CN1526448A - 用于治疗肛门直肠病的药物和方法 - Google Patents
用于治疗肛门直肠病的药物和方法 Download PDFInfo
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- CN1526448A CN1526448A CNA200410008292XA CN200410008292A CN1526448A CN 1526448 A CN1526448 A CN 1526448A CN A200410008292X A CNA200410008292X A CN A200410008292XA CN 200410008292 A CN200410008292 A CN 200410008292A CN 1526448 A CN1526448 A CN 1526448A
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Abstract
本发明提供ATP-敏感性K+通道活化剂用于制造治疗肛门直肠病并控制相关痛症的药物的用途以及包含ATP-敏感性K+通道活化剂的药物。
Description
本申请是2001年6月14日提交的99814430.4号,名为“用于治疗肛门直肠病的组合物和方法”的申请的分案申请。
发明背景
本发明涉及治疗肛门直肠病的组合物和方法,所述疾病例如肛裂、肛门溃疡、痔疮和提肌痉挛,所述治疗包括在患者肛门的相应部位(例如肛门内)给予可松弛肛门内括约肌的一种或多种药物。更具体地说,本发明描述的治疗肛门直肠病的组合物和方法可诱导患病括约肌组织内环核苷酸增加,或模拟环核苷酸的作用,或诱导患病括约肌组织内细胞内钙浓度降低,从而舒解肛门括约肌的过度紧张和/或患者的痉挛。
通常,肛裂、肛门溃疡、痔疮和提肌痉挛是较为常见的良性肛门直肠病,各年龄、种族和性别的人都可能发生。然而,这些疾病可能很难治愈,并对患者造成痛苦。肛裂或肛门溃疡即肛门通道末端粘膜的撕裂或溃疡。肛裂和肛门溃疡可能与其他全身性或局部性疾病相关联,但更多的是单独发生。典型的自发性肛裂和溃疡发生于肛门粘膜,通常位于臀中线内,齿状线远端。肛裂或溃疡患者一般发生肛门疼痛和出血,在排便时或排便后尤其严重。
痔疮是紧邻肛门粘膜的特化血管组织。痔疮的症状表现为出血、形成血栓和/或痔组织脱垂。通常,排便时,内痔组织向肛道内隆起,造成出血和疼痛。随着痔组织增大,继续出血,疼痛,就会发生脱垂和血栓。痔疮血栓形成则是引起出血和疼痛的又一原因。
提肌痉挛在妇女中更多见。该综合征的特征是作为肛门括约肌复合体一部分的提肌发生强直。患者会感到剧烈的阵发性直肠疼痛。检查可发现耻骨肌痉挛,直接压迫该肌肉可以再现疼痛。该病一般不发生出血。
括约肌是一个环状平滑肌群,控制中空器官的开口。整个胃肠(GI)都有括约肌,控制物质在该系统中通过。收缩时,括约肌关闭进入胃、肠、肛门等中空器官的入口。要使括约肌开放,就必须使肌肉松弛。关闭肛门的括约肌(肛门括约肌)由两个括约肌群组成。肛外括约肌是一片由条纹肌纤维构成的薄的平板,贴附与肛门周围的皮肤。内肛括约肌(IAS)是一个平滑肌环,环绕着直肠末端,由随意性平滑肌纤维聚集而成。局部炎症会引起括约肌痉挛和疼痛。
肛门括约肌痉挛即内肛括约肌肌肉张力异常。括约肌痉挛引起的内肛括约肌强烈收缩常引起肛门周围的痛性线性溃疡或开裂样疼痛,又称肛裂,特别在排便后。肛门括约肌痉挛还被认为是引起直肠手术后疼痛或血栓型痔疮的原因之一。目前对于肛裂的治疗以缓解括约肌痉挛为目的,包括(麻醉)下的扩张手术或切去部分括约肌(内侧括约肌切除术)。对直肠疼痛的治疗还包括热疗、冷疗、金缕梅、局部麻醉,局部甾体,软化粪便和卧床休息。然而,这些方法都不能显著从根本上改善括约肌痉挛。
例如,对于肛裂的治疗已有150多年未有明显改变。通常采用容积性缓泻剂和/或坐浴等非手术疗法。用这种疗法,约60%急性肛裂患者能在3周内痊愈。未能痊愈的急性肛裂则演变成慢性的肛裂和肛门溃疡。被认为是肛裂主要原因的内肛括约肌过度紧张可通过括约肌切除手术来缓解。The Standards Task Force ofthe American Society of Colon and Rectal Surgeons推荐用“皮下或侧内括约肌开口术,使用高级皮瓣(flap)的臀内括约肌切除术,或人工扩张”来治疗慢性肛裂。括约肌切除后的治愈率是95%。成功的括约肌切除术(或肛门扩张)可显著降低肛内压力。然而,许多患者会在术后发生失禁。
一种已知的括约肌紧张性调节剂是氧化氮(NO)。体外试验显示,氧化氮可浓度依赖性地引起内括约肌平滑肌条静息压下降(Rattan等,美国生理学杂志262:G107-112(1992)),例如硝化甘油、异山梨醇二硝酸酯、异山梨醇一硝酸酯等NO供体可降低人的肛门压力。已知,NO还能引起消化道其他括约肌的适应性松弛,其中包括食管末端括约肌(Conklin等,消化道学104:1439-1444(1993);Tottrup等,英国药理学杂志104:113-116(1991)),幽门括约肌(Bayguinoc等,美国生理学杂志264:G975-983(1993)),Oddi括约肌(Mourelle等,消化道学105:1299-1305(1993))和回肠括约肌(Ward等,英国药理学杂志105:776-782(1992))。NO或NO样物质被认为是消化道适应性松弛的重要调控机制。
