CN1290163A - 用于铁螯合治疗的含有n,n′-双(2-羟基苄基)乙二胺-n,n′-二乙酸的药物 - Google Patents
用于铁螯合治疗的含有n,n′-双(2-羟基苄基)乙二胺-n,n′-二乙酸的药物 Download PDFInfo
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- CN1290163A CN1290163A CN99802721A CN99802721A CN1290163A CN 1290163 A CN1290163 A CN 1290163A CN 99802721 A CN99802721 A CN 99802721A CN 99802721 A CN99802721 A CN 99802721A CN 1290163 A CN1290163 A CN 1290163A
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Abstract
本发明公开了N,N’-双(2-羟基苄基)乙二胺-N,N’-二乙酸(HBED)在铁螯合疗法中的应用。具体是本发明涉及皮下使用HBED来治疗患有铁螯合剂可治疗疾病如铁超载,特别是输血铁超载的动物。
Description
本发明得到国家卫生研究所授权的DK49108,AI35827和HL57607的部分支持。在该发明中美国政府具有权利。
本发明涉及N,N’-双(2-羟基苄基)乙二胺-N,N’-二乙酸(HBED)在铁螯合治疗中的应用。具体来说,本发明涉及皮下使用HBED来治疗患有铁螯合剂可治疗的疾病状态即铁超载特别是输血铁超载的灵长类动物尤其是人。
在人和其他灵长类动物中,铁在体内是以作为蛋白络合物的铁蛋白和含铁血黄素的形式储藏的,在血浆内通过其他蛋白络合物即转铁蛋白运送的。使用铁的方式是非常有效的,但是除去额外的铁不存在特殊的机理。在铁超载的条件下,蛋白络合物逐渐与铁铁饱和,导致额外铁沉积在组织中,从而诱发铁毒性,最终导致组织的过氧化损坏。人体中出现铁超载的一个普通过程是反复性输血。
治疗铁超载的方法是服用铁螯合剂。一般来说,该螯合剂把沉积的铁转化成可溶形式,然后能够排泄。但是,为该目的可得到的所用的铁螯合剂没有一种是理想的;该螯合剂具有很差的胃肠道吸收,或者具有低效和/或不希望的副作用。
克服这些缺点并且广泛用于治疗的一种铁螯合剂是去铁胺B甲磺酸盐(DFO)。一般,DFO能够控制患有铁超载患者体内的额外铁,能够延长存活并防止或改善器官机能障碍。但对铁超载来说,DFO远不是一种理想的疗法。对患者来说它是麻烦的、无效的、昂贵的和令人不愉快的。这是因为DFO在胃肠道中吸收较差并从循环中快速释放,对治疗来说需要延长非肠道输液;一般每天通过手提式输液泵给药9-12小时。并不令人惊奇的是,几乎很少患者能够符合这种要求的治疗方案。另外,作为一种铁螯合剂DFO是非常无效的,一般所服用的5%或更少化合物与铁结合。
还有其他的缺点是DFO的费用,DFO是一种细菌含铁血黄素噬菌体,商业上是通过多毛链霉素菌株的大规模发酵生产的,生产方法非常昂贵。另外,几乎所有患者都对DFO具有过敏反应,这种过敏反应是不舒服的并且有时很痛。人们认为过敏反应是由细胞素和/或在纯化粗产物混合物过程中没有完全除去在发酵过程中形成的其他发酵产物引起的。
所以需要提供一种除DFO外使用安全和廉价的治疗铁超载的方法。理想的是,该铁螯合剂将不需要延长的胃肠外输液,在患者中没有过敏反应,并且将是比DFO更有效的螯合剂。如果它不需要口服也将是一个优点,因为口服疗法需要患者每天摄取三次或更多次的大量螯合剂,因为涉及到这类配位体可能加重铁毒性并且其自身具有不希望的副作用。
HBED是一种公知的铁螯合剂化合物。美国专利3,758,540公开了HBED铁螯合剂和其他化合物用作植物营养的铁源。美国专利4,528,196公开了以大鼠和小鼠筛选试验为基础的HBED及其烷基酯口服在治疗铁超载具有活性并且口服给药比DFO的腹膜内给药活性更好。但是,在啮齿类动物的发现不能在高等动物中替代。Cebus apella猴子筛选试验,其被公认可良好地预测螯合剂在人类中的行为,显示皮下给予DFO比口服HBED或其二甲基酯具有显著高的活性(Bergeron等,血液,81:2166(1993),Peter等,“在灵长类动物模型中对铁螯合剂的对比评价”,第373页,临床使用的铁螯合剂的开发,Boca Raton,CRC出版社(1994))。这也已经证实了当把HBED口服给患者时,提供的铁排泄程度对治疗铁超载是无效的(Grady等,“HBED第Ⅰ期临床试验的主要结果”,临床使用的铁螯合剂的开发,Boca Raton,CRC出版社(1994)第395页)。
所以,以上述发现为基础,完全出人意料的是HBED将显示当其皮下给药时是治疗铁超载的高效化合物。一旦把HBED皮下给药,它不需要为有效的铁螯合和排泄的延长性胃肠外输液,在患者中没有过敏反应并且是比DFO更有效的铁螯合剂。
本发明的一个目的是提供一种治疗灵长类动物尤其是人的铁螯合剂可治疗疾病状态的进方法。
本发明的另一个目的是提供皮下治疗铁螯合剂可以治疗的疾病状态尤其是铁超载的组合物。
本发明的又一个目的是提供制备用于治疗铁螯合剂可以治疗的疾病状态尤其是铁超载的皮下给药的组合物的方法。
