲基甲酰胺(DMF)、六甲基磷酰胺(HMPA)、丙酮、1,4-二烷和乙腈,以及偶极质子溶剂比如2-丙醇。溶剂体系还可包括偶极非质子溶剂与脂肪族醚的组合,所述脂肪族醚比如为四氢呋喃(THF)、1,2-二甲氧基乙烷(甘醇二甲醚)、二乙二醇二甲醚(二甘醇二甲醚)、1,4-二烷、甲基叔丁基醚(甲基1,1-二甲基乙基醚、或2-甲基-2-甲氧基丙烷)二乙醚,其它极性溶剂也可包括在一些实施方案中。例如,所述溶剂体系可包括丙酮、甲基乙基酮、二乙基酮(3-戊酮)、以及叔丁基甲基酮(3,3-二甲基丁-2-酮)。烷基化溶剂体系还可包括任何上述化合物的脂肪族或脂环同源物。溶剂体系可包括任何比例的两种或多种溶剂,并且用于具体烷基化反应的适当比例可通过常规试验进行确定。令人惊讶地,虽然已经描述,证实NMP是优选的溶剂。
可以以小于、大于或等于约1、2、3、4、5、10或以上体积的比例使用溶剂。在一些情形下,其可优选以最小化所用溶剂的量,比如当利用液/液萃取从所述溶剂中转移产物时或当待产物结晶时或当从产物中除去所述溶剂时。
所述烷基化剂可以以各种摩尔比例加到原料中,比如小于8、12、16、20、24或大于24当量/当量原料。在一些情形下,已发现反应效率(S-MNTX的产量)可基本上不依赖于所用烷基化剂的量。
在一系列实施方案中,可利用Finkelstein反应进行烷基化。烷基卤(比如环丙基甲基氯)可与卤化物盐(比如碘化钠)化合,以连续地提供反应性卤化烷基化剂(比如环丙基甲基碘),随着其消耗而补充。
在大气压、在开放容器中或在压力下可将原料烷基化。进行所述反应使得利用本领域公知的方法/设备在反应时间将温度维持或控制在预定温度。用于在整个烷基化反应中维持可控温度的一种设备是加热器/冷却器单元。在整个烷基化反应中控制温度以抑制或降低温度波动。在一个实施方案中,所述温度不超过110℃,优选不超过100℃。例如,可在开放或封闭容器中、在50至100℃、60至90℃、或65至75℃的范围内将羟吗啡酮烷基化。允许所述反应进行至多约22小时,优选约15至22小时,更优选约16至20小时。预期通过使用微波辐照可缩短反应时间。在一个实施方案中,将反应物放置在封闭容器中、在70℃进行约17小时,以制备羟吗啡酮与S-MNTX比例为约1∶1的产物。在一个优选实施方案中,所述烷基化在包裹以减少暴露于光的开放容器(大气压)中、在70℃进行约20小时。
在一些实施方案中,可从制备S-MNTX的溶剂中分离S-MNTX。例如,所述溶剂可从含有S-MNTX的剩余物中除去,或任何S-MNTX可从烷基化溶剂转移到转移溶液中。转移溶剂可以是极性或非极性的并且沸点可低于100℃。转移溶剂可包括酯、醛、醚、醇、脂肪族烃、芳香烃和卤代烃。特定的转移溶剂包括例如二烷、乙酸乙酯、乙酸异丙酯、甲醇、乙醇、二氯甲烷、乙腈、水、HBr水溶液、庚烷、和MTBE。在一个实施方案中,乙酸异丙酯和二烷可用于至少部分地从NMP中分离S-MNTX。混合一种或多种这些溶剂与NMP中的S-MNTX溶液时,可形成浅色的固体,所述浅色的固体随时间推移变成油。
可处理从溶剂中得到的任何剩余物,以纯化和分离产物S-MNTX。利用本领域技术人员公知的方法,比如通过例如色谱、重结晶的分离技术,或本领域公知的多种分离技术的组合,可进行纯化和分离。在一个实施方案中,利用C18柱的快速色谱可使用由0.2%HBr改性的含水甲醇溶剂。甲醇含量可从例如约2.5%变化至约50%。在一个优选实施方案中,利用重结晶纯化S-MNTX。可重复所述方法直到得到理想纯度的产物。在一个实施方案中,S-MNTX重结晶至少两次、三次、或四次或更多次,以得到理想的纯度水平。例如,可以以基于色谱技术大于或等于50%、80%、85%、90%、95%、97%、98%、98.5%、99.8%(AUC)的纯度得到S-MNTX。任何杂质可包含原料,少于0.2%的羟吗啡酮、以及不含有可检测的R-MNTX。利用单一溶剂或溶剂组合可实现重结晶。通过将S-MNTX溶解在极性溶剂中,然后添加极性较小的助溶剂,来实现优选的重结晶。在更优选的实施方案中,通过从甲醇和助溶剂CH2Cl2/IPA(6∶1)中重结晶,来纯化S-MNTX。重复所述重结晶以得到理想纯度。
以盐的形式制备S-MNTX及其衍生物。包括衍生物,比如S-MNTX的两性离子。如图1中所示,S-MNTX可包括带正电荷的季铵基团并可与反离子例如单价或多价阴离子进行配对。这些阴离子可包括例如卤离子、硫酸根、磷酸根、硝酸根和带电有机物质比如磺酸根和羧酸根。优选的阴离子包括卤离子比如溴离子、氯离子、碘离子、氟离子、以及其组合。在一些实施方案中,溴离子是最优选的。可基于以下因素选择具体的阴离子:例如反应性、溶解性、稳定性、活性、成本、可得到性和毒性。
S-MNTX盐的反离子可交换成替代的反离子。当需要替代的反离子时,S-MNTX盐的水溶液可经过阴离子交换树脂柱,以将S-MNTX盐的一些或全部反离子交换成优选的替代反离子。阴离子交换树脂的实例包括可从Bio-Rad购得的100至200目级别的AG 1-X8。在另一个实施方案中,S-MNTX阳离子可保留在阳离子交换树脂上,然后可通过用盐溶液从所述树脂除去所述S-MNTX阳离子来交换,在溶液中形成理想的S-MNTX盐,所述盐溶液包括优选的阴离子,比如溴离子或氯离子。
本发明的S-MNTX具有多种效用。本发明的一个方面是在色谱分离中、确定和区分S-MNTX与样品的其它成分中,将S-MNTX作为色谱标准。本发明的另一个方面是在从含有S-MNTX和R-MNTX的混合物中确定和区分S-MNTX时,将S-MNTX用作色谱标准。分离的S-MNTX还可用于在反应混合物中纯化和区分R-MNTX与S-MNTX的方案的研发中。这些方案描述在本文中并且还描述在代理机构卷号P0453.70119US00的同日提交的名称为“Synthesis of(R)-N-Methylnaltrexone”的共同未决的申请中。
S-MNTX可作为标准提供在含有使用说明书的药盒形式中。所述药盒可进一步包含可信的R-MNTX作为标准。用作标准的S-MNTX优选地具有99.8%或更高的纯度并且不含有可检测的R-MNTX。
本发明的一个方面是拆分和确定MNTX溶液中S-MNTX和R-MNTX的方法。S-MNTX还用于定量组合物或混合物中S-MNTX量的HPLC分析方法中,其中所述方法包括将组合物或混合物样品应用于色谱柱,拆分组合物或混合物成分,以及通过比较样品中拆分成分的百分率和标准浓度S-MNTX的百分率计算样品中S-MNTX的量。所述方法尤其用于反相HPLC色谱。本发明的S-MNTX依靠其对阿片样物质受体的激动剂活性,在比如本文所述的体外和体内阿片样物质受体分析中用作激动剂活性的标准。
S-MNTX可用于预防性地或治疗性地调节由一种或多种外周阿片样物质受体介导的病症,以兴奋外周阿片样物质受体,尤其是外周μ阿片样物质受体。正在施用S-MNTX的对象可短期、长期或根据所需基础接受治疗。
施用S-MNTX的对象是脊椎动物,尤其是哺乳动物。在一个实施方案中,所述哺乳动物是人类、非人灵长类、狗、猫、绵羊、山羊、马、牛、猪和啮齿动物。在一个优选实施方案中,所述哺乳动物是人类。
μ和其它阿片样物质受体存在于胃肠(GI)道中。GI道中主要类型的阿片样物质受体之中,μ受体主要涉及调节GI活性。κ阿片样物质受体可起作用(Manara L et al Ann.Rev.Phamacol.Toxicol,1985,25:249-73)。一般而言,S-MNTX用于预防或治疗与需要活化或调节阿片样物质受体尤其是外周阿片样物质受体相关的病症。感兴趣的是使用S-MNTX预防或治疗与需要活化或调节GI道中阿片样物质受体尤其是μ阿片样物质受体相关的病症。可预防或治疗的这种病症包括腹泻,并且可用于预防或抑制某些形式的胃肠道功能障碍,其包括某些形式的炎性肠综合征、以及进食和消化障碍。
一方面,S-MNTX可用于治疗腹泻。通过一种或多种阿片样物质受体以及内源性阿片样物质至少部分地调节胃肠功能。已知阿片样物质拮抗剂增加胃肠蠕动并因此可有效用于便秘的治疗。另一方面,已知阿片样物质激动剂,尤其是外周阿片样物质激动剂比如洛哌丁胺降低胃肠蠕动并可用于治疗哺乳动物腹泻。如申请人发现的,S-MNTX作为阿片样物质激动剂可施用于需要治疗腹泻的患者。本文所用的腹泻定义为以下的一种或多种:1)大便稠度降低;2)每天排便3次以上;和/或3)每天排便体积≥200g(150ml)。以有效延长肠内容物转运时间的量施用S-MNTX导致减少的粪便体积、增加粪便粘度和体积密度并且减少流体和电解质的丢失。
本发明的S-MNTX依靠其阿片样物质激动剂活性用于不同病因学的腹泻(包括急性和慢性形式的腹泻、慢性功能性(特发性)腹泻)的预防和治疗。
本文所用的急性腹泻或短期腹泻是持续时间少于1周,通常1至3天的腹泻。本文所用的慢性腹泻、进行性或长期腹泻是持续1周或更长时间的腹泻。慢性腹泻可持续数月或甚至数年并且可以是连续的或间歇性的。可受益于使用S-MNTX治疗的腹泻的多种形式和原因包括但不限于下述那些。
由任何病毒(包括但不限于轮状病毒、诺沃克病毒、巨细胞病毒、单纯疱疹病毒、肝炎病毒和腺病毒)引起的病毒性胃肠炎或“胃流感”可适于使用S-MNTX治疗。
由于进食污染有生物体比如细菌和寄生虫的食物或饮用污染有生物体比如细菌和寄生虫的水引起的食物中毒和旅行者腹泻可适于使用S-MNTX治疗。一般地引起腹泻的细菌包括大肠杆菌(Escherichiacoli)、沙门氏菌(Salmonella)、志贺氏菌属(Shigella)、梭菌(Clostridia)、弯曲杆菌(Campylobacter)、耶尔森氏菌(Yersinia)、和利斯特氏菌(Listeria)。引起腹泻的寄生虫包括蓝氏贾第鞭毛虫(Giardia lamblia)、溶组织内阿米巴(Entamoeba histolytica)和隐孢子虫(Cryptosporidium)。可引起腹泻的真菌包括念珠菌(Candida)。
某些医学病症还可引起腹泻,包括吸收不良综合征比如乳糖不耐受、乳糜泻(口炎性腹泻或谷蛋白吸收不良)、囊肿性纤维化、对牛奶中蛋白质或其它特定食物例如豆或水果不耐受。对特定食物过敏是另外的可引起导致腹泻的胃肠刺激和/或过敏反应的病症。典型的食物过敏原包括花生、玉米和贝类。由这些医学病症引起或与这些医学病症相关的腹泻可适于使用本发明的S-MNTX治疗。
其它导致腹泻,尤其是慢性腹泻的医学病症包括炎性肠疾病,所述炎性肠疾病包括克罗恩病和溃疡性结肠炎、肠易激综合征(IBS),和免疫缺陷,也可受益于预防或治疗腹泻的S-MNTX。
S-MNTX用于预防和治疗由药物和/或治疗剂比如抗生素、含有镁的轻泻剂、癌症治疗的化学疗法以及高剂量放射治疗引起的腹泻。
腹泻还与Zollinger-Ellison综合征,神经病比如自主神经病变或糖尿病性神经病变,类癌瘤综合征,分泌血管活性肠肽的肿瘤,以及胃肠道的解剖学病况包括短肠综合征、胃切除术、具有或不具有回肠造口术或结肠造口术的肠切除术、和胆囊切除。这些病症可适于使用S-MNTX治疗。
可通过任何途径,口服或胃肠外施用S-MNTX,包括腹膜内、静脉内、阴道、直肠、肌肉内、皮下、气雾剂、鼻喷雾剂、经粘膜、透皮、局部、结肠等用于预防和治疗腹泻。
S-MNTX还用于降低对象中回肠造口术或结肠造口术的流出物体积的方法。与不存在S-MNTX的造口术流出物体积相比,以有效降低回肠造口术或结肠造口术的流出物体积的量提供S-MNTX。S-MNTX还用于控制造口术的流出速率,尤其是在需要降低流出速率的对象中降低流出速率。
根据本发明的另外一个方面,提供用于抑制对象中胃肠蠕动的方法。所述方法包括以有效抑制对象中胃肠蠕动的量向需要这种抑制的对象施用含有S-MNTX的药物组合物。根据本发明,S-MNTX可以与其它不是S-MNTX的蠕动抑制剂联合施用。在一个实施方案中,所述药剂是阿片样物质或阿片样物质激动剂。阿片样物质和阿片样物质激动剂如上所述。在另外一个实施方案中,所述药剂不是阿片样物质或阿片样物质激动剂。这样的非阿片样物质胃肠蠕动抑制剂的实例包括例如西沙比利,抗酸剂,氢氧化铝,硅酸镁铝,碳酸镁,氢氧化镁,碳酸钙,聚卡波菲(Polycarbophil),聚二甲基硅氧烷,莨菪碱,阿托品,呋喃唑酮,地芬诺新,善得定,兰索拉唑,高岭土,果胶,活性炭,磺胺脒,琥珀酰磺胺噻唑,邻苯二甲酰基磺胺噻唑(phthalylsulphathiazole),含铋的制剂比如铝酸铋、碱式碳酸铋、碱式柠檬酸铋、柠檬酸铋、三钾二枸橼酸铋、酒石酸铋、碱式水杨酸铋、碱式硝酸铋和碱式没食子酸铋,阿片酊剂(止痛剂)、草药、和植物衍生的抗腹泻剂。而且这样的药剂包括苯二氮类化合物、抗痉挛剂、选择性5-羟色胺再摄取抑制剂(SSRIs)、胆囊收缩素(CCK)受体拮抗剂、自然杀伤(NK)受体拮抗剂、促肾上腺皮质激素释放因子(CRF)受体激动剂、抗酸剂、G1弛缓剂、抗气体化合物、戊聚糖多硫酸酯、止吐的多巴胺D2拮抗剂、促性腺激素释放激素类似物(醋酸亮丙瑞林)、促肾上腺皮质激素-1拮抗剂、神经激肽2受体拮抗剂、胆囊收缩素-1拮抗剂、β-阻滞剂、抗食管反流剂、抗炎剂、5HT1激动剂、5HT3拮抗剂、5HT4拮抗剂、胆盐螯合剂、容积性药物(bulk-forming agent)、α2-肾上腺素激动剂、抗抑郁剂比如三环类抗抑郁剂。另外的这样的药剂包括抗毒蕈素性药物、神经节阻滞剂、激素和激素类似物、以及促胃动素受体拮抗剂。抗毒蕈素性药物包括莨菪类生物碱、季铵抗毒蕈素性化合物和叔胺抗毒蕈素性化合物。莨菪类生物碱的实例包括莨菪叶提取物、莨菪酊剂、和莨菪提取物。季铵抗毒蕈素性化合物的实例包括辛托品或溴甲辛托品(Valpin)、克利溴铵或溴化克利溴铵(Quarzan)、格隆溴胺(Robinul)、环苯甲哌甲硫酸盐(Tral)、后马托品、异丙阿托品或溴化异丙阿托品、异丙酰胺或碘化异丙酰胺(Darbid)、甲哌酯或溴化甲哌酯(Cantil)、甲胺太林或溴甲胺太林(Banthine)、甲基东莨菪碱或溴化甲基东莨菪碱(Pamine)、奥芬溴铵、以及溴丙胺太林或溴化丙胺太林。叔胺抗毒蕈素性化合物的实例包括阿托品、双环维林或盐酸双环维林(Bentyl等)、盐酸黄酮哌酯(Urispas)、奥昔布宁或盐酸奥昔布宁(Ditropan)、羟苄利明或盐酸羟苄利明(Daricon)、丙哌凡林、东莨菪碱、托特罗定、以及曲地碘铵或氯化曲地碘铵(Pathilon)。其它的抗毒蕈素性药物包括哌仑西平、替仑西平、AF-DX116、Methoctranine、喜巴辛、以及Hexahydrosiladifenidol。神经节阻滞剂包括合成的胺类比如六甲溴铵、美加明、四乙铵以及乙酰胆碱。抗胃肠蠕动剂的激素或激素类似物的实例包括:促生长素抑制素和促生长素抑制素受体激动剂。促生长素抑制素类似物的实例包括善得定(例如Sandostatin)和伐普肽(vapreotide)。促胃动素拮抗剂包括(Phe3,Leu-13)猪促胃动素,214th American Chemical Society(ACS)Meeting(Part V);Highlights from Medicinal Chemistry Poster Session,Wednesday 10 September,Las Vegas,Nevada,(1997),Iddb MeetingReport September 7-11(1997);和ANQ-I 1125,Peeters T.L.等,Biochern.Biophys.Res.Commun.,Vol.198(2),pp.411-416(1994)。
另一方面,S-MNTX可用于治疗进食和消化障碍。可适于使用本发明的S-MNTX治疗的进食障碍和消化障碍包括但不限于病理性不均衡食欲的调节、食欲丧失或食欲减退,由例如以下诱导:怀孕,癌症,传染病比如流感、HCV或HIV,作为分解代谢的结果,恶病质,厌食,尤其是神经性厌食症,食欲障碍,dysponderosis,肥胖倾向,易饿病,肥胖,胃轻瘫、尤其是神经性胃轻瘫、糖尿病胃轻瘫、肌源性胃轻瘫或由药物引起的胃轻瘫,胃弛缓,胃麻痹或enteroparesis,和胃肠道狭窄,尤其是幽门狭窄的结果。
疼痛已被定义为多种形式。例如,疼痛可被定义为通过对象产生撤退反应的对象的有害刺激的感觉,镇痛是疼痛感觉的减少。选择性阻滞动物对强刺激的响应而不使一般行为或运动功能迟钝的药剂被称为镇痛剂。阿片和阿片样物质激动剂通过与特定阿片样物质受体相互作用影响疼痛。基于S-MNTX对大鼠胃肠传输具有阿片激动剂活性这一发现,在疼痛治疗中利用S-MNTX具有理论基础。
一般而言,根据本发明的S-MNTX及其衍生物的施用可用于利于控制与任何多种紊乱、病症或疾病相关的疼痛。除非另外指明,本文所用的“疼痛”意欲包含任何持续时间和频率的疼痛,包括但不限于急性疼痛、慢性疼痛、间歇性疼痛等。疼痛的原因可以是可确认的或不可确认的。当可确认时,疼痛的起因可例如是恶性的、非恶性的、传染性的、非传染性的、或自身免疫起源的。一个实施方案是控制与需要短期治疗的疾病、紊乱或病症(例如牙科操作、骨折、门诊患者手术)相关的疼痛,其中治疗包括数小时到最长3天期间内的治疗。特别感兴趣的是控制与需要长期治疗的疾病、紊乱或病症(例如慢性和/或持续性疾病或病症)相关的疼痛,其中治疗包括数天(例如约3天至10天)、至数周(例如约2周或4周至6周)、至数月或数年,最长至并包括对象的剩余寿命的期间内的治疗。目前未患有疾病或病症、但是易患这些疾病或病症的对象也可受益于利用本发明的组合物和方法的预防性疼痛控制,例如外伤手术之前。可适于根据本发明治疗的疼痛可包括疼痛与无疼痛间隔交替的延长的事件、或严重程度变化的基本上无间断的疼痛。