美国专利5,504,117和5,693,676描述了NO供体治疗肛门直肠病的用途。然而,例如头痛等副作用的发生限制了NO供体的单用,尤其是高剂量治疗用途。
显然,目前需要一种治疗肛门直肠病的新的非手术疗法,用于治疗肛门括约肌痉挛和/或过度紧张引起的肛裂等肛门直肠病,包括急性痔疮和肛门痛。
发明概述
本发明提供治疗肛门直肠病的组合物,其中包含氧化氮供体与第二药物(通常是调节cAMP或cGMP水平的药物)的混合物。所述的第二药物可以是V型(PDEV),II型(PDE II)和IV型(PDE IV)磷酸二酯酶抑制剂,非特异性PDE抑制剂,β-肾上腺素能激动剂,cAMP依赖性蛋白质激酶活化剂,雌激素或雌激素样化合物,或α1-肾上腺素能拮抗剂。该药物也可以是超氧化物阴离子(O2 -)清除剂,ATP-敏感性K+通道活化剂或平滑肌松弛剂,虽然这些药物不直接调节cAMP或cGMP水平。本发明还提供此类组合物的使用方法。
本发明还提供另一类治疗肛门直肠病的组合物,其中包含磷酸二酯酶抑制剂,优选PDE II、PDE IV或PDE V抑制剂,单用或与另一种药物联用,该药物选自β-肾上腺素能激动剂,α1-肾上腺素能拮抗剂,雌激素,L型Ca2+通道阻滞剂,ATP-敏感性K+通道活化剂或平滑肌松弛剂,还有药学上认可的载体。本发明还提供此类组合物的使用方法。
本发明还提供另一类治疗肛门直肠病的组合物,其中包含β-肾上腺素能激动剂,优选β2或β3肾上腺素能受体激动剂,单用或与另一种药物联用,该药物选自cAMP-水解性PDE抑制剂(例如PDE IV抑制剂),非特异性PDE抑制剂,α1-肾上腺素能拮抗剂,雌激素或雌激素样化合物,L型Ca2+通道阻滞剂或ATP-敏感性K+通道活化剂。本发明还提供此类组合物的使用方法。
本发明还提供另一类治疗肛门直肠病的组合物,其中包含ATP-敏感性K+通道活化剂,单用或与另一种药物联用,该药物选自cAMP依赖性蛋白质激酶活化剂,α1-肾上腺素能拮抗剂,雌激素,L型Ca2+通道阻滞剂或平滑肌松弛剂。本发明还提供此类组合物的使用方法。
本发明还提供另一类治疗肛门直肠病的组合物,其中包含α1-肾上腺素能拮抗剂,单用或与另一种药物联用,该药物选自cAMP-水解性PDE抑制剂(例如PDEIV抑制剂),或平滑肌松弛剂。本发明还提供此类组合物的使用方法。
本发明还提供另一类治疗肛门直肠病的组合物,其中包含环核苷酸依赖性蛋白质激酶活化剂,单用或与另一种药物联用。本发明还提供此类组合物的使用方法。一类实施例单独使用cGMP依赖性蛋白质激酶活化剂。另一类实施例单独使用非特异性环核苷酸依赖性蛋白质激酶活化剂。另一类实施例将非特异性环核苷酸依赖性蛋白质激酶活化剂与平滑肌松弛剂联用。另一类实施例将cAMP依赖性蛋白质激酶活化剂与L型Ca2+通道阻滞剂联用。
本发明还提供另一类治疗肛门直肠病的组合物,其中包含雌激素或雌激素样化合物,单用或与另一种药物联用。本发明还提供此类组合物的使用方法。一类实施例单独使用雌激素样化合物。另一类实施例将雌激素与第二药物联用,后者选自磷酸二酯酶抑制剂,β-肾上腺素能激动剂,α1-肾上腺素能拮抗剂,L型Ca2+通道阻滞剂,ATP-敏感性K+通道活化剂或平滑肌松弛剂,还含有药学上认可的载体。本发明还提供此类组合物的使用方法。
本发明还提供治疗肛门直肠病的方法。本发明的方法包括将一种或多种上述组合物的合适制剂按治疗有效量给予患者。在此类进行治疗方法中,通过以相同或不同途径按次序给予两种或更多种药物。
附图简述
图1是对照实验条件下,大鼠静息IASP的典型波形。
图2是给予20μl以丙二醇配制的1%硝化甘油溶液后大鼠的IASP波形。
图3显示cGMP模拟物对大鼠内肛括约肌的作用。该图显示给予20μl 10%二丁酰基-cGMP盐水溶液后大鼠的IASP波形。
图4显示磷酸二酯酶抑制剂对大鼠内肛括约肌的作用。该图显示给予20μl以1-甲基-2-吡咯烷酮配制的5%扎普司特溶液后大鼠的IASP波形。
图5显示钾通道开放剂对大鼠内肛括约肌的作用。该图显示给予20μl以62.5%丙二醇配制的4%米诺地尔溶液后大鼠的IASP波形。
本发明的详细描述
缩写与定义
cAMP:环单磷酸腺苷;cGMP:环单磷酸鸟苷;NO:氧化氮;NTG:硝化甘油;SOD:超氧化物歧化酶;PDE:磷酸二酯酶;IASP:内肛括约肌压力;Rp-cAMPS:Rp-腺苷-3′,5′-环单硫代磷酸酯;Sp-cAMP:Sp-腺苷-3′,5′-环单硫代磷酸酯;8-CPTcAMP:8-(4-氯苯硫基)-腺苷-3′,5′-环单磷酸酯钠盐;Sp-5,6-DCI-cBiMPS:Sp-5,6-二氯-1-b-D-呋喃核糖苯并咪唑-3′,5′-单硫代磷酸酯;二丁酰基-cAMP:N6,2′-O-二丁酰基腺苷-3,′5′-环单磷酸酯一水合钠盐;Sp-8-pCPT-cGMP:Sp-8-(4-氯苯硫基)-鸟苷-3,′5′-环单磷酸酯钠盐;8-溴-cGMP:8-溴-鸟苷-3,′5′-环单磷酸酯钠盐;Rp-8-Br-cGMP:Rp-8-溴-鸟苷-3,′5′-环单硫代磷酸酯钠盐;二丁酰基-cGMP:N2,2′-O-二丁酰基鸟苷-3,′5′-环单磷酸酯一水合钠盐;EHNA:赤型-9-(2-羟基-3-壬基)腺嘌呤HCl;IBMX:3-异丁基-1-甲基黄嘌呤;MY-5445:1-(3-氯苯基氨基)-4-苯基-2,3-二氮杂萘;Ro 20-1724:4-(3-丁氧基-4-甲氧基苄基)-2-咪唑烷酮。