本发明还有一个目的是提供用铁螯合剂治疗的疾病状态的改进方法和组合物,该方法和组合物不需要患者延长的治疗(例如胃肠外输液)。
本发明的又一个目的是提供把用铁螯合剂治疗患者的过敏反应降到最低的治疗方法和组合物。
本发明的其他目的对本领域技术人员来说在阅读了下面说明书和权利要求书后就可以清楚。相关文献
美国专利3,758,540,4,116991和4,528,196。
本发明涉及一种治疗患有铁螯合剂可治疗的疾病状态的哺乳动物的方法。该方法包括皮下给予治疗有效量式(Ⅰ)化合物即N,N’-双(2-羟基苄基)乙二胺-N,N’-二乙酸(HBED)或其药用盐或其酯。该方法特别适合于治疗灵长类动物的铁超载。
本发明的另一方面是药物组合物,它含有适合于皮下注射的药学上可接受的赋型剂及HBED或其药学上可接受的盐或其酯。
本发明的又一方面是制备产品,它含有装有药物组合物的容器,该药物组合物含有适合于皮下注射的药学上可接受的赋型剂及HBED或其药学上可接受的盐或其酯,其中容器装有治疗有效量的HBED并附有说明皮下给予该组合物治疗铁螯合剂以治疗疾病状态的打印标签。
本发明的又一方面是制备药物组合物的方法,该方法包括把药学上可接受的赋型剂和HBED或其药学上可接受的盐或酯混合。
本发明的其他方面在阅读该专利说明书后将会清楚。治疗方法
本发明一方面是治疗患有铁螯合剂可治疗的疾病状态的哺乳动物的方法。该方法包括皮下给予治疗有效量的HBED或其可接受的盐或酯。用铁螯合剂可治疗的疾病状态包括个体哺乳动物特别是灵长类如人的任何疾病,其中当服用铁螯合剂后个体显示出改善。可以使用铁螯合剂的这类疾病包括疟疾、癌症、HIV感染、肠道疾病、宿主对移植体的排斥、移植体对宿主的排斥、反复输液的损伤、神经疾病和铁超载。该方法最有用的疾病状态是铁超载。其特征是在体内组织中大于正常病灶或一般的铁沉积(含铁血黄素沉着症)。当体内总铁大约为15克左右时,这种病灶的或全身化的沉积就与组织损伤有关,人们称之为血色素沉着症。一般地,原发性血色素沉着症起因于基因决定的错误,这种错误会导致人体从正常饮食中增加铁吸收。通常是因为正染色体隐性特性所造成的,但也包括无转铁蛋白血症、重型地中海贫血症和y-连接的血红蛋白过少贫血。继发性含铁血黄素沉着症或血色素沉着症显示出增加的非肠道铁摄取如通过重复的输液(输液铁超载)或肌肉内摄取的铁葡聚糖。这些也可以由因增长的铁消化而增长的铁吸收或来自于正常量的饮食铁的增加的铁吸收而引起,但伴随红细胞系增生的贫血和可能通过巨量维生素C也可引起。病灶性血色素沉着症可能是肺部的、肾的或肝部的。
当第15版默克手册列出了这些疾病的分类时,区分诊断是很困难的。诊断将依赖于铁给药的历史、患者的相关检查、铁超载的程度和局部化迹象的存在与否。对原发性血色素沉着症来说,最常见发病率是千分之3到8人,中年前迹象和症状几乎很少。典型的表现是肝硬化、皮肤的棕色色素沉着、糖尿病的糖尿症和心肌病,它可以表现为心肥大、充血性衰竭和心律失常或传导紊乱。在垂体衰竭时,可以看到睾丸萎缩和性欲丧失。有时偶尔会出现腹痛、关节炎和假痛风。病灶性血色素沉着症主要出现在肺和肾上。肺部含铁血黄素沉着症可能是由于复发性肺出血引起的,这种复发性肺出血是作为一种自发性病种出现的如作为古德帕斯彻综合症的一部分。这些疾病的诊断可以在默克手册中找到。应当把这些疾病中的每一种作为铁螯合剂可治疗的疾病。
如前文所述,治疗的关键是把本文前面通式Ⅰ所示的化合物HBED或其药学上可接受的盐或酯皮下给药。
“药学上可接受的盐或酯”指保留HBED的生理有效性和特性的盐或酯,并且无生物或副作用。HBED能够在羧酸和氨基的存在形成酸和碱的盐并且凭借羧基化基团形成酯类。1.由无机和有机碱可以制备药学上可接受的碱加成盐。来自无机碱的盐包括,但不限定为钠、钾、锂、铵、钙、和镁盐。来自于有机碱的盐包括,但不限定为伯、仲和叔胺盐,包括天然存在取代的胺和环胺的取代胺包括,异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二甲基氨基乙醇、氨丁三醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺、胆碱、甜菜碱、乙二胺、胍基乙酸、N-烷基葡糖胺、可可碱、嘌呤、哌嗪、哌啶和N-乙基哌啶。也应当理解为其他羧酸衍生物可用于实施本发明,例如,羧酸胺类,包括氨基甲酰类、低级烷基氨基甲酰类、二(低级烷基)氨基甲酰类等。2.药学上可接受的酸加成盐可以由无机酸和有机酸制得。来自于无机酸类的盐包括盐酸、氢溴酸、硫酸、硝酸、磷酸等。来自于有机酸的盐包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。3.药学上可接受的酯类包括低级烷基酯类如单-或二烷基酯类如甲基、乙基、异丙基、叔丁基等。优选使用二甲酯。
优选的是二钠盐、单钠盐、二盐酸盐和单盐酸盐。
本文所用的术语“治疗”包括对哺乳动物特别是人的铁螯合剂可治疗的疾病的任何治疗,并且包括:
(ⅰ)预防易感染该疾病但还没有诊断患有该疾病的患者出现该疾病;
(ⅱ)抑制该疾病,即阻止它的发展;或
(ⅲ)缓解该疾病,即引起该疾病的衰退。
现已发现出人意料有效的给药方法是HBED或其药学上可接受的盐或酯皮下给药。皮下给药,它意指把适当注射组合物形式的药物注射到皮肤下的网眼状空隙的结缔组织中。注射液可以是溶液、悬浮液或能够控制释放活性实体的制剂。一般将与适合于皮下给药的赋形剂进行皮下给药,赋形剂意指适合于注射组合物的赋形剂将符合美国药典的要求。这样,该组合物将需要灭菌以避免由于注射部位没有消毒引起的任何并发症。