一般而言,疼痛可以是疼痛引起反应的、躯体原的、神经性的、或心理性的。躯体原疼痛可以是肌肉的或骨骼的(即骨关节炎、腰骶部背部疼痛、外伤后的、肌筋膜的)、内脏的(即胰腺炎、溃疡、易激肠)、缺血的(即闭塞性动脉硬化症)、或与癌症(例如恶性的或非恶性的)的发展有关。神经性疼痛可归因于外伤后的和手术后的神经痛、可与神经病相关(即糖尿病、毒性等),并且可与神经卡压、面神经痛、会阴神经痛、截肢后、丘脑、灼痛、以及反射性交感神经性营养不良相关。
根据本发明可适于控制的病症、疾病、紊乱和疼痛来源的具体实例包括但不必限于癌症疼痛(例如转移性或非转移性癌症)、炎性疾病疼痛、神经病性疼痛、手术后疼痛、因医生的治疗而引起的疼痛(例如入侵性手术或高剂量放射治疗之后的疼痛,例如包括瘢痕组织形成导致运动自由度和显著性疼痛的衰弱折衷)、复杂性区域疼痛综合征、背部手术失败疼痛(failed-back pain)(例如急性或慢性背痛)、软组织疼痛、关节和骨疼痛、中枢性疼痛、损伤(例如衰弱的损伤,例如截瘫、四肢瘫痪等,以及非衰弱的损伤(例如对背部、颈部、脊柱、关节、腿、臂、手、足等))、关节炎疼痛(例如类风湿性关节炎、骨关节炎、不明原因的关节炎症状等)、遗传病(例如镰刀形红细胞贫血症)、传染病和作为结果的综合征(例如莱姆(Lyme)病、AIDS等)、头痛(例如偏头痛)、灼痛、感觉过敏、交感神经性营养不良、幻肢综合征、神经切除术等。疼痛可与任何身体部分相关,例如骨骼肌肉系统、脏器、皮肤、神经系统等。
本发明的方法可用于控制未用过阿片样物质的或不再未用过阿片样物质的患者中的疼痛。示例性未用过阿片样物质的患者是未长期接受阿片样物质治疗用于疼痛控制的患者。示例性非未用过阿片样物质的患者是接受短期或长期阿片样物质治疗并产生耐受性、依赖性、或其它不希望副作用的患者。例如,采用S-MNTX及其衍生物的递送,可对采用口服、静脉内、或鞘内吗啡,透皮芬太尼贴片,或芬太尼、吗啡或其它阿片样物质的常规地施用的皮下输注而具有难治疗的不良副作用的患者实现良好的镇痛并维持有利的副作用特征。
术语“疼痛控制或治疗”在本文用于一般地描述疼痛的消退、抑制或减轻以使得对象更舒服(如通过主观标准、客观标准或同时确定的)。一般而言,通过患者报告,用卫生专业考虑患者年龄、文化背景、环境、以及改变个人对疼痛的主观反应公知的其它心理背景因素,来主观地评价疼痛。
如上所述,S-MNTX可与不是S-MNTX的治疗剂一起施用,包括但不限于是疼痛减轻剂的治疗剂。在一个实施方案中,所述疼痛减轻剂是阿片样物质或阿片样物质激动剂。在另一个实施方案中,所述疼痛减轻剂是非阿片样物质疼痛减轻剂,比如皮质甾类或非甾体抗炎药(NSAID)。疼痛减轻剂包括:盐酸阿芬他尼、氨基苯甲酸钾、氨基苯甲酸钠、阿尼多昔、氨苄哌替啶、盐酸氨苄哌替啶、盐酸亚尼诺屏、艾利洛克、安替比林、阿司匹林、苯洛芬、盐酸苄达明、盐酸比西发定、盐酸Brifentanil、马来酸溴马多灵、溴芬那酸钠、盐酸丁丙诺啡、丁醋苯胺、布替西雷、布托啡诺、酒石酸环丁羟吗喃、卡马西平、卡巴匹林钙、盐酸卡比芬、枸橼酸卡芬太尼、琥珀酸环丙法多、西拉马多、盐酸西拉马多、氯尼舍林、氯尼克辛、可待因、磷酸可待因、硫酸可待因、盐酸柯洛呋酮、赛拉佐辛、盐酸右苯啶、Dexpemedolac、地佐辛、二氟尼柳、重酒石酸二氢可待因、二甲法登、安乃近、盐酸多西可明、氨甲茚酮、盐酸依那多林、依匹唑、酒石酸麦角胺、盐酸依托沙秦、依托芬那酯、丁香酚、非诺洛芬、非诺洛芬钙、枸橼酸芬太尼、弗洛非宁、氟苯沙酸、氟尼克辛、氟尼克辛葡甲胺、马来酸氟吡啶、氟丙喹酮、盐酸氟拉多宁、氟比洛芬、盐酸氢吗啡酮、异丁布芬酸、吲哚洛芬、酮唑新、开托法醇、酮咯酸、盐酸来替米特、左旋乙酰美沙酮、盐酸左旋乙酰美沙酮、盐酸左南曲多、酒石酸羟甲左吗喃、盐酸罗非咪唑、草酸罗芬太尼、罗兴拉多、氯诺昔康、水杨酸镁、甲灭酸、盐酸美纳比坦、盐酸哌替啶、盐酸美普他酚、盐酸美沙酮、阿法美沙酯、美托复林、左美丙嗪、Metkephamid Acetate、盐酸明朴痛、盐酸米芬他尼、吗啉那宗、硫酸吗啡、莫咯佐辛、盐酸钠比坦、盐酸纳布啡、盐酸纳美酮、纳莫雷特、盐酸南曲多、甲氧奈丙酸、甲氧奈丙酸钠、萘普醇、盐酸奈福泮、盐酸奈西利定、盐酸去甲乙酰美沙醇、盐酸Ocfentanil、奥塔酰胺、欧法利、富马酸奥昔托隆、羟可酮、盐酸羟可酮、对苯二甲酸羟考酮、盐酸羟吗啡酮、美多勒克、戊达马酮、镇痛新、盐酸镇痛新、乳酸镇痛新、盐酸非那吡啶、盐酸苯吡胺醇、盐酸甲丙哌酯、泊来多林、哌非尼酮、吡罗昔康Olamine、马来酸Pravadoline、盐酸甲苯吡丙酯、盐酸普罗法多、富马酸哌丙吡胺、盐酸丙氧芬、萘磺酸丙氧芬、普罗沙唑、枸橼酸普罗沙唑、酒石酸普罗少芳、盐酸双苄乙酯、盐酸瑞芬太尼、柳胆来司、马来酸三乙水杨胺、水杨酰胺、水杨酸葡胺、双水杨酯、水杨酸钠、甲磺酸螺拉多林、舒芬太尼、枸橼酸舒芬太尼、他美达辛、他尼氟酯、他洛沙酯、琥珀酸塔查多能、泰布芬隆、四氢达明、替呋拉酸钠、盐酸替利定、噻平酸、甲磺酸托那佐辛、盐酸曲马多、盐酸曲芬太尼(Trefentanil)、三乙硝胺、盐酸屋那多林、盐酸外瑞洛喷、伏拉佐辛、甲磺酸少法醇、盐酸甲苯噻嗪、甲磺酸泽来佐辛、佐美酸钠、Zucapsaicin、及其组合。
痛觉过敏是升高的对疼痛的敏感性或升高的疼痛感强度。当对象对刺激过度敏感时,可导致痛觉过敏,导致对给定刺激的扩大的疼痛响应。痛觉过敏通常是局部炎性状态的结果并且可出现在身体组织的外伤或损伤之后。炎症可随后出现、或与局部感染,水疱,疖子,皮肤损伤比如切口、刮伤、灼伤、晒伤、擦伤、手术切口,炎性皮肤病症比如毒葛、过敏性皮疹、虫咬伤及蜇伤、以及关节炎症有关。S-MNTX可用于预防和治疗外周痛觉过敏,以及降低炎症引起的疼痛和/或症状。本文所用的痛觉过敏包括瘙痒症、或痒,并且S-MNTX可用作抗瘙痒治疗。
本文的组合物和方法意欲用于预防和治疗与多种炎性病症和损伤相关的痛觉过敏。本文提供的组合物和方法可用于治疗多种与灼伤(包括但不限于热伤、辐照灼伤、化学灼伤、太阳灼伤、和风灼伤)、擦伤(包括例如角膜擦伤、碰伤、挫伤、冻伤)、皮疹(包括例如过敏热和接触性皮炎比如例如毒葛和尿疹)、痤疮、虫咬伤/蜇伤、皮肤溃疡(包括但不限于糖尿病溃疡和褥疮)、粘膜炎、炎症(例如牙周炎、正牙炎症、使用化妆品或皮肤护理产品引起的炎症/刺激、炎性结膜炎、痔疮和生殖器炎症)、齿龈炎、支气管炎、喉炎、喉咙痛、带状疱疹(singles)、真菌刺激(例如足癣和股癣)、发热性疱疹、疖子、脚底疣、或阴道损伤(包括例如真菌和性传播的阴道损伤)相关的痛觉过敏病症。
与皮肤表面相关的痛觉过敏病症包括灼伤(包括但不限于热伤、放射灼伤、化学灼伤、太阳灼伤、和风灼伤)、擦伤(比如例如角膜擦伤、挫伤、挫伤、冻伤)、皮疹(包括过敏、热接触性皮炎(例如毒葛)和尿疹)、痤疮、虫咬伤/蜇伤和皮肤溃疡(包括糖尿病溃疡和褥疮)。口、喉和支气管的痛觉过敏病症包括粘膜炎、拔牙后、牙周炎、齿龈炎、正牙炎症、支气管炎、喉炎和喉咙痛。眼睛的痛觉过敏病症包括角膜擦伤、后放射状(post-radial)角膜切割手术和炎性结膜炎。直肠/肛门的痛觉过敏病症包括痔疮和生殖器炎症。与传染体相关的痛觉过敏病症包括带状疱疹、真菌刺激(包括足癣和股癣)、发热性疱疹、疖子、脚底疣和阴道损伤(包括例如与真菌和性传播疾病相关的损伤)。痛觉过敏病症还可与手术后恢复有关,比如乳房肿瘤切除术、会阴切开术、腹腔镜检查、关节镜检查、放射状角膜切割手术和拔牙后的恢复。
作为外周痛觉过敏的预防或治疗,可采用任何将化合物递送到感染区的途径施用S-MNTX。施用可以是口服或胃肠外的。施用方法还包括局部(topical)和局部(local)施用。S-MNTX可施用于任何身体表面,包括皮肤、关节、眼睛、嘴唇和粘膜。
S-MNTX可与其它提供抗痛觉过敏作用的化合物(比如本文所述的那些)联合递送,包括但不限于治疗疼痛药物、止痒药物、抗炎剂等。S-MNTX还可与其它化合物一起施用用于治疗引起炎症的病症,比如抗病毒剂、抗细菌剂、抗真菌剂和抗感染剂。这些其它的化合物可起作用并且局部或全身施用,并且可作为相同组合物的一部分或可单独施用。下面将更详细描述这样的化合物。
炎症通常与肿瘤坏死因子(TNF)产生的增加有关,相信TNF产生的降低将导致炎症的减少。已显示外周作用的阿片样物质激动剂以降低TNF的产生(美国专利6,190,691)。已显示外周选择性κ-阿片样物质阿西马朵林在佐剂诱导的关节炎动物模型中是有效的抗关节炎剂(Binder,W.和Walker,J.S.Br.J.Pharma 124:647-654)。因此,S-MNTX及其衍生物的外周阿片样物质激动剂活性用于炎性病症的预防和治疗。不被任何理论约束,S-MNTX及其衍生物的抗炎作用可能是直接或间接抑制TNF产生。S-MNTX或其衍生物可全身或局部施用。S-MNTX可与另外一种TNF抑制剂比如洛哌丁胺和地芬诺酯或与本文所述的其它抗炎剂联合施用。
本发明的另外一个方面是使用S-MNTX或其衍生物预防和/或治疗全身性炎性病症,优选炎性肠疾病、类风湿性关节炎、恶病质、哮喘、克罗恩病、内毒素休克、成人呼吸窘迫综合征、缺血/再灌注损伤、移植物抗宿主反应、骨重吸收、移植或狼疮。
在仍另外的一组实施方案中,可适于使用S-MNTX或其衍生物治疗的炎性病症与下述症状有关:多发性硬化、糖尿病、或与获得性免疫缺陷综合征(AIDS)或癌症相关的消瘦。
在一组实施方案中,皮肤炎性病症,优选牛皮癣、异位性皮炎、UV引起的炎症、接触性皮炎或其它药物(包括但不限于RETIN-A(全反式视黄酸))引起的炎症可适于使用S-MNTX或其衍生物治疗。
本发明的另外一个方面是治疗非过敏性炎性皮肤病症的方法,所述方法包括以有效治疗炎性病症的量施用S-MNTX。非过敏性炎性皮肤病症与刺激性接触性皮炎、牛皮癣、湿疹、瘙痒症、脂溢性皮炎、货币状皮肤炎、扁平苔藓、寻常痤疮、粉刺、多形、nodulokystic痤疮、集簇性痤疮、老年性痤疮、二级痤疮、药物性痤疮、角质化病症、和水疱样真皮有关。
某些尤其可适于治疗的患者是具有任何一种前述病症之症状的患者。所述患者利用其它治疗可能未能得到减轻或停止以得到其症状的减轻或得到其症状减轻的一致程度。这样的患者据说是采用常规治疗难治愈的。所述病症可由一种或多种不良病症诱导或是其结果,所述不良病症包括但不限于疾病病症、身体病症、药物诱导的病症、生理不平衡、压力、焦虑等。病症可以是急性病症或慢性病症。
可利用S-MNTX和除S-MNTX以外治疗剂的组合治疗对象。在这些情况下,在时间上足够接近地通常同时施用S-MNTX以及其它的治疗剂,使得对象经受如所希望的多种药剂的作用。在一些实施方案中,在时间上首先递送S-MNTX,在一些实施方案中,在时间上第二递送S-MNTX,并且也在一些实施方案中同时递送。如下面更详细地讨论的,本发明计划其中S-MNTX以包含其它药剂的制剂施用的药物制剂。这些制剂可以是例如描述于美国专利申请10/821,809中的那些,所述美国专利申请10/821,809以其整体形式通过引用并入本文。包括固体、半固体、液体、控释制剂、以及其它这样的制剂。
可以是与S-MNTX一起成为预防和治疗方案的一部分的一种重要类别的治疗剂是阿片样物质。申请人令人惊讶地发现S-MNTX与阿片样物质吗啡组合使用导致对胃肠传输增加的和明显的协同抑制。因此,本发明提供含有S-MNTX与一种或多种阿片样物质组合的药物组合物。这将允许之前不能得到的改变。例如,当在治疗某些外周介导的病症中需要更低剂量的阿片样物质时,现在将通过与S-MNTX联合治疗而变得可能。
所述阿片样物质可以是任何药学上可接受的阿片样物质。常用的阿片样物质选自:阿芬他尼、阿尼利定、阿西马朵林、布马佐辛、burprenorphine、布托啡诺、可待因、地佐辛、二乙酰吗啡(海洛因)、二氢可待因、地芬诺酯、非多托嗪、芬太尼、funaltrexamine、氢可酮、氢吗啡酮、左洛啡烷、左旋乙酰美沙酮、羟甲左吗喃、洛哌丁胺、美吡利啶(哌替啶)、美沙酮、吗啡、吗啡-6-葡糖苷酸、纳布啡、烯丙吗啡、阿片、羟可酮、羟吗啡酮、镇痛新、哌丙吡胺、丙氧芬、瑞芬太尼、舒芬太尼、替利定、曲美布丁和曲马多。
根据待实现的理想作用,所述阿片样物质可胃肠外施用或以其它同时影响中枢神经体系(CNS)和外周阿片样物质受体的全身途径施用。与S-MNTX组合的阿片样物质的理想作用可以是预防或治疗腹泻、预防或治疗任何原因或病因的疼痛包括预防或治疗外周痛觉过敏。当所述指示是预防或治疗外周痛觉过敏时,理想的是:提供不具有伴随CNS作用的阿片样物质或作为替代地局部(topically)或局部(locally)施用所述阿片样物质使得所述阿片样物质基本上不穿过血脑屏障而提供对外周阿片样物质受体的作用。
与S-MNTX相组合的尤其用于预防或治疗腹泻或预防或治疗外周痛觉过敏的阿片样物质包括但不限于:
(i)洛哌丁胺[4-(对氯苯基)-4-羟基-N-N-二甲基-α,α-二苯基-1-哌啶丁酰胺盐酸盐]、洛哌丁胺类似物以及本文所定义的相关化合物[见美国专利3,884,916和3,714,159;还见美国专利4,194,045、4,116,963、4,072,686、4,069,223、4,066,654]、洛哌丁胺的N-氧化物和其类似物、代谢物和前药以及本文所定义的相关化合物[也见美国专利4,824,853]、以及比如以下的(a)、(b)和(c)的相关化合物:
(a)4-(芳酰基氨基)吡啶-丁酰胺衍生物以及本文定义的其N-氧化物[也见美国专利4,990,521];
(b)5-(1,1-二苯基-3-(5-或6-羟基-2-氮杂二环-(2.2.2)辛-2-基)丙基)-2-烷基-1,3,4-二唑、5-(1,1-二苯基-4-(环氨基)丁-2-反式-烯-1-基)-2-烷基-1,3,4-二唑、2-[5-(环氨基)-乙基-10,11-二氢-5H-二苯并[a,d]-环庚烯-5-基]-5-烷基-1,3,4-二唑]和相关化合物[见美国专利4,013,668、3,996,214和4,012,393];
(c)2-取代-1-氮杂二环[2,2,2]辛烷[见美国专利4,125,531];
(ii)3-羟基-7-氧代吗啡喃和3-羟基-7-氧代异吗啡喃[见例如美国专利4,277,605];
(iii)本文提供的脒脲[也见美国专利4,326,075、4,326,074、4203,920、4,060,635、4,115,564、4,025,652]和2-[(氨基苯基和酰胺基苯基)氨基]-1-氮杂环烷烃[见美国专利4,533,739];
(iv)不穿过血脑屏障的美克法胺(metkephamid)[H-L-Tyr-D-Ala-Bly-L-Phe-N(Me)Met-NH2;见例如美国专利4,430,327;Burkhart等(1982)Peptides 3-869-871;Frederickson等(1991)Science211:603-605]和其它合成的阿片样物质肽,比如H-Tyr-D-Nva-Phe-Orn-NH2、H-Tyr-D-Nle-Phe-Orn-NH2、H-Tyr-D-Arg-Phe-A2bu-NH2、H-Tyr-D-Arg-Phe-Lys-NH2和H-Lys-Tyr-D-Arg-Phe-Lys-NH2[见美国专利5,312,899;也见Gesellchen等(1981)Pept:Synth,Struct.,Funct,Proc.Am.Pept.Symp.,7th,;Rich等(Eds),Pierce Chem.Co.,Rochford,I11.,pp.621-62];
(v)如美国专利5,236,947中定义的丙胺类等。
S-MNTX还可与其它抗腹泻化合物和组合物组合用于治疗腹泻。例如,S-MNTX可与公知的抗腹泻剂组合施用于对象。可以联合施用两种或多种化合物或可使用相同或不同的施用途径分别施用所述化合物。公知的抗腹泻剂包括例如洛哌丁胺,洛哌丁胺类似物,洛哌丁胺N-氧化物及其类似物、代谢物以及前药,地芬诺酯,西沙比利,抗酸剂,氢氧化铝,硅酸镁铝,碳酸镁,氢氧化镁,碳酸钙,聚卡波菲(Polycarbophil),聚二甲基硅氧烷,莨菪碱,阿托品,呋喃唑酮,地芬诺新,善得定,兰索拉唑,高岭土,果胶,活性炭,磺胺脒,琥珀酰磺胺噻唑,邻苯二甲酰基磺胺噻唑,铝酸铋,碱式碳酸铋,碱式柠檬酸铋,柠檬酸铋,三钾二枸橼酸铋,酒石酸铋,碱式水杨酸铋,碱式硝酸铋和碱式没食子酸铋,阿片酊剂(止痛剂)、草药、和植物衍生的抗腹泻剂。
可以与S-MNTX一起成为治疗方案的一部分的其它治疗剂是肠易激综合征(IBS)剂、抗生素、抗病毒剂、抗真菌剂、抗传染剂、抗炎剂,包括抗组胺剂、血管收缩剂、抗腹泻剂等。
可以与S-MNTX组合使用的IBS治疗剂包括但不限于苯二氮类化合物、抗痉挛剂、选择性5-羟色胺再摄取抑制剂(SSRIs)、胆囊收缩素(CCK)受体拮抗剂、促胃动素受体激动剂或拮抗剂、自然杀伤(NK)受体拮抗剂、促肾上腺皮质激素释放因子(CRF)受体激动剂、促生长素抑制素受体激动剂、抗酸剂、GI弛缓剂、抗气体化合物、含铋的制剂、戊聚糖多硫酸酯、止吐的多巴胺D2拮抗剂、前列腺素E类似物、促性腺激素释放激素类似物(亮丙瑞林)、促肾上腺皮质激素-1拮抗剂、神经激肽2受体拮抗剂、胆囊收缩素-1拮抗剂、β-阻滞剂、抗食管反流剂、抗毒蕈素性药物、抗腹泻剂、抗炎剂、抗蠕动剂、5HT1激动剂、5HT3拮抗剂、5HT4拮抗剂、5HT4激动剂、胆盐螯合剂、容积性药物、α2-肾上腺素激动剂、矿物油、抗抑郁剂、草药。
IBS治疗剂的具体实例包括但不限于以下:
通过与A型γ-氨基丁酸(GABA)受体(GABAA)相互作用用于抑制惊厥作用的苯二氮类化合物及其类似物,例如DIASTAT和VALIUM、LIBRIUM、以及ZANAX。
SSRI,例如氟伏沙明、氟西汀、帕罗西汀、舍曲林、西酞普兰、万拉法新、西克拉明、度洛西汀、米那普仑、奈法唑酮和cyanodothiepin(见Prous J.R.的The Year Drugs News,1995Edition,pp.47-48)和WO 97/29739。