除非另作说明,本文所用科技术语的含义都与本领域一般技术人员的常识相同。本领域技术人员可从以下参考文献中查到本发明所用许多术语的通用解释:Singleton等,微生物学和细胞生物学辞典(第二版,1994);剑桥科技辞典(Walker编辑,1988);和Hale & Marham,Harper Collins生物学辞典(1991)。后文术语,除非另作说明,都如以下所述。虽然例举了优选的方法和材料,可用与本文所述相同或相当的多种方法和材料来实施和验证本发明。就本发明目的而言,各术语解释如下。
“处理”、“治疗”等包括但不限于改变受主的状态。这种改变可以是主观或客观的,可与被处理的疾病或情况的症状或表现相关。例如,如果患者称瘙痒减轻,出血减少,不适减轻或疼痛减轻,则说明处理有效。同样,如果医生指称某些客观变化,例如生物组织样本的组织分析,也说明处理有效。或者,医生也可能在对患者检查后指称损伤或其他病变减小。这也表示一定的改善或处理有效。这些术语也包括避免受主状态恶化。疗效包括可表明上述反应的各种主观或客观因素。
“药物”,“有效物质”在此通用,都取其最广义的解释,指各种疗效物质,即给予生物体以期获得预想的,通常是良性效果的物质。
“药学上认可的”或“治疗学上认可的”表示某一物质不影响有效成分的效力或生物活性,对接受给予的人或动物等受主无毒。“治疗有效量”表示有效物质的量足以诱导产生理想的生物学效应。这样的效应可以是表现、症状或病因减轻,或生物系统其他各种良性改变。“治疗有效量”在此表示:在一段时间内重复给予患区,从而使病情得到基本改善的各种制剂用量。这样的量取决于所处理的情况、病情发展的阶段和所用制剂的类型和浓度。各种情况下的合适量,对本领域技术人员来说不难确定,也可以通过常规实验来确定。
“肛门直肠部位”在此包括哺乳动物的肛门和直肠区。更具体地说,它包括肛门内,肛门外和直肠末端。
“过度紧张”指肌肉张力高于正常或松弛不完全的状态。
“环核苷酸”指环单磷酸腺苷和环单磷酸鸟苷。
“调节”指某一持续性振荡的某一特征(例如频率、浓度、振幅、效力等)的系统性或分级变化,并足以引起某一生物学功能。“变化”包括某特征的增强或减弱。
“主体”包括底物,为包括人在内的哺乳动物。
“肛门直肠病”包括与肛门直肠病变有关的各种疾病,包括:急性或慢性肛裂,内部或外部血栓性痔疮,痔疮性疾病,与内痔粘连相关的疾病或由此引起的痛症,提肌痉挛,便秘,以及肛门括约肌过度紧张或痉挛引起的其他肛门直肠病。“肛裂”又称“肛门皲裂”,肛门括约肌痉挛又称“里急后重”。此外,“肛门直肠病”还包括与上述各种疾病相关的痛症。
“钾通道开放剂”和“钾通道活化剂”指这样的一类药物:它可以使得具有至少一个钾通道的可电激活细胞内的钾透过细胞膜向细胞外的流量增强。钾通道开放剂的活性可通过测定钾离子通过细胞膜内的钾通道由内向外流量增加引起的细胞膜电势超极化(即更大的负膜电势)来观察。
“药物组合物”指适合给人或动物等受主作为药物使用的组合物。药物组合物一般包括有效量的有效物质和药学上认可的载体。
“药学上认可的载体”包括各种标准药物载体,缓冲剂和赋型剂,包括磷酸盐缓冲剂,水和乳液(例如水包油乳液或油包水乳液),以及各种类型的润湿剂和/或佐剂。合适的药学载体及其配制可参见Remington药物科学(Mack Publishing Co.Easton,第19版,1995)。药物载体的优选取决于有效物质的给予方式。典型的给予方式参见后文。
“有效量”指足以产生所需效果的剂量。所需效果包括该剂量受主的主观或客观改善。
“预防性处理”指对尚没有疾病表现或仅表现出疾病早期特征的主体的处理,其目的在于降低发病的危险性。
“治疗性处理”指对于已经表现出病理特征的主体的处理,其目的在于减轻或消除这些病理特征。
“相应的肛门区域”指发生肛门疾病或受其影响的肛门或括约肌部位或组织,包括,例如肛门内部或外部,内或外肛门括约肌,或内或外肛道。
“NO供体”指各种可在生理条件下提供氧化氮的有机或无机化合物。还包括可经体内代谢而产生提供氧化氮的化合物的化合物(例如NO供体的前药形式,或二元NO发生系统)。
概述
在相应的肛门区域局部使用氧化氮(NO)供体,这有望成为治疗肛门疾病中的一种新方法。已知氧化氮可在体外引起内括约肌平滑肌群静息压的浓度依赖性降低(Rattan等,美国生理学杂志,262:G107-112(1992)),而且,NO供体(例如硝化甘油,异山梨醇二硝酸酯、异山梨醇一硝酸酯和L-精氨酸)可降低人的肛门压力。Schouten,W.R.等,“给慢性肛裂患者肛内使用异山梨醇二硝酸酯后的病理生理学研究和临床结果”Gut 39:465-9(1996);Farid,M.,英国外科学杂志84:1(1997);和Hechtman,H.B.等,外科文献131:775-778(1996)。还知道,NO还可引起包括食管末端括约肌(Conklin等,胃肠学104:1439-1444(1993);Tottrup等,英国药物学杂志104:113-11(1991)),幽门括约肌(Bayguinov等,美国生理学杂志264:G975-983(1993)),Oddi括约肌(Mourella等,胃肠学105:1299-1305(1993))和回结肠括约肌(Ward等,英国药物学杂志105:776-782(1992))在内的消化道其他括约肌适应性松弛。
尽管NO供体产生了早期的希望,但发现,此类药物会产生急性免疫反应。出人意料的是,本发明提供了可克服现有疗法副作用及相关问题的组合物。