注射组合物中存在的和将注射的活性成分的量是治疗有效量,即,在对患有铁螯合剂可治疗的疾病状态如铁超载的疾病状态的哺乳动物给药时,用量足以导致上述定义的成功治疗。该治疗有效量将随着治疗的患者和疾病状态、患病的程度和给药的方式而变化,并且可以由本领域普通技术人员按照本说明书的公开合理地确定。一般HBED的每日剂量随个体需要、治疗疾病的严重程度和所选择的特殊盐或酯来变化。通常,以每千克(Kg)为准给患者服用大约5微摩尔(μM)到大约500微摩尔的活性部分即HBED。一般适当的剂量在大约1到大约200mg/Kg患者体重/天的范围内,优选在大约5到大约100mg/Kg的范围内,最优选在大约10到大约80mg/Kg的范围内。本发明的药物组合物
广义上讲,本发明的组合物是HBED或其药学上可接受的盐或酯与适合于注射的药物赋性剂的混合物。一般地,本发明组合物可以属于下列6类中的一种:1.一备用注射的溶液,2.在使用前与溶剂混合的备用干性可溶组合物,3.备用注射的悬浮液,4.在使用前与载体混合的备用干性不溶性组合物,5.备用注射的乳浊液,和6.在给药前随时可以稀释的备用液体浓缩物。在制备皮下给药的组合物中,必须对张力的调整进行重视,以避免在该解剖区域对丰富神经末梢的刺激。
皮下注射液一般是完全稀释液并且存在的最高比例组份是载体。载体通常没有治疗活性并且是无毒的,但能够以适合于吸收的形式送活性组份到人体组织中。当HBED作为含水溶液存在时,一般吸收将最快和最完全。但是,用水溶性液体载体或水不溶性替代物改进的载体能够影响吸收的速率。悬浮液的影响将受这些因素的影响如载体的粘度、湿润固体颗粒的能力、由载体所产生的溶解度平衡,及载体和含水体系之间的分布系数。优选皮下组合物的最大量载体是符合USP标准的注射用水。一般对混合来说,适当质量的水可以通过蒸馏或者反渗透制得,以符合USP的要求。在Remington:药物的科学与实践,第19版,第1526-1528页中列出了适当的要求。在制备适合于皮下给药的组合物中,人们可以使用含水载体、水溶性载体和无水载体。由于一些含水载体一般用于非肠道尤其是皮下注射,因此官方对这些载体予以许可。这些载体可用作等渗载体,给药时把药物加入其中。等渗溶液是它与细胞接触时既不引起细胞萎缩也不引起细胞膨胀的液体。制备这些载体,这样当皮下注射药物时,药物的额外渗透作用不足以产生任何不适。用于本发明的这些含水载体包括氯化钠注射液、林格注射液、右旋糖注射液、右旋糖和氯化钠注射液和乳酸化林格注射液。优选使用HBED单钠盐的磷酸盐缓冲水溶液。
水溶性载体也可以用于本发明皮下组合物的配制。这些溶剂主要用来影响各种形式的HBED的溶解度并减少该化合物的水解。这类溶剂中最重要的是乙醇、聚乙二醇和丙二醇。
对相对来说水不溶的HBED盐或酯例如HBED的二盐酸盐也可以使用无水载体。这些载体包括不易挥发的油,例如能够适当代谢的植物来源的那些。对于USP皮下注射的可注射组合物来说,USP的要求限制了不饱和的程度和游离脂肪酸的含量。最常用的油是玉米油、棉花籽油、花生油和芝麻油。一些近来开发的中性油类,这些油类是中等链长脂肪酸的酯类并也称作精馏可可油,也是可以使用的。中等链长的脂肪酸即大约是8到10个碳原子的那些,包括由Dynamit Nobel出售的MIGLYOL的化合物类。以MIGLYOL810、812、818、829和840区分的五种类型的MIGLYOL都是可以使用的。在Dynamit Nobel的商业文献中更全面地对这些进行描述。一种有用的配方是在MIGLYOL载体中含有大约33%wt./vol.HBED的二盐酸盐。一些其他酯类也可用作无水载体,例如三甘油酯、丙二醇二酯类等等。
在皮下可注射的组合物中可以包括其他用于改进或保护组合物质量的物质。这样,所加入的物质可以影响溶解度、给患者提供舒适、提高化学稳定性或者保护制剂抗微生物生长。所以,该组合物可以包括适当的增溶剂、使溶液等渗的物质、作为抗氧化剂或缓冲液的物质和作为防止微生物生长的防腐剂物质。这些物质将以适合它们功能的用量存在,但没有不利地影响该组合物的超载铁治疗。适当的抗微生物剂的例子有硫柳汞、苄索氯胺、氯苄烷铵、苯酚、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯。在Remington第1529页中可以找到适当的缓冲液和抗氧化剂。
一般,本发明无菌皮下可注射组合物包括大约.01%wt到50%wt的HBED或其相应的盐或酯,剩余的是适当的赋性剂或赋性剂类。制备方法
本发明的另一个方面来自于把该药物皮下给药所获得的特殊结果的发现。这方面是制备适合于皮下给药的药用组合物的方法,该方法包括在能够提供适合于皮下给药的无菌组合物的条件下,把HBED或其药学上可接受的盐或酯与适合于皮下给药的药用赋性剂混合。这样,在制备本发明的组合物中,必须注意确保最终组合物是无菌的和适合于皮下注射。为了获得理想的皮下用产品,该方法一般采用按照当前批准的好的生产步骤(GMP)。当使用含水载体时,USP注射用水必须用来处理该组合物本身并优选用于处理制备该组合物的设备。制备皮下用制剂的一般说明可以在Remington:药物的科学和实践,第19版第87章中找到。产品