CCK受体拮抗剂,例如地伐西匹、氯戊米特、dexioxiglumide、氯谷胺,D′Amato,M.等,Br.J.Pharmacol.Vol.102(2),pp.391-395(1991);Cl 988;L364,718;L3637260;L740,093和LY288,513;美国专利5,220,017中公开的CCK受体拮抗剂,Bruley-Des-Varannes,S,等Gastroenterol.Clin.Biol.Vol.15.(10)9pp.744-757(1991),和Worker C:EUPHAR′99-Second European Congress of Pharmacology(Part IV)Budap est,Hungary Iddb Meeting Report 1999July 3-7。
促胃动素受体激动剂或拮抗剂,包括例如促胃动素激动剂ABT-269,(红霉素,8,9--二脱氢-N--二甲基脱氧-4”,6,12-三脱氧-6,9-环氧-N-乙基)、脱(N-甲基-N-乙基-8,9-酐红霉素A)和脱(N-甲基)-N-异丙基-8,9-酐红霉素A),Sunazika T.等,Chem.Pharm.Bull.,Vol.37(10),pp.2687-2700(1989);A-173508(Abbot Laboratories);促胃动素拮抗剂(Phe3,Leu-13)猪促胃动素,214th American Chemical Society(ACS)Meeting(Part V);Highlights from Medicinal Chemistry Poster Session,Wednesday 10 September,Las Vegas,Nevada,(1997),Iddb MeetingReport September 7-11(1997);和ANQ-11125,Peeters T.L.等,Biochern.Biophys.Res.Commun.,Vol.198(2),pp.411-416(1994)。
NK受体拮抗剂,包括例如FK 888(Fujisawa)、GR 205171(GlaxoWellcome)、IY 303870(Lilly)、MK 869(Merck)、GR82334(GlaxoWellcome)、L758298(Merck)、L 733060(Merck)、L 741671(Merck)、L 742694(Merck)、PD 154075(Parke-Davis)、S18523(Servier)、S1 9752(Servier)、OT 7100(Otsuka)、WIN 51708(Sterling Winthrop)、NKP-608A、TKA457、DNK333、CP-96345、CP-99994、CP122721、L-733060、L-741671、L742694、L-758298、L-754030、GR-203040、GR-205171、RP-67580、RPR-100893(达匹坦)、RPR-107880、RPR-111905、FK-888、SDZ-NKT-343、MEN-10930、MEN-11149、S-18523、S-19752、PD-154075(CAM-4261)、SR-140333、LY-303870(lanepitant)、EP-00652218、EP00585913、L-737488、CGP-49823、WIN-51708、SR-48968(沙瑞度坦)、SR-144190、YM383336、ZD-7944、MEN-10627、GR-159897、RPR-106145、PD-147714(CAM-2291)、ZM253270、FK-224、MDL-105212A、MDL-105172A、L-743986、L-743986类似物、S-16474、SR-142801(奥沙奈坦)、PD-161182、SB-223412、以及SB-222200。
例如公开于WO 99/40089中的CRF受体激动剂或拮抗剂、AXC2219、Antalarmin、NGD 1、CRA 0165、CRA 1000、CRA 1001。
促生长素抑制素受体激动剂,例如善得定、伐普肽(vapreotide)、兰瑞肽(Lanreotide)。
抗炎化合物,尤其是免疫调节类型的那些,例如,NSAIDS;肿瘤坏死因子(TNF,TNFα)抑制剂;巴利昔单抗(basiliximab)(例如SIMULECT);达克珠单抗(daclizumab)(例如ZENAPAX);英夫单抗(例如REMICADE);etanercept(例如ENBREL)霉酚酸酯(例如CELLCEPT);硫唑嘌呤(例如IMURAN);他克莫司(例如PROGRAF);类固醇;甲氨喋呤和GI抗炎剂,例如柳氮磺吡啶(例如AZULFIDINE);奥沙拉嗪(例如DIPENTUM);和美沙拉秦(例如ASACOL、PENTASA、ROWASA)。
抗酸剂,比如铝和镁抗酸剂;以及氢氧化钙比如MAALOX。
抗气体化合物,例如,以商品名MYLANTA和MYLICON市售的聚二甲基硅氧烷;和酶制剂包括PHAZYME和BEANO。
含铋的制剂,例如,还被称为PEPTO-BISMOL的碱式水杨酸铋。
以商品名ELMIRON市售的戊聚糖多硫酸酯,化学地和结构地类似葡糖胺多糖的肝素样大分子烃衍生物。
止吐的多巴胺D2拮抗剂,包括例如多潘立酮。
前列腺素E类似物、促性腺激素释放激素类似物(亮丙瑞林)、促肾上腺皮质激素-1拮抗剂、神经激肽2受体拮抗剂、胆囊收缩素-1拮抗剂、β-阻滞剂。
抗食管反流剂包括但不限于PRILOSEC。
抗痉挛剂和抗毒蕈素性药物包括但不限于双环胺、奥昔布宁(例如,盐酸奥昔布宁)、托特罗定(例如酒石酸托特罗定)、阿尔维林、辛托品、阿托品(例如硫酸阿托品)、颠茄、后马托品、甲溴后马托品、莨菪碱(例如硫酸莨菪)、甲基东莨菪碱、东莨菪碱(例如盐酸东莨菪碱)、克利溴铵、西托溴铵、环苯甲哌、吡喹利乌、奥替溴铵、格隆溴胺、和麦皮凡林。
抗腹泻剂包括但不限于异丙阿托品、异丙酰胺、甲哌酯、溴丙胺太林、羟苄利明、哌仓西平、地芬诺酯(例如盐酸地芬诺酯)、硫酸阿托品、盐酸阿洛斯琼、盐酸地芬诺新、碱式水杨酸铋、嗜酸乳杆菌、曲美布汀、阿西马朵林、和乙酸善得定。
抗炎剂还包括但不限于美沙拉秦、柳氮磺吡啶、巴柳氮二钠、氢化可的松和奥沙拉嗪钠。
5HT1激动剂包括但不限于丁螺旋酮。
5HT3拮抗剂包括但不限于奥丹西隆、西兰司琼和阿洛斯琼。
5HT4拮抗剂包括但不限于piposcrod。
5HT4激动剂包括但不限于替加色罗(tegaserod)(例如马来酸替加色罗)、和povcalopride。
抗抑郁剂包括但不限于去甲丙咪嗪(desiprimine)、阿米替林、丙咪嗪(imiprimine)、氟西汀、和帕罗西汀。
其它的IBS治疗剂包括右氯谷胺、TAK-637、他奈坦(talnetant)、SB 223412、AU 244、神经营养因子-3、GT 160-246、免疫球蛋白(IgG)、雷冒拉宁、risaxmin、rimethicone、达非那新、扎氟普汀(zamifenacin)、氯谷胺、米索前列醇(Misoprostil)、亮丙瑞林、多潘立酮、促生长素抑制素类似物、苯妥英、NBI-34041、沙瑞度坦、和右氯谷胺。
抗生素包括但不限于四环素系抗生素比如氯四环素、土霉素、四环素、去甲氯四环素、美他环素、多西环素、米诺环素和氢吡四环素;比如卡那霉素、阿米卡星、庆大霉素C1a、庆大霉素C2、庆大霉素C2b或庆大霉素C1、西索米星(sisomycin)、netilmicin、大观霉素、链霉素、要布霉素、新霉素B、地贝卡星和卡那霉素;大环内酯类比如麦利多霉素和红霉素;林可霉素类比如氯林可霉素和林可霉素;分别具有6β-或7β-酰氨基基团的青霉烷酸(6-APA)-和头孢烷酸(7-ACA)-衍生物,其存在于发酵的、半合成或完全合成可得到的3-位修饰的7β-酰氨基头孢烷酸衍生物和/或6β-酰氨基青霉烷酸或7β-酰氨基头孢烷酸衍生物中,比如已经公知的以青霉素G或V命名的青霉烷酸衍生物,比如苯氧乙基青霉素、苯氧丙基青霉素、萘夫西林、oxycillin、氯唑西林、双氯西林、氟氯西林、环己西林、依匹西林、美西林、甲氧苯青霉素、阿洛西林、磺苄西林、替卡西林、美洛西林、哌拉西林、苄茚西林、叠氮西林或环己西林,以及已经公知的以头孢克洛、头孢氨呋肟、头孢氮氟(cefazlur)、头孢乙氰、头孢唑啉、头孢氨苄、头孢羟氨苄、头孢甘酸、头孢西丁、头孢噻啶、头孢磺啶、头孢替安、ceftazidine、头孢尼西、头孢氨噻、头孢甲肟、头孢唑肟、头孢噻吩、头孢拉定、头孢孟多、唑酮头孢菌素、头孢吡硫、头孢沙定、头孢曲秦、头孢吡酮、ceftrixon和头孢雷特命名的头孢菌素衍生物;以及其它的克拉维烷(clavam)、青霉烯和碳青霉烯类型的β-内酰胺抗生素,比如拉氧头孢、克拉维酸、诺卡杀菌素A、青霉烷砜、氨曲南和硫霉素;以及其它的抗生素包括双环霉素、新生霉素、氯霉素或甲砜霉素、利福平、磷霉素、粘菌素和万古霉素。
抗病毒剂包括但不限于核苷类似物、非核苷类逆转录酶抑制剂、核苷类逆转录酶抑制剂、蛋白酶抑制剂、整合酶抑制剂,包括以下:乙酰吗喃、无环鸟苷、无环鸟苷钠、阿德福韦、alovudine、阿韦舒托(alvirceptsudotox)、盐酸金刚烷胺、珠囊壳素、阿立酮、甲磺酸阿的维定、阿夫立定、西多福韦、西潘茶碱(cipamfylline)、盐酸阿糖胞苷、甲磺酸地拉韦定、地昔洛韦、地达诺新、二沙利、依度尿苷、氨韦拉登、韦罗肟、泛昔洛韦、氯苯氢异喹、非西他滨、非阿尿苷、膦利酯、膦甲酸钠、膦乙酸钠、更昔洛韦、更昔洛韦钠、碘苷、吲哚那韦、凯托沙、拉米夫定、洛布卡韦、lopinovir、盐酸甲氧苯异喹、甲吲噻腙、奈非那韦、奈韦拉平、戊昔洛韦、pirodavir、利巴韦林、盐酸金刚乙胺、利托那韦、甲磺酸沙喹那韦、盐酸索金刚胺、索利夫定、匐枝青霉素、司他夫定、泰诺福韦(tenofovir)、盐酸乙胺芴酮、三氟尿苷、盐酸valacyclovir、阿糖腺苷、磷酸阿糖腺苷、磷酸阿糖腺苷钠(vidarabine sodium phosphate)、viroxime、扎西他滨、司他夫定、齐多夫定(AZT)、和净韦肟(zinviroxime)。
抗感染剂包括但不限于盐酸双氟沙星;lauryl isoqumolmiumbromide;拉氧头孢二钠;氯丙硝唑;表紫苏霉素;盐酸沙拉沙星(sarafloxacin hydrochloride);HIV和其它逆转录病毒的蛋白酶抑制剂;HIV和其它逆转录病毒的整合酶抑制剂;头孢克洛(头孢氯氨苄);阿昔洛韦(Zovirax);诺氟沙星(氟哌酸);头孢西丁钠(头孢西丁);头孢呋辛酯(头孢他啶);环丙沙星(环丙氟哌酸);盐酸氨基吖啶(aminacrinehydrochloride);氯化苄乙氧铵:硫双二氯酚钠;bromchlorenone;过氧化氢脲;西他氯铵;西吡氯铵:盐酸洗必太;氯碘羟喹;溴化度米芬;硫双对氯酚;氯氟哒唑;碱式品红;呋喃唑酮;龙胆紫;二氢氯喹,六氯酚:过氧化氢;鱼石脂;咪癸碘(imidecyl iodine);碘;异丙醇;乙酸磺胺米隆;汞林钠(meralein sodium);mercufenol chloride;氨基汞;甲氯化苄乙氧铵(methylbenzethonium chloride);呋喃西林;硝甲酚汞;盐酸奥克太啶;奥昔氯生;奥昔氯生钠;樟脑化对氯苯酚;高锰酸钾;聚维酮碘;氯化三苯唑;硝酸银;磺胺嘧啶银;氯氧三嗪;苯磺硫汞钠;硫柳汞:曲氯新钾。
抗真菌剂(抗生素)包括:多烯类比如两性霉素-B、克念菌素、制皮菌素、菲律平、戊霉素、曲古霉素、哈霉素、光明霉素、美帕曲星、那他霉素、制霉素、变曲霉素、真菌霉素;以及其比如氮丝氨酸、灰黄霉素、寡霉素、吡咯尼林、西卡宁、杀结核菌素和绿色菌素(viridin)。抗真菌剂合成物包括:烯丙胺类比如萘夫替芬和特比奈芬;咪唑类比如:联苯苄唑、布康唑、氯海因、氯苄甲咪唑、氯康唑、克霉唑、益康唑、恩康唑、芬康唑、异康唑、酮康唑、咪康唑、奥莫拉唑、硝酸奥昔康唑、硫康唑和噻康唑;三唑类比如氟康唑、伊曲康唑(itraconazole)、特康唑。其它包括吖啶琐辛、阿莫罗芬、苯柳胺酯、溴柳氯苯胺(bromosalicylchloranilide)、丁氯柳胺、chlophenesin、环己吡酮乙醇胺、氯羟喹啉、coparaffmate、地马唑、二盐酸盐、水杨胺己醚、氟胞嘧啶、氯苯噻唑、海克替啶、洛氟卡班、硝呋拉太、碘化钾、丙酸酯、丙酸、巯氧吡啶、水杨酰苯胺、舒苯汀、替诺尼唑、托西拉酯、托林达酯、托萘酯、3’,4’,5’,5,7-五羟黄酮、苄硫嗪酸、和十一烯酸。抗真菌剂还包括刺球白素类或包括卡泊芬净(caspofungin)、micafungin、阿尼芬净(anidulafungin)、aminocandin等的抗真菌剂。
血管收缩剂包括但不限于肾上腺素、去甲肾上腺素、伪麻黄碱、去氧肾上腺素(phenylephrine)、羟甲唑啉、丙己君、萘甲唑啉、tetrahydrolozine、赛洛唑啉、乙基去甲肾上腺素、甲氧明、phenylhexedrine、美芬丁胺、间羟胺、多巴胺、肾上腺素异戊酯、norphedrine和ciraxzoline,可有利地用于本文的组合物和方法中。这些血管收缩剂的使用将有助于降低活性抗痛觉过敏剂的全身性递送。
当单独使用或联合使用时,以治疗有效量施用本发明的药物制剂。治疗有效量将通过下面讨论的参数进行确定,但是,无论如何,其是确立有效治疗患有本文所述病症之一的对象(例如人类对象)的药物水平的量。有效量指延迟待治疗病症或其相关症状发作,减轻其严重程度,或完全抑制、减轻其进展,或同时停止正在治疗的病症或其相关症状发作或进展必需的单独或多剂量、或递送速率的量。在腹泻情况下,例如,有效量是导致下述一种或多种症状的量:1)降低肠蠕动频率;2)增加大便稠度,和/或3)降低大便体积至少于200g/天。在一个实施方案中,有效量指导致每天肠蠕动3次或更少的量,优选每天2次或更少,更优选每天1次肠蠕动。在某些情况下,取决于施用方式,所述量在施用MNTX后12小时、10小时、8小时、6小时、4小时、2小时、1小时内和甚至在施用时立即足以降低肠蠕动。静脉内施用可产生即时的作用。在恢复胃肠功能中,有效量可以是例如增加口-盲肠转运时间所需的量。对于疼痛的护理或治疗,有效量可以是例如足以使得对象更舒服(根据主观标准、客观标准或同时确定)的量。在外周痛觉过敏情形下,有效量可以是例如减轻外周痛觉过敏的症状(比如对疼痛或瘙痒症的高敏感性)的量。对于炎症的预防或治疗,有效量可以是例如足以降低或减轻与炎症相关的红、肿或组织损伤或足以增加感染区域比如关节的活动性的量。当施用给对象时,当然,有效量将取决于治疗的特定症状;病症的严重程度;个体患者参数包括年龄、身体状况、体形和体重;同时治疗;治疗频率;以及施用方式。这些因素是本领域一般技术人员熟知的并且可利用常规试验进行解决。
一般而言,S-MNTX的口服剂量将为约0.05至约40mg/kg体重/天、约0.05至约20.0mg/kg体重/天、约0.05至约10mg/kg体重/天、约0.05至约5mg/kg体重/天。一般而言,胃肠外施用,包括静脉内和皮下施用,将约0.001至1.0mg/kg体重、约0.01至1.0mg/kg体重、或约0.1至约1.0mg/kg体重,这取决于施用是推注或随时间扩散比如利用I.V.点滴。希望约0.05至0.5mg/kg体重的剂量将得到理想的结果。取决于施用方式,可适当地调整剂量以实现理想的局部或全身药物水平。例如,希望肠溶包衣制剂中S-MNTX的口服施用剂量将比立即释放口服制剂中的量更低。在患者对该剂量不足以响应的情形下,甚至可施用更高的剂量(或通过不同、更局部化的递送途径的有效的更高剂量)到患者耐受允许的程度。期望每日多剂量以实现适当的化合物全身水平。适当的全身水平可通过例如测量患者的峰值血浆药物水平或持续血浆药物水平来确定。“剂量(Dose)”和“剂量(dosage)”在本文中可互换使用。
可利用多种施用途径。当然,所选的具体方式将取决于所选药物的特定组合、待治疗或预防病症的严重程度、患者的病症、以及治疗功效所需的剂量。一般而言,可利用医疗可接受的任何施用方式,即产生有效水平的活性化合物而不引起临床上不可接受的副作用的任何方式实施本发明的方法。这样的施用方式包括口服、直肠、局部、透皮、舌下、静脉内输注、肺部、动脉内、脂肪组织内、淋巴内、肌肉内、腔内、气雾剂、耳(例如通过滴耳剂)、鼻内、吸入、关节内、无针注射、皮下或皮内(例如透皮)递送。对于连续输注,可应用患者控制的镇痛(PCA)设备或可植入的药物递送设备。对于预防或长期治疗,口服、直肠或局部施用可能是重要的。优选的直肠递送方式包括作为栓剂或灌肠剂洗剂施用。
药物制剂可便利地以单位剂型存在并且可通过药物领域中熟知的任何方法制备。所有的方法包括将本发明的化合物与组成一种或多种助剂成分的载体结合的步骤。一般地,通过均一地并密切地使本发明的化合物引入到液体载体、精细分散的固体载体中,或引入到液体载体和精细分散的固体载体两者中来制备组合物,如果需要,然后成形为产品。
当施用时,以药学上可接受的组合物施用本发明的药物制剂。这样的制剂可常规地包含盐、缓冲剂、防腐剂、可相容的载体、润滑剂、以及任选的其它治疗成分。当用于医疗时,所述盐将是药学上可接受的,但是非药学上可接受的盐可常规地用于制备其药学上可接受的盐并且不排除在本发明的范围之外。这样的药理学上和药学上可接受的盐包括但不限于由以下酸制备的那些盐:盐酸、氢溴酸、硫酸、硝酸、磷酸、马来酸、乙酸、水杨酸、对甲苯磺酸、酒石酸、柠檬酸、甲磺酸、甲酸、琥珀酸、萘-2-磺酸、扑酸、3-羟基-2-萘羧酸和苯磺酸。