实施例的描述
NO供体与第二药物的组合
本发明内容之一提供了用于治疗肛门疾病的组合物,其中,氧化氮供体与可调节cAMP或cGMP水平的第二药物组合。在一组实施例中,该第二药物是V型磷酸二酯酶(PDE V)抑制剂。另一组实施例中,该第二药物是IV型磷酸二酯酶(PDE IV)抑制剂。另一组实施例中,该第二药物是II型磷酸二酯酶(PDE II)抑制剂。另一组实施例中,该第二药物是非特异性PDE抑制剂。另一组实施例中,该第二药物是超氧离子(O2-)清除剂。另一组实施例中,第二药物是β-肾上腺素能激动剂。另一组实施例中,第二药物是cAMP依赖性蛋白质激酶活化剂。另一组实施例中,第二药物是α1-肾上腺素能拮抗剂。另一组实施例中,第二药物是雌激素或雌激素类似物或雌激素样化合物。另一组实施例中,第二药物是L型Ca2+通道阻滞剂。另一组实施例中,第二药物是ATP敏感性K+通道活化剂。本发明还提供使用上述组合物的方法。本发明的一项相关内容是提供含NO供体和平滑肌松弛剂的组合物。
以上各实施例中,氧化氮供体可以是各种类型的,例如有机NO供体,无机NO供体,和NO供体的前药形式。较好的是,NO供体包括至少一种有机硝酸盐(包括硝酸酯),并且可以是环化或非环化的化合物。例如,合适的NO供体包括硝化甘油(NTG),异山梨醇二硝酸酯(ISDN),异山梨醇一硝酸酯(ISMN)(包括异山梨醇-2-单磷酸酯(IS2N)和/或异山梨醇-5-单磷酸酯(IS5N)),丁四硝酯(ETN),戊四硝酯(PETN),乙二醇二硝酸酯,硝酸异丙酯,甘油-1-一硝酸酯,甘油-1,2-二硝酸酯,甘油-1,3-二硝酸酯,1,2,4-丁三醇三硝酸酯,等。NO供体以NTG为佳。硝化甘油和其他有机硝酸酯包括ISDN,ETN和PETN,这些已获准用于人的治疗。其他NO供体包括钠硝普盐,N,O-二乙酰基-N-羟基-4-氯苯磺酰胺,NG-羟基-L-精氨酸(NOHA),硫酸羟基胍,吗多明,3-吗啉基悉尼酮胺(3-morpholinsydnonimine)(SIN-1),(±)-S-亚硝基-N-乙酰基青霉素胺(SNAP),S-亚硝基谷胱甘肽(GSNO),(±)-(E)-乙基-2-[(E)-羟基亚氨基]-5-硝基-3-己烯酰胺(FK409),(±)-N-[(E)-4-乙基-3-[(Z)-羟基亚氨基]-5-硝基-3-己烯-1-基]-3-吡啶羧酰胺(FR144420)和4-羟基甲基-3-(噁二唑)羧酰胺。
通常,有机氧化氮供体(包括有机硝酸酯)的含量低于其单用于治疗时的用量。本发明中有机氧化氮供体的含量约为0.01-10重量%浓度。本文中所有的重量百分比都以组合物总重量为基数。就NTG而言,其优选浓度约0.01-5重量%。
在一组实施例中,组合物包含V型磷酸二酯酶(PDE V)抑制剂。磷酸二酯酶(PDE)抑制剂是可抑制组织中cAMP和cGMP降解的化合物。PDE抑制剂包括非特异性PDE抑制剂和特异性PDE抑制剂(仅抑制一种类型的PDE,对其他类型则几乎没有作用)。V型磷酸二酯酶抑制剂包括扎普司特,MBCQ,MY-5445,双嘧达摩和sildenifil。
在另一组实施例中,组合物包含II型磷酸二酯酶(PDE II)抑制剂。合适的II型磷酸二酯酶抑制剂包括EHNA。
在另一种实施例中,组合物包含IV型磷酸二酯酶(PDE IV)抑制剂。合适的IV型磷酸二酯酶抑制剂包括ariflo(SB207499),RP73401,CDP840,咯利普兰和LAS31025。
在另一种实施例中,组合物包含非特异性PDE抑制剂。合适的非特异性PDE抑制剂包括IBMX,茶碱,氨茶碱,己酮可可碱,帕吉维林和咖啡因。
另一组实施例中,组合物包含超氧离子(O2 -)清除剂。超氧化物会与NO反应并显著降低其生物学作用。所以,可清除超氧离子的物质(例如,外源性Mn-或Zn-超氧化物歧化酶(SOD)或小分子SOD模拟物,例如Mn(III)四(4-苯甲酸)卟啉氯(MnTBAP)和M40403,参见Salvemini等,科学286(5438):304-306(1999))可增强NO的作用。SOD是一类较稳定的酶,可与NO供体(例如NTG)一起用作局用制剂,增强NTG产生的NO的区域效力。NTG产生的氧化氮因其半衰期短而只具有区域效力。然而,NTG本身的稳定性却足以允许它在粘膜吸收后发挥全身性作用。因为用SOD或SOD模拟物增强了NTG的区域效力,所以减少了获得相同程度肛门括约肌松弛效果的NTG所需量,被吸收的NTG因而减少,从而降低了全身性副作用。
在另一组实施例中,组合物包含β-肾上腺素能激动剂,以β2-或β3-肾上腺素能受体激动剂为佳。文献中记载的大量β-肾上腺素能激动剂都可用于本发明。合适的β3-肾上腺素能激动剂可参见Bristol等,医学化学年度报告第33卷,第19章,pp.193-202,Academic Press(1998)。优选的β-肾上腺素能激动剂包括沙丁胺醇,特布他林,丙卡特罗,克仑特罗,异丙肾上腺素,净特罗,BRL37344,CL316243,CGP-12177A,GS332,L-757793,L-760087,L-764646和L-766892。
另一组实施例中,所述的药物是cAMP依赖性蛋白质激酶活化剂。许多蛋白质激酶活化剂可用于本发明,例如,cAMP模拟物和cGMP/cAMP双依赖性蛋白质激酶活化剂。cAMP模拟物是本领域所熟知的,包括8-溴-cAMP,二丁酰基-cAMP,Rp-cAMPS和Sp-cAMPS。双活化剂包括Sp-8-pCPT-cGMP,Sp-8-溴-cGMP和8-CPT-cAMP。