本发明的又一个方面是制备的的产品,该产品含有容器,其中该容器中装有适合于注射的组合物并附有提供怎样把该组合物皮下给药的打印标签。治疗有效量的组合物含在任何不与该组合物显著反应的适当容器中并且用说明它仅用于皮下给药的适当标签标明。由FDA批准的标签说明附在该容器上,得到许可的是使用HBED或其盐或酯用于治疗该疾病状态。该标签与上述治疗方法一致。装有本发明组合物的容器可以是装有适合于注射的液体组合物的容器,它有合适的注射针头和注射器从而使患者、医生、护士或其他实施者能够给药。适当容器的代表性例子包括Wyeth-Ayerst TUBEX封闭式注射系统、SmithKline Beecham可注射产品COMPRAZINE和Hoechst-Rousell注射用的产品LASIX预装注射器。或者,该组合物可以是含有可溶解的或可悬浮形式的HBED的干性组合物,其可与含水或无水载体混合来溶解或悬浮该组合物。或者,该容器可以装有液体悬浮液或者可以装有与载体混合时不溶形式的HBED,其中不溶形式是可以悬浮的。在Remington:第37章中讨论了适当的容器。无论什么特殊容器,标签是本发明的主要方面,其中最终到美国FDA批准才能标记该产品。
实施例
下面的实施例是以本发明各种方面的非限定型代表例给出的,从而使本领域普通技术人员能够实施该发明。在实施例中,甲磺酸盐形式的去铁胺B(DFO)(商品名:DESFERAL)是由Ciba-Geigy公司(Basel,瑞士)生产的。从Strem化学公司(Newburyport,MA)能够得到HBED二盐酸盐二水合物。从BASF(Parsippany,NJ)能够获得Cremophor RH-40。从Charles River(Wilmington,MA)可以买到Sprague-Dawley鼠。从World Wide Primates(Mlami,FL)可以得到Cebus apella猴。所有的试剂和标准铁铁溶液都可以从Aldrich化学公司(Milwaukee,WI)得到。
实施例1
该实施例解释了怎样处理受试鼠和Cebus apella猴以用于测定本发明的方法和组合物的有效性。A.鼠的胆道插管法
在该试验期间把平均400g体重的雄性Sprague-Dawley鼠关在Nalgene塑料代谢笼中并让其随意喝水。把戊巴比妥钠腹膜内给药(55mg/Kg)麻醉动物。用22-口径的聚乙烯管从距离十二指肠约1cm处插入胆道。把插管插入胆道大约2厘米,一旦出现胆汁的流动,就把插管在该部位隐藏性打结。皮肤通道针从肩胛区插入腹部切口附近。用针穿过插管直到它从肩胛开口处出现。然后把插管从小鼠通向金属扭矩传递栓里面的转环,其附在动物胸腔周围的啮齿目动物背夹上。通过固定在代谢笼上的液体旋环把插管从小鼠导向Gilson微量馏分收集器。该系统可以使动物在笼中自由移动,同时收集持续的胆汁样品。在24小时内以3小时为间隔收集胆汁样品。每24小时收集尿样。样品的收集和处理和前面所描述的一样(Bergeron等,药物化学杂志34:2072(1991);Bergeron等,血液79:1882(1992))。B.Cebus apella猴子的铁负载
在用氯胺酮肌肉内麻醉后,在腿静脉开始静脉输液。向铁右旋糖中加入大约90mL无菌正常生理盐水并以每Kg体重200到300mg铁的剂量在45到60分钟内缓慢输液的方式给药。在10至14天之间分为两到三次输液以提供每Kg体重大约500mg的铁。铁右旋糖给药后,血浆转铁蛋白的铁饱和度上升到70-80%。人血浆中铁右旋糖的半衰期为2.5到3.0天。在评价铁螯合剂的试验中于使用动物前至少要通过20个半衰期,60天。C.在Cebus anella猴中的铁-平衡试验
在给药前7天,把动物放在代谢笼中并开始喂低铁液体饮食。在试验过程中持续给猴子喂低铁液体饮食。按照它们的体重给食物并且仔细监测它们的摄取量。
给药前3天,2天到0天测定铁摄取和排出的基线。在第1天到第3天进行相同的测定。把铁摄取的重量与铁排出的重量进行比较。D.灵长类动物的粪便和尿液样本
在24小时的间隔收集粪便和尿液。收集开始于给药前4天并持续到给药后又5天。检查粪便样品中是否有隐藏的血液存在,给粪便样本称重,并与蒸馏的去铁水混合,高压灭菌30分钟。然后把该混合物冷冻干燥,把已知比例的该粉与低铁硝酸混合并回流24小时。一旦离心分离除去消化的样本中的任何特殊物质,就用火焰自动吸收法测定铁的浓度。把猴子的尿液样本酸化,如果必要的话,在灭菌后重新配制到最初的体积。
实施例2
该实施例解释了怎样制备和服用制剂,从而把本发明的方法(皮下给药)和组合物与现有技术的已知方法(口服)作比较。A.药物制剂和给药
以150moles/Kg的剂量给小鼠服用于40%Cremophor RH-40中的DFO。以150moles/Kg的剂量给小鼠皮下服用和经管饲法口服于磷酸缓冲液中的HBED。
在灵长类动物中,以150moles/Kg的剂量皮下注射无菌水中的DFO,而HBED首先溶于磷酸缓冲液并以40%wt./vol皮下给药。CremophorRH-40的剂量为75或150moles/Kg。另外,为了更相似地模拟患者的临床应用,也给猴子以150moles/Kg的剂量把HBED的磷酸缓冲液皮下给药,但无Cremophor载体。B.铁螯合剂效力的计算