应当理解,当提及MNTX、R-MNTX和S-MNTX、以及本发明的治疗剂时,其表示包含其盐。这样的盐是多种本领域那些或一般技术人员熟知的。当用于药物制剂时,所述盐优选地药学上可接受地用于人类。溴化物是一种这样的盐的实例。
本发明的药物制剂可包含药学上可接受的载体或稀释到药学上可接受的载体中。本文所用的术语“药学上可接受的载体”指适于向人类或其它哺乳动物例如非人灵长类、狗、猫、马、牛、绵羊、猪、或山羊施用的一种或多种可相容的固体或液体填充剂、稀释剂或包封物质。术语“载体”代表天然的或合成的有机或无机成分,活性成分与这些载体组合以方便应用。所述载体能以使得没有明显削弱理想的药物功效或稳定性的方式与本发明的制剂混合并互相混合。适于口服施用、栓剂、以及胃肠外施用等的载体制剂可见Remington′s Pharmaceutical Sciences,Mack Publishing Company,Easton,Pa。
含水制剂可包含螯合剂、缓冲剂、抗氧化剂,以及任选地等渗剂,优选pH调节至3.0至3.5之间。这样的对高压灭菌和长期储存稳定的制剂的实例记载于共同未决的名称为“Pharmaceutical Formulation”的美国申请10/821,811中。
螯合剂包括例如乙二胺四乙酸(EDTA)及其衍生物,柠檬酸及其衍生物、烟酰胺及其衍生物、去氧胆酸钠及其衍生物、以及L-谷氨酸、N,N-二乙酸及其衍生物。
缓冲剂包括选自柠檬酸、柠檬酸钠、乙酸钠、乙酸、磷酸钠和磷酸、抗坏血酸钠、酒石酸、马来酸、甘氨酸、乳酸钠、乳酸、抗坏血酸、咪唑、碳酸氢钠和碳酸、琥珀酸钠和琥珀酸、组氨酸、以及苯甲酸钠和苯甲酸、或其组合的那些。
抗氧化剂包括选自抗坏血酸衍生物、丁基羟基茴香醚、丁基羟基甲苯、没食子酸烷基酯、偏亚硫酸氢钠、亚硫酸氢钠、连二硫酸钠、巯基乙酸钠、甲醛合次硫酸氢钠、生育酚及其衍生物、单硫代甘油、以及亚硫酸钠。优选的抗氧化剂是单硫代甘油。
等渗剂包括选自氯化钠、甘露醇、乳糖、右旋糖、甘油和山梨醇的那些。
可以与本发明组合物一起使用的防腐剂包括苄醇、对羟基苯甲酸酯、乙基汞硫代水杨酸钠、氯丁醇并且优选苯扎氯铵。通常,所述防腐剂将以至多约2%(以重量计算)的浓度存在于组合物中。然而,防腐剂的准确浓度会根据希望的用途变化,并且可由本领域中技术人员容易地确定。
本发明的组合物可配制在冻干组合物中,优选在冷冻保护剂例如甘露醇、或乳糖、蔗糖、聚乙二醇、和聚乙烯吡咯烷酮存在下。导致重新构建6.0或更低的pH的冷冻保护剂是优选的。因此,本发明提供本发明治疗剂的冻干制剂。所述制剂可包含优选在水中是中性或酸性的冷冻保护剂(例如甘露醇或乳糖)。
药剂的口服、胃肠外和栓剂制剂是熟知的并且可商业购得。本发明的治疗剂可加到这样的熟知制剂中。其可在这样的制剂中的溶液或半固体溶液中混合在一起、可提供于这样的制剂内的悬液中或可包含在这样的制剂中的颗粒中。
可将含有本发明治疗剂以及任选地一种或多种其它活性剂的产品配制成口服制剂。所述口服制剂可以是液体、半固体或固体。阿片样物质可任选地包含在口服制剂中。所述口服制剂可配制成在其它药剂(和/或阿片样物质)之前、之后或同时释放本发明的治疗剂。所述口服制剂可配制成使得本发明的治疗剂与其它药剂完全释放在胃中、部分释放在胃中以及部分释放在肠中、释放在肠中、释放在结肠中、部分释放在胃中、或全部释放在结肠中。还可配制口服制剂,由此将本发明治疗剂的释放限制于胃或肠而其它活性剂的释放不受到如此限制或不同于本发明治疗剂地限制。例如,本发明的治疗剂可以是包含在丸剂或胶囊中的肠溶包衣的核或小丸,所述丸剂或胶囊首先释放其它药剂并且仅在本发明治疗剂通过胃并到达肠之后释放本发明的治疗剂。本发明的治疗剂还可位于持续释放材料中,由此在整个胃肠道释放本发明的治疗剂并且在相同或不同的时间释放其它药剂。可利用与本发明肠溶包衣治疗剂组合的本发明治疗剂的快速释放可实现本发明治疗剂释放的相同目的。在这些情况下,其它药剂可快速释放在胃中、整个胃肠道或仅释放在肠中。
用于实现这些不同释放特征的材料是本领域一般技术人员熟知的。通过具有在胃中溶解的粘合剂的常规片剂可获得快速释放。在胃的pH下溶解或在升高的温度下溶解的包衣将实现相同的目的。利用常规的肠溶包衣例如在肠(而不是胃)的pH环境中溶解的pH敏感包衣或随时间溶解的包衣,实现仅在肠中的释放。利用持续释放材料和/或快速释放体系与持续和/或延迟目的的释放体系的组合(例如在不同pH下溶解的小丸),实现整个胃肠道的释放。
在希望首先释放本发明治疗剂的情况下,本发明的治疗剂可包衣在控制释放制剂的表面,所述控制释放制剂处于适于这样的包衣并允许释放本发明治疗剂的药学上可接受的载体中,例如处于用于常规控制释放的温敏的药学上可接受的载体中。当置于身体内时溶解的其它包衣是本领域一般技术人员熟知的。
本发明的治疗剂还可混合在整个控制释放制剂中,由此在其它药剂之前、之后或同时释放。本发明的治疗剂可以是游离的,换句话说,溶解在制剂的材料中。本发明的治疗剂还可以是载体形式,例如分散在整个制剂材料中的蜡包衣的微丸。包衣小丸可制成基于温度、pH等快速释放的本发明治疗剂。还可配制小丸以延迟本发明治疗剂的释放,允许其它药剂在本发明的治疗剂发挥其作用之前在一定时期内起作用。还可配制本发明治疗剂小丸,以实质上任何持续释放方式释放本发明的治疗剂,包括利用现有技术和本领域一般技术人员熟知的材料显示一级释放动力学或S形释放动力学的方式。
本发明的治疗剂还可包含在控制释放制剂内的核内。所述核可具有上述与小丸有关的特征的任何一种或任何组合。例如,本发明的治疗剂可处于包衣有材料的、分散在整个材料中、包衣到材料上或吸收到材料中或吸收到整个材料中的核中。
应当理解,所述小丸或核实质上可以是任何类型。它们可以是由释放材料包衣的药物、分散到整个材料中的药物、吸收到材料中的药物等。所述材料可以是可侵蚀的或不可侵蚀的。
本发明的治疗剂可以以颗粒提供。本文所用的颗粒指可全部或部分由本发明治疗剂或本文所述其它药剂组成的纳米或微米颗粒(或在一些情况下更大)。颗粒可含有在由包衣包围的核中的治疗剂,所述包衣包括但不限于肠溶包衣。治疗剂还可分散在整个颗粒中。治疗剂还可吸收到颗粒中。颗粒可以是任何级别的释放动力学,包括零级释放、一级释放、二级释放、延迟释放、持续释放、快速释放、以及其任何组合等。除了治疗剂以外,颗粒可包括药学和医学领域中常规使用的任何这些材料,包括但不限于可侵蚀的、不可侵蚀的、生物可降解的、或非生物可降解的材料或其组合。颗粒可以是微胶囊,所述微胶囊包含处于溶液或半固体状态的拮抗剂。颗粒实质上可以是任何形状。
非生物可降解的或生物可降解的聚合物材料都可用于制备递送治疗剂的颗粒。这样的聚合物可以是天然的或合成的聚合物。根据释放所需的时间段选择聚合物。特别感兴趣的生物粘附聚合物包括H.S.Sawhney,CP.Pathak和J.A.Hubell在Macromolecules,(1993)26:581-587描述的生物可侵蚀的水凝胶,将其教导并入本文。这些包括聚透明质酸、酪蛋白、明胶、明胶蛋白、聚酸酐、聚丙烯酸、藻酸盐、壳聚糖、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸异丁酯)、聚(甲基丙烯酸己酯)、聚(甲基丙烯酸异癸酯)、聚(甲基丙烯酸十二烷基酯)、聚(甲基丙烯酸苯酯)、聚(丙烯酸甲酯)、聚(丙烯酸异丙酯)、聚(丙烯酸异丁酯)、和聚(丙烯酸十八基酯)。
治疗剂可包含在控制释放体系中。术语“控制释放”意欲指其中药物从制剂中的释放方式和特性是可控的任何含有药物的制剂。这指快速以及非快速释放制剂,其中非快速释放制剂包括但不限于持续释放和缓释制剂。术语“持续释放”(也称为“延长释放”)以其常规意义使用,以表示在延长的时期内提供药物的逐步释放的药物制剂,并且优选地(尽管不是必需地)在延长时期内得到基本上恒定的药物血液水平。术语“缓释”以其常规意义使用,以表示其中在制剂施用和由此的药物释放之间具有时间延迟的药物制剂。“缓释”可以包括或可以不包括延长时期内的药物的逐步释放,因此可以是或可以不是“持续释放”。这些制剂可以适于任何施用方式。
特别用于胃肠道的递送体系概略地分成三种类型:第一种是设计成响应于例如pH变化来释放药物的缓释体系;第二种是设计成在预定时间之后释放药物的定时释放体系;第三种是利用胃肠道下部的大量肠细菌的微生物区系酶体系(例如在结肠定位释放制剂中)。
缓释体系的一个实例是利用例如丙烯酸类或纤维素包衣材料并随pH变化溶解的一种。因为易于制备,已经得到许多关于“肠溶包衣”的报道。一般地,肠溶包衣是经过胃而在胃中不释放明显量的药物(即在胃中释放小于10%、释放5%以及甚至释放1%)并且在肠道中充分崩解(通过与大约中性或碱性肠液相接触)以允许通过肠道壁传送(主动或被动)活性剂的包衣。
用于测定包衣是否归类为肠溶包衣的多种体外试验已经公布在多个国家的药典中。与人工胃液例如pH 1的36至38℃的HCl相接触时保持完整至少2小时,并且其后在人工肠液例如pH 6.8的KH2PO4缓冲液中在30分钟内崩解的包衣是一个实例。一种这样的熟知体系是EUDRAGIT材料,其是商业可购得的并且由Behringer,ManchesterUniversity,Saale Co.,等报道。下面进一步讨论肠溶包衣。
定时释放体系以Fuiisawa Pharmaceutical Co.,Ltd.的TimeErosion System(TES)和R.P.Scherer的Pulsincap为代表。根据这些体系,通过制剂在胃肠道中转运的时间确定药物释放部位。由于制剂在胃肠道中的转运很大程度上受胃排空时间的影响,因此一些定时释放体系也是肠溶包衣的。
利用肠细菌的体系可分类为利用肠细菌产生的偶氮还原酶降解偶氮芳香聚合物的那些,如Ohio University研究组(M.Saffran等,Science,Vol.233:1081(1986))和Utah University研究组(J.Kopecek等,Pharmaceutical Research,9(12),1540-1545(1992))所报道的;和利用肠细菌的β-半乳糖苷酶降解多糖的那些,如Hebrew University研究组(基于PCT申请的未审查的公开的日本专利申请5-50863)和FreibergUniversity研究组(K.H.Bauer等,Pharmaceutical Research,10(10),S218(1993))所报道的。此外,还包括Teikoku Seiyaku K.K.(未审查的公开的日本专利申请4-217924和未审查的公开的日本专利申请4-225922)的利用可被壳聚糖酶降解的壳聚糖的体系。
虽然不是必需地,肠溶包衣通常是聚合物材料。优选的肠溶包衣材料包括生物可侵蚀的、可逐步水解的和/或可逐步水溶的聚合物。每个胶囊的“包衣重量”或包衣材料的相对量,一般指示摄取和药物释放之间的时间间隔。任何包衣应当应用到足够的厚度,使得整个包衣不溶解在pH低于约5的胃肠道流体中,但是在pH约5和以上的确溶解。预期表现出pH依赖溶解特性的任何阴离子聚合物可用作实施本发明的肠溶包衣。具体肠溶包衣材料的选择将取决于下述特性:在胃中耐溶解和崩解、当在胃中时对胃液的不可渗透性和药物/载体/酶、在目标肠部位快速溶解或崩解的能力、储存期间的物理和化学稳定性、无毒性、易于用作包衣(底物友好的)、以及经济实用性。
适当的肠溶包衣材料包括但不限于:纤维素聚合物例如邻苯二甲酸醋酸纤维素、偏苯三酸醋酸纤维素、邻苯二甲酸羟丙基甲基纤维素、琥珀酸羟丙基甲基纤维素、和羧甲基纤维素钠;丙烯酸聚合物和共聚物,其优选由丙烯酸、甲基丙烯酸、丙烯酸甲酯、甲基丙烯酸铵、丙烯酸乙酯、甲基丙烯酸甲酯和/或甲基丙烯酸乙酯形成(例如以商品名EUDRAGIT出售的那些共聚物);乙烯基聚合物和共聚物,例如聚醋酸乙烯酯、聚邻苯二甲酸醋酸乙烯酯、醋酸乙烯酯巴豆酸共聚物、和乙烯-醋酸乙烯酯共聚物;以及虫胶(纯化lac)。还可使用不同包衣材料的组合。用于本文的公知肠溶包衣材料是来自Rohm Pharma(德国)的以商品名EUDRAGIT可商业购得的那些丙烯酸聚合物和共聚物。可作为溶解在有机溶剂中的、作为水分散体、或作为干粉末得到EUDRAGIT系列E、L、S、RL、RS和NE共聚物。EUDRAGIT系列RL、NE和RS共聚物在胃肠道中不可溶但是为可渗透的并且主要用作延长释放。EUDRAGIT系列E共聚物在胃中溶解。EUDRAGIT系列L、L-30D和S共聚物在胃中不可溶解但是在肠中溶解,因此在本文中是最优选的。
特别的甲基丙烯酸共聚物是EUDRAGIT L,尤其是L-30D和EUDRAGIT L100-55。在EUDRAGIT L-30D中,游离羧基与酯基的比率是约1∶1。而且,已知共聚物在pH低于5.5,一般1.5至5.5(即通常存在于上胃肠道流体中的pH)的胃肠道流体中不可溶解,但是在pH高于5.5(即通常存在于下胃肠道流体中的pH)时易于溶解或可部分溶解。另外一种特别的甲基丙烯酸聚合物是EUDRAGIT S,其不同于EUDRAGIT L-30D之处在于游离羧基与酯基的比率是约1∶2。EUDRAGIT S在pH低于5.5时不溶解,但是与EUDRAGIT L-30D不同,在5.5至7.0pH范围内(例如小肠)的胃肠道流体中溶解性差。该共聚物在pH7.0和以上即通常在结肠中发现的pH下可溶解。EUDRAGIT S可单独用作包衣以在大肠中提供药物递送。作为替代,在pH低于7的肠道流体中溶解性差的EUDRAGIT S可与在pH高于5.5的肠道流体中可溶解的EUDRAGIT L-30D组合使用,以提供缓释组合物,所述缓释组合物能配制为将活性剂递送到肠道的各段。所用的EUDRAGIT L-30D越多,在越近处开始释放和递送,所用EUDRAGITS越多,在越远处开始释放和递送。本领域技术人员应当理解,EUDRAGIT L-30D和EUDRAGIT S都可被其它具有相似pH溶解特性的药学上可接受的聚合物替代。在本发明的某些实施方案中,优选的肠溶包衣是ACRYL-EZETM(C型甲基丙烯酸共聚物;Colorcon,West Point,PA)。
肠溶包衣提供活性剂的控制释放,使得可在一些通常可预期的位置实现药物的释放。肠溶包衣还防止治疗剂和载体暴露于口腔、咽、食道和胃的上皮和粘膜组织以及暴露于与这些组织相关的酶。因此,肠溶包衣有助于在理想的递送部位释放药物之前保护活性剂、载体和患者的内部组织免受任何不良事件。此外,本发明的包衣材料能优化药物吸收、活性剂保护、以及安全性。在胃肠道多个区域靶向释放活性剂的多肠溶包衣将能够甚至更有效并且持续地改善在整个胃肠道中的递送。
包衣可以并且通常含有增塑剂以防止形成孔和裂痕,所述孔和裂痕会允许胃液的渗透。适当的增塑剂包括但不限于柠檬酸三乙酯(Citroflex 2)、三乙酸甘油酯(甘油三乙酸酯)、乙酰柠檬酸三乙酯(Citroflec A2)、Carbowax 400(聚乙二醇400)、邻苯二甲酸二乙酯、柠檬酸三丁酯、乙酰化的单甘油酯、甘油、脂肪酸酯、丙二醇、和邻苯二甲酸二丁酯。尤其是,由阴离子羧基丙烯酸聚合物组成的包衣将通常含有约10wt%至25wt%的增塑剂,尤其是邻苯二甲酸二丁酯、聚乙二醇、柠檬酸三乙酯和三乙酸甘油酯。包衣还可含有其它的包衣赋形剂比如脱粘剂、抗泡沫剂、润滑剂(例如硬脂酸镁)、和稳定剂(例如羟丙基纤维素、酸和碱)以溶解或分散包衣材料,以及改善包衣性能和包衣的产品。
利用常规的包衣方法和设备,可将包衣应用于治疗剂的颗粒、治疗剂的片剂、含有治疗剂的胶囊等。例如,利用包衣锅、无空气喷雾技术、流化床包衣设备等,可将肠溶包衣应用于胶囊。可在PharmaceuticalDosage Forms:Tablets,eds.Lieberman等(New York:Marcel Dekker,Inc.,1989)和Ansel等,Pharmaceutical Dosage Forms and DrugDelivery Systems,6th Ed.(Media,PA:Williams & Wilkins,1995)中发现涉及用于制备包衣剂型的材料、设备和方法的详细信息。如上所述,包衣厚度必须足以保证口服剂型保持完整直到到达下肠道的理想局部递送部位。
在另一个实施方案中,提供药物剂型,所述药物剂型含有容纳本发明制剂的肠溶包衣的、渗透活化的装置。在该实施方案中,含有药物的制剂包封在含有小孔的可半渗透的膜或屏障中。如本领域已知的关于所谓的“渗透泵”药物递送装置,半透膜允许在任何方向透过水,而不是药物。因此,当所述装置被暴露于水流体中时,由于装置内部和外部之间的渗透压不同,水将流入装置。当水流入装置时,装置内部中含有药物的制剂将通过孔被“泵”出。药物释放速率将等于水的流入速率乘以药物浓度。水流入和药物流出的速率可由装置的组成和孔的大小控制。用于半渗透膜的合适材料包括但不限于聚乙烯醇、聚氯乙烯、可半渗透的聚乙二醇、可半渗透的聚氨酯、可半渗透的聚酰胺、可半渗透的磺化聚苯乙烯和聚苯乙烯衍生物、可半渗透的聚(苯乙烯磺酸钠)、可半渗透的聚(乙烯基苄基三甲基氯化铵)、和纤维素聚合物比如醋酸纤维素、二醋酸纤维素、三醋酸纤维素、丙酸纤维素、醋酸丙酸纤维素、醋酸丁酸纤维素、三戊酸纤维素、cellulose trilmate、三棕榈酸纤维素、三辛酸纤维素、三丙酸纤维素、二琥珀酸纤维素、二棕榈酸纤维素、cellulose dicylate、醋酸琥珀酸纤维素、丙酸琥珀酸纤维素、醋酸辛酸纤维素、戊酸棕榈酸纤维素、醋酸庚酸纤维素、乙醛二甲基乙缩醛纤维素、醋酸乙基氨基甲酸纤维素、二甲基氨基乙酸纤维素和乙基纤维素。