另一组实施例中,组合物包含雌激素或雌激素类似物或模拟物。在此,“雌激素”包括各种形式的雌激素和雌激素样化合物,例如具有雌激素样活性的化合物(例如在竞争性结合试验中与雌激素受体结合的化合物)。这些雌激素可以是甾体或非甾体(参见,Bristol等,医学化学的年度报告第31卷,第19章,pp.181-190,Academic Press(1996)以及其中的参考文献)。雌激素样化合物包括但不限于17-β-雌二醇,雌酮,美雌醇,雌二醇戊酸酯,雌二醇dypionate,乙炔雌二醇,炔雌醇,硫酸雌酮,植物雌激素,例如黄酮(falvones),异黄酮(isofalvones)(例如三羟异黄酮),白藜芦醇,coumestan衍生物,其他雌激素样合成化合物,包括杀虫剂(例如p,p′-DDT),增塑剂(如双酚A),和其他多种工业化合物(例如多氯联苯)。
另一组实施例中,组合物包含α1-肾上腺素能拮抗剂。交感神经递质去甲肾上腺素通过α1-肾上腺素能受体使括约肌平滑肌收缩。向患者相应的肛门部位给予交感神经阻滞药,从而药物性干扰去甲肾上腺素的释放或其与α1-肾上腺素能受体的结合,也可以使肛门括约肌松弛,改善肛门直肠病的症状。这样的交感神经阻滞药包括α1-肾上腺素能受体拮抗剂(例如哌唑嗪,多沙唑嗪,酚妥拉明,妥拉唑啉等,Goodman & Gilman的治疗学的药物学基础,第9版,JG Hardman等,McGraq-Hill(1996)),阻滞去甲肾上腺素释放的α2-肾上腺素能激动剂(例如可乐定),神经末梢去甲肾上腺素消耗剂(例如胍乙啶,溴苄铵,利血平),去甲肾上腺素合成抑制剂(例如,α-甲基酪氨酸),以及破坏交感神经的药物(例如6-羟基多巴胺)。因此,在一相关实施例中,所述组合物包含其他交感神经阻滞剂,例如α2-肾上腺素能受体激动剂,神经末梢去甲肾上腺素消耗剂,去甲肾上腺素合成抑制剂或另一种破坏交感神经末梢的药物。
另一组实施例中,所述药物是ATP敏感性K+通道活化剂。ATP和NO一起被认为具有抑制性神经递质的作用,这样的神经递质一般由肠非肾上腺素能非胆碱能神经释放,可介导消化道括约肌的适应性松弛(Burnstock,药物性评论24:509-81(1972))。ATP的作用主要是打开ATP敏感性钾(KATP)通道,这样的通道可使细胞膜超极化,降低胞内钙浓度,使平滑肌松弛。可活化ATP敏感性K+通道的合成化合物即平滑肌松弛剂,例如米诺地尔,硫酸米诺地尔,哌诺地尔(pinocidil),二氮嗪,levcromokalim,cromokalim等(参见White等,欧洲药物学杂志357(1):41-51(1998))。ATP敏感性K+通道由GI平滑肌表达(Koh等,生物生理学75:1793-80(1998))。因此,特异性钾通道开放剂可用于松弛内肛括约肌,以及改善肛门直肠病的症状。必须指出的是,其他K+通道也会影响平滑肌的紧张度,包括蜂毒明肽敏感性低电导钙活化的K+通道和charybdotoxin敏感性高电导钙活化的K+通道。
在其他实施例中,组合物还含有NO供体和平滑肌松弛剂。优选的平滑肌松弛剂包括肼苯达嗪,罂粟碱,苯酰胺桂胺,环扁桃酯,异克舒令或布酚宁。
磷酸二酯酶抑制剂组合物
本发明还提供另一类治疗肛门直肠病的组合物,其中包含磷酸二酯酶抑制剂(优选PDE II抑制剂,PDE IV抑制剂或PDE V抑制剂),单用或与另一种药物联用,该药物选自β-肾上腺素能受体激动剂,α1-肾上腺素能拮抗剂,雌激素,L-型Ca2+通道阻滞剂,ATP-敏感性K+通道活化剂或平滑肌松弛剂,以及药学上认可的载体。本发明还提供以上组合物的使用方法。
磷酸二酯酶抑制剂(PDE抑制剂)能抑制组织内cAMP和cGMP的降解。PDE抑制剂包括非特异性的和特异性的。非特异性PDE抑制剂可抑制一种以上磷酸二酯酶,特异性PDE抑制剂则只抑制一种类型的磷酸二酯酶,对其他类型的作用极小。已经鉴定了5种环核苷酸PDE同工酶家族的特异性抑制剂:8-甲氧基甲基-IBMX(异丁基甲基黄嘌呤)或长春西汀(Ca2+、camodulin依赖性I型PDE);EHNA(赤-9-(2-羟基-3-壬基)腺嘌呤HCl)(cGMP激发的II型PDE);米力农(cGMP抑制的III型PDE);咯利普兰(cAMP特异性IV型PDE)和扎普司特及DMPPO(1,3-二甲基-6-(2-丙氧基-5-甲磺酰氨基苯基)-吡唑并[3,4-d]嘧啶-4-(5H)-酮(cGMP特异性V型PDE)。目前认为,至少有9种PDE同工酶,最近发现的是9A型(参见,Fisher等,生物化学杂志273(25):15559-64(1998))。非特异性PDE抑制剂包括,例如IBMX,茶碱,氨茶碱,咖啡因等(参见,Vemulapalli等,心血管药物学杂志28(6):862-9(1996))。
较好的是,治疗肛门直肠病的组合物在适合用于局部处理的制剂中含一种或多种选自PDE II,PDE IV和PDE V抑制剂的化合物。以上各类的成员宜与一种第二药物组合,该第二药物选自β-肾上腺素能受体激动剂(以β2-或β3-肾上腺素能受体激动剂为佳),α1-肾上腺素能拮抗剂,L型Ca2+通道阻滞剂,雌激素,ATP敏感性K+通道活化剂或平滑肌松弛剂。优选的参见前文就与NO供体联用部分所述。
β-肾上腺素能受体激动剂组合物