以1;1的配位体-铁络合物为基础计算每种螯合剂的效力。在猴子中,数值是这样产生出来的:给药前4天的铁排泄量平均,从给药后两天的铁清除量中减去这些数值,然后除以理论排泄量;结果用百分数表示。计算灵长目类动物模型的效力是通过从治疗动物的铁排泄量中减去对照动物的铁排泄量,然后把数值除以理论排泄量;结果用百分数表示。C.统计分析
数据是以平均值±平均标准误差表示。为了比较两组平均值,用两种-样本的t-试验法(没有变量相同的假设)来分析啮齿类动物的数据,用成对t-试验分析灵长类动物的数据。所有的试验都是去掉两个端值,P<0.05表示显著水平。
实施例3
该实施例是比较本发明HBED对小鼠皮下给药与口服HBED和DFO皮下给药的效果。比较包括由铁螯合剂诱发的铁排泄的时间线和所排泄铁的峰量。
在没有铁超载并且胆道已经插管的小鼠中进行这些试验。以150moles/Kg体重的剂量把螯合剂给药。对小鼠皮下注射DFO(n=6)或者通过管饲法口服HBED(n=4)或者皮下注射HBED(n=3)。在每组小鼠中由螯合剂诱发的胆汁铁排泄的平均时间过程用g Fe/Kg体重来表示。用皮下注射HBED排泄的铁的峰量是皮下注射DFO或管饲法给药HBED后所排泄的铁的峰量的两倍多(在t=3小时时P<0.05并且在t=6小时时P<0.01)。在每组小鼠中通过螯合剂诱发的铁排泄表达为在尿液和在胆汁中所排泄铁的净平均量(g Fe/Kg体重)并且作为铁螯合剂的功效(铁净排泄量/螯合剂给药的铁结合总能力,表达为百分数)。
皮下给药的FDO诱发了209±59 gFe/Kg体重的排泄并发现有2.5±0.7%(范围1.7到3.7%)的效力,大约有74%螯合剂-诱发的铁排泄是通过胆汁而大约26%是通过尿液。与皮下DFO相比,管饲法口服给予HBED导致了两倍多的铁排泄即436±176 gFe/Kg体重(P<0.02);效力为5.2±2.1%(范围3.5到8.3%),大约有97%的螯合剂-诱发的铁排泄是通过胆汁而大约3%是通过尿液。把HBED给啮齿目类动物皮下注射给药是DFO皮下给药的效力包括铁的排泄的三倍多(P<0.001),包括679±8g Fe/Kg体重具有8.1±0.1%的总效力(范围7.9到8.2%)。大约83%的铁是在胆汁中排泄的而17%在尿液中。在啮齿目类动物中没有发现不利的副作用。
实施例4
该实施例在Cebus apella猴子中比较了皮下服用本发明的HBED与口服HBED和皮下服用DFO的效力。比较包括了由铁螯合剂所诱发的铁排泄的时间线和铁排泄的最大量。Cebus apella猴子中螯合剂所诱发的铁排泄
用Cebus apella猴子进行该试验,这些猴子已如上所述静脉内给予铁右旋糖以提供每Kg体重大约500mg的铁。对猴子组(每组n=6)皮下注射DFO或HBED。DFO水溶液是以150moles/Kg的剂量皮下给药的并且诱发了435±115g Fe/Kg体重,发现有5.1±1.3%的效力(范围3.3到6.6%),大约65%的螯合剂诱发的铁排泄是在粪便中而大约35%在尿液中。在我们的最初试验中,把HBED溶于磷酸缓冲液并以40%wt./vol.给药。因为HBED二盐酸盐二水合物的低水溶性,对低水溶性化合物来说,用聚乙氧化的蓖麻油Cremopho RH-40作为载体。HBED-Cremophor以75或150g Fe/Kg体重的剂量皮下注射给药。在剂量为75g Fe/Kg体重时,HBED-Cremophor诱发了793±410g/Kg的铁廓清率并具有18.4±9.1%(范围7.4到27.8%)。多数铁(92%)是在粪便中排泄的,而8%是在尿液中排泄的。在剂量为150g Fe/Kg体重时,HBED-Cremophor诱发了1349±474g/Kg的铁廓清率并具有16.1±5.6%(范围9.3到23.0%)。再进行一次,大多数铁90%排泄在粪便中,10%在尿液中发现。
最后,为了更相似地模拟潜在的临床应用,对用于前面试验的相同组的猴子以150moles/Kg的剂量也皮下给药HBED(如单钠盐)的磷酸缓冲液;没有使用Cremophor载体。再进行一次,皮下的HBED诱发了DFO的大约两倍多的铁的排泄,899±193g Fe/Kg体重(P<0.001),已经发现有10.7±2.3%(范围8.3d到13.8%),大约92%的螯合剂-诱发的铁排泄在粪便中而大约8%在尿液中。在剂量为150moles/Kg时,在磷酸缓冲液或在Cremophor制备的HBED所诱发的平均净铁排泄量之间没有发现显著性差异(P<0.2)。由以150moles/Kg体重的剂量皮下给药DFO水溶液和皮下给药HBED的缓冲液所诱导的平均铁排泄表达为在尿液中和在粪便中所排泄的铁的净平均量(gFe/Kg的体重)并表达为铁螯合剂的效力。该试验的结果能够与前述具有相似程度的铁超载的Cebus apella猴子组口服HBED的磷酸缓冲液的结果作比较。口服HBED仅诱发了50±44gFe/Kg体重的排泄并且已经发现有0.5±0.5%的效力(范围0.1到1.1%),大约56%螯合剂-诱发的铁排泄在粪便中而大约44%的在尿液中。在猴子中没有发现副作用;所有的血液学和生物化学试验都保持在正常范围。
实施例5
为了制备本发明的含水、缓冲的皮下注射组合物,把60mg HBED二钠盐溶于1ml适合于注射的无菌磷酸缓冲水溶液得到本发明的组合物溶液。
实施例6