在另一个实施方案中,提供药物剂型,所述药物剂型含有容纳本发明制剂的持续释放包衣装置。在该实施方案中,含有药物的制剂包封在持续释放的膜或薄膜中。如上所述,所述膜可以是可半渗透的。可半渗透膜允许水进入到包衣装置内部以溶解药物。溶解的药物通过可半渗透膜向外扩散。药物释放速率取决于包衣薄膜的厚度,并且药物释放可能开始于GI道的任何部分。适当的用于这种膜的膜材料包括乙基纤维素。
在另一个实施方案中,提供药物剂型,所述药物剂型含有容纳本发明制剂的持续释放的装置。在该实施方案中,含有药物的制剂与持续释放聚合物均匀地混合。这些持续释放聚合物是高分子量的水可溶性聚合物,当与水接触时,所述聚合物膨胀并产生用于使水扩散到内部并溶解药物的通道。随聚合物膨胀和溶解在水中,更多药物暴露于水用于溶出。这样的体系一般称为持续释放基质。用于这种装置的适当材料包括羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素和甲基纤维素。
在另一个实施方案中,提供药物剂型,所述药物剂型含有容纳本发明持续释放制剂的肠溶包衣装置。在该实施方案中,用肠溶聚合物包被上述含有药物的产品。这样的装置不会在胃中释放任何药物,当所述装置到达肠时,肠溶聚合物首先溶解并且仅在随后会开始释放药物。将以持续释放的方式发生药物的释放。
可利用常规的材料、方法和设备制备肠溶包衣的、渗透活化的装置。例如,首先通过在药学上可接受的软胶囊中包封如前所述的本发明化合物的液体或半固体制剂,来制备渗透活化的装置。然后例如利用空气悬浮机,用半渗透膜组合物(例如包含在适当的溶剂比如二氯甲烷-甲醇混合物中的醋酸纤维素和聚乙二醇4000)包被该内部胶囊,直到形成足够厚的层合物,例如约0.05mm。然后利用常规的技术干燥可半渗透的层合胶囊。其后,利用例如机械钻孔、激光钻孔、机械破裂、或可蚀性元件比如明胶塞的腐蚀,提供透过半渗透层状胶囊壁的具有理想直径(例如约0.99mm)的孔。然后,如前所述,渗透活化的装置可被肠溶包衣。对于含有固体载体而不是液体或半固体载体的渗透活化的装置,内部胶囊是任选的,换句话说,可直接在载体-药物组合物周围形成可半渗透的膜。然而,优选的用于渗透活化装置的含药物制剂的载体是溶液、混悬液、液体、不可互溶的液体、乳剂、溶胶、胶体、以及油。特别优选的载体包括但不限于那些用于含有液体或半固体药物制剂的肠溶包衣胶囊的载体。
纤维素包衣包括邻苯二甲酸醋酸纤维素和偏苯三酸醋酸纤维素;含有至少40%甲基丙烯酸的甲基丙烯酸共聚物,例如衍生于甲基丙烯酸及其酯的共聚物;尤其是邻苯二甲酸羟丙基甲基纤维素。甲基丙烯酸酯包括基于例如比率约1∶1的甲基丙烯酸酯与甲基丙烯酸甲酯或甲基丙烯酸乙酯的分子量高于100,000道尔顿的那些。典型的产品包括由RohmGmbH,Darmstadt,Germany市售的Endragit L,例如L 100-55。典型的邻苯二甲酸醋酸纤维素的乙酰基含量为17至26%,邻苯二甲酸酯含量为30至40%并且粘度为约45至90cP。典型的偏苯三酸醋酸纤维素的乙酰基含量为17至26%,偏苯三酰基含量为25至35%并且粘度为约15至20cS。偏苯三酸醋酸纤维素的一个实例是市售的产品CAT(Eastman Kodak Company,USA)。邻苯二甲酸羟丙基甲基纤维素的分子量通常为20,000至130,000道尔顿,羟丙基含量为5至10%,甲氧基含量为18至24%,并且邻苯二甲酰基含量为21至35%。邻苯二甲酸醋酸纤维素的一个实例是市售的产品CAP(Eastman Kodak RochesterN.Y.,USA)。邻苯二甲酸羟丙基甲基纤维素的实例是以商品名HP50销售的并可得自Shin-Etsu Chemical Co.Ltd.,Tokyo,Japan的羟丙基含量为6~10%、甲氧基含量为20~24%、邻苯二甲酰基含量为21~27%的分子量约84,000道尔顿的市场化产品,以及已知的商品名HP50可得自相同供应商的羟丙基含量、甲氧基含量、以及邻苯二甲酰基含量分别为5~9%、18~22%、27~35%的分子量约78,000道尔顿的市场化产品。
治疗剂可提供在包衣或无包衣的胶囊中。胶囊材料可以是硬的或软的,并且本领域技术人员应当理解,所述胶囊材料通常包含无味、易于施用并且可水溶性的化合物比如明胶、淀粉或纤维素材料。胶囊优选被密封,比如利用明胶带等。例如见Remington:The Science andPractice of Pharmacy,Nineteenth Edition(Easton,Pa.:Mack PublishingCo.,1995),其描述了用于制备胶囊药物的材料和方法。
含有本发明治疗剂的产品可配制成栓剂。本发明的治疗剂可置于栓剂之内或之上的任何位置以有利地影响治疗剂的相对释放。如所需的,释放的性质可以是零级、一级或S形。
栓剂是意欲通过直肠施用的药物的固体剂型。配制栓剂以在体腔内(约98.6)融化、软化、或溶解,由此释放其中包含的药物。栓剂基质应当是稳定的、无刺激性的、化学惰性的、以及生理上惰性的。许多商业可购得的栓剂包含油状或脂肪基材料,比如可可油、椰子油、棕榈仁油、以及棕榈油,其通常在室温下融化或变形,必需冷藏或具有其它储存限制。Tanaka等人的美国专利4,837,214描述了由与1~20wt%的脂肪酸二甘油酯(其中芥酸是一实例)相结合的80~99wt%的月桂型脂肪组成的栓剂基质,所述月桂型脂肪的羟基值为20或更小并且含有具有8至18个碳原子的脂肪酸甘油酯。由于降解,这些类型栓剂的保存期受到限制。其它栓剂基质包括醇、表面活性剂、以及升高融化温度但是也可导致药物的弱吸收和由于局部粘膜刺激引起的副作用的类似物(例如见Hartelendy等人的美国专利6,099,853、Ahmad等人的美国专利4,999,342、以及Abidi等人的美国专利4,765,978)。
一般而言,用于本发明药物栓剂组合物的基质包括含有三酸甘油酯作为主要成分的油和脂肪,比如可可油酯、棕榈脂肪、棕榈仁油、椰子油、分馏椰子油、猪油和WITEPSOL、蜡比如羊毛脂和还原羊毛脂;烃比如VASELINE、角鲨烯、角鲨烷和液体石蜡;长链至中链脂肪酸比如辛酸、月桂酸、硬脂酸和油酸;高级醇比如月桂醇、鲸蜡醇和硬脂醇;脂肪酸酯比如硬脂酸丁酯和丙二酸二月桂酯;中链至长链的羧酸甘油酯,比如三油酸甘油酯和三硬脂酸甘油酯;甘油取代的羧酸酯比如乙酰乙酸甘油酯;以及聚乙二醇及其衍生物,比如聚乙二醇(macrogols)和聚西托醇(cetomacrogol)。它们可单独使用或两种或多种组合使用。如果需要,本发明的组合物还可包含表面活性剂、着色剂等,这通常用于栓剂中。
可通过在搅拌器或研磨机中均匀地混合预定量的活性成分、吸收助剂和任选的基质等,来制备本发明的药物组合物,如果需要,可在升高的温度下进行。通过例如在模具中铸造混合物、或通过利用胶囊填充机将所得的混合物形成为明胶胶囊,可将所得组合物制成单位剂型的栓剂。
根据本发明的组合物还可作为鼻喷雾剂、滴鼻剂、混悬液、凝胶、软膏、霜剂或粉末施用。组合物的施用还可包括利用含有本发明组合物的鼻塞或鼻海绵。
可用于本发明的鼻递送体系可具有多种形式,包括水制剂、非水制剂及其组合。水制剂包括例如水凝胶、水混悬液、水脂质体分散体、水乳剂、水微乳剂及其组合。非水制剂包括例如非水凝胶、非水混悬液、非水脂质体分散体、非水乳剂、非水微乳剂及其组合。多种形式的鼻递送体系可包括维持pH的缓冲剂、药学上可接受的增稠剂和保湿剂。可选择缓冲剂的pH以最优化治疗剂在鼻粘膜上的吸收。
关于非水鼻制剂,可选择适当形式的缓冲剂使得当制剂递送到哺乳动物鼻腔内时,在与例如鼻粘膜相接触时在其中达到所选的pH范围。在本发明中,组合物的pH应当维持在约2.0至约6.0。理想的组合物的pH是施用时不引起对接受者鼻粘膜的显著刺激。
利用药学上可接受的增稠剂可将本发明组合物的粘度维持在理想水平。可用于根据本发明的增稠剂包括甲基纤维素、黄原胶、羧甲基纤维素、羟丙基纤维素、卡波姆、聚乙烯醇、藻酸盐、阿拉伯树胶、壳聚糖及其组合。增稠剂的浓度将取决于所选的药剂和所需的粘度。这样的药剂还可用于上述粉末制剂中。
本发明的组合物还可包括保湿剂以降低或预防粘膜干燥以及预防组合物的刺激。可用于本发明的适当保湿剂包括山梨醇、矿物油、植物油和甘油;抚慰剂(soothing agent);膜修复剂(membrane conditioner);甜味剂;以及其组合。本发明组合物中保湿剂的浓度将根据所选的药剂进行变化。
一种或多种治疗剂可被引入到鼻递送体系或本文所述的任何其它递送体系中。
配制用于局部施用的组合物可以是液体或半固体(包括例如凝胶、洗剂、乳剂、霜剂、软膏、喷雾剂或气雾剂)或可与“限定的”载体组合提供,所述“限定的”载体例如为保持其形式的非扩散材料,所述形式包括例如贴剂、生物粘附剂、敷料或绷带。其可以是含水的或非含水的;其可配制为溶液、乳剂、分散体、混悬液或任何其它混合物。
重要的施用方式包括局部施用于皮肤、眼睛或粘膜。因此,典型的载体是适于药用地或化妆用地施用于身体表面的载体。本文提供的组合物可局部地(topically)或局部性地(locally)施用于患者身体中的多个区域。如上所述,局部(topical)施用意欲指施用于可到达的身体表面的组织,比如例如皮肤(外部皮肤或覆盖物)和粘膜(产生、分泌和/或含有粘液的表面)。示例性的粘膜表面包括眼睛、口腔(比如嘴唇、舌头、齿龈、颊、舌下和口腔顶)、喉、食道、支气管、鼻通道、阴道和直肠/肛门的粘膜表面;在一些实施方案中,优选口腔、喉、食道、阴道和直肠/肛门的粘膜表面;在其它实施方案中,优选眼睛、喉、食道、支气管、鼻通道、阴道和直肠/肛门的粘膜表面。如上所述,本文的局部(local)施用指施用于离散的身体内部区域,比如例如关节、软组织区域(例如肌肉、腱、韧带、眼内或其它肉质内部区域)、或身体的其它内部区域。因此,本文所用的局部施用指施用于身体的离散区域。
关于局部和/或局部性施用本发明的组合物,理想的功效可包括例如将本发明的治疗剂渗透到皮肤和/或组织中以充分地到达痛觉过敏部位来提供理想的抗痛觉过敏的疼痛减轻。本发明组合物的功效可以大致与例如利用中枢性阿片类镇痛剂达到的功效相同。但是,如本文详细论述,因为认为本发明的治疗剂不穿过血脑屏障,所以优选不出现通常与中枢阿片相关的不希望的作用(包括例如呼吸抑制、镇静和成瘾)来得到本发明治疗剂达到的功效。
同样在某些优选实施方案中,包括在含有水载体的实施方案中,组合物还可包含二元醇,即,含有两个或多个羟基基团的化合物。特别优选用于组合物的二元醇是丙二醇。在这些优选实施方案中,所述二元醇优选地以大于0至约5wt%(基于组合物的总重量)的浓度包含在组合物中。更优选地,所述组合物含有约0.1至小于约5wt%的二元醇,其中甚至更优选约0.5至约2wt%。还更优选组合物含有约1wt%的二元醇。
对于局部内部施用,例如关节内施用,组合物优选配制成在水基介质(比如等渗缓冲盐水)中的溶液或混悬液、或与意欲用于内部施用的生物可相容的载体或生物粘附剂相组合。
洗剂(例如可以处于混悬液、分散体或乳剂形式)包含有效浓度的一种或多种化合物。优选所述有效浓度以递送有效量(通常在约0.1~50%[以重量计]的浓度)、或更多量的本文提供的一种或多种化合物。洗剂还可包含[以重量计]1%~50%的润肤剂和补足量的水、适当的缓冲剂、以及如上所述的其它试剂。可以使用适于施用于人类皮肤的本领域技术人员公知的任何润肤剂。这些包括但不限于下述物质:(a)烃油和蜡,包括矿物油、矿脂、石蜡、纯地蜡、天然地蜡、微晶蜡、聚乙烯和全氢化角鲨烯。(b)硅油,包括二甲基聚硅氧烷、甲基苯基聚硅氧烷、水可溶和醇可溶的硅氧烷-二醇共聚物。(c)甘油三酸酯脂肪和油,包括衍生于植物、动物和海洋来源的那些。实例包括但不限于蓖麻油、红花油、棉籽油、玉米油、橄榄油、鱼肝油、杏仁油、鳄梨油、棕榈油、芝麻油、和大豆油。(d)乙酸甘油酯,比如乙酰化的单甘油酯。(e)乙氧基化的甘油酯,比如乙氧基化的单硬脂酸甘油酯。(f)10至20个碳原子的脂肪酸的烷基酯。脂肪酸的甲基酯、异丙基酯和丁基酯是本文可用的。实例包括但不限于月桂酸己酯、月桂酸异己酯、棕榈酸异己酯、棕榈酸异丙酯、肉豆蔻酸异丙酯、油酸癸酯、油酸异癸酯、硬脂酸十六酯、硬脂酸癸酯、异硬脂酸异丙酯、己二酸二异丙酯、己二酸二异己酯、己二酸二己基癸酯、癸二酸二异丙酯、乳酸月桂酯、乳酸肉豆蔻酯、和乳酸鲸蜡酯。(g)10至20个碳原子的脂肪酸的烯基酯。其实例包括但不限于肉豆蔻酸油醇酯、硬脂酸油醇酯、和油酸油醇酯。(h)9至22个碳原子的脂肪酸。适当的实例包括但不限于壬酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、异硬脂酸、羟基硬酯酸、油酸、亚油酸、蓖麻油酸、花生四烯酸、山嵛酸、芥酸。(i)10至22个碳原子的脂肪醇,比如但不限于月桂醇、肉豆蔻醇、鲸蜡醇、十六醇、硬脂醇、异硬脂醇、羟基硬脂醇、油醇、蓖麻油醇、山嵛醇、芥醇、和2-辛基十二烷醇。(j)脂肪醇醚,包括但不限于乙氧基化的10至20个碳原子的脂肪醇,比如但不限于在其上结合1至50个环氧乙烷基团或1至50个环氧丙烷基团或其混合物的月桂醇、鲸蜡醇、硬脂醇、异硬脂醇、油醇和胆固醇。(k)醚-酯,比如乙氧基化脂肪醇的脂肪酸酯。(l)羊毛脂及其衍生物,包括但不限于羊毛脂、羊毛脂油、羊毛脂蜡、羊毛脂醇、羊毛脂脂肪酸、羊毛脂酸异丙酯、乙氧基化的羊毛脂、乙氧基化的羊毛脂醇、乙氧基化的胆固醇、丙氧基化的羊毛脂醇、乙酰化的羊毛脂、乙酰化的羊毛脂醇、亚油酸羊毛脂醇酯、蓖麻油酸羊毛脂醇酯、蓖麻油酸羊毛脂醇酯的醋酸酯、乙氧基化醇-酯的醋酸酯、羊毛脂的氢解产物、乙氧基化的氢化羊毛脂、乙氧基化的山梨醇羊毛脂、以及液体和半固体羊毛脂吸收基质。(m)多元醇和聚醚衍生物,包括但不限于丙二醇、二丙二醇、聚丙二醇[M.W.2000-4000]、聚环氧乙烷聚环氧丙烷二醇、聚环氧丙烷聚环氧乙烷二醇、甘油、乙氧基化甘油、丙氧基化的甘油、山梨醇、乙氧基化的山梨醇、羟丙基山梨醇、聚乙二醇[M.W.200-6000]、甲氧基聚乙二醇350、甲氧基聚乙二醇550、甲氧基聚乙二醇750、甲氧基聚乙二醇2000、甲氧基聚乙二醇5000、聚环氧乙烷均聚物[M.W.100,000-5,000,000]、聚亚烷基二醇以及衍生物、己二醇(2-甲基-2,4-戊二醇)、1,3-丁二醇、1,2,6-己三醇、乙基己二醇USP(2-乙基-1,3-己二醇)、C15-C18邻二醇、以及三羟甲基丙烷的聚环氧丙烷衍生物。(n)多元醇酯,包括但不限于单脂肪酸乙二醇酯和二脂肪酸乙二醇酯、单脂肪酸二乙二醇酯和二脂肪酸二乙二醇酯、单脂肪酸聚乙二醇[M.W.200-6000]酯和二脂肪酸聚乙二醇[M.W.200-6000]酯、单脂肪酸丙二醇酯和二脂肪酸丙二醇酯、单油酸聚丙二醇2000酯、单硬脂酸聚丙二醇2000酯、乙氧基化的单硬脂酸丙二醇酯、单脂肪酸甘油酯和二脂肪酸甘油酯、多脂肪酸聚甘油酯、乙氧基化的单脂肪酸甘油酯、单硬脂酸1,3-丁二醇酯、二硬脂酸1,3-丁二醇酯、脂肪酸聚环氧乙烷多元醇酯、脂肪酸山梨聚糖酯、和聚环氧乙烷山梨聚糖脂肪酸酯。(o)蜡酯,包括但不限于蜂蜡、鲸蜡、肉豆蔻酸肉豆蔻酯、和硬脂酸硬脂酯;以及蜂蜡衍生物包括但不限于聚环氧乙烷山梨醇蜂蜡,其是蜂蜡与不同环氧乙烷含量的乙氧基化的山梨醇的反应产物,所述反应产物形成醚-酯混合物。(p)植物蜡,包括但不限于巴西棕榈蜡和小烛树蜡(candelilla wax)。(q)磷脂类,比如卵磷脂及其衍生物。(r)固醇类,包括但不限于胆固醇和脂肪酸胆固醇酯。(s)酰胺类,比如脂肪酸酰胺、乙氧基化的脂肪酸酰胺、和固体脂肪酸烷醇酰胺。
洗剂还优选地包含[以重量计]的1%至10%,更优选2%至5%的乳化剂。乳化剂可以是非离子型的、阴离子型的或阳离子型的。令人满意的非离子型乳化剂的实例包括但不限于10至20个碳原子的脂肪醇、与2至20摩尔环氧乙烷或环氧丙烷缩合的10至20个碳原子的脂肪醇、与2至20摩尔环氧乙烷缩合的烷基链中具有6至12个碳原子的烷基酚、环氧乙烷的单脂肪酸酯和二脂肪酸酯、乙二醇的单脂肪酸酯和二脂肪酸酯(其中脂肪酸部分含有10至20个碳原子)、二乙二醇、分子量200至6000的聚乙二醇、分子量200至3000的聚丙二醇、甘油、山梨醇、山梨聚糖、聚环氧乙烷山梨醇、聚环氧乙烷山梨聚糖和亲水性蜡酯。适当的阴离子型乳化剂包括但不限于脂肪酸皂,例如钠、钾和三乙醇胺皂,其中脂肪酸部分含有10至20个碳原子。其它适当的阴离子型乳化剂包括但不限于烷基硫酸、烷基芳基磺酸、以及烷基部分中具有10至30个碳原子的烷基乙氧基醚磺酸的碱金属、铵或取代的铵盐。所述烷基乙氧基醚磺酸盐含有1至50个环氧乙烷单元。令人满意的阳离子型乳化剂之中是季铵化合物、吗啉化合物和吡啶化合物。前面段落中所述某些润肤剂也具有乳化特性。当洗剂配制成含有这样的润肤剂时,不需要另外的乳化剂,尽管其可包含在组合物中。
洗剂的平衡成分是水或C2或C3醇,或水和醇的混合物。通过简单地将所有成分混合在一起来配制洗剂。优选地,化合物比如洛哌丁胺溶解、混悬或以其它方式均匀地分散在混合物中。
可包含这样洗剂的其它常规成分。一种这样的添加剂是以组合物的1wt%至10wt%水平的增稠剂。适当的增稠剂的实例包括但不限于:交联羧基聚乙烯聚合物、乙基纤维素、聚乙二醇、黄蓍胶、刺梧桐(kharaya)胶、黄原胶和膨润土、羟乙基纤维素和羟丙基纤维素。
可配制霜剂以含有将有效量的本发明治疗剂递送到治疗组织的有效浓度,所述浓度通常在本发明治疗剂的约0.1%(优选大于1%)直到大于50%之间,优选地在约3%和50%之间,更优选地在约5%和15%之间。所述霜剂还可包含5%至50%,优选10%至25%的润肤剂,并且剩余的是水或其它适当的无毒载体,比如等渗缓冲剂。如上对于洗剂所述的,所述润肤剂还可用于霜剂组合物。如上所述,所述霜剂还可包含适当的乳化剂。乳化剂以3%至50%,优选以5%至20%的水平包含在组合物中。
