CN101208344B - (r)-n-甲基纳曲酮、其合成方法以及其药物用途 - Google Patents
(r)-n-甲基纳曲酮、其合成方法以及其药物用途 Download PDFInfo
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- CN101208344B CN101208344B CN200680022957XA CN200680022957A CN101208344B CN 101208344 B CN101208344 B CN 101208344B CN 200680022957X A CN200680022957X A CN 200680022957XA CN 200680022957 A CN200680022957 A CN 200680022957A CN 101208344 B CN101208344 B CN 101208344B
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Abstract
本发明涉及R-MNTX及其中间体的立体选择性合成、含有R-MNTX或其中间体的药物制剂和它们的使用方法。
Description
技术领域
本发明涉及(R)-N-甲基纳曲酮(R-MNTX)及其中间体的立体选择性合成、含有R-MNTX或其中间体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,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形成带电荷的化合物,所述带电荷的化合物与纳曲酮相比具有更大的极性和更小的脂溶性。MNTX的这个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。文献中描述的所有报道的MNTX功能显示MNTX是外周阿片样物质拮抗剂。一些这样的拮抗剂的功能描述于美国专利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(2003/0022909 A1)、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。文献中报道MNTX不但降低源自阿片样物质镇痛治疗的副作用,而且降低由单独的内源性阿片样物质或与外源性阿片样物质联合治疗所介导的副作用。这样的副作用包括胃肠蠕动抑制、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的这些病症。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。
文献提示分离的化合物立体异构体有时可能具有差别明显的物理和功能特性,尽管不可预知在任何特定情况下都是如此。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(methylphenidate)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。对于治疗胃灼热,奥美拉唑的S对映体比R对映体更有效。
Bianchetti等(1983 Life Science 33(Sup I):415-418)研究了三对季麻醉拮抗剂的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怎样制备的而变化。在每个系列中,仅仅通过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-纳曲酮中以及在豚鼠回肠中用作吗啡拮抗剂是有效的。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结果一致。因此仅仅“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,制备的材料显示为纯的,但是这些方法是不准确的。作者引用了参考文献用于纳洛芬的“N-甲基非对映异构体”的R构型的归属。对于左洛啡烷和纳洛酮非对映异构体没有提出归属。推断这些非对映异构体的构型将是冒险的(R.J.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描述了合成MNTX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。Goldberg等人和Cantrell等人都没有公开由合成产生的一种或多种立体异构体。作者谨慎地没有公开立体化学是因为基于现有技术不能确定立体化学。纳曲酮中的环丙基甲基侧链不同于现有技术的侧链,并且如其它反应参数例如温度和压力一样可能影响MNTX合成中的立体化学产物。基于各自所述的合成方法,不知道由此产生的MNTX是否是R、S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。在不存在作为标准的纯S-MNTX时,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,相对于R-MNTX的保留时间,能在色谱中表征S-MNTX的相对保留时间。发现纯S-MNTX具有不同于文献中所报道MNTX活性的活性。这突出了对制备和纯化R-MNTX至高纯度的方法的需求。
本发明提供基本上纯的R-MNTX及其中间体、基本上纯的R-MNTX及其中间体的晶体、制备基本上纯的R-MNTX的新方法、分析和定量R-MNTX和S-MNTX混合物中R-MNTX的方法、从R-MNTX和S-MNTX混合物中分离R-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R-MNTX的立体选择性合成的合成路线、基本上纯的R-MNTX、基本上纯的R-MNTX的晶体、含有基本上纯的R-MNTX的药物制剂、以及其使用方法。
根据本发明的一个方面,提供含有以大于99.5%存在的关于氮为R构型的MNTX的组合物。在另外实施方案中,组合物中关于氮为R构型的MNTX以大于约99.6%、或约99.7%、或约99.8%、或约99.9%、或约99.95%或甚至更优选以大于99.95%存在。在一个实施方案中,利用本文所述的色谱方法没有可检测的S-MNTX。优选地,组合物不含有HPLC可检测的S-MNTX。在一个实施方案中,在0.02%的检测限和0.05%的定量限下,没有HPLC可检测的S-MNTX。在又一另外实施方案中,本发明的组合物包含99.85%的有关氮为R构型的MNTX,并且其在0.02%的检测限和0.05%的定量限下包含HPLC可检测的S-MNTX。
根据本发明的一个方面,提供含有MNTX(其中组合物中至少99.6%、99.7%、99.8%、99.85%、99.9%、和甚至99.95%的MNTX关于氮为R构型)、和一种或多种缓冲剂、螯合剂、保存剂、冷冻保护剂、润滑剂、防腐剂、抗氧化剂或粘结剂的组合物。
R-MNTX是盐。因此对于本发明的应用,将有反离子,包括两性离子。典型地,反离子为卤离子、硫酸根、磷酸根、硝酸根或带电的阴离子的有机物质。卤离子包括溴离子、碘离子、氯离子和氟离子。在某些实施方案中,所述卤离子是碘离子,在另一个重要的实施方案中,所述卤离子是溴离子。在某些实施方案中,所述具有阴离子的有机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。
根据本发明的另外一个方面,在一些重要的实施方案中,前述的包含关于氮为R构型的MNTX的组合物是MNTX的晶体、溶液或溴化物盐。在另一些实施方案中,前述的组合物是药物制剂,优选是有效量的并且具有药学上可接受的载体。
根据本发明的一个方面,提供MNTX的晶体,所述MNTX的晶体是至少约99.5%、或约99.6%、或约99.7%、或约99.8%、或约99.9%、或最优选大于99.95%的关于氮为R构型的MNTX。
根据本发明的一个方面,提供下式的化合物:
其中R是羟基保护基。所述羟基保护基可以是任意数目的这种基团。在重要的实施方案中,其选自以下基团:异丁酰基、2-甲基丁酰基、叔丁基羰基、甲硅烷基醚、2-四氢吡喃醚、和烷基碳酸酯。最优选地,羟基保护基是异丁酰基。
根据本发明的一个方面,提供下式的化合物:
其中R是羟基保护基。所述羟基保护基选自以下基团:异丁酰基、2-甲基丁酰基、叔丁基羰基、甲硅烷基醚、2-四氢吡喃醚、和烷基碳酸酯。最优选地,羟基保护基是异丁酰基。在一个实施方案中,分离化合物。通过分离,这意味着化合物是至少50%纯的。可以得到甚至更大纯度水平的化合物,例如60%、70%、80%、90%、或甚至大于95%的纯度。在另一些实施方案中,化合物关于氮为R构型,相对于S型,R型以大于50%、60%、70%、80%、90%、95%、99%、或甚至99.5%存在。
根据本发明的另外一个方面,提供立体选择性合成R-MNTX的方法。该方法包括:将羟基保护基加入到纳曲酮中以得到3-O-保护的纳曲酮;将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。在本发明的一些实施方案中,可在任一种有机溶剂和/或不是纳曲酮的叔胺或两者的存在下加入羟基保护基团。在本发明的一些实施方案中,通过3-O-保护的纳曲酮与甲基碘反应而甲基化纳曲酮以制备3-O-保护的-R-MNTX碘化物盐。在重要的实施方案中,可通过羟基保护基例如异丁酰基保护3-O-保护的纳曲酮。在本发明的一个优选实施方案中,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,将溴化物盐/碘化物盐通过阴离子交换树脂柱(溴化物形式)以得到R-MNTX溴化物。在本发明的任何前述方面,不是MNTX的叔胺可以是三乙胺。在本发明的任何前述方面,有机溶剂可以是四氢呋喃。在本发明的任何前述方面,羟基保护基可以是异丁酰基。