本发明还提供包含β-肾上腺素能受体激动剂的用于治疗肛门直肠病的药物组合物,其中包含β-肾上腺素能受体激动剂,优选β2-或β3-肾上腺素能受体激动剂,单用或与选自cAMP-水解性PDE抑制剂(例如PDE IV抑制剂),非特异性PDE抑制剂,α1-肾上腺素能拮抗剂,雌激素,L型Ca2+通道阻滞剂,ATP敏感性K+通道活化剂,或平滑肌松弛剂另一种药物组合,还含有药学上认可的载体。本发明还提供以上组合物的使用方法。
在本发明的这方面内容中,所述的β-肾上腺素能受体激动剂可以是几乎所有前文与NO供体联用的那些β-肾上腺素能受体激动剂。较好的是β2-或β3-肾上腺素能受体激动剂。特别优选的是Bristol等在医学化学年度报告第33卷第9章,pp.193-202,Academic Press(1998)中所述的那些,或选自沙丁胺醇,特布他林,丙卡特罗,克仑特罗,异丙肾上腺素,净特罗,BRL37344,CL316243,CGP-12177A,GS332,L-757793,L-760087,L-764646和L-766892。
另一组实施例中,本发明组合物包含一种合适的β-肾上腺素能受体激动剂和药学上认可的载体,尤其好的是适合肛门直肠病部位局部使用的制剂。
另一组实施例中,组合物还含另一种药物,选自cAMP-水解性PDE抑制剂(例如PDE IV抑制剂),非特异性PDE抑制剂,α1-肾上腺素能拮抗剂,雌激素,L型Ca2+通道阻滞剂,ATP敏感性K+通道活化剂,或平滑肌松弛剂。
在一组优选实施例中,上述药物是cAMP-水解性PDE抑制剂,尤其是IV型磷酸二酯酶抑制剂。优选的IV型磷酸二酯酶抑制剂(又称PDE IV和PDE4)可参见Bristol等在医学化学年度报告第33卷第9章,pp.193-202,AcademicPress(1998)。最好,PDE IV抑制剂是咯利普兰,Ro20-1724或依他唑酯。
另一组优选实施例中,该药物是非特异性PDE抑制剂,例如IBMX,IBMX,茶碱,氨茶碱,己酮可可碱,lisophylline和罂粟碱。
另一组优选实施例中,该药物是α1-肾上腺素能拮抗剂。合适的α1-肾上腺素能受体拮抗剂(例如哌唑嗪,多沙唑嗪,酚妥拉明,妥拉唑啉等),可参见Goodman& Gilman的治疗学的药物学基础,第9版,JG Hardman等,McGraq-Hill(1996)。
本发明组合物中优选的是哌唑嗪,多沙唑嗪,酚妥拉明,妥拉唑啉以及它们的衍生物。
另一组优选实施例中,β-肾上腺素能受体激动剂与L型Ca2+通道阻滞剂组合,后者例如硝苯地平,尼莫地平,非洛地平,尼卡地平,伊拉地平,氨氯地平,地尔硫卓,维拉帕米。
另一组优选实施例中,β-肾上腺素能受体激动剂与ATP敏感性K+通道活化剂组合。优选与NO供体联用的那些。
在其他组合物中,β-肾上腺素能受体激动剂与雌激素或雌激素样化合物,或与平滑肌松弛剂组合。合适的以上两类化合物即前文与NO供体联用的那些。
K+通道活化剂组合物
本发明还提供单含ATP敏感性K+通道活化剂的组合物,该活化剂单用或与选自cAMP依赖性蛋白质激酶活化剂,雌激素,α1-肾上腺素能拮抗剂,L型Ca2+通道阻滞剂或平滑肌松弛剂的药物联用,以及药学上认可的载体。本发明还提供了此类化合物的使用方法。
在本发明的此项内容中,所选的组合物由前文NO供体组合物中列举的组分构成。有关ATP敏感性K+通道活化剂的描述可参见Bristol等在医学化学年度报告第33卷第9章,pp.193-202,Academic Press(1998)。在一优选实施例中,该钾通道活化剂是二氮嗪,米诺地尔,PCO400,pinocidil,levcromokalin或cromokalim。
部分实施例中,组合物还含有cAMP依赖性蛋白质激酶活化剂,雌激素或雌激素样化合物,α1-肾上腺素能拮抗剂,L型Ca2+通道阻滞剂或平滑肌松弛剂。较好的是,cAMP依赖性蛋白质激酶活化剂是cAMP模拟物或cGMP/cAMP双依赖性蛋白质激酶活化剂。更好的是,所述cAMP模拟物是8-溴-cAMP,二丁酰基-cAMP,Rp-cAMPS或Sp-cAMPS。双活化剂选自Sp-8-pCPT-cGMP,Sp-8-溴-cGMP和8-CPT-cAMP。
另一组实施例中,α1-肾上腺素能拮抗剂与ATP敏感性K+通道活化剂组合。较好的是,α1-肾上腺素能拮抗剂是哌唑嗪,酚妥拉明或妥拉唑啉。
另一组实施例中,L型Ca2+通道阻滞剂与ATP敏感性K+通道活化剂组合。较好的是,L型Ca2+通道阻滞剂是硝苯地平,尼莫地平,非洛地平,尼卡地平,伊拉地平,氨氯地平,地尔硫卓,维拉帕米。
另一组实施例中,平滑肌松弛剂与ATP敏感性K+通道活化剂组合。较好的是,平滑肌松弛剂是肼苯达嗪,罂粟碱,苯酰胺桂胺,环扁桃酯,异克舒令或布酚宁。
α1-肾上腺素能拮抗剂组合物
本发明还提供如下用于治疗肛门直肠病的组合物,其中含α1-肾上腺素能拮抗剂的,单用或与其他药物组合,其他药物选自cAMP-水解性PDE抑制剂(优选PDEIV抑制剂),雌激素或平滑肌松弛剂,还有药学上认可的载体。本发明还提供此类组合物的使用方法。
可用于本发明的α1-肾上腺素能拮抗剂已在前文中说明,还可参见Goodman& Gilman的治疗学的药物学基础,第9版,JG Hardman等,McGraq-Hill(1996)。优选的α1-肾上腺素能拮抗剂是哌唑嗪,酚妥拉明或妥拉唑啉。
环核苷酸依赖性蛋白质激酶活化剂组合物