配制成溶液或混悬液的这些组合物可施用于皮肤、或可配制成气雾剂或泡沫剂并作为喷雾施用于皮肤。气雾剂组合物通常包含[以重量计]的25%至80%,优选以30%至50%的适当推进剂。这样的推进剂的实例是氯化、氟化和氟氯化的低分子量烃。氧化氮、二氧化碳、丁烷、和丙烷也用作推进剂气体。如本领域理解的,以适于排出容器内的内含物的量和压力下使用这些推进剂。
适当地制备的溶液和混悬液还可局部施用于眼睛和粘膜。溶液(尤其是意欲眼科使用的那些)可与适当的盐一起配制为pH约5至7的0.01%至10%的等渗溶液,并且优选地含有浓度为约0.1%,优选大于1%,至多50%或更多的一种或多种本文的化合物。适当的眼科溶液是已知的[见例如美国专利5,116,868,其描述典型的眼科冲洗溶液和局部施用溶液的组成]。这样的pH调整到约7.4的溶液包含例如90至100mM氯化钠、4至6mM磷酸氢二钾、4至6mM磷酸氢二钠、8至12mM柠檬酸钠、0.5至1.5mM氯化镁、1.5至2.5mM氯化钙、15至25mM醋酸钠、10至20mM的D.L-β-羟丁酸钠和5至5.5mM葡萄糖。
通过简单地将适当的增稠剂混合到前述溶液或混悬液组合物中可配制凝胶组合物。之前关于洗剂已经描述了的适当增稠剂的实例。
凝胶组合物包含有效量的本发明治疗剂(通常浓度为约0.1~50wt%或更多的一种或多种本文提供的化合物);5%至75%,优选10%至50%的前述有机溶剂;0.5%至20%,优选1%至10%的增稠剂;平衡物是水或其它水载体或非水载体(比如例如有机液体),或载体混合物。
可被配制制剂并设置成引起稳态血浆水平。如本领域技术人员公知的,采用HPLC技术可检测稳态血浆浓度。当药物可利用速率等于循环中的药物消除速率时达到稳态。在典型的治疗护理中,按照周期性给药方案或恒定输注方案将本发明的治疗剂施用给患者。施用开始后血浆中的药物浓度将倾向于立即升高,并且由于通过分布到细胞和组织、通过代谢、或通过排泄而从循环中而消除药物,所以倾向于随时间下降。当平均药物浓度随时间保持恒定时将达到稳态。在间歇性给药情形下,在剂量之间的每个间隔中,药物浓度循环方式相同地重复,平均浓度保持恒定。在恒定输注的情形下,平均药物浓度将保持恒定并具有非常小的波动。通过测量至少一个给药循环期间血浆中的药物浓度,使得能确认所述循环从剂量到剂量相同地重复,来确定稳态的实现。通常,在间歇性给药方案中,仅仅在施用另一个剂量之前,通过测定循环的连续波谷的药物浓度可确认稳态的维持。在恒定输注方案中,当浓度波动低时,通过任何两次连续的药物浓度检测可确认稳态。
图7显示根据本发明的药盒。所述药盒10包含含有阿片样物质片剂的小瓶12。所述药盒10还包括含有S-MNTX片剂的小瓶14,所述S-MNTX片剂含有小丸,一些小丸用pH敏感性材料肠溶包衣,并且配制并设置一些小丸以立即在胃中释放S-MNTX。药盒还包括说明书20用于将片剂施用给腹泻或具有腹泻症状的对象。所述说明书包括标记,例如写明、指示S-MNTX是不含有R-MNTX的纯S-MNTX。
在本发明的一些方面,药盒10可任选地或替代地包含药物制剂小瓶16,以及药物制剂稀释剂小瓶18。含有用于药物制剂的稀释剂的小瓶是任选的。稀释剂小瓶包含稀释剂比如用于稀释可以是S-MNTX的浓缩溶液或冻干粉末的生理盐水。说明书可包括用于混合特定量稀释剂与特定量浓缩药物制剂并由此制备用于注射或输注的最终制剂的说明。说明书20可包含用有效量S-MNTX治疗患者的说明。还应当理解,不管容器是瓶子、带有隔膜的小瓶、带有隔膜的安瓿、输注袋等,含有制剂的容器可含有另外的标记,比如当制剂已被高压灭菌或以其它方式灭菌时改变颜色的常规标记。
本发明不将其应用限制于下述说明阐明或附图举例说明的成分的配制和设置细节。本发明能具有另外的实施方案并能以多种方式实施或实现。而且,本文所用的措词和术语是为了说明的目的并且不应当认为是限制性的。本文中“包括”(“including”)、“包含”(“comprising”)、或“具有”(“having”)、“含有”(“containing”)、“包括”(“involving”)以及其变体的使用是指包含其后列举的项目和其等价物以及另外的项目。
实施例
尝试了多种不同的合成途径和方案以发现制备和纯化S-MNTX的有效方法。下面提供一些这些方法的描述。还提供了制备试剂、中间体和原料的方法。
实施例I
羟考酮脱保护为羟吗啡酮。由羟考酮合成羟吗啡酮。利用之前文献(Iijima,I.;Minamikawa,J.;Jacobson,A.E.;Brossi,A.;Rice,K.C.J.Med.Chem.1978,21(4),398)中描述的条件,将羟考酮脱保护为羟吗啡酮。产率范围为58至64%,并且利用由通过短硅胶塞的过滤组成的纯化,以除去原料。纯化的羟吗啡酮用于烷基化反应。不需要纯化,得到产率至多95%的羟吗啡酮。该粗原料的HPLC纯度通常为约94%。
(碘甲基)环丙烷的制备。通过Finkelstein反应由(溴甲基)环丙烷制备(碘甲基)环丙烷。典型的产率范围为68至70%,并且以原始的溴化物作为唯一的主要杂质,通过GC,典型的纯度为89至95%(AUC)。
羟吗啡酮的直接烷基化。证明利用环丙基甲基碘化物作为烷基化剂直接烷基化羟吗啡酮得到有生产价值的S-MNTX产率。图2中举例说明途径。如通过HPLC(AUC)观察的,观察到羟吗啡酮的直接烷基化进行至接近50%的转化率,并进一步研究。
在NMP(10体积)中合并羟吗啡酮和环丙基甲基碘,并加热至70℃。结果总结在下述表1中。在反应时间期间烷基化剂的分解未完全消耗试剂,因此不限制反应进行到完成。此外,羟吗啡酮与S-MNTX的比率显示不管烷基化剂的当量数,反应进行至接近1∶1。
表1:所用烷基化剂当量的作用的研究
项目 | 烷基碘(当量) | 70℃16小时后的反应成分(HPLC,AUC) | ||
羟吗啡酮% | S-MNTX% | 烷基碘% | ||
1 | 8 | 33 | 30 | 16 |
2 | 12 | 29 | 27 | 25 |
3 | 16 | 27 | 23 | 35 |
4 | 20 | 23 | 20 | 42 |
5 | 24 | 22 | 18 | 44 |
操作步骤。由于发现在粗产物中存在的NMP阻止保留,因此需要除去其的方法。乙酸异丙酯和二烷的混合物形成絮凝状、浅色固体,所述絮凝状、浅色固体最终变成油。使用乙酸异丙酯以及乙酸异丙酯/二烷的混合物进行比较以确定在除去NMP时哪种更有效。在每种情形下,产物和原料从混合物中沉淀出来并且NMP保留在溶液中。通过HPLC的上清液和沉淀物质的分析显示两者之间没有显著差异。
纯化。一旦从产物中除去NMP,利用装有C18柱的Biotage快速色谱体系,对剩余物进行重复的连续的反相色谱。利用含有0.2%HBr作为调节剂的50%甲醇水溶液进行初始色谱。所述溶剂体系中甲醇含量递减地降低直到固定为5%甲醇水溶液。重复所述色谱直到以89%的纯度(AUC)分离S-MNTX。通过MS不可检测到反离子,但是希望反离子是碘离子和溴离子的混合物。
利用定义的操作和纯化,按比例放大化学并且通过该方法达到28g盐酸羟考酮。第一步,利用文献中描述的方法在一个反应中进行脱甲基化,从热乙醇(10体积)中重结晶后得到17g羟吗啡酮。由于压力管的大小和加热模式造成的设备局限性,在5个相等的更小的反应中进行第二步。虽然单独分析,但是在分析标明相似组成后,合并混合物用于处理和纯化。如所希望进行乙酸异丙酯滴定,将沉淀的剩余物溶解在含有0.2%HBr的20%甲醇水溶液中并在装有C18柱的Biotage Flash40s上通过色谱进行纯化,用含有0.2%HBr的5%甲醇水溶液洗脱。级分通过HPLC进行分析并合并相似组成的级分、分离成<80%、80至90%、以及<90%的纯度(AUC)。浓缩合并的级分并重新在装有C18柱的Biotage Flash 75L上进行色谱。重复该色谱方法以提高纯度。最后发现HBr调节剂是不必要的并从洗脱液中除去。6次色谱纯化后,以约80%的纯度(AUC)分离出约11g的S-MNTX碘化物。
很明显在级分浓缩期间,发生一些形式的分解,导致产物显著变黑。分解归因于碘离子反离子,因此,将所述物质通过离子交换柱以将碘离子交换成溴离子。一旦收集含有产物的洗脱液,浓缩似乎不导致相似的变黑并得到黄色油。继续进行色谱,通过纯度水平(通过HPLC的AUC)分离产物流。一旦本体物质已经提高到约90%的纯度,利用2.5%甲醇水溶液作为洗脱液进行另外的色谱并最终将一些物质的纯度提高到>95%(AUC)。
合并所有的产物流并冻干以得到自由流动的粉末,以95%的纯度分离741mg的S-MNTX、以90%的纯度分离2.5g的S-MNTX、和以79%的纯度分离1.0g的S-MNTX(AUC)。收集回收的羟吗啡酮的级分并从乙醇中进行重结晶得到2.4g(>99%纯度,AUC)。
试剂制备。在一系列涉及制备S-MNTX的试验中,如下所述得到或制备原料和试剂。还提供了设备和仪器数据。
所有的无水反应在干燥氮气中进行。除非另外指出,试剂购自商业来源并直接使用。在300MHz的Bruker Avance 300波谱仪上利用四甲基硅烷作为内参得到质子核磁共振谱。在75MHz的Bruker Avance300质谱仪上利用溶剂峰作为参照得到碳核磁共振谱。在Perkin-ElmerSpectrum 1000红外分光光谱计上得到红外谱。在Finnigan质谱仪上得到质谱。
利用2.5×10cm的Analtech硅胶GF板(25微米厚)进行薄层色谱(TLC)。利用UV和高锰酸钾染色进行TLC板的显色。利用下述方法在Varian Star软件控制的Varian ProStar HPLC上进行HPLC分析:
HPLC方法I:
柱:Luna C18(2),150×4.6mm,5μ
流速:1mL/分钟
检测:UV@230nm
梯度程序:
时间(分钟) | %A | %B |
0:00 | 95 | 5 |
8:00 | 65 | 35 |
12:00 | 35 | 65 |
15:00 | 0 | 100 |
16:00 | 95 | 5 |
18:00 | 95 | 5 |
流动相A=0.1%TFA水溶液
流动相B=0.1%TFA甲醇溶液
HPLC方法II:
色谱条件和参数:分析柱描述:Phenomenex Inertsil ODS-3,150×4.6mm,5μm;柱温:50.0℃;流速:1.5mL/分钟;进样体积:20μL;检测波长:280nm;流动相A=水∶MeOH∶TFA(95∶5∶0.1%;v/v/v)B=水∶MeOH∶TFA(35∶65∶0.1%;v/v/v);分析时间:50分钟
定量限:0.05%
检测限:0.02%
梯度特征:
时间(分钟) | %A | %B | 曲线 |
0:00 | 100 | 0 | 初始 |
45 | 50 | 50 | 线性 |
48 | 100 | 0 | 线性 |
55 | 100 | 0 | 保持 |
流动相A(水∶MeOH∶TFA::95∶5∶0.1%;v/v/v)
流动相B(水∶MeOH∶TFA::35∶65∶0.1%;v/v/v)
MeOH=甲醇,TFA=三氟乙酸
利用上述HPLC方法监测S-MNTX的合成和纯化。利用上述HPLC条件区分R-MNTX与S-MNTX。利用本文所述的方案可制备用作标准的可信的R-MNTX。在典型的HPLC运行中,在洗脱R-MNTX之前约0.5分钟洗脱S-MNTX。S-MNTX的保留时间是约9.3分钟;R-MNTX的保留时间是约9.8分钟。
利用下述方法在HP 3365化学工作站软件控制的HP 5890 SeriesII GC上进行气相色谱(GC)分析:GC方法:
柱:J&W Scientific DB-1,30m×0.53mm,3μ
初始温度:40℃
初始时间:10.00分钟
速度:20℃/分钟
最终温度:250℃
最终时间:2.00分钟
进样器温度:250℃
检测器:火焰-离子化
典型的烷基化反应。将底物和10体积的烷基化剂一起加入到250-mL Parr烧瓶中。如果二甲基甲酰胺(DMF)或NMP用作助溶剂,则加入2.5体积。将所述烧瓶置于Parr振荡器中(关闭氢罐)并在压力下在振摇下加热至反应温度。反应期间通常看到的压力为10至15psi。周期性地对反应物取样并通过MS和HPLC进行分析以确定反应程度和产物性质。反应结束时,利用甲醇将混合物转移到圆底烧瓶中并除去挥发物。然后将剩余物在硅胶上用90∶10∶0.1的二氯甲烷/甲醇/氢氧化铵洗脱来进行色谱。
离子交换柱的制备。将AG 1-X8树脂(Bio-Rad,分析级,100-200目,氯化物形式)填充到玻璃柱(50mm×200mm)中并用1N HBr(1L,用去离子(DI)水制备)进行冲洗。用DI水(约10L)冲洗柱直到洗脱液达到pH 6至7。
S-MNTX的制备。将羟吗啡酮(3.6g,11.9mmol)、环丙基甲基碘(17.39g,95.6mmol)、和N-甲基吡咯烷酮(3.6mL)合并到5个25mL的螺纹封闭的压力管中。所述管用螺纹Teflon帽密封并置于6-孔反应器组中,预加热至70℃。24小时后,反应显然地是双相的并且HPLC分析(固相和液相都取样)显示反应进行至约50%的转化率。停止加热并利用甲醇将5个反应混合物转移到1-L圆底烧瓶中以转移混合物并冲洗所述管。减压除去甲醇并用乙酸异丙酯(900mL)处理所得的NMP溶液,得到固体和油状的沉淀物。利用刮铲搅拌油得到粘性固体。从固体中倾析上清液到有凹槽的滤纸中。将收集在滤纸中的固体与初始固体合并,用甲醇辅助回收。将所得的溶液浓缩至黑色、粘稠的油。将所述油溶解在含有0.2%HBr的20%甲醇水溶液(20mL)中并在装有C18柱的Biotage Flash 75L上进行色谱纯化。通过HPLC在Luna C18(2)柱(4×20mm)上分析级分,合并并浓缩产物级分。所得的“纯化”产物溶解在DI水(约20mL)中并利用正在重复的方法重复色谱直到纯度提高到约70%(AUC)。将约70%纯度的产物(约18g)溶解在DI水(20mL)中,并通过AG 1-X8阴离子交换树脂柱以转化成溴化物形式(见另外的方法)(5×25cm)。用DI水洗脱柱直到在洗脱的流中没有可检测的MNTX。浓缩水溶液并将剩余物溶解在DI水(10mL)中,进一步利用装有C18柱的Biotage Flash 75L体系通过色谱来纯化所述剩余物,用5%甲醇水溶液进行洗脱。通过HPLC在Luna C18(2)柱(4.6×150mm)上分析级分,基于纯度(AUC)将产物流分成4个流:>90%纯度、含有快速杂质的50至90%纯度、含有慢速杂质的50至90%纯度、以及<50%纯度。更不纯的物质通过色谱重新循环以提高纯度,最终得到3.0g的90%纯(AUC)的S-MNTX。更不纯的级分进一步通过色谱纯化以提供约1.0g的90%纯的物质,所述约1.0g的90%纯的物质与之前通过装有C18柱的Biotage Flash 75L体系上进行分离和纯化并用2.5%甲醇水溶液洗脱的1.0g的90%纯的物质合并。重复色谱以提高纯度直到达到>95%(AUC)纯度。结束时,从水中冻干所述产物流以得到741mg的95.6%纯度(AUC)的S-MNTX、2.54g的90%纯度(AUC)的S-MNTX、以及1.08g的79%纯度(AUC)的S-MNTX。
图3提供通过该方法制备的S-MNTX的质子NMR谱图。图4提供S-MNTX产物的红外谱图。图5提供S-MNTX产物的HPLC色谱图。图6提供S-MNTX产物的质谱图。这些分析数据确定纯度大于95%的MNTX的“S”立体异构体。
实施例II
S-MNTX的合成和纯化的优化
离子交换柱的制备。将AG 1-X8树脂(Bio-Rad,分析级,100-200目,氯化物形式,50wt相当量)装填到玻璃柱中并用1N HBr(约100体积,用DI水制备)进行冲洗。用DI水冲洗柱直到洗脱液达到pH 6至7。
S-MNTX的制备。在250mL、具有夹套的、三口烧瓶中加入羟吗啡酮(5.0g,16.6mmol)、NMP(5mL)和铜线(1.2g,切成3至4mm的段)。用铝箔包裹所述烧瓶并连接到设置在70℃的预平衡的加热器/冷却器中。将环丙基甲基碘(24.16g,132.7mmol)加入到混合物中并搅拌反应20小时。通过HPLC进行的反应等份的分析显示1∶1比率的2∶3。将反应混合物转移到利用顶置机械搅拌器剧烈搅拌的含有IPAc(250mL)的Erlenmeyer烧瓶中。油状物质固化后,过滤掉固体并转移回所述烧瓶中,通过HPLC分析滤液并丢弃。将合并的固体剩余物溶解在甲醇水溶液中并通过离子交换树脂(Bio-Rad AG 1-X8,50wt相当量,转化成溴化物形式)柱进行过滤。用DI水洗脱所述柱并冲洗直到检测不到UV活性物质(254nm)。浓缩所得的水溶液并用最小量的甲醇将剩余物溶解在IPA(5体积)中以实现溶解。除去溶剂以除去痕量的水,并将所得固体溶解在热甲醇(3体积约50℃)中。加入环境温度的二氯甲烷/异丙醇(CH2Cl2/IPA)(6体积/1体积)混合物,允许所得溶液维持在环境条件下直到开始结晶。然后将混合物保持在-20℃制冷器中2天。过滤收集固体,得到2.8g的2与S-MNTX的约1∶1的混合物。通过加入CH2Cl2/IPA(6体积/1体积)并允许混合物冷却,来从热甲醇(MeOH)(3体积,约50℃)中重结晶所述固体。通过HPLC分析发现分离的固体(2.1g,基于重量的29%)是94.1%纯的(AUC)。