根据本发明的另外一个方面,提供分离和纯化R-MNTX的方法,其包括将粗R-MNTX通过色谱柱并收集在R-MNTX保留时间洗脱的R-MNTX。该过程可以是上述方法的补充,在脱保护步骤和/或阴离子交换树脂柱步骤之后。
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R-MNTX的方法。该方法包括进行高效液相色谱(HPLC)并且将R-MNTX应用于色谱柱作为标准。该方法优选包括应用S-MNTX和R-MNTX作为标准以测定相对保留时间/洗脱时间。R和S的相对保留时间如本文所述。
根据以下步骤可得到纯S-MNTX:通过在偶极非质子溶剂中化合碘甲基环丙烷或另外的环丙基甲基衍生物与羟吗啡酮,可以合成S-MNTX盐。所述环丙基甲基衍生物包含离去基团,优选卤,例如碘或磺酸酯。所述偶极非质子溶剂可以是:N-甲基吡咯烷酮(NMP)、二甲基甲酰胺、甲基磷酰胺(methylphosphoramide)、丙酮、1,4-二烷、乙腈、或其组合。合成的S-MNTX可通过色谱、重结晶、多次重结晶、或其组合进行纯化。所述反应可在跨越宽的温度范围的大气条件下进行,例如在70℃,或在65℃至75℃的可控反应温度下进行。任选地,将S-MNTX碘盐转移到第二种溶剂例如醋酸异丙酯或二烷中并将碘交换为非碘的反离子,可以使反离子取代碘离子。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(besylate)、甲苯磺酸根、和三氟甲磺酸根。所述羧酸根可以是甲酸根、乙酸根、柠檬酸根和富马酸根。可在室温下进行第二种溶剂中的反应。
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,柱凝胶的孔尺寸是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 |
通过紫外(UV)波长230nm可方便地进行检测。定量限是不管实验室、分析者、仪器或试剂批号的变化而可以始终如一地检测并报告的S-MNTX的最低量。检测限是可检测但是不必定量为准确值的样品中S-MNTX的最低量。
通过检测产生的色谱中的各自R和S曲线下的面积,前述的HPLC也可用于检测S-MNTX和R-MNTX以及其合成中间体的相对量。根据本发明的另外一个方面,提供分离并纯化R-MNTX和3-O-保护的-R-MNTX盐中间体的方法,其包括从溶剂或溶剂混合物中重结晶粗R-MNTX或其中间体。该过程可以是上述方法的补充,在脱保护步骤和/或阴离子交换树脂柱步骤之后。
根据本发明的另外一个方面,提供立体选择性合成3-O-保护的-R-MNTX的方法,该方法包括用甲基化剂甲基化3-O-保护的纳曲酮以得到3-O-保护的-R-MNTX盐。在某些实施方案中,3-O-保护的-纳曲酮的羟基保护基是异丁酰基、2-甲基丁酰基、叔丁基羰基、甲硅烷基醚、2-四氢吡喃醚、和烷基碳酸酯。3-O-保护的R-MNTX是与阴离子的盐,所述阴离子可以是例如卤离子、硫酸根、磷酸根、硝酸根或带电的有机阴离子物质。卤离子是溴离子、碘离子、氯离子或氟离子。所述带电的有机阴离子物质可以是例如磺酸根或羧酸根。示例性的磺酸根是甲磺酸根、苯磺酸根(besylate)、甲苯磺酸根、和三氟甲磺酸根。示例性的羧酸根是甲酸根、乙酸根、柠檬酸根或富马酸根。该方法还可包括用不同的阴离子交换阴离子。甲基化剂可以是易受亲核进攻的甲基基团、和离去基团。示例性的甲基化剂选自甲基卤、硫酸二甲酯、硝酸甲酯和磺酸甲酯。甲基卤是甲基碘、甲基溴、甲基氯和甲基氟。磺酸甲酯包括甲磺酸甲酯、苯磺酸甲酯、甲苯磺酸甲酯、和三氟甲磺酸甲酯。在一个实施方案中,在约>70℃至约100℃、或约80℃至约90℃的温度范围内,或优选地在约88℃进行甲基化。甲基化反应进行约1小时至24小时,或约5小时至16小时,并且在一个实施方案中,进行约10小时。该方法还可包括利用至少一种纯化技术例如色谱或重结晶纯化3-O-保护的R-MNTX。色谱可以是反相色谱或正相色谱。在一些实施方案中,所述正相色谱可以使用氧化铝或硅胶。可在甲基化之前纯化3-O-保护的-纳曲酮。
根据本发明的一个方面,提供药物组合物,所述药物组合物包含R-MNTX、或3-O-保护的-R-MNTX盐中间体以及药学上可接受的载体,所述R-MNTX不含通过本文所述色谱方法可检测的S-MNTX。在一个实施方案中,药物组合物是包装的单位剂型或多单位剂型。在又一另外实施方案中,包装的单位剂型是溶液。在一个实施方案中,药物组合物是溶液。在另外一个实施方案中,其是肠溶包衣的固体剂型。在又一另外实施方案中,其是缓释制剂。根据本发明的又一另外方面,通过结合冷冻保护剂例如甘露醇与R-MNTX制剂,制备为冻干制剂的含有R-MNTX或3-O-保护的-R-MNTX盐中间体的药物制剂。所述冻干制剂还可包含缓冲剂、抗氧化剂、等渗剂和阿片样物质的任何一种、任何组合、或全部。在一些实施方案中,前述的药物组合物还可包含一种不是阿片样物质拮抗剂的药剂。在本发明的一个实施方案中,前述的药物组合物可包含是阿片样物质的药剂。在又一另外实施方案中,药物组合物还可包含至少一种阿片样物质,以及至少一种不是阿片样物质或阿片样物质拮抗剂的药剂。在一个优选实施方案中,不是阿片样物质或阿片样物质拮抗剂的药剂是抗病毒剂、抗感染剂、抗癌剂、抗痉挛剂、抗毒蕈素性药物、甾体抗炎剂或非甾体抗炎剂、pro-motility agent、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(bulk-forming agent)、α2-肾上腺素能激动剂、矿物油、抗抑郁剂、草药、止泻药、轻泻剂、大便软化剂、纤维或造血刺激剂。
本发明的药物组合物可以以药盒提供。所述药盒是含有密封容器和使用说明书的包装,所述密封容器含有本发明的药物制剂。所述药盒含有R-MNTX,所述R-MNTX不含有HPLC可检测的S-MNTX。在一个实施方案中,药盒含有40mg/mL R-MNTX。在另一个实施方案中,药盒含有30mg/mL R-MNTX。药盒进一步可包含阿片样物质或阿片样物质激动剂,或其可包含至少一种不是阿片样物质或阿片样物质拮抗剂的药剂。在一个实施方案中,药盒是含有密封容器和使用说明书的包装,所述密封容器含有药物制剂或3-O-保护的-R-MNTX盐。在一个实施方案中,药盒含有40mg/mL 3-O-保护的-R-MNTX盐。在另一个实施方案中,药盒含有30mg/mL 3-O-保护的-R-MNTX盐。药盒进一步可包含阿片样物质或阿片样物质激动剂,或其可包含至少一种不是阿片样物质或阿片样物质拮抗剂的药剂。
根据本发明的另外一个方面,提供确保制备不含有S-MNTX(其为阿片样物质激动剂)的R-MNTX(其为阿片样物质拮抗剂)的方法。该方法首次能确保意欲用于拮抗剂活性的R-MNTX药物制剂不被对抗R-MNTX活性的化合物污染。因为阿片样物质表现出与S-MNTX协同作用以对抗R-MNTX的活性,所以当施用R-MNTX用于对抗阿片样物质疗法的副作用时,这是特别希望的。在本发明的此方面,提供制备R-MNTX的方法。所述方法包括:
(a)得到含有R-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S-MNTX作为标准,对纯化的第一组合物样品进行HPLC,和(d)测定样品中存在或不存在S-MNTX。在一个重要的实施方案中,R-MNTX和S-MNTX都被用作标准,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,进行纯化直到如通过HPLC测定的样品中不含有S-MNTX。然而,应当理解,在本发明的一些方面,纯化的第一组合物不必不含有可检测的S-MNTX。例如,这种S-MNTX的存在可能指示:如果需要更纯的R-MNTX,应当进行进一步的纯化步骤。该方法可进一步包括包装不含有HPLC可检测的S-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,提示所述包装的、纯化的第一组合物不含有HPLC可检测的S-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。含有R-MNTX和S-MNTX的第一组合物可通过本文所述的方法得到。
根据本发明的一个方面,进行纯化直到如通过0.02的检测限和0.05%的定量限的HPLC检测的,纯化的第一组合物中的S-MNTX小于0.4%、0.3%、0.2%、0.15%、0.1%、0.05%、甚至不含有S-MNTX。在一个实施方案中,所述方法提供在包装的纯化的第一组合物之上或之内的标记,指示包装的第一纯化的组合物中S-MNTX的水平。
根据本发明的一个方面,提供含有组合物的包装,所述组合物含有R-MNTX和标记,所述标记位于包装之上或之内以指示组合物中S-MNTX的水平。在一个实施方案中,样品中S-MNTX水平小于0.4%、0.3%、0.2%、0.15%、0.1%、0.05%、或不含有S-MNTX。在另一个实施方案中,所述包装进一步包含与R-MNTX混合在一起的一种或多种缓冲剂、螯合剂、保存剂、冷冻保护剂、润滑剂、防腐剂、抗氧化剂、或粘结剂。