为了制备本发明的无水皮下可注射的组合物,把60mg HBED二盐酸盐二水合物溶于1ml无菌聚乙氧化蓖麻油CREMOPHOR RH-40得到本发明的组合物。
在说明书中所提到的所有出版物和专利申请在本文中都在某种程度上作为参考文献,即使每个个人出版物或专利申请特殊和单独说明作为参考文献。
现在本发明已经被详细描述,在不超出所附的权利要求书的构思或范围能够作许多变化和改良对本领域普通技术人员都是显而易见的。
Claims (20)
1.药物组合物,它含有适合于皮下注射的药学上可接受的赋型剂及治疗有效量的N,N’-双(2-羟基苄基)乙二胺-N,N’-二乙酸或其药学上可接受的盐。
2.按照权利要求1的组合物,其中药学上可接受的盐是二盐酸盐。
3.按照权利要求1的组合物,其中药学上可接受的盐是二钠盐。
4.按照权利要求1的组合物,其中药学上可接受的盐是单钠盐。
5.按照权利要求1的组合物,其中该混合物与药学上可接受的赋型剂混合为注射溶液。
6.按照权利要求1的组合物,其中该混合物与药学上可接受的赋型剂混合为注射混悬液。
7.按照权利要求1的组合物,其中该混合物与药学上可接受的赋型剂混合为含水组合物。
8.按照权利要求1的组合物,其中该混合物与药学上可接受的赋型剂混合为无水组合物。
9.一种治疗患有铁螯合剂可治疗的疾病状态的哺乳动物的方法,该方法包括把治疗有效量的权利要求1的组合物皮下给药。
10.按照权利要求9的方法,其中疾病状态是铁超载。
11.按照权利要求10的方法,其中疾病状态是原发性血色素沉着症。
12.按照权利要求10的方法,其中疾病状态是继发性血色素沉着症。
13.按照权利要求10的方法,其中疾病状态是病灶性血色素沉着症。
14.一种产品,它含有容器,该容器中装有由适合于皮下注射用的药学上可接受的赋型剂和化合物N,N’-双(2-羟基苄基)乙二胺-N,N’-二乙酸或其药学上可接受的盐组成的药物组合物,其中该容器中载有治疗有效量的化合物并附有说明把该化合物皮下给药治疗铁螯合剂可治疗的疾病状态的打印标签。
15.按照权利要求14的产品,其中疾病状态是铁超载状态,其为原发性血色素沉着症、继发性血色素沉着症或病灶性血色素沉着症。
16.按照权利要求14的产品,其中药学上可接受的盐是二盐酸盐、二钠盐或单钠盐。
17.按照权利要求14的产品,其中化合物与药学上可接受的赋型剂混合成注射溶液、注射悬浮液、含水组合物或无水组合物。
18.一种制备药物组合物的方法,其包括把适合于皮下注射用的药学上可接受的赋型剂和化合物N,N’-双(2-羟基苄基)乙二胺-N,N’-二乙酸或其药学上可接受的盐混合。
19.按照权利要求18的方法,其中药学上可接受的盐是二盐酸盐、二钠盐或单钠盐。
20.按照权利要求18的方法,其中化合物与药学上可接受的赋型剂混合成注射溶液、注射悬浮液、含水组合物或无水组合物。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101189216B (zh) * | 2005-04-04 | 2011-10-19 | 佛罗里达大学研究基金会 | Desferrithiocin聚醚类似物 |
CN104706631A (zh) * | 2013-12-14 | 2015-06-17 | 于莹莹 | 一种铁螯合剂作为制备抗癌药物的应用 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7232830B2 (en) * | 1998-06-26 | 2007-06-19 | Elaine A Delack | Method for treatment of neurodegenerative diseases and effects of aging |
KR20110049875A (ko) | 1999-10-01 | 2011-05-12 | 디엠아이 바이오사이언시스, 인크 | 금속 결합 화합물 및 그의 용도 |
WO2001046114A1 (en) * | 1999-12-21 | 2001-06-28 | Geltex Pharmaceuticals, Inc. | Method for making hbed |
US7160855B2 (en) * | 2002-03-14 | 2007-01-09 | Children's Hospital & Research Center At Oakland | Enhancement of iron chelation therapy |
WO2010032489A1 (ja) | 2008-09-22 | 2010-03-25 | 国立大学法人旭川医科大学 | 鉄キレート剤及びその製造方法、並びに鉄イオンの定量・捕捉方法 |
WO2010133907A1 (en) * | 2009-05-18 | 2010-11-25 | Carlo Ghisalberti | Hexadentate chelators in inflammatory bowel disease |
US20110077417A1 (en) * | 2009-09-30 | 2011-03-31 | General Electric Company | Intermediates for Hydroxylated Contrast Enhancement Agents |