S-MNTX的纯化。合并纯度>94%(AUC)的S-MNTX的批次,并进行溶解在热甲醇(MeOH)(3体积,约50℃)中并然后加入CH2Cl2/IPA(6体积/1体积)混合物的重结晶步骤。允许所述混合物冷却至环境温度并通过过滤收集固体。需要重复4次将S-MNTX的纯度从94%提高至>99%,并且总体质量收率是60%。总之,如通过HPLC分析测定的,8.80g的S-MNTX被纯化至99.8%(AUC)。1H NMR、13CNMR和MS谱图与归属的结构一致。Karl Fischer分析(KF):4.7%水;C21H26BrNO4的分析计算:C,57.80;H,6.01;N,3.21;Br,18.31。实测:C,54.58;H,6.10;N,2.82;Br,16.37。
实施例III
(S)-N-甲基纳曲酮的阿片受体结合
利用从科技文献(Simonin,F等1994,Mol.Pharmacol46:1015-1021;Maguire,P.等1992,Eur.J.Pharmacol 213:219-225;Simonin,F.等PNASUSA 92(15):1431-1437;Wang,JB 1994,.FEBS Lett338:217-222)中适应改变的方法进行放射配体结合分析来测定S-N-甲基纳曲酮对μ-阿片受体、κ-阿片受体、和δ-阿片受体的结合特异性。
显示S-MNTX以Ki=0.198μM结合人重组μ阿片样物质受体、以Ki=1.76μM结合人重组κ阿片样物质受体、并且不结合人重组δ阿片样物质受体。
实施例IV
S-MNTX的体外药理学:μ(μ,MOP)受体生物测定
试验条件。将豚鼠末端回肠段悬浮在20-ml的组织浴槽中,所述组织浴槽填充有充氧的(95%O2和5%CO2)、预先温热(37℃)的生理盐溶液,所述生理盐溶液的组成如下(以mM计):NaCl 118.0,KCl4.7,MgSO41.2,CaCl22.5,KH2PO41.2,NaHCO325.0以及葡萄糖11.0(pH 7.4)。另外的试验条件如Hutchinson等(1975)Brit.J.Pharmacol.,55:541-546中所述的。
吲哚美辛(1μM)、nor-binaltorphimine(0.01μM)、美西麦角(1μM)、奥丹西隆(10μM)、和GR113808(0.1μM)也存在于整个试验中来预防前列腺素类释放以及分别阻滞κ-阿片样物质受体、5-HT2受体、5-HT3受体和5-HT4受体。将所述组织连接到拉力传感器上用于等度量张力记录。将它们拉伸到1g的静张力,然后允许平衡60分钟,在该时间期间反复清洗它们并重新调节张力。其后,用最小强度的脉冲电刺激它们,以引发最大的收缩和并保持1毫秒的持续时间,所述脉冲电刺激通过恒定电流刺激器以0.1Hz传递。采用具有8个组织浴槽和多通道数据采集的半自动离体组织体系进行试验。
试验方案
激动剂活性试验。将组织暴露于亚最大浓度的参比激动剂DAMGO(0.1μM)以验证响应度并得到对照响应。广泛洗涤和恢复对照骤然收缩之后,将组织暴露于增加浓度的S-MNTX或相同激动剂中。累积地加入不同的浓度,每个浓度与组织相接触直到得到稳定的响应或15分钟的最大极限。如果获得激动剂样响应(抑制骤然收缩),则相对于最高浓度的S-MNTX测试参比拮抗剂纳洛酮(0.1μM),以证明该响应涉及μ受体。
拮抗剂活性试验。将组织暴露于亚最大浓度的参比激动剂DAMGO(0.1μM)以得到对照响应。稳定DAMGO诱导的响应后,累积地加入增加浓度的S-MNTX或参比拮抗剂。每个浓度与组织相接触直到得到稳定的响应或15分钟的最大极限。如果出现,则S-MNTX对DAMGO诱导的响应的抑制表明对μ受体的拮抗剂活性。
结果的分析与表达。所测量的参数是每个化合物浓度诱导的电诱发骤然收缩的幅度中的最大变化。结果表示为DAMGO的对照响应的百分率(平均值)。通过浓度-响应曲线的线性回归分析测定EC50值(产生半最大响应浓度)或IC50值(引起DAMGO响应的半最大抑制浓度)。
结果。表IV.1表示在豚鼠回肠生物测试中所研究的1.0E-08M至1.0E-04M的S-MNTX对μ阿片样物质受体的激动剂和拮抗剂活性作用,还报道了参比化合物的作用。表IV.2显示对于S-MNTX测定的EC50和IC50值。
在电场刺激的豚鼠回肠中,μ受体激动剂DAMGO引起骤然收缩幅度的浓度依赖性降低,所述骤然收缩幅度被拮抗剂纳洛酮以浓度依赖性方式逆转。
在未处理的组织中,S-MNTX还引起骤然收缩幅度的浓度依赖性和纳洛酮敏感性的降低。
在之前采用DAMGO抑制的组织中,S-MNTX不产生任何骤然收缩幅度的恢复而是引起进一步的降低。
这些结果显示在该组织中S-MNTX起到μ阿片样物质受体激动剂的作用。
表IV.1
在豚鼠回肠中评价S-MNTX对μ阿片样物质受体的激动剂和拮抗剂活性
作用
激动剂活性评价
化合物 | 对DAMGO(1.0E-07M)的对照响应 | 对增加化合物浓度的响应(M) | +纳洛酮(1.0E-07M) | ||||||||
S-MNTX | 100 | 1.0E-08 | 3.0E-08 | 1.0E-07 | 3.0E-07 | 1.0E-06 | 3.0E-06 | 1.0E-05 | 3.0E-05 | 1.0E-04 | 1.0E-04M |
0 | 0 | 5 | 16 | 35 | 59 | 92 | 109 | 109 | 17 | ||
DAMGO | 100 | 1.0E-09 | 1.0E-08 | 1.0E-07 | 1.0E-07 | ||||||
12 | 49 | 99 | 3 | ||||||||
拮抗剂活性评价
化合物 | 对DAMGO(1.01E-07M)的对照响应 | 在增加化合物浓度存在下对DAMGO(1.0E-07M)的响应(M) | ||||||||
S-MNTX | 100 | 1.0E-08 | 3.0E-08 | 1.0E-07 | 3.0E-07 | 1.0E-06 | 3.0E-06 | 1.0E-05 | 33.0E-05 | 1.0E-04 |
100 | 100 | 100 | 100 | 100 | 102 | 105 | 109 | 110 | ||
纳洛酮 | 100 | 5.015-09 | 2.0E-08 | 1.0E-07 | ||||||
83 | 43 | -7 | ||||||||
结果表示为对DAMGO的对照响应的百分率(骤然收缩幅度的降低)(平均值;n=2)
表IV.2
在豚鼠回肠中测定的S-MNTX对μ阿片样物质受体的EC50和IC50值
化合物 | 激动剂活性 | 拮抗剂活性 |
S-MNTX | EC50值 | IC50值 |
2.0E-06M | 无拮抗剂活性 |
实施例V
S-N-甲基纳曲酮对大鼠胃肠转运的作用
采用A.F.Green,Br.J.Pharmacol.14:26-34,1959;L.B.Witkin,C.F.等J Pharmacol.Exptl.Therap.133:400-408,1961;D.E.Gmerek,等J.Pharmacol.Exptl.Ther.236:8-13,1986;以及O.Yamamoto等Neurogastroenterol.Motil.10:523-532,1998中描述的方法,测定S-N-甲基纳曲酮(纯度-99.81%的S-N-甲基纳曲酮;0.19%的羟吗啡酮;不可检测的R-MNTX),以及可信来源的R-MNTX(纯度99.9%)对吗啡诱导的大鼠胃肠转运的抑制作用。
以1.0、3.0、或10.0mg/kg的浓度将S-MNTX或R-MNTX皮下施用给大鼠(Crl:CD(SD)BR;5至8周龄;180至250gms wt)。对照组大鼠接受2mL/kg的0.9%盐水溶液(n=10)。15分钟后,对大鼠皮下注射盐水(1mL/kg)或吗啡(3mg/kg)。皮下给予吗啡或盐水后20分钟(±2分钟),将活性炭在0.25%甲基纤维素中的10%混悬液以10mL/kg口服施用给大鼠。接受活性炭后25分钟(±3分钟),大鼠被安乐死,取出肠并沿米尺轻轻地伸展到湿纸上。测量从幽门括约肌至盲肠的小肠,炭经过的距离作为对每只大鼠评价的长度部分。
通过ANOVA和Tukey HSD多重比较检验确定统计学显著性作用。认为P值<0.05的差异是统计学显著性的。
炭运动的值表示为百分比效应并以下述方式计算:以厘米计的炭经过的个体距离除以以厘米计的每只大鼠的肠总长度(幽门括约肌至盲肠)。计算每组的平均值,利用下式计算百分比效应:
结果
表1显示GI转运研究的结果。如文献所报道的,吗啡(已知既影响中枢阿片样物质受体又影响外周阿片样物质受体)降低GI蠕动。当单独施用时,R-MNTX(外周选择性μ阿片样物质受体拮抗剂)对GI转运没有影响。如从阿片样物质拮抗剂所期望的,在吗啡之前施用R-MNTX逆转吗啡的GI慢化效应。R-MNTX对吗啡的拮抗剂活性是剂量依赖性的,在1mg/kg时部分逆转,在3或10mg/kg时逆转至GI转运返回到与对照值相比不具有统计学显著性差异的值的程度。与R-MNTX的拮抗剂活性相比,当单独使用时S-MNTX具有激动剂活性,即其导致降低的GI蠕动(如GI转运的统计学显著性降低所反映的)。采用S-MNTX与吗啡的组合,S-MNTX在降低GI蠕动中的激动剂活性甚至更明显。S-MNTX+吗啡的组合在降低GI蠕动中具有显著的协同激动剂作用,所述协同激动剂作用达到单独采用任一化合物不能观察到的水平。S-MNTX的激动剂活性证明当单独施用时减慢GI转运并且当两种药剂组合使用时还增加吗啡的抑制作用。
表1
S-MNTX对GI蠕动的作用
处理 | 平均蠕动 | 下降百分率 |
盐水+盐水盐水+吗啡R-MNTX 10mg/kg+盐水R-MNTX 1mg/kg+吗啡R-MNTX 3mg/kg+吗啡R-MNTX 10mg/kg+吗啡S-MNTX 10mg/kg+盐水S-MNTX 1mg/kg+吗啡S-MNTX 3mg/kg+吗啡S-MNTX 10mg/kg+吗啡 | 0.6060.407*0.5720.463*0.5580.5570.476*0.281*0.258*0.122* | -33%6%24%8%8%21%54%57%80% |
途径-sc
吗啡剂量=3mg/kg
平均蠕动-炭传输长度/肠总长度的比率
与载体组对比,*统计学显著性(p<0.05)变化
实施例VI
抗腹泻活性试验
(a)大鼠蓖麻油试验[见例如Niemegeers等(1972)Arzneim Forsch22:516-518;美国专利4,867,979、4,990,521、4,824,853]
大鼠禁食过夜。采用待测试化合物的理想剂量静脉内处理每只动物。其后1小时,动物口服接受1ml蓖麻油。每只动物保持在单独的笼中并且在蓖麻油处理后约2小时,评价每只动物存在或不存在腹泻。ED50值确定为50%的测试动物中不存在腹泻时的以mg/kg体重计的剂量。
例如,年幼的雌性Wistar大鼠(230至250g体重)禁食过夜并在早晨采用待测试化合物的剂量水平口服处理每只动物。其后1小时,动物口服接受1ml蓖麻油。每只动物保持在单独的笼中。在蓖麻油处理后在不同的所选时间间隔(例如1、2、3、4、6和8小时),记录存在或不存在腹泻。在95%以上的500只对照动物中,在蓖麻油处理后1小时观察到严重腹泻。利用该全或无的标准,如果在蓖麻油处理后1小时没有观察到腹泻,则测试化合物出现显著的阳性作用。使用每种药物的5个剂量水平的最小值,在10个不同的天数将每个剂量水平给予10只大鼠。化合物(比如式(II)的化合物)的ED50值(即在50%动物中观察到这种作用的剂量水平)一般地约0.01至约10mg/kg。
(b)小鼠蓖麻油试验[见例如美国专利4,326,075]
小鼠组口服给予测试化合物,1.5小时后所有小鼠给予0.3ml蓖麻油。施用蓖麻油后3小时,检查所有小鼠的腹泻并且保护50%小鼠免受腹泻的测试化合物剂量是ED50剂量。
(c)蓖麻油(Ricinus Oil)试验[见例如美国专利4,990,521]
大鼠(比如雌性Wistar大鼠或其它实验室品系)禁食过夜。采用测试化合物的剂量水平口服处理每只动物。其后1小时,动物通常口服给予1ml蓖麻油的量,每只动物保持在单独的笼中。在蓖麻油处理后1小时,记录存在或不存在腹泻。ED50值确定为50%的处理动物中不存在腹泻时的以mg/kg体重计的剂量。
(d)PGE2诱导的小鼠腹泻的拮抗作用
通过评价化合物作为PGE2诱导的小鼠腹泻的拮抗剂的效应可确定抗腹泻活性[见例如Dajani等1975European Jour.Pharmacol.34:105-113、以及Dajani等(1977)J Pharmacol.Exp.Ther.203:512-526;见例如美国专利4,870,084]。该方法在15分钟内可靠性地引起另外未处理小鼠的腹泻。其中未出现腹泻的预先用试验药剂处理的动物被认为是受到所述试验药剂的保护。试验药剂的便秘作用被测定为“全或无”响应,并且腹泻定义为水样不成形的大便,所述水样不成形的大便显著不同于正常粪便物质,所述正常粪便物质是形状良好的团并且是坚固的和相对干燥的。
使用标准实验室小鼠,比如Charles River CD-1品系的白化变种小鼠。它们通常被保持在群体笼中。当试验时动物的重量范围是20至25g。球状的大鼠食料随意可得,直到试验前18小时将食物移走。将动物称重并标记用于鉴别。通常在每个药物处理组中使用5只动物并与对照相比较。重20至25g的小鼠养在群体笼中,并在试验之前禁食过夜。可得到水。试验药物处理后1小时,动物接受PGE2[0.32mg/kg i.p.,在5%ETOH中],并且立即单独放置在例如透明的丙烯酸盒子中。15分钟结束时,基于全或无基础,将盒子底部的一次性纸板片用于检查腹泻。
实施例VII
S-MNTX在疼痛模型中的镇痛活性
下述疼痛模型可用于测定S-MNTX的镇痛活性。
1.小鼠乙酸扭体测试
将小鼠(CD-1,雄性)称重并放置于单独的方形中。施用试验或对照品,适当吸收时间之后,腹膜内施用乙酸溶液。腹膜内(i.p.)注射乙酸后10分钟,记录5分钟期间内的扭体次数。
记录每只小鼠的总扭体次数。利用ANOVA比较对照和每个试验品组的平均扭体次数,随后是相关的多重比较试验并计算抑制百分率。
2.苯醌(PPQ)扭体测试
将小鼠(CD-I,雄性)称重并放置于单独的方形中。施用试验或对照品,适当吸收时间之后,腹膜内施用PPQ溶液(0.02%水溶液)。密切观察每只小鼠10分钟用于表现扭体。
记录每只小鼠的总扭体次数。利用ANOVA比较对照和每个试验品组的平均扭体次数,随后是相关的多重比较试验,并计算抑制百分率。
3.大鼠中的Randall-Selitto法
该方法的目的是确定试验品对大鼠痛阈的作用。
过夜禁食后,将大鼠分成每组10只的组。20只大鼠用作载体对照。然后顺序地将20%的啤酒酵母(Brewer′s yeast)混悬液注射到大鼠的左后爪的趾底面中。2小时后给大鼠施用试验品、参比药物、或对照载体。剂量施用后1小时,通过“测痛仪”测量红肿爪和非红肿爪的痛阈,所述“测痛仪”施加以恒定速度沿线性尺度增加的力。
计算对照组的红肿爪和非红肿爪的阈和标准偏差。如果个体痛阈超过对照组平均阈两个平均标准偏差,则认为试验品组和参比组中的大鼠受到保护。
4.热板镇痛测试
在整个试验中每只小鼠(CD-I,雄性)用作其自身对照。小鼠被顺序放置于热板镇痛仪(设置在55℃±2℃)上。小鼠通过以下行为对热刺激特征性地作出反应:
1.舔前爪
2.快速扇动后爪
3.突然跳离热板
任何三种类型的反应都认为是热刺激的终点。当表现出终点时立即将小鼠从热板上移走。通过将小鼠放置于热板上和表现出最后的终点之间经历的秒数定量地测量反应时间。通过精确至至少1/5秒的秒表测量经历的时间。仅使用对照反应时间在10.0秒或更少的小鼠。施用试验品或对照品后15、30、60和120分钟(±1至5分钟),顺序得到并记录所述组的反应时间。
镇痛响应是小鼠对热刺激的反应时间增加。在特定的时间间隔下,由每个剂量水平的10只小鼠组的平均响应计算镇痛百分率:
然后进行ANOVA和适当的多重比较试验。
5.大鼠尾辐射热试验(甩尾)
评价试验品在大鼠中对热刺激产生镇痛响应的潜能。
过夜禁食后,将大鼠称重并分成每组10只的组。施用试验品、载体对照品。使用甩尾痛觉测试仪。口服施用后60分钟(或如发起人推荐的),将每只大鼠的尾巴暴露于特定强度的热刺激下并记录引起响应(特征性的甩尾)所需的时间。
利用与平均试验品响应对照的平均对比响应计算镇痛百分率。
实施例VIII
化合物用作外周抗痛觉过敏剂的确定
一般而言,上述的方法还用于评价试验化合物的外周抗痛觉过敏活性。评价抗痛觉过敏活性的方法中最优选的方法是描述于Niemegeers等(1974)Drug Res.24:1633-1636中的那些。
1.在抗腹泻活性试验(比如蓖麻油试验)中的ED50值[A]与CNS作用(比如甩尾试验)中的ED50值[B]的比率[C]的评价
意欲用于方法和组合物的药剂可通过其作为抗腹泻剂的活性、以及其缺乏CNS作用进行确定。具体而言,所选的化合物在任何上述标准模型中表现出抗痛觉过敏活性,并且,优选地,或(a)如标准方法测量的,这些活性的比率[B/A]基本上大于或等于[至少等于,更优选至少约2倍]地芬诺酯的这种活性的比率;或(b)在测量CNS活性的方法中的化合物的活性基本上小于[至少2倍,优选3倍或更多]地芬诺酯。
实施例IX
S-MNTX的体外药理学:表达人μ(μ,MOP)受体的CHO细胞中的
cAMP测试
μ阿片样物质受体是Gi耦联的,其通过抑制cAMP的增加起作用。因此,在这些试验中,通过添加10μM的福斯高林增加细胞内cAMP。在添加DAMGO,或相似激动剂例如内吗啡肽-1(endomorphin-1)、芬太尼、或吗啡之前,抑制该福斯高林诱导的增加。不存在激动剂作用产生了等于单独福斯高林的结果。因此,增加激动剂浓度降低cAMP水平。
拮抗剂(比如CTOP、纳洛酮和ciprodime)抑制cAMP抑制。因此,全拮抗剂作用等于不添加任何μ阿片样物质激动剂的福斯高林。在这些试验中,加入拮抗剂,然后加入30μM的DAMGO,然后加入福斯高林。因此,增加拮抗剂浓度增加cAMP。