根据本发明的一个方面,通过选择R-MNTX的组合物(因为组合物中包含水平小于0.4%、0.3%、0.2%、0.15%、0.1%、0.05%的S-MNTX、或不含有S-MNTX)并将组合物配制成用于施用给患者的单位或多单位剂型,来提供制备药物产品的方法。
根据本发明的另外一个方面,提供包装产品。所述包装包含含有R-MNTX的组合物和标记,其中所述组合物不含有HPLC可检测的S-MNTX,所述标记在包装之上或包含在包装内以指示组合物不含有可检测的S-MNTX。组合物可呈现多种形式,包括但不限于实验室试验中使用的标准、制备规程中使用的标准、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药品说明书上以描述药物制剂的特征。所述标记可直接指示组合物不含有S-MNTX,或其可例如通过声明组合物是纯的或100%R-MNTX间接地指示相同内容。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R-MNTX并且可处于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。
根据本发明的一个方面,提供用于治疗或预防阿片样物质诱导的副作用的方法,其包括以有效治疗阿片样物质诱导的副作用的量向患者施用本发明任何前述方面的R-MNTX或3-O-保护的-R-MNTX盐中间体组合物,所述R-MNTX不含有通过本文所述色谱法可检测的S-MNTX。在本发明的一个实施方案中,患者长期施用阿片样物质。在另一个实施方案中,患者短期施用阿片样物质。阿片样物质诱导的副作用优选选自便秘、免疫抑制、胃肠蠕动抑制、抑制胃排空、恶心、呕吐、不完全排空、气胀、腹部膨胀、增强的胃食管反流、低血压、心动过缓、胃肠功能障碍、搔痒、烦躁不安、和尿潴留。在一个优选的实施方案中,阿片样物质诱导的副作用是便秘。在另一个优选的实施方案中,阿片样物质诱导的副作用是胃肠蠕动抑制或抑制胃排空。在又一个另外优选的实施方案中,阿片样物质诱导的副作用是恶心或呕吐。在又一个另外优选的实施方案中,阿片样物质诱导的副作用是搔痒。在又一个另外优选的实施方案中,阿片样物质诱导的副作用是烦躁不安。在又一个另外优选的实施方案中,阿片样物质诱导的副作用是尿潴留。
根据本发明的一个方面,提供用于治疗由手术引起的疼痛而接受阿片样物质的患者的方法,其包括以有效促进胃肠蠕动、胃排空或减轻便秘的量向患者施用R-MNTX组合物或3-O-保护的-R-MNTX盐中间体,所述R-MNTX组合物不含有通过本文所述色谱法可检测的S-MNTX。
根据本发明的另外一个方面,提供引起需要轻泻的患者轻泻的方法,其包括以有效量向患者施用R-MNTX组合物或3-O-保护的-R-MNTX盐中间体,所述R-MNTX组合物不含有通过本文所述色谱法可检测的S-MNTX。
根据本发明的又一个另外方面,提供用于预防和/或治疗需要这种预防和/或治疗的患者的阻塞的方法,其包括以有效量向患者施用R-MNTX组合物或3-O-保护的-R-MNTX盐中间体,所述R-MNTX组合物不含有通过本文所述色谱法可检测的S-MNTX。
根据本发明的又一个另外方面,提供用于预防和/或治疗需要这种预防和/或治疗的患者手术后尤其是腹部手术后的术后肠功能障碍的方法,其包括以有效量向患者施用R-MNTX组合物或3-O-保护的-R-MNTX盐中间体,所述R-MNTX组合物不含有通过本文所述色谱法可检测的S-MNTX。
根据本发明的一个方面,提供用于治疗或预防内源性阿片样物质诱导的胃肠功能障碍的方法,其包括以有效治疗内源性阿片样物质诱导的胃肠功能障碍的量向患者施用R-MNTX组合物或3-O-保护的-R-MNTX盐中间体,所述R-MNTX组合物不含有通过本文所述色谱法可检测的S-MNTX。所述胃肠功能障碍可选自胃肠蠕动抑制、便秘和肠梗阻。在本发明的一些实施方案中,所述肠梗阻选自:术后肠梗阻、产后肠梗阻、麻痹性肠梗阻。
根据本发明的一个方面,提供用于预防或治疗特发性便秘的方法,其包括以有效预防或治疗特发性便秘的量向患者施用R-MNTX组合物或3-O-保护的-R-MNTX盐中间体,所述R-MNTX组合物不含有通过本文所述色谱法可检测的S-MNTX。
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,其包括以有效减轻肠易激综合征的至少一种症状的量向患者施用R-MNTX组合物或3-O-保护的-R-MNTX盐中间体,所述R-MNTX组合物不含有通过本文所述色谱法可检测的S-MNTX。在本发明的一些实施方案中,所述R-MNTX组合物或3-O-保护的-R-MNTX盐组合物进一步包含至少一种肠易激综合征治疗剂。所述肠易激综合征治疗剂可选自抗痉挛剂、抗毒蕈素剂、抗炎剂、pro-motility agent、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-肾上腺素能激动剂、矿物油、抗抑郁剂、草药、止泻药及其组合。
根据本发明的一个方面,提供胃肠外施用本发明的化合物和组合物的方法,其包括但不限于静脉内、肌肉内和皮下施用。在本发明的一个实施方案中,本发明的化合物是适用于预充式注射器、预充笔式注射器的药物制剂,用于笔式注射器、可再用注射器或其它医疗注射器、液体干燥注射器、无针笔式体系、西雷特(Syrettes)皮下注射器、自动注射器、或其它患者可控的注射装置的针管(cartridges)的药物制剂。
本文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溴化物盐的化学结构。
图2是显示分离S-MNTX和R-MNTX混合物中MNTX的R和S构型的色谱图。
图3是添加约0.1%S-MNTX异构体的R-MNTX的色谱图。
图4是添加约1.0%S-MNTX异构体的R-MNTX的色谱图。
图5是添加约3.0%S-MNTX异构体的R-MNTX的色谱图。
图6显示利用优选的羟基保护基团合成R-MNTX的反应方案。
图7显示利用优选的羟基保护基合成R-MNTX的替代反应方案。
图8显示根据本发明的药盒。
具体实施方式
本发明提供立体选择性合成R-MNTX,[17R,17-(环丙基甲基)-4,5-环氧-3,14-二羟基-17-甲基-6-氧代-吗啡烷盐,(5α)-(9Cl)]的合成路线、基本上纯的R-MNTX、基本上纯的R-MNTX的晶体、含有基本上纯的R-MNTX的药物制剂、以及其使用方法。
R-MNTX具有下式的结构:
其中X-是反离子。反离子可以是任何反离子,包括两性离子。优选地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。所述阴离子有机物质可以是磺酸根或羧酸根。磺酸根可以是甲磺酸根、苯磺酸根(besylate)、甲苯磺酸根、或三氟甲磺酸根。羧酸根可以是甲酸根、乙酸根、柠檬酸根或富马酸根。
本发明进一步提供R-MNTX中间体,下式的分离的3-O-保护的-R-MNTX盐:
其中R是羟基保护基,基本上纯的3-O-保护的-R-MNTX盐,基本上纯的3-O-保护的-R-MNTX盐的晶体,含有基本上纯的3-O-保护的-R-MNTX盐的药物制剂,以及其使用方法。本发明还提供立体选择性合成3-O-保护的-R-MNTX盐的合成路线。
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。
“烷化剂”是可以与原料反应以将烷基基团结合(典型地共价地)到原料的化合物。所述烷化剂典型地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、卤化磺酸酯或卤化醋酸酯。烷化剂的一个实例是环丙基甲基碘。
“甲基化剂”指具有亲电特性、能在纳曲酮的氮原子上引入“甲基基团”以与其形成共价键的活性物质。示例性的甲基化剂可由式CH3Z表示,其中“Z”是当其离开时能使得CH3与纳曲酮的氮原子形成共价键而形成MNTX的离去基团。一般而言,甲基化剂和离去基团是本领域普通技术人员熟知的并且广泛地描述于专利文献和化学教科书中。适当的Z基团包括但不限于氟、氯、溴、碘、-OSO2CF3、CH3OSO2O-、-OSO2CH3、-OSO2C6H4-p-CH3、-OSO2C6H4-p-Br。
一般而言,“烯基”指链中含有至少一个碳-碳双键并具有2至约10个碳原子的烷基基团,以及该范围内的所有组合和亚组合。在某些优选实施方案中,所述烯基是C2-C10烷基基团,即具有2至约10个碳的支链或直链烯基基团。在另外的优选实施方案中,所述烯基是C2-C6烯基基团,即具有2至约6个碳的支链或直链烯基基团。在又一另外优选实施方案中,所述烯基是C3-C10烯基基团,即具有约3至约10个碳的支链或直链烯基基团。在又一另外优选实施方案中,所述烯基是C2-C5烯基基团,即具有2至约5个碳的支链或直链烯基基团。示例性的烯基基团包括例如乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基、壬烯基和癸烯基。
一般而言,“亚烷基”指具有1至约6个碳原子的直链或支链二价脂肪族烃基,以及该范围内的所有组合和亚组合。所述亚烷基可以是直链、支链或环状的。示例性的亚烷基包括例如亚甲基(-CH2-)、亚乙基(-CH2-CH2-)和亚丙基(-(CH2)3-)。可任选地沿亚烷基基团插入一个或多个氧、硫或任选取代的氮原子,其中所述氮取代基是前述的烷基。优选的亚烷基基团具有约1至约4个碳。
一般而言,“亚烯基”指含有至少一个碳-碳双键的亚烷基基团。示例性的亚烯基基团包括例如亚乙烯基(-CH=CH-)和亚丙烯基(-CH=CHCH2-)。优选的亚烯基基团具有2至约4个碳。