本发明还提供如下用于治疗肛门直肠病的组合物,其中含环核苷酸依赖性蛋白质激酶活化剂,单用或与另一种药物组合。本发明还提供了此类组合物的使用方法。在一组实施例中,单用cGMP依赖性蛋白质激酶活化剂。另一组实施例单用非特异性环核苷酸依赖性蛋白质激酶活化剂。另一组实施例中,非特异性环核苷酸依赖性蛋白质激酶活化剂与平滑肌松弛剂联用。另一组实施例中,cAMP依赖性蛋白质激酶活化剂与L型C2+通道阻滞剂组合。
各种情况中,以上类别化合物的优选成员都和前文所述单用或与用在其他组合物中时相同。
雌激素和雌激素模拟物组合物
本发明还提供如下用于治疗肛门直肠病的组合物,其中含雌激素或雌激素模拟物,单用或与其他药物组合,该其他药物参见前文所述。雌激素样化合物包括但不限于17-β雌二醇,雌酮,美雌醇,雌二醇戊酸酯,雌二醇dypionate,乙炔雌二醇,炔雌醇,硫酸雌酮,植物雌激素,例如黄酮(falvones),异黄酮(isofalvones)(例如三羟异黄酮),白藜芦醇,coumestan衍生物,其他合成雌激素样化合物,包括杀虫剂(例如p,p′-DDT),增塑剂(如双酚A),和其他多种工业化合物(例如多氯联苯)(Goodman & Gilman的治疗学的药物学基础,第9版,JG Hardman等,McGraq-Hill(1996))。优选的是前文含一种或多种药物组合物中所述的那些。本发明还提供此类组合物的使用方法。
治疗肛门直肠病的制剂
上述组合物中的各组分许多已被用于多种疾病的治疗。然而,现在发现,有些类别以及类别的组合物可用于治疗肛门直肠病,并可制备成适合向相应的肛门区域传递的制剂。优选的制剂是含有多种组分的局部制剂,适合局部用于肛门内或外,内或外肛门括约肌,肛门括约肌,内或外肛道,以及肛道上部的直肠末端。
因此,以上各种组合物一般包含在合适的药物制剂中,其中含有有效量的所述药物,例如NO供体,β2-或β3-肾上腺素能受体激动剂,cAMP-水解性PDE抑制剂,非特异性PDE抑制剂,α1-肾上腺素能拮抗剂,L型Ca2+通道阻滞剂,ATP-敏感性K+通道活化剂等。
本领域技术人员可以看出,合适的制剂取决于采用的传递方式,而所有这些形式本发明均可考虑采用。此外,部分实施例中,多种药物配制在一种制剂中,其他一些实施例中,则将不同药物分开配制,然后一起或先后给予。在后文中,含一种药物的组合物应理解成也包括含两种或两种以上药物的组合物。而且,在分开或依次使用不同药物的实施例中,可以不同的给药途径使用不同的制剂。
局用组合物
综上所述,本发明提供了一种用于治疗肛门直肠病(包括与内肛括约肌过度紧张和/或痉挛相关的那些疾病,例如痔痛),用于治疗哺乳动物(包括人)痉挛的局用组合物,其中包含有效量的可阻止肛门括约肌收缩的药物和药学上认可的载体。实施例之一中,该药物是ATP敏感性钾通道开放剂。另一实施例中,该药物是磷酸二酯酶抑制剂,环核苷酸模拟物,β-肾上腺素能激动剂,雌激素或雌激素样化合物,α1-肾上腺素能拮抗剂。
在相关的实施例中,本发明提供了单位剂量形式的局用药物组合物,每单位剂量包含一定量的上述药物或药物组合物,可有效治疗患者的肛门疾病。通常,所述药物与药学上认可的载体形成组合物。这样的组合物可用于治疗肛门疾病或减轻相关痛症,例如痔疮痛,并可用于治疗括约肌痉挛和/或过度紧张,所示括约肌包括内肛括约肌,食管末端括约肌,幽门括约肌,Oddi括约肌和回肠括约肌。该局用组合物可用于治疗因肛门直肠区域括约肌痉挛或过度紧张引起的病情,包括肛裂,术后直肠疼痛,幽门增生性狭窄和胰腺炎,以及因一般性消化道肌肉痉挛,如Zenker憩室,驰缓不能,食管痉挛(核桃夹食管),应激性肠病和先天性巨结肠(肠梗阻)等引起的病情。此外,该局用组合物还可松弛括约肌,从而缓解肛门、直肠和下消化系统检查,仪器置入和手术等过程之前、期间和之后的疼痛。
剂型
本发明肛门括约肌松弛剂的局用剂型包括粉剂、喷雾剂、膏剂、糊剂、霜剂、搽剂、凝胶剂、溶液剂、药贴、栓剂和脂质体制剂。可用粘膜粘附性聚合物来配制剂型,从而延缓有效成分在肛门粘膜内的释放。可在无菌条件下将活性化合物与药学上认可的载体,必要的防腐剂、缓冲剂或推进剂混合。可将肛门括约肌松弛剂与局用无水、液剂、霜剂和喷雾剂等制剂中常用的药学上认可的稀释剂和载体混合,制备成本发明的局用制剂。膏剂和霜剂,可用水性或油性基质,并添加合适的增稠剂和/或胶凝剂来配制。上述基质包括水和/或油,例如液体石蜡或植物油(例如花生油和蓖麻油)。增稠剂可根据基质的性质来选用,包括软石蜡,硬脂酸铝,十六十八混合醇,丙二醇,聚乙二醇,羊毛脂,氢化羊毛脂,峰蜡等。搽剂可用水性或油性基质来配制,通常还包含一种或多种:稳定剂,乳化剂,分散剂,悬浮剂,增稠剂,色素,香精等。粉剂可用合适的粉剂基质来配制,例如滑石粉,乳糖,淀粉等。滴剂可用水性或非水性基质来配制,还包含一种或多种分散剂,悬浮剂,助溶剂等物质。
膏剂、糊剂、霜剂和凝胶剂中还可含有赋型剂,例如动植物油,脂肪,蜡,凡士林,淀粉,黄耆胶,纤维素衍生物,聚乙二醇,硅酮,皂土,硅酸,滑石粉和氧化锌,或它们的混合物。粉剂和喷雾剂中还可含有如下赋型剂,例如乳糖,滑石粉,硅酸,氢氧化铝,硅酸钙和聚酰胺粉末,或它们的混合物。喷雾剂中还可含有常用的推进剂,例如氯氟烃和挥发性非取代烃,例如丁烷和丙烷。