US8378134B2 (en) * | 2009-09-30 | 2013-02-19 | General Electric Company | Hydroxylated contrast enhancement agents |
US20110077396A1 (en) * | 2009-09-30 | 2011-03-31 | General Electric Company | Intermediates for hydroxylated contrast enhancement agents |
EP2664333B1 (en) | 2011-01-14 | 2016-10-12 | Disease Adsorption System Technologies Co., Ltd. | Polymeric iron chelating agent |
WO2012104204A1 (en) | 2011-01-31 | 2012-08-09 | Vifor (International) Ag | Iron-carbohydrate complex compounds for the intravenous therapy of malaria |
MX2017016399A (es) | 2015-06-25 | 2018-03-02 | Akzo Nobel Chemicals Int Bv | Proceso para preparar compuestos de acido etilendiaminodiacetico fenolico. |
TR201909965T4 (tr) | 2015-06-25 | 2019-07-22 | Akzo Nobel Chemicals Int Bv | Fenolik etilendiamin diasetik asit bileşikleri hazırlama prosesi. |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3005848A (en) | 1957-09-09 | 1961-10-24 | Geigy Chem Corp | Ethylenediamine derivatives containing aromatic rings |
US3758540A (en) | 1968-02-13 | 1973-09-11 | A Martell | Ferric chelates of n-(2-hydroxybenzyl) substituted aminopoly carboxylic acids |
BE786946A (fr) | 1971-07-29 | 1973-01-29 | Ciba Geigy | Chelates pour combattre des symptomes de carences en metaux dans des systemes biologiques |
GB1439048A (en) | 1973-09-11 | 1976-06-09 | Ciba Geigy Ag | Metal complexes of bis-azomethines and processes for their manufacture |
FR2267308B1 (zh) | 1974-04-12 | 1976-10-08 | Protex Manuf Prod Chimiq | |
CH602857A5 (zh) | 1976-12-10 | 1978-08-15 | Ciba Geigy Ag | |
US4130582A (en) | 1977-04-19 | 1978-12-19 | Ciba-Geigy Corporation | Preparation of phenolic ethylenediaminepolycarboxylic acids |
US4352751A (en) | 1979-09-10 | 1982-10-05 | Analytical Radiation Corporation | Species-linked diamine triacetic acids and their chelates |
US4528196A (en) * | 1981-02-23 | 1985-07-09 | The United States Of America As Represented By The Department Of Health And Human Services | Chelating agents for the treatment of iron overload |
US4647447A (en) | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
US4454106A (en) | 1982-06-07 | 1984-06-12 | Gansow Otto A | Use of metal chelate conjugated monoclonal antibodies |