一般而言,“环烷基”指具有约3至约10个碳的任何稳定的单环或双环,以及该范围内的所有组合和亚组合。在优选实施方案中,所述环烷基是C3-C8环烷基基团,即具有约3至约8个碳的环烷基基团,并且更优选C3-C6环烷基基团,即具有约3至约6个碳的环烷基基团。环烷基基团可以任选地被一个或多个环烷基取代基取代。优选的环烷基取代基包括烷基,优选C1-C3烷基、烷氧基,优选C1-C3烷氧基、或卤素。示例性的环烷基基团包括例如环丙基、环丁基、环戊基、环己基、环庚基、和环辛基基团。
一般而言,“环烷基取代的烷基”指末端碳被环烷基基团(优选C3-C8环烷基基团)取代的直链烷基基团,优选低级烷基基团。典型的环烷基取代的烷基基团包括环己基甲基、环己基乙基、环戊基乙基、环戊基丙基、环丙基甲基等。
一般而言,“环烯基”指具有约4至约10个碳的烯属不饱和环烷基基团,以及该范围内的所有组合和亚组合。在优选实施方案中,所述环烯基是C5-C8环烯基基团,即具有约5至约8个碳的环烯基基团。
一般而言,“烷氧基”指烷基-O-基团,其中烷基如前所述。示例性的烷氧基基团包括例如甲氧基、乙氧基、丙氧基、丁氧基和庚氧基。
一般而言,“烷氧基-烷基”指烷基-O-烷基基团,其中烷基如前所述。
一般而言,“酰基”指烷基-CO-基团,其中烷基如前所述。优选的酰基基团包括低级烷基基团,例如约1至约3个碳的烷基。示例性的酰基包括乙酰基、丙酰基、2-甲基丙酰基、和丁酰基。
一般而言,“芳基”指含有6、10或14个碳的芳香碳环基。苯基可任选地被一个或两个或多个取代基取代。优选的芳基基团取代基包括烷基基团,优选C1-C5烷基基团。示例性的芳基基团包括苯基和萘基。
一般而言,“芳基取代的烷基”指在碳上被任选取代的芳基基团(优选任选取代的苯环)取代的直链烷基基团,优选低级烷基基团。示例性的芳基取代的烷基基团包括例如苯甲基、苯乙基和3-(4-甲基苯基)丙基。
一般而言,“杂环”指含有约4至约10元环原子的单环或多环体系基团,以及该范围内的所有组合和亚组合。其中一个或多个所述环原子是碳以外的元素,例如氮、氧或硫。所述杂环基团可以是芳族或非芳族的。示例性的杂环基团包括例如异唑、吡咯和哌啶基团。
“有机溶剂”具有相对于本领域普通技术人员而言的常规普通含义。可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。
“叔胺”具有其常规、普遍含义。一般而言,用于本发明的叔胺具有一般式:
其中R1、R2、和R3是相同的或是不同的直链或支链烷基基团、烯基基团、亚烷基基团、亚烯基基团、环烷基基团、环烷基取代的烷基基团、坏烯基基团、烷氧基基团、烷氧基-烷基基团、酰基基团、芳基基团、芳基取代的烷基基团、和杂环基团的组合。根据本发明可用的示例性的叔胺是那些其中R1-3是式(CnH2n+1,n=1-4)的烷基基团,或式(C6H5(CH2)n-[n=1-2])的芳烷基基团。根据本发明可用的示例性的叔胺还是环烷基叔胺(例如N-甲基吗啉、N-甲基吡咯烷、N-甲基哌啶)、吡啶和Proton Sponge(N,N,N’,N’-四甲基-1,8-萘)。
应当容易地理解,存在的官能团可能包含合成过程期间的保护基。保护基本身被称为能选择性地连接到官能团(例如羟基和羧基基团)上并从其上除去的化学官能团。这些基团存在于化学化合物中,以使得这样的官能团对化合物所暴露的化学反应条件呈惰性。任何多种保护基可用于本发明。优选的保护基是在形成、分离和纯化期间稳定的那些基团。优选的保护基是异丁酰基基团;甲硅烷基醚(SiR3,其中每个R可以独立地是直链或支链的C1-C6烷基);2-四氢吡喃醚、烷基碳酸酯;苄氧基羰基基团和叔丁氧基羰基基团。可以用于本发明的另外的优选保护基描述于Greene,T.W.和Wuts,P.G.M.,Protective Groups in OrganicSynthesis 2d.Ed.,Wiley & Sons,1991。以下所用的表达“羟基保护基团”意欲表示插入代替OH基团的氢原子的基团。
当羟基保护基是脂肪族酯时,其优选地表示选自具有3至8个碳原子的烷酰基;具有一个或两个双键和3至8个碳原子的烯酰基;
其中环烷基部分含有3至7个环原子并且r是0、1、2或3;苯氧基乙酰基;吡啶羰基和
其中r是0、1、2或3并且苯基是未取代的或被1至3个烷基基团(每个具有1至4个碳原子)、具有1至4个碳原子的烷氧基、卤素、三氟甲基、具有2至8个碳原子的二烷基氨基或具有2至6个碳原子的烷酰基氨基取代。
当酰基基团是烷酰基时,包括直链的和支链的烷酰基,例如丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、2-甲基丁酰基、三甲基乙酰基(新戊酰基)、3-甲基戊酰基、3,3-二甲基丁酰基、2,2-二甲基戊酰基等。新戊酰基、异丁酰基和异戊酰基是重要的实例。
当酰基基团是烯酰基时,包括例如巴豆酰基、2,5-己二烯酰基和3,6-辛二烯酰基。
当酰基基团是
时,包括环烷羰基和环烷基烷酰基基团,其中环烷部分可任选地具有1或2个烷基基团作为取代基,例如环丙烷羰基、1-甲基环丙烷羰基、环丙烷乙酰基、α-甲基环丙烷乙酰基、1-甲基环丙烷乙酰基、环丙烷丙酰基、α-甲基环丙烷丙酰基、2-异丁基环丙烷丙酰基、环丁烷羰基、3,3-二甲基环丁烷羰基、环丁烷乙酰基、2,2-二甲基-3-乙基环丁烷乙酰基、环戊烷羰基、环己烷乙酰基、环己烷羰基、环庚烷羰基和环庚烷丙酰基。环己烷羰基是特别优选的。
当酰基是吡啶羰基时,包括吡啶甲酰基(2-吡啶羰基)、烟酰基(3-吡啶羰基)和异烟酰基(4-吡啶羰基)。
当酰基是
时,包括例如苯甲酰基、苯乙酰基、α-苯丙酰基、β-苯丙酰基、对甲苯甲酰基、间甲苯甲酰基、邻甲苯甲酰基、邻乙基苯甲酰基、对叔丁基苯甲酰基、3,4-二甲基苯甲酰基、2-甲基-4-乙基苯甲酰基、2,4,6-三甲基苯甲酰基、间甲基苯乙酰基、对异丁基苯乙酰基、β-(对乙基苯基)丙酰基、对甲氧苯甲酰基、间甲氧苯甲酰基、邻甲氧苯甲酰基、间异丙氧基苯甲酰基、对甲氧基苯乙酰基、间异丁氧基苯乙酰基、间二乙基氨基苯甲酰基、3-甲氧基-4-乙氧基苯甲酰基、3,4,5-三甲氧基苯甲酰基、对二丁基氨基苯甲酰基、3,4-二乙氧基苯乙酰基、β-(3,4,5-三甲氧基苯基)丙酰基、邻碘代苯甲酰基、间溴代苯甲酰基、对氯代苯甲酰基、对氟代苯甲酰基、2-溴-4-氯代苯甲酰基、2,4,6-三氯代苯甲酰基、对氯代苯乙酰基、α-(间溴代苯基)丙酰基、对三氟甲基苯甲酰基、2,4-二(三氟甲基)苯甲酰基、间三氟甲基苯乙酰基、β-(3-甲基-4-氯代苯基)丙酰基、对二甲基氨基苯甲酰基、对(N-甲基-N-乙基氨基)苯甲酰基、邻乙酰胺基苯甲酰基、间丙酰胺基苯甲酰基、3-氯-4-乙酰胺基苯乙酰基、对正丁氧基苯甲酰基、2,4,6-三乙氧基苯甲酰基、β-(对三氟甲基苯基)丙酰基、2-甲基-4-甲氧基苯甲酰基、对乙酰胺基苯基丙酰基和3-氯-4-乙氧基苯甲酰基。
当羟基保护基是碳酸酯类时,其具有下面结构式:
即其是能被认为是通过从COOH部分除去羟基而衍生于碳酸的有机基团。Y’优选地表示具有1至7个碳原子的烷基;具有一个或两个双键和2至7个碳原子的烯基;
环烷基-CrH2r-
其中环烷基部分含有3至7个环原子并且r是0、1、2或3;苯氧基;2-吡啶基、3-吡啶基或4-吡啶基;或
苯基-CrH2r-
其中r是0、1、2或3并且苯基是未取代的或被1至3个烷基(每个具有1至4个碳原子)、具有1至4个碳原子的烷氧基、卤素、三氟甲基、具有2至8个碳原子的二烷基氨基或具有2至6个碳原子的烷酰基氨基取代。最优选地,Y’是C1-C7烷基,尤其是乙基或异丙基。
优选的保护基是能选择性地连接到官能团的那些保护基。这些基团使得这样的官能团对化合物可能暴露于的化学反应条件呈惰性。当保护基发挥其作用之后,其可选择性地从官能团中除去而不改变分子结构。最优选的保护基是能在温和条件下高产率地选择性连接到官能团并从其中除去的那些。
优选的3-O-保护的纳曲酮的保护基包括与乙酰基保护基相比较更稳定和更具有位阻的那些,发现所述乙酰基保护基在制备和纯化期间不稳定,因此导致较低的产率和纯度,并且难于处理。用于本发明方法的优选保护基实例包括异丁酰基、2-甲基丁酰基、叔丁基羰基等。在一个优选实施方案中,保护基是异丁酰基,这是因为其更好的稳定性得到更高的产率和纯度。这样的保护基使得3-O-保护的纳曲酮的产率大于70,优选大于75%。在一个实施方案中,3-O-保护的纳曲酮的产率是约80%或更高。
虽然一些前述的保护基和叔胺是未取代的,本领域普通技术人员应当理解在一些情况下可能存在取代基。
本发明提供立体选择性合成R-MNTX的方法,其包括:
(a)用甲基化剂甲基化3-O-保护的纳曲酮以得到3-O-保护的-R-MNTX盐;和
(b)水解以除去3-羟基保护基以得到R-MNTX。优选的3-O-保护的-R-MNTX盐的羟基保护基包括异丁酰基、2-甲基丁酰基、叔丁基羰基、甲硅烷基醚、2-四氢吡喃醚、和烷基碳酸酯。
与Goldberg等人描述的方法(该方法教导在室温下进行3周或在70℃下进行7天甲基化反应以制备N-MNTX)不同,本发明的立体选择性甲基化条件是在高于70℃温度下进行的,更优选高于80℃。在一个实施方案中,在约88℃进行反应。基于涉及立体异构体的化学反应的标准原理,人们将希望在更高的温度下,所述反应将以动力学控制的方式进行,得到高百分率的两种立体异构体的R-MNTX和S-MNTX的混合物。令人惊讶地是,在升高温度下,本发明的方法主要提供R-MNTX而不是具有较高S-MNTX百分率的混合物。
本发明的甲基化反应允许进行1小时至约24小时,优选约5小时至约16小时,更优选约8小时至12小时,最优选约10小时。该反应时间提供优于Goldberg等人教导的在室温下进行3周或在70℃下进行7天的主要工业规模优点。