试验方案
测试特征:
ED50(DAMGO):12nM
cAMP产生
(含有福斯高林和IBMX):3.4pmol/孔
抑制(10μM的DAMGO):90%
材料和方法
细胞来源:人重组/CHO细胞
参比激动剂:DAMGO
参比抑制剂:CTOP(见拮抗剂SAP)
参比曲线:DAMGO(细胞活化)
cAMP(EIA对照曲线)
培养细胞以群集在96-孔板中。分析之前在生理缓冲液中清洗并平衡细胞。加入20μl的药物、100μM的IBMX和10μM的福斯高林,并在室温下培养25分钟,然后加入0.1N的HCl中止反应。通过利用碱性磷酸酶的竞争性EIA测试确定提取的cAMP水平。另外的试验条件如Toll L.,J Pharmacol Exp Ther.(1995)273(2):721-7中所述。
结果
激动剂活性:如表IX.1所示,S-MNTX显示出激动剂响应,其中EC50为600nM。(6.0E-7M)。激动剂响应是完全的(不是部分的)。
表IX.1
log{M}浓度 | S-MNTX | SD | DAMGO | SD |
-4.0 | 3 | 6 | -1 | 3 |
-4.5 | -3 | 1 | ||
-5.0 | 4 | 9 | 2 | 5 |
-5.5 | 11 | 6 | ||
-6.0 | 32 | 7 | 1 | 6 |
-6.5 | 66 | 21 | ||
-7.0 | 70 | 17 | 2 | 6 |
-7.5 | 79 | 24 | ||
-8.0 | 104 | 10 | 68 | 28 |
-9.0 | 86 | 5 | 63 | 10 |
-10.0 | 88 | 22 | ||
-11.0 | 105 | 13 |
拮抗剂测试:如表X.2中所示的结果证明的,S-MNTX没有显示拮抗剂作用。
表IX.2
log{M}浓度 | S-MNTX | 范围 | Ctop | 范围 |
-4.0 | -13 | 5 | ||
-4.5 | -13 | 1 | ||
-5.0 | -9 | 3 | 91 | 11 |
-5.5 | -8 | 7 | ||
-6.0 | -1 | 17 | 109 | 11 |
-6.5 | 9 | 1 | ||
-7.0 | 5 | 7 | 48 | 3 |
-7.5 | 6 | 7 | ||
-8.0 | 4 | 6 | 1 | 1 |
-9.0 | 0 | 4 | ||
-10.0 | ||||
-11.0 | -1 | 1 |
已经如此描述了本发明的至少一个实施方案的几个方面,应当理解,多种改变、变动和改进将是本领域技术人员容易想到的。这样的改变、变动和改进意欲是本公开内容的一部分,并意欲包含在本发明的精神和范围内。因此,前述描述和附图仅仅是举例说明的。
Claims (104)
2.权利要求1的分离的化合物,其中所述反离子是卤离子、硫酸根、磷酸根、硝酸根或带电阴离子有机物质。
3.权利要求2的分离的化合物,其中所述反离子是卤离子。
4.权利要求3的分离的化合物,其中所述卤离子是溴离子。
5.权利要求3的分离的化合物,其中所述卤离子是碘离子。
6.权利要求1的分离的化合物,其具有至少75%的纯度。
7.权利要求1的分离的化合物,其具有至少90%的纯度。
8.权利要求1的分离的化合物,其具有至少95%的纯度。
9.权利要求4的分离的化合物,其具有至少75%的纯度。
10.权利要求4的分离的化合物,其具有至少90%的纯度。
11.权利要求4的分离的化合物,其具有至少95%的纯度。
12.权利要求1至11的分离的化合物,其中所述分离的化合物处于晶体形式。
13.含有MNTX的组合物,其中存在于所述组合物中10%以上的MNTX关于氮为S构型。
14.权利要求13的组合物,其中存在于所述组合物中30%以上的MNTX关于氮为S构型。
15.权利要求13的组合物,其中存在于所述组合物中50%以上的MNTX关于氮为S构型。
16.权利要求13的组合物,其中存在于所述组合物中约75%的MNTX关于氮为S构型。
17.权利要求13的组合物,其中存在于所述组合物中约90%的MNTX关于氮为S构型。
18.权利要求13的组合物,其中存在于所述组合物中约95%的MNTX关于氮为S构型。
19.权利要求13的组合物,其中存在于所述组合物中约98%的MNTX关于氮为S构型。
20.权利要求13的组合物,其中存在于所述组合物中99%以上的MNTX关于氮为S构型。
21.权利要求13的组合物,其中MNTX具有反离子,所述反离子是卤离子、硫酸根、磷酸根、硝酸根或带电阴离子有机物质。
22.权利要求21的组合物,其中所述反离子是卤离子。
23.权利要求22的组合物,其中所述卤离子是碘离子。
24.权利要求22的组合物,其中所述卤离子是溴离子。
25.权利要求13至24中任一项的组合物,其中所述组合物是溶液。
26.权利要求13至24中任一项的组合物,其中所述组合物是固体。
27.含有有效量的权利要求13至24中任一项的组合物、以及药学上可接受载体的药物组合物。
28.权利要求27的药物组合物,进一步包含除了MNTX以外的治疗剂。
29.权利要求28的药物组合物,其中所述治疗剂是阿片样物质或阿片样物质激动剂。
30.权利要求29的药物组合物,其中所述阿片样物质选自阿芬他尼、阿尼利定、阿西马朵林、布马佐辛、burprenorphine、布托啡诺、可待因、地佐辛、二乙酰吗啡(海洛因)、二氢可待因、地芬诺酯、非多托嗪、芬太尼、funaltrexamine、氢可酮、氢吗啡酮、左洛啡烷、左旋乙酰美沙酮、羟甲左吗喃、洛哌丁胺、美吡利啶(哌替啶)、美沙酮、吗啡、吗啡-6-葡糖苷酸、纳布啡、烯丙吗啡、阿片、羟可待酮、羟吗啡酮、镇痛新、哌丙吡胺、丙氧芬、瑞芬太尼、舒芬太尼、替利定、曲美布丁、曲马多和其组合。
31.权利要求29的药物组合物,其中所述阿片样物质或阿片样物质激动剂基本上没有中枢神经系统(CNS)活性。
32.权利要求28的药物组合物,其中所述治疗剂不是阿片样物质、阿片样物质激动剂、或阿片样物质拮抗剂。
33.权利要求28的药物组合物,其中所述治疗剂是抗病毒剂、抗生素、抗真菌剂、抗细菌剂、杀菌剂、抗原生动物剂、抗寄生虫剂、抗炎剂、血管收缩剂、局部麻醉剂、抗腹泻剂、抗痛觉过敏剂或其组合。
34.权利要求28的药物组合物,其中所述治疗剂是抗腹泻剂,所述抗腹泻剂是洛哌丁胺,洛哌丁胺类似物,洛哌丁胺N-氧化物及其类似物、代谢物以及前药,地芬诺酯,西沙比利,抗酸剂,氢氧化铝,硅酸镁铝,碳酸镁,氢氧化镁,碳酸钙,聚卡波菲,聚二甲基硅氧烷,莨菪碱,阿托品,呋喃唑酮,地芬诺新,善得定,兰索拉唑,高岭土,果胶,活性炭,磺胺脒,琥珀酰磺胺噻唑,邻苯二甲酰基磺胺噻唑,铝酸铋,碱式碳酸铋,碱式柠檬酸铋,柠檬酸铋,三钾二枸橼酸铋,酒石酸铋,碱式水杨酸铋,碱式硝酸铋和碱式没食子酸铋,阿片酊剂(止痛剂)、草药、和植物衍生的抗腹泻剂或其组合。
35.权利要求28的药物组合物,其中所述治疗剂是抗炎剂,所述抗炎剂是非甾体抗炎剂(NSAID)、肿瘤坏死因子抑制剂、巴利昔单抗、达克珠单抗、英夫单抗、霉酚酸酯、mofetil、硫唑嘌呤、他克莫司、类固醇、柳氮磺吡啶、奥沙拉嗪、美沙拉秦、或其组合。
36.权利要求28的药物组合物,其中所述治疗剂是抗病毒剂。
37.权利要求28的药物组合物,其中所述治疗剂是抗细菌剂。
38.权利要求28的药物组合物,其中所述治疗剂是抗痛觉过敏剂。
39.权利要求27的药物组合物,其中所述组合物是肠溶包衣的。
40.权利要求27的药物组合物,其中所述组合物是控制释放或持续释放制剂。
41.权利要求27的药物组合物,其中所述组合物是溶液。
42.权利要求27的药物组合物,其中所述组合物是局部制剂。
43.权利要求27的药物组合物,其中所述组合物是冻干的。
44.权利要求27的药物组合物,其中所述组合物是栓剂。
45.含有权利要求27的药物组合物的吸入剂。
46.含有权利要求27的药物组合物的鼻喷雾装置。
47.用于合成S-MNTX的盐的方法,包括:
在第一溶剂中化合(碘甲基)环丙烷与羟吗啡酮以制备S-MNTX的碘化物盐。
48.权利要求47的方法,进一步包括:将所述S-MNTX的碘化物盐转移到第二溶剂中;并用除碘离子以外的反离子交换碘离子。
49.权利要求47的方法,进一步包括:将所述S-MNTX的碘化物盐转移到第二溶剂中;并将碘离子交换成溴离子以制备S-MNTX的溴化物盐。
50.权利要求47的方法,其中所述第一溶剂包含N-甲基吡咯烷酮。
51.权利要求49的方法,其中所述第二溶剂包含至少乙酸异丙酯或二烷。
52.权利要求49的方法,其中所述第一溶剂是N-甲基吡咯烷酮并且所述第二溶剂是乙酸异丙酯或二烷。
53.权利要求47的方法,进一步包括通过色谱法、重结晶、或其组合纯化所述S-MNTX的盐。
54.权利要求49的方法,进一步包括通过色谱法、重结晶、或其组合纯化所述S-MNTX的盐。
55.权利要求54的方法,其中所述纯化是通过多次重结晶进行的。
56.权利要求47的方法,其中所述方法是在65至75℃的控制反应温度下进行的。
57.权利要求50的方法,其中所述方法是在65至75℃的控制反应温度下进行的。
58.权利要求52的方法,其中在第一溶剂中化合(碘甲基)环丙烷与羟吗啡酮以制备S-MNTX的碘盐是在65℃至75℃的控制反应温度下进行的,其中将碘离子交换成溴离子以制备S-MNTX的溴盐是在室温下进行的,并且其中所述第一溶剂是N-甲基吡咯烷酮和所述第二溶剂是乙酸异丙酯或二烷。
59.用于抑制对象中腹泻的方法,包括以有效治疗或预防腹泻的量向需要这种治疗的对象施用权利要求27的药物组合物。
60.权利要求59的方法,进一步包括向对象施用不是S-MNTX的抗腹泻剂。
61.权利要求60的方法,其中所述不是S-MNTX的抗腹泻剂是阿片样物质或阿片样物质激动剂。
62.用于减少对象中由回肠造口术或结肠造口术引起的流出物体积的方法,包括以有效减少由回肠造口术或结肠造口术引起的流出物体积的量向需要这种减少的对象施用权利要求27的药物组合物。
63.用于降低对象中由回肠造口术或结肠造口术引起的流出速度的方法,包括以有效降低由回肠造口术或结肠造口术引起的流出速度的量向需要这种降低的对象施用权利要求27的药物组合物。
64.用于抑制需要这种治疗的对象中胃肠蠕动的方法,包括以有效抑制对象胃肠蠕动的量向对象施用权利要求27的药物组合物。
65.权利要求64的方法,进一步包括向对象施用阿片样物质或阿片样物质激动剂。
66.用于治疗肠易激综合征的方法,包括以有效改善肠易激综合征的至少一种症状的量向需要这种治疗的患者施用权利要求27的药物组合物。
67.用于抑制对象中疼痛的方法,包括以足以预防或治疗疼痛的量施用权利要求27的药物组合物。
68.权利要求67的方法,进一步包括向对象施用除了S-MNTX以外的治疗剂。
69.权利要求68的方法,其中所述除了S-MNTX以外的治疗剂是阿片样物质。
70.权利要求68的方法,其中所述除了S-MNTX以外的治疗剂是抗病毒剂、抗生素、抗真菌剂、抗细菌剂、杀菌剂、抗原生动物剂、抗寄生虫剂、抗炎剂、血管收缩剂、局部麻醉剂、抗腹泻剂或抗痛觉过敏剂。
71.权利要求67的方法,其中所述疼痛是外周痛觉过敏。
72.权利要求67的方法,其中所述药物组合物局部施用于疼痛部位。
73.权利要求67的方法,其中所述施用是关节内。
74.权利要求67的方法,其中所述施用是全身的。
75.权利要求67的方法,其中所述施用是局部的。
76.权利要求67的方法,其中所述药物组合物施用于眼睛。
77.用于抑制对象中炎症的方法,包括以有效抑制炎症的量向需要其的对象施用权利要求27的药物组合物。
78.权利要求77的方法,进一步包括向对象施用除了S-MNTX以外的治疗剂。
79.权利要求78的方法,其中所述除了S-MNTX以外的治疗剂是抗炎剂。
80.权利要求77的方法,其中所述施用是在炎症部位的局部施用。
81.权利要求77的方法,其中所述施用是全身施用。
82.权利要求77的方法,其中所述施用是局部施用。
83.抑制对象中肿瘤坏死因子(TNF)产生的方法,包括:
向对象施用组合物,所述组合物含有抑制TNF产生的量的权利要求27的药物组合物。
84.一种药盒,其包括含有密封容器的包装,所述密封容器含有权利要求27的药物组合物和使用说明书。
85.根据权利要求84的药盒,进一步包含除了S-MNTX以外的治疗剂。
86.根据权利要求85的药盒,其中所述治疗剂是阿片样物质或阿片样物质激动剂。
87.根据权利要求86的药盒,其中所述阿片样物质或阿片样物质激动剂基本上没有CNS活性。
88.根据权利要求86的药盒,其中所述治疗剂是抗病毒剂、抗生素、抗真菌剂、抗细菌剂、杀菌剂、抗原生动物剂、抗寄生虫剂、抗炎剂、血管收缩剂、局部麻醉剂、抗腹泻剂、抗痛觉过敏剂或其组合。
89.根据权利要求85的药盒,其中所述治疗剂是外周阿片样物质拮抗剂。
90.根据权利要求89的药盒,其中所述外周阿片样物质拮抗剂是R-MNTX。
91.根据权利要求89的药盒,其中所述外周阿片样物质拮抗剂是N-烷基羧酸哌啶、去甲羟基吗啡酮的季衍生物、阿片生物碱衍生物、或季苯并吗吩烷。
92.用于调节胃肠功能的方法,其包括向需要其的对象施用S-MNTX,和向所述对象施用外周μ阿片样物质拮抗剂。
93.权利要求92的方法,其中所述外周μ阿片样物质拮抗剂是R-MNTX。
94.权利要求92的方法,其中所述外周阿片样物质拮抗剂是N-烷基羧酸哌啶、去甲羟基吗啡酮的季衍生物、阿片生物碱衍生物、或季苯并吗吩烷。
95.制备S-MNTX的方法,包括下述步骤:
(a)得到含有S-MNTX的第一组合物,
(b)通过色谱法、重结晶或其组合纯化所述第一组合物,
(c)利用S-MNTX作为标准,在纯化的第一组合物样品上进行HPLC,
(d)测定所述样品中存在或不存在R-MNTX。
96.权利要求95的方法,其中所述纯化包括多次重结晶步骤或多次色谱步骤。
97.权利要求95的方法,其中进行纯化直到如通过HPLC检测的样品中不存在R-MNTX。
98.权利要求96的方法,其中进行纯化直到如通过HPLC检测的样品中不存在R-MNTX。
99.权利要求97的方法,进一步包括包装不含有HPLC可检测的R-MNTX的纯化第一组合物。
100.权利要求98的方法,进一步包括包装不含有HPLC可检测的R-MNTX的纯化第一组合物。
101.权利要求99的方法,进一步包括提供位于所述包装的纯化第一组合物之上或之内的标识,指示所述包装的纯化第一组合物不含有HPLC可检测的R-MNTX。
102.权利要求100的方法,进一步包括指示所述包装的纯化第一组合物不含有HPLC可检测的R-MNTX。
103.含有组合物和标识的包装,所述组合物含有S-MNTX,其中所述组合物不含有HPLC可检测的R-MNTX,并且所述标识位于所述包装之上或包含在所述包装内来指示所述组合物不含有可检测的R-MNTX。
104.权利要求103的包装,其中所述组合物是药物组合物。
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US20120136019A1 (en) | 2012-05-31 |
WO2006127898A2 (en) | 2006-11-30 |
PL1928882T3 (pl) | 2014-01-31 |
AR057325A1 (es) | 2007-11-28 |
EP2450360A2 (en) | 2012-05-09 |
EP1928882A2 (en) | 2008-06-11 |
ES2429159T3 (es) | 2013-11-13 |
CN101208345B (zh) | 2013-10-16 |
SI1928882T1 (sl) | 2013-11-29 |
WO2006127898A3 (en) | 2007-02-08 |
BRPI0611476A2 (pt) | 2010-09-14 |
MX2007014879A (es) | 2008-02-15 |
JP2008542286A (ja) | 2008-11-27 |
JP5266048B2 (ja) | 2013-08-21 |
US8916581B2 (en) | 2014-12-23 |
US20070265293A1 (en) | 2007-11-15 |
EP2450360A3 (en) | 2012-08-22 |
US8003794B2 (en) | 2011-08-23 |
DK1928882T3 (da) | 2013-11-04 |
HN2006019066A (es) | 2011-03-02 |
US20100105911A1 (en) | 2010-04-29 |
CN103257189A (zh) | 2013-08-21 |
CA2609393C (en) | 2015-02-17 |
CN103257189B (zh) | 2016-05-11 |
CA2609393A1 (en) | 2006-11-30 |
EP1928882B1 (en) | 2013-09-04 |
US7563899B2 (en) | 2009-07-21 |
TWI478927B (zh) | 2015-04-01 |
PT1928882E (pt) | 2013-10-23 |
TW200716646A (en) | 2007-05-01 |
AU2006249910A1 (en) | 2006-11-30 |
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