US4909257A (en) | 1986-05-01 | 1990-03-20 | The Regents Of The University Of California | Method for attaining in vivo tissue-specific contrast by nuclear magnetic resonance imaging |
US5057302A (en) * | 1987-02-13 | 1991-10-15 | Abbott Laboratories | Bifunctional chelating agents |
US5227474A (en) * | 1987-02-13 | 1993-07-13 | Abbott Laboratories | Bifunctional chelating agents |
NZ231180A (en) | 1988-10-31 | 1994-11-25 | Dow Chemical Co | Bifunctional chelants;complexes,conjugates and pharmaceutical compositions thereof |
US5376154A (en) | 1991-05-13 | 1994-12-27 | The Lubrizol Corporation | Low-sulfur diesel fuels containing organometallic complexes |
US5840739A (en) * | 1992-11-16 | 1998-11-24 | University Of Florida Research Foundation, Inc. | Thiazoline acid derivatives |
US5534241A (en) * | 1993-07-23 | 1996-07-09 | Torchilin; Vladimir P. | Amphipathic polychelating compounds and methods of use |
EP0734374A1 (en) * | 1993-12-16 | 1996-10-02 | Novartis AG | N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents |
US5539138A (en) | 1994-07-28 | 1996-07-23 | Merck Frosst Canada, Inc. | High affinity chelates containing isothiocyanate groups, useful for coupling with peptides and proteins |
AU2958397A (en) | 1996-05-21 | 1997-12-09 | Novartis Ag | N,n'-di(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives |
-
1999
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- 1999-02-03 AT AT99905716T patent/ATE285232T1/de not_active IP Right Cessation
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- 1999-12-21 US US09/467,943 patent/US6242492B1/en not_active Expired - Lifetime
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101189216B (zh) * | 2005-04-04 | 2011-10-19 | 佛罗里达大学研究基金会 | Desferrithiocin聚醚类似物 |
CN104706631A (zh) * | 2013-12-14 | 2015-06-17 | 于莹莹 | 一种铁螯合剂作为制备抗癌药物的应用 |
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US6531510B1 (en) | 2003-03-11 |
DE69922787D1 (de) | 2005-01-27 |
ATE285232T1 (de) | 2005-01-15 |
CA2319255C (en) | 2010-01-26 |
CN1227006C (zh) | 2005-11-16 |
NZ506528A (en) | 2002-11-26 |
AU752383B2 (en) | 2002-09-19 |
JP2002502816A (ja) | 2002-01-29 |
PT1052985E (pt) | 2005-04-29 |
CA2319255A1 (en) | 1999-08-12 |
ES2235461T3 (es) | 2005-07-01 |
US6242492B1 (en) | 2001-06-05 |
AU2581499A (en) | 1999-08-23 |
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