在一个优选实施方案中,在约88℃进行甲基化反应10小时。这些反应参数是开发能放大至工业规模的方法所特别希望的。
本发明还提供从R-MNTX和S-MNTX的立体异构体混合物中纯化R-MNTX的方法,该方法包括至少一次、两次或多次重结晶。重结晶产物高度富集R-MNTX并且基本上不含有S-MNTX。在一个实施方案中,重结晶产物是大于98%纯的R-MNTX。应当理解本领域普通技术人员能最优化该方法以得到更高纯度和/或更高产率的R-MNTX,其中重结晶产物是大于99%纯的R-MNTX,甚至是大于99.9%纯的R-MNTX。
重结晶溶剂可以是有机溶剂或有机溶剂混合物或有机溶剂和水的混合物。优选的溶剂是醇,更优选低分子量的醇。在一个实施方案中,低分子量的醇是甲醇。
Goldberg等人以及Cantrell等人利用有机溶剂/水进行重结晶。这是纯化反应混合物的标准方法。因为Goldberg等人和Cantrell等人没有注意到立体异构体的存在或是否优先得到一种立体异构体,所以这既不是Goldberg等人也不是Cantrell等人声明的以得到超过另一种立体异构体的一种立体异构体的目标。因此,Goldberg等人和Cantrell等人都没有注意到重结晶可能对立体异构体组成的影响。本发明公开了重结晶可能有利地用于增加R-MNTX和S-MNTX混合物中R-MNTX纯度的条件。
本发明的一个方面是拆分并确定MNTX溶液中R-MNTX和S-MNTX的方法。R-MNTX还用于定量组合物或混合物中R-MNTX的量的HPLC分析法,其中该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中的成分,并通过比较样品中拆分成分的百分率和R-MNTX标准浓度的百分率来计算样品中R-MNTX的量。该方法尤其可用于反相HPLC色谱。
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。有效量指延迟正在治疗的病症或其相关症状的发作,减轻其严重程度,或完全抑制、减轻其发展,或一起停止其发作或发展所必需的单独的量或多剂量的量。在便秘情况下,例如,有效量是减轻便秘症状、引起肠蠕动、增加肠蠕动频率、或降低口-盲肠传输时间的量。已知的和常规的便秘定义是(i)在之前3天少于1次肠蠕动或(ii)在之前1周少于3次肠蠕动(见例如美国专利6,559,158)。换句话说,如果患者每3天具有至少1次肠蠕动和每1周具有至少3次肠运动,则所述患者未患有便秘(即具有如本文所用的“规律的肠蠕动”)。因此,每2天至少1次肠蠕动将被认为是规律的肠蠕动。同样地,每1天至少1次肠蠕动是规律的肠蠕动。因此有效量可以是确立或维持规律的肠蠕动所必需的那些量。
在某些情况下,取决于施用方式,所述量是施用R-MNTX或R-MNTX中间体、3-O-保护的-R-MNTX盐12小时、10小时、8小时、6小时、4小时、2小时、1小时内以及甚至施用后立即足以引起肠蠕动的量。静脉内施用可在长期阿片样物质使用者中产生即使效应。皮下施用可在施用12小时内引起肠蠕动,优选在施用4小时内。当施用给对象时,当然,有效量将取决于:待治疗的特定病症;病症的严重程度;个体患者参数包括年龄、身体状况、体积和体重;同时治疗(尤其是当长期施用阿片样物质时,与阿片样物质同时治疗);治疗频率;以及施用方式。这些因素是本领域普通技术人员熟知的并且可仅仅利用常规试验来解决。
可适于本发明治疗的患者包括但不限于末期疾病(termianlly ill)患者、患有晚期医疗疾病(advanced medical illness)的患者、癌症患者、AIDS患者、术后患者、慢性疼痛患者、神经病患者、类风湿性关节炎患者、骨关节炎患者、慢性背痛患者、脊髓损伤患者、慢性腹部疼痛患者、慢性胰腺疼痛患者、骨盆/会阴疼痛患者、纤维肌痛(fibromyalgia)患者、慢性疲劳综合征患者、感染HCV的患者、肠易激综合征患者、偏头痛或紧张性头疼患者、镰刀型细胞贫血病患者、进行血液透析的患者等。
可适于本发明治疗的患者还包括但不限于患有由内源性阿片样物质引起的功能障碍的患者,尤其是术后护理。在某些实施方案中,R-MNTX或其中间体以足够加速术后出院(包括腹部手术例如直肠切除术、结肠切除术、胃、食管、十二指肠、阑尾切除术、子宫切除术、或非腹部手术例如整形外科、外伤损伤、胸或移植手术)的量存在。这种治疗可有效缩短住院时间,或通过缩短手术后肠鸣音或第一次放屁的时间,或缩短手术后第一次轻泻时间或固体饮食摄入时间,来缩短术后书写的出院常规检查(hospital discharger order)的时间。患者术后停止接受阿片样物质疼痛医疗后可继续提供R-MNTX或其中间体。
某些尤其可适于治疗的患者是患有便秘和/或胃肠不蠕动的患者、以及利用轻泻剂或大便软化剂(或单独或组合施用)不能得到减轻或停止以得到症状减轻或症状减轻一致程度的患者,或另外耐受轻泻剂和/或大便软化剂的患者。据说这样的患者是常规轻泻剂和/或大便软化剂难以治愈的。便秘和/或胃肠不蠕动可由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、焦虑等一种或多种不同病症诱导或是其结果。诱导便秘和/或胃肠不蠕动的病症可以是急性病症或慢性病症。
可利用R-MNTX、或其3-O-保护的-R-MNTX中间体与轻泻剂和/或大便软化剂(以及任选地,阿片样物质)的组合治疗对象。在这些情况下,在足够接近的时间通常是同时施用R-MNTX或其中间体以及其它的治疗剂,使得对象经受如希望的多种药剂的作用。在一些实施方案中,R-MNTX或其中间体将在时间上第一被递送,在一些实施方案中,在时间上第二被递送,并且也在一些实施方案中是同时被递送。如本文更详细地讨论的,本发明期望药物组合,其中R-MNTX或其中间体以包含R-MNTX或其中间体与轻泻剂和大便软化剂(以及任选地,阿片样物质)一种或两者的制剂形式施用。这些制剂可以是胃肠外或口服的,例如描述于美国序列号10/821,809中的那些。包括固体、半固体、液体、控释制剂、冻干制剂以及其它这样的制剂。
在一个重要的实施方案中,R-MNTX的施用量足够诱导轻泻。当对象是慢性阿片样物质使用者时,这具有特别的应用。本文所用的慢性阿片样物质使用包括1周或以上的每日阿片样物质治疗或至少两周的间歇式阿片样物质使用。之前确定了长期接受阿片样物质的患者变得耐受阿片样物质并且需要增加剂量。因此,长期接受阿片样物质口服剂量的患者将典型地接受40至100mg/天的与吗啡等同剂量的阿片样物质。同样令人惊讶地确定了这样的对象变得更响应于MNTX的作用并且令人惊讶地是更低剂量诱导副作用。因此,为了诱导即时轻泻,需要按照仅约0.15mg/kg MNTX的级别静脉内施用。对于口服施用,认为足够的剂量是未包衣的小于3mg/kg,当R-MNTX被肠溶性包衣时,甚至剂量更小。
长期使用阿片样物质的患者包括晚期癌症患者、患有骨关节炎变化的老年患者、美沙酮维持患者、神经性疼痛和慢性背痛患者。从生命质量观点看,以及为了降低慢性便秘引起的并发症例如痔疮、食欲抑制、粘膜破坏、败血症、结肠癌风险、以及心肌梗塞,对这些患者的治疗是重要的。
所述阿片样物质可以是任何药学上可接受的阿片样物质。常见的阿片样物质是选自阿芬他尼、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)和曲马多的那些。所述阿片样物质还可与R-MNTX或其中间体相混合并且以任何上述形式与R-MNTX或其中间体相结合地提供。
一般地,R-MNTX和其中间体的口服剂量将从约0.25至约19.0mg/kg体重/天。一般地,取决于施用是否是推注或随时间分布例如I.V.滴,胃肠外施用(包括静脉内和皮下施用)将从约0.01至约1.0mg/kg体重。一般地,术后肠功能失调(POBD)的I.V.剂量是0.3mg/kg。希望0.01至0.45mg/kg体重范围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,预期肠溶包衣制剂中的阿片样物质拮抗剂的口服施用剂量将低于速释口服制剂中的计量。在这样剂量时患者响应不足的情况下,可施用甚至更高的剂量(或通过不同的、更局部的递送途径的有效地更高剂量)至患者耐受允许的程度。预期每日多剂量实现化合物的适当全身水平。例如,可通过测量患者的药物峰值血浆水平或持续血浆水平,来测定适当的全身水平。在一些情况下,低于100ng/ml的峰值血浆水平是优选的。“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,意味着产生有效的活性化合物水平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,可使用患者控制的镇痛(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冲洗施用。
药物制剂可常规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。所有的方法包括使本发明的化合物与组成一种或多种助剂的载体相结合的步骤。一般地,通过均一地并紧密地使本发明的化合物与液体载体、精细分散的固体载体、或两者结合,来制备组合物,如果必要,然后使产品成形。
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、以及任选地其它治疗成分。当用于药物时,所述盐应是药学上可接受的,但是非药学上可接受的盐可便利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:氢溴酸、氢溴酸、硫酸、硝酸、磷酸、马来酸、醋酸、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、双羟萘酸(pamoic acid)、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,其表示包括其盐。这样的盐是本领域那些或一般技术人员熟知的多种盐。当用于药物制剂时,所述盐优选对于人而言,是药学上可接受的。溴化物是一种这样的盐的实例。
本发明的药物制剂可包括药学上可接受的载体或可被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”指可适于施用于人类或其它哺乳动物例如非人类的灵长类、狗、猫、马、牛、绵羊、猪、或山羊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”代表有机或无机成分,天然的或合成的,活性成分与这些载体相组合以方便应用。所述载体能以使得没有会明显影响所需药物功效或稳定性的相互作用的方式与本发明的制剂相混合,并且彼此混合。适于口服施用、栓剂、以及胃肠外施用等的载体制剂可发现于Remington′s Pharmaceutical Sciences,Mack Publishing Company,Easton.Pa。
含水制剂可包括螯合剂、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描述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、醋酸钠、醋酸、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、丁基化的羟基茴香醚、丁基化的羟基甲苯、没食子酸烷基酯、偏亚硫酸氢钠、亚硫酸氢钠、连二硫酸钠、巯基醋酸钠、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、葡萄糖、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、对羟基苯甲酸酯类、乙基汞硫代水杨酸钠、氯丁醇并且优选苯扎氯铵。典型地,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,防腐剂的精确浓度将根据希望的用途进行变化并且可被本领域中技术人员容易地确定。
本发明的组合物可配制为冻干组合物,优选在冷冻保护剂例如甘露醇、或乳糖、蔗糖、聚乙二醇、和聚乙烯吡咯烷酮的存在下。导致重新构成6.0或更低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公知的并且可商业购得的。本发明的治疗剂可添加到这种公知的制剂中。其可一起混合在这种制剂的溶液或半固体溶液中,并可以以这种制剂内的混悬液提供或可包含在这种制剂的颗粒中。
可将含有本发明治疗剂以及任选的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,而不如此限制其它活性剂的释放或不同于本发明的治疗剂来限制。例如,本发明的治疗剂可以是肠溶包衣的核或包含在丸剂或胶囊中的小丸,所述丸剂或胶囊首先释放其它药剂并且仅在本发明的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处于持续释放的材料中,从而在整个胃肠道释放本发明的治疗剂并且同时或以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相组合的本发明治疗剂的快速释放,来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、整个胃肠道中或仅释放在肠中。
用于实现这些不同释放特性的材料是本领域普通技术人员熟知的。通过常规片剂与在胃中溶解的粘结剂可获得快速释放。在胃的pH下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,来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),可实现在整个胃肠道的释放。
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种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。当置于体内时溶解的其它包衣是本领域普通技术人员熟知的。
本发明的治疗剂还可与控制释放制剂完全混合,由此在其它药剂之前、之后释放或同时释放。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处于载体形式,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等快速释放本发明的治疗剂。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的任何持续释放形式释放本发明的治疗剂,包括利用现有技术和本领域普通技术人员熟知材料的表现出一级释放动力学或S形释放动力学的形式。
本发明的治疗剂还可包含在控制释放制剂内的核内。所述核可具有与小丸有关的上述特性的任何一种或任何组合。例如,本发明的治疗剂可处于由材料包衣的核中、分散在整个材料中、包衣到材料之上或吸收到材料中或吸收到整个材料中。
应当理解,所述小丸或核可以是实际上的任何类型。它们可以是被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。
可以以颗粒提供本发明的治疗剂。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)。颗粒可含有被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。颗粒可以是任何级的释放动力学,包括零级释放、一级释放、二级释放、缓释、持续释放、快速释放、以及其任何组合等。除了治疗剂以外,颗粒可包括那些在药学和医学领域中常规使用的任何材料,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。颗粒可以是实际上的任何形状。
非生物可降解的聚合物材料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聚合物或合成聚合物。根据需要的释放时间选择聚合物。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中描述的生物可侵蚀的水凝胶,其教导被并入本文。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Fujisawa 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中请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,肠溶包衣典型地是聚合物材料。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,而在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,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)时可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。药物释放速率将等同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膜的厚度,并且药物释放可能开始于GI(肠胃)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厚。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典型地为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 KodakRochester N.Y.,USA)。邻苯二甲酸羟丙基甲基纤维素的实例是以商品名HP50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HP55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,所述胶囊材料典型地包含无味、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、霜剂或粉末进行施用。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。希望组合物的pH是施用时不引起对接受者鼻粘膜的显著刺激的pH。
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。根据本发明可使用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含保湿剂以降低或预防粘膜干燥以及避免组合物的刺激。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);膜调节剂(membrane conditioner);甜味剂;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、舌下和上腭)、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、乙氧基化的甘油、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,将化合物比如洛哌丁胺(loperamide)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22%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应用于皮肤、或可配制成气雾剂或泡沫剂并作为喷雾应用于皮肤。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适于排出容器内的内含物的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。
可配制制剂并设置成产生稳态血浆水平。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。典型地,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8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R-MNTX片剂的小瓶14,所述R-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R-MNTX。药盒还包括说明书20用于将片剂施用给便秘或具有便秘或胃肠不蠕动症状的对象。所述说明书包括标记,例如写明、指示R-MNTX是不含有S-MNTX的纯R-MNTX。
在本发明的一些方面,药盒10可最佳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R-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R-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组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
实施例1
R-MNTX和S-MNTX的HPLC分析
利用下述方法在通过Varian Star软件控制的Varian ProStarHPLC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:UV230nm
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
TFA=三氟乙酸
HPLC方法II:
色谱条件和参数:分析柱描述:Phenomenex Inettsil 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方案监测R-MNTX的合成和纯化。利用上述HPLC条件从R-MNTX中区分S-MNTX。利用本文所述的方案可制备用作标准的可信的S-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。
如图2举例说明的,可在HPLC色谱图上清楚地区分MNTX的S和R型。图3是添加到99.5wt%可信的R型中的0.1wt%可信的S型的混合物的HPLC色谱图;图4是添加到99.0wt%可信的R型中的1.0wt%可信的S型的色谱图;图5是添加到98.0wt%可信的R型中的3.0wt%可信的S型的色谱图。这已允许申请人首次设计并测试由3-O-保护的纳曲酮得到高纯度R-MNTX的立体选择性合成和纯化方案。
实施例2
R-MNTX的立体选择性合成
实施例2的合成方案显示在图6中。
概要。在烘干的(130℃)玻璃器具中在干燥氮气(N2)气氛下进行所有的无水反应。不需要任何另外的纯化使用所有的商品化试剂和溶剂。利用Varian Gemini或Varian Mercury 300MHz波谱仪得到核磁共振(NMR)谱。在Finnigan LCQ上测定质谱。利用Waters 717自动进样器和Waters 996光电二极管阵列检测器测定HPLC纯度。
3-O-异丁酰基-纳曲酮(2)。在0℃下,向无水四氢呋喃(THF)(120mL)中的化合物(1)(1.62g,4.75mmol)溶液中添加三乙胺(NEt3)(1.4mL,10mmol)。在0℃下搅拌反应15分钟后,逐滴加入异丁酰氯(1.05mL,10mmol)。在0℃下搅拌反应混合物1小时,然后在用饱和碳酸氢钠(NaHCO3)(水)(70mL)和30ml水淬熄之前,在室温下搅拌18小时。采用二氯甲烷(CH2Cl2)(2×200mL)萃取反应物。合并萃取物,用盐水(130ml)洗、硫酸钠(Na2SO4)(50g)干燥、真空过滤并浓缩。通过快速色谱在硅胶(柱规格40×450mm,负载硅胶40×190mm)(9.8∶0.2→9.6∶0.4→9.4∶0.6 CH2Cl2/MeOH)上纯化粗原料得到化合物(2)(1.5g 76.8%),为白色固体。
1H NMR(300MHz,CDCl3)δ6.82(d,J=8.0Hz,1H),6.67(d,J=8.0Hz,1H),4.69(s,1H),3.21(d,J=6.0Hz,1H),3.12-2.96(m,2H),2.93-2.82(m,1H),2.71(dd,J=4.5Hz,1H),2.62(dd,J=6.2Hz,1H),2.48-2.28(m,4H),2.19-2.10(m,1H),1.93-1.86(m,1H),1.68-1.59(m,2H),1.34(d,J=0.8Hz,3H,CH3-异丁酰基),1.31(d,J=0.8Hz,3H,CH3-异丁酰基),0.90-0.83(m,1H,CH-环丙基),0.60-0.54(m,2H,CH2-环丙基),0.18-0.13(m,2H,CH2-环丙基).13C NMR(75.5MHz,CDCl3)δ207.6(CO),174.7(COO/Pr)147.8,132.8,130.1,130.0,122.8,119.2,90.5,70.0,61.9,59.2,50.6,43.4,36.1,33.8,31.2,30.7,22.9,19.0,18.9,9.4,4.0,3.8.MS[M+H]+:412.
3-O-异丁酰基-N-甲基纳曲酮碘化物盐(3)。利用刮铲将化合物(2)(689mg,1.67mmol)转移到玻璃压力容器中。在多支管上用氮温和地吹扫所述容器5分钟,然后在高真空下抽空。当真空恒定时,容器的底部被浸入到液氮中。在氮气氛中的多支管上将甲基碘(973mg,6.85mmol)分散到单独的烧瓶中并在液氮中冷冻。在高真空下抽空冷冻的碘甲烷容器。从所述高真空泵中分离主要的多支管室。允许碘甲烷升温到室温并通过主室升华到液氮冷却的3-O-异丁酰基-纳曲酮上。当升华完成时,允许氮缓慢地滤到玻璃压力容器中。然后紧紧地密封容器并将其从多支管中除去,并且在88至90℃的油浴中加热17小时。在允许氮流入到容器中之前,允许将容器冷却至室温。然后在高真空下抽空容器以除去未反应的碘甲烷剩余物得到白色固体。取出固体样品用于1HNMR分析。这显示良好地转化成产物。产物的薄层色谱(TLC)[二氯甲烷/甲醇9∶1(v∶v),正相硅胶,UV检测]显示痕量的原材料(2)(Rf=0.8)和扩散区域(Rf=0至0.4)。固体溶解在二氯甲烷/甲醇(4∶1,最小体积)中并应用于硅胶柱(超纯硅胶,22g在二氯甲烷中,床尺寸:200mm×20mm内径)。按以下方式洗脱柱:
二氯甲烷/甲醇98∶2(300ml)
二氯甲烷/甲醇97∶3(300ml)
二氯甲烷/甲醇94∶6(200ml)
二氯甲烷/甲醇92∶8(400ml)
通过TLC[二氯甲烷/甲醇9∶1(v∶v),正相硅胶,UV检测]分析级分。合并仅含有主要成分的级分(Rf=0.4),一起用甲醇冲洗,并浓缩得到867mg白色固体。这表示基于3-O-异丁酰基-纳曲酮的91%的产率。1H NMR是一致的。
N-甲基纳曲酮溴化物/碘化物盐(4)。将化合物(3)(862mg,1.56mmol)溶解在甲醇(13ml)中。向该混合物中添加无菌水(11.5ml),随后添加48%氢溴酸水溶液(1.5ml)。在氮气下搅拌所得的混合物并在64至65℃的油浴中加热6.5小时。反应混合物样品(分散在甲醇中)的TLC分析显示没有剩余的原料(3)(Rf=0.4),并且转化成在Rf=0至0.15的材料。用22至25℃的浴在旋转蒸发仪上浓缩混合物直到剩余约1ml油状液体。加入乙腈(10ml)并再次浓缩混合物。采用10ml乙腈再重复3次,得到姜色易碎的泡沫(590mg,86%粗产率)。
阴离子交换树脂柱的制备。用100ml水将30g AG 1-X8树脂装填到中压液相色谱(MPLC)柱(20mm内径)中,以形成树脂浆。用1.0N氢溴酸水溶液(200ml)然后用无菌水洗树脂床,直到洗脱水溶液的pH是pH 6至7。需要约1.5L水。
N-甲基纳曲酮溴化物(5)。将泡沫(4)(597mg)分散在水(6ml)/甲醇(2ml)中。一些暗色油保持未溶解。倾析出清澈的上清液并应用于制备的阴离子交换树脂柱。剩余物用甲醇(0.2ml)/水(3ml)洗两次。将上清液应用于柱。用4.2L无菌水洗脱柱并收集~20ml级分。通过液相色谱/质谱(LC/MS)检测N-甲基纳曲酮盐的存在。主要的N-甲基纳曲酮位于最初的1.5L洗出液中,通过TLC(4∶1二氯甲烷/甲醇,正相硅胶),最初600ml所述洗出液包含最纯的物质。合并最初的600ml洗出液并在旋转蒸发仪上浓缩,以得到略带白色的玻璃。水浴维持在~35℃。需要注意在蒸发时控制洗出液形成泡沫。
N-甲基纳曲酮溴化物(5)的纯化。从甲醇中重结晶。在氮气下在甲醇(60ml)中温热剩余物至刚刚低于回流,其后通过玻璃烧结漏斗过滤来除去少量的不可溶解的物质。然后在氮气流下将该滤出液吹至约10ml并随后在氮气下在冰/水中冷却。形成一些白色沉淀而且明显地许多固体保留在溶液中。然后通过蒸发浓缩混合物,以得到略带颜色的胶。用甲醇(3ml×2)研磨所述胶。通过吸管在研碎物之间小心地倾析甲醇。将白色剩余物溶解在甲醇(60ml)中并通过玻璃烧结漏斗过滤。滤出液浓缩至约1ml并加入另一份甲醇(1ml)来研磨固体。如前所述倾析上清液。干燥固体得到白色固体,A批(178.0mg)。HPLC分析显示97.31%的R-MNTX和2.69%的S-MNTX。
合并甲醇中所有滤出液/上清液并浓缩,以得到白色玻璃。用甲醇(3ml×2)研磨该剩余物,如前所述小心地移出上清液。将剩余物溶解在甲醇(50ml)中并通过玻璃烧结漏斗过滤。滤出液浓缩至约1ml并加入另外一份甲醇(1ml)来研磨固体。如前所述倾析上清液,进一步用甲醇(2ml)研磨剩余物。倾析上清液并干燥剩余物,得到白色固体,B批(266.0mg)。B批的HPLC分析显示97.39%的R-MNTX和2.61%的S-MNTX。A批和B批一起表示总产率为436.8mg(64%)。1H NMR是一致的。MS[M+H]+:356。
如A批和B批中所示,从甲醇中重结晶得到具有高R-MNTX百分率的产物。在利用14CH3-标记的材料和相同条件下进行的反应中,发现从甲醇中重结晶之前粗反应混合物的成分是94.4%的R-MNTX*和4.7%的S-MNTX*。从甲醇中重结晶得到含有98.0%的R-MNTX*和1.5%的S-MNTX*的产物。从甲醇中二次重结晶得到98.3%的R-MNTX*和1.2%的S-MNTX*。
应当理解,认为所述合成方案得到大于94%的R型并且仅具有小百分率的S型。利用合成方案1,可在色谱柱、制备HPLC上或通过重结晶进一步处理基本上纯的材料。在一次重结晶和随后的离子交换中,R型纯度大于98%。第二次重结晶得到98.3%的R-MNTX。应当理解进一步重结晶和/或色谱,无论如何在一次和四次(或甚至六或和多至十次)之间保证大于99.95%的R型并且消除痕量的S型(如果存在)。
实施例3
R-MNTX的立体选择性合成
实施例3的合成方案显示在图7中。在实施例3中,遵循Goldberg等人教导的用于保护基团的方法。乙酰基(Goldberg等人的优选保护基)替代异丁酰基用作保护基。如实施例2中所述进行反应。令人惊讶地发现利用图7中所示的方案,在中间体2(O-乙酰基-纳曲酮)的纯化期间,乙酰基保护基倾向于脱落。这使得难于得到纯的中间体2。含有乙酰基的中间体2的产率仅仅是36.3%,使得图7中所示的方案不适于商业化规模放大。相比较,采用利用异丁酰基作为保护基的合成方案(图6),中间体2(3-O-乙酰基-纳曲酮)在纯化期间相当稳定,得到76.8%的产率。
实施例4
R-MNTX的药物制剂的制备方法
制备方法可概括如下:
1.将所需量的注射用水(~80%或终体积)加到不锈钢罐中。
2.将螯合剂添加到所述罐中并搅拌直到溶解。
3.将缓冲剂添加到所述罐中并搅拌直到溶解。
4.将R-MNTX添加到所述罐中并搅拌直到溶解。
5.将等渗剂添加到所述罐中并搅拌直到溶解。
6.将溶液的pH调节到pH 3.25。
7.加入注射用水以将体积增加到所需量。
8.转移材料以供应到压力容器中。
9.无菌过滤到无菌不锈钢压力容器中。
10.填充到瓶/小瓶中,用氮吹扫,随后塞住所述瓶/小瓶。
11.通过高压对所述填充小瓶进行灭菌。
待用赋形剂的准确量:
乙二胺四乙酸二钠=0.75mg/ml 在步骤2中加入
柠檬酸钠=0.199mg/ml 在步骤3中加入
柠檬酸=0.35mg/ml 在步骤3中加入
氯化钠=8.5mg/ml 在步骤5中加入
赋形剂的添加顺序如上所述。步骤2至5可以任何顺序进行。
当已经加入所有赋形剂和药物时(步骤6),通过加入酸调节溶液的pH。如果在溶液中使用缓冲剂,可不需要pH调节。
在配制期间不具体要求温度或搅拌速度。配制期间温度可高至80℃。
实施例5
R-MNTX的药物制剂的优选制备方法
100ml的R-MNTX溶液的20mg/ml溶液的优选制备方法如下:
1.将80ml注射用水(~80%或终体积)添加到不锈钢罐中。
2.将75mg乙二胺四乙酸二钠(螯合剂)添加到所述罐中并搅拌直到溶解。
3.将19.9mg柠檬酸钠和35mg柠檬酸(作为缓冲剂)添加到所述罐中并搅拌直到溶解。
4.将2000mg的R-MNTX添加到所述罐中并搅拌直到溶解。
5.将850mg氯化钠(等渗剂)添加到所述罐中并搅拌直到溶解。
6.如果需要,调节溶液的pH。
7.加入注射用水以将体积增加到100ml。
8.转移材料以供应到压力容器中。
9.用0.22微米的过滤器无菌过滤到无菌不锈钢压力容器中。
10.填充、用氮吹扫,随后塞住所述瓶/小瓶。
11.通过高压对所述填充小瓶进行灭菌。
实施例6
R-MNTX的皮下制剂的制备
下面列举低柠檬酸盐/EDTA制剂的配方:
成分 mg/mL
R-MNTX 30mg
氯化钠 4mg
柠檬酸 0.0875mg
柠檬酸三钠 0.0496mg
乙二胺四乙酸二钠 0.75mg
注射用水 补足至1g
该溶液的pH是3.5并且可耐受高压灭菌过程。
实施例7
R-MNTX的冻干药物制剂的制备方法
使用冻干循环制备R-MNTX的冻干制剂。40mg的R-MNTX与32mg的冷冻保护剂、甘露醇相混合并利用注射用水补足至1mL。
1.室温(20至25℃)下装载入室中
2.以1.0℃/分钟降低架温度至-45℃
3.架温度在-45℃维持120分钟
4.当冷凝器低于-50℃时,将所述室抽空至100-125mt。
5.以0.5℃/分钟升高架至-20℃
6.在-20℃维持16小时
7.以0.10℃/分钟升高架至+27℃
8.维持最少8小时。在整个循环中维持室压力在100至125mt。
9.利用无菌过滤的氮将室恢复至11.0PSIA+或-1.0,其后关闭(2”Hg),然后利用N2排放至大气压以卸载。冷冻和重构后溶液的pH是5.0。
已经如此描述了本发明至少一个实施方案的几个方面,应当理解,本领域技术人员将容易地进行各种改变、改动和改进。这些改变、改动和改进认为是本公开内容的一部分,并且意欲包括在本发明精神和范围内。因此,前述描述和附图仅仅作为举例。
Claims (36)
2.权利要求1的3-O-保护的-R-MNTX盐,其中R是异丁酰基。
3.权利要求1的3-O-保护的-R-MNTX盐,其中所述卤离子是溴离子。
4.权利要求1的3-O-保护的-R-MNTX盐,其中所述卤离子是碘离子。
5.权利要求1的3-O-保护的-R-MNTX盐,其中所述卤离子是氯离子。
6.权利要求1的3-O-保护的-R-MNTX盐,其中所述卤离子是氟离子。
7.权利要求1的3-O-保护的-R-MNTX盐,其中所述带电的有机阴离子物质是磺酸根或羧酸根。
8.权利要求7的3-O-保护的-R-MNTX盐,其中所述磺酸根是甲磺酸根、苯磺酸根、甲苯磺酸根、或三氟甲磺酸根。
9.权利要求7的3-O-保护的-R-MNTX盐,其中所述羧酸根是甲酸根、乙酸根、柠檬酸根或富马酸根。
11.权利要求10的方法,其中所述卤离子是溴离子。
12.权利要求10的方法,其中所述卤离子是碘离子。
13.权利要求10的方法,其中所述卤离子是氯离子。
14.权利要求10的方法,其中所述卤离子是氟离子。
15.权利要求10的方法,其中所述带电的有机阴离子物质是磺酸根或羧酸根。
16.权利要求15的方法,其中所述磺酸根是甲磺酸根、苯磺酸根、甲苯磺酸根、或三氟甲磺酸根。
17.权利要求15的方法,其中所述羧酸根是甲酸根、乙酸根、柠檬酸根或富马酸根。
18.权利要求10的方法,进一步包括用不同的阴离子交换所述阴离子。
19.权利要求10的方法,其中所述甲基化剂包含易受亲核进攻的甲基基团、和离去基团。
20.权利要求19的方法,其中所述甲基化剂选自甲基卤、硫酸二甲酯、硝酸甲酯和磺酸甲酯。
21.权利要求20的方法,其中所述磺酸甲酯选自甲磺酸甲酯、苯磺酸甲酯、甲苯磺酸甲酯、和三氟甲磺酸甲酯。
22.权利要求10的方法,其中通过酸催化除去3-羟基保护基R。
23.权利要求22的方法,其中所述酸选自硫酸、氢氯酸或氢溴酸。
24.权利要求10的方法,其中通过碱催化除去所述3-羟基保护基R。
25.权利要求24的方法,其中所述碱是氢氧化钠或氢氧化钾。
26.权利要求10至25中任一项的方法,其中在高于70℃至100℃的温度范围内进行所述甲基化。
27.权利要求26的方法,其中在80℃至90℃的温度范围内进行所述甲基化。
28.权利要求26的方法,其中在约88℃的温度下进行所述甲基化。
29.权利要求26的方法,其中所述甲基化反应进行1小时至24小时。
30.权利要求29的方法,其中所述甲基化反应进行5小时至16小时。
31.权利要求28的方法,其中所述甲基化反应进行约10小时。
33.权利要求32的方法,进一步包括用不同的卤离子交换所述卤离子。
34.权利要求33的方法,其中所述卤离子是碘离子并且所述不同的卤离子是溴离子。
36.权利要求35的方法,其中在纯化后所述R-MNTX溴化物盐的纯度大于98%。
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