代表性的组合物包括含一种或多种第一药物,药学上认可的载体,以及至少一种第二药物的局用组合物,所述第一药物是:NO供体,磷酸二酯酶抑制剂,环核苷酸模拟物,β-肾上腺素能激动剂,L型Ca2+通道阻滞剂,α-肾上腺素能拮抗剂,ATP-敏感性K+通道活化剂,雌激素或雌激素样化合物或肉毒毒素(botulinumtoxin),所述的第二药物是:局部麻醉剂(例如吲哚卡因,普鲁卡因等),局部消炎药(例如萘普生,普莫卡因等),糖皮质素(例如可地松,氢可地松等),止痒药(例如洛哌丁胺diphylenoxalate等),外周传感神经元活化干扰剂(包括锰、钙、锶、镍、镧、铯、锌等二价和三价金属离子),镇痛剂,酵母产物(例如冻干酵母,酵母提取物等),已知可促进上皮再生成的生长促进剂和/或愈创促进剂(例如血小板衍生生长因子PDGF,包括白介素-11(IL-11等),抗微生物剂(例如neosporin,硫酸多粘菌素B,杆菌肽等),粘膜粘附剂(例如纤维素衍生物等),细胞保护剂(例如胶体铋,米索前列腺素等,但不包括硫糖铝)(参见Goodman & Gilman的治疗学的药物学基础,第9版,JG Hardman等,McGraq-Hill(1996)),一种促进局部组织硬化的药物(例如明矾等),或孟醇。单位剂量形式组合物中至少一种的第一药物通常是用来治疗第一病理情况,例如肛门疾病或相关痛症。单位剂量形式组合物中至少一种的第二药物通常是用来治疗与第一病理情况相关或由其引起的第二病理情况、症状或后果。
本发明内容之一提供了治疗肛门直肠病的组合物,其中包含活性药物和药学上认可的载体。该活性药物包含可激发或升高cGMP或cAMP(通过激活鸟苷酸环化酶或腺苷酸环化酶)的药物,环核苷酸模拟物,PDE抑制剂,α肾上腺素能受体拮抗剂,β-肾上腺素能受体激动剂,或钾通道开放剂。本发明内容之一中,该活性药物在本发明组合物中的含量约为组合物重量的0.001-15%。另一方面的内容中,其含量约为组合物重量的0.01-7.5%,或0.05-2%。
例如,在一组实施例中,本发明提供了治疗肛门直肠病的组合物,其中包含药学上认可的载体和约0.001-15重量%sildenafil。另一种组合物中,含有药学上认可的载体和约0.01-7.5重量%或0.05-2重量%sildenafil。
所述的局用组合物还可包含一种或多种防腐剂或杀菌剂,例如羟基苯甲酸甲酯,羟基苯甲酸丙酯,氯甲酚,苯扎氯铵等。局用药物组合物还可包含一种或多种其他活性成分,例如抗微生物剂,尤其是抗生素,麻醉剂,镇痛剂和止痒剂。
一例局用制剂含有75%(w/w)白矿脂USP,4%(w/w)石蜡USP/NF,14%(w/w)羊毛脂,2%(w/w)脱水山梨醇倍半油酸酯NF,4%(w/w)丙二醇USP和1%肛门括约肌松弛剂。
肛门括约肌松弛剂的具体剂量取决于许多因素,这些都是本领域技术人员所熟知的,例如具体药物,所治疗的病情,年龄,体重和接受者的临床情况,以及主治医生的经验和判断。化合物的有效量或可提供主观上的症状缓解,或产生可由医生或专业观察者鉴定的客观上的改善。剂量的范围根据所用的化合物,给药途径以及具体化合物的下列而不同。
透粘膜(例如舌下、直肠、结肠,肺、颊和阴道)药物传递可使活性物质有效进入全身循环,并减少肝和小肠壁菌群对药物的立即代谢(参见,Chien Y.W.,新的药物传递系统,第4章,“粘膜药物传递”,Marcel Dekker,Inc.(1992))。透粘膜药物剂型(例如片剂,栓剂,膏剂,凝聚剂,阴道栓剂,薄膜和粉剂)一般可与粘膜保持接触,同时迅速崩解和/或溶解,从而引起局部性和全身性吸收。此类制剂可与本发明的消炎药联用,用于减轻或消除粘膜炎症。
缓释或控释制剂
另一些实施例中,本发明提供的是用于治疗肛门直肠病的局用缓释和长释药物组合物,其中包含一种或多种肛门括约肌松弛剂(包括氧化氮供体(例如硝化甘油,异山梨醇二硝酸酯和L-精氨酸)和药学上认可的载体。此类组合物可用于治疗这些疾病,并可控制和减轻与之相关的痛症。这样的组合物可含有单位剂量的一种或多种特定活性药物(例如氧化氮供体),该活性药物可有效治疗肛门直肠病并可控制和减轻与之相关的痛症。较好的是,所述的组合以单位剂量的形式给予患者。另一些实施例中,组合物中NO供体的含量低于其单用时的有效用量,但与调节患者体内cAMP或cGMP水平的第二药物联用时仍然有效。局用缓释或长释组合物具有多种形式,包括:1)亲水性基质的吸收剂;2)疏水性基质的吸收剂;和3)包衣粒,内含的吸收性基质分散于合适的载体中。本发明还提供了治疗肛门或消化道疾病的方法,包括在患者相应的肛门区域局部给予有效量的上述组合物(例如单位剂型的组合物)。
本发明的所述亲水性组合物和制剂包含氧化氮供体(或其他药物,或药物组合物),聚合物(例如纤维素(甲基纤维素,乙基纤维素,羟基丙基纤维素等)),较高分子量的聚乙二醇,甲基丙烯酸-丙烯酸乳液,水凝胶,聚羧乙烯,乙烯乙酸乙烯酯共聚物或聚酯等,使得氧化氮供体与聚合物结合。然后,将氧化氮供体-聚合物基质或药物-聚合物制剂分散在合适的载体中,形成半固体。将这样的亲水性组合物给予到相应的肛门区域(例如肛道或肛门括约肌)后,半固体制剂的水被吸收,含活性成分(氧化氮供体或其他药物)的聚合物基质成为涂层留在使用区。然后,氧化氮从该涂层中缓慢释放。
本发明的疏水性组合物和制剂使用的聚合物与亲水性制剂的相同,但将聚合物/氧化氮供体基质分散在疏水性组合物和制剂所用的载体中,例如塑料性基质(plastibase)。塑料性基质是一种矿物油基质,仅能部分溶解NO供体。半固体组合物可在组合物的使用区(例如肛道或肛门括约肌)形成一层薄涂层,并缓慢释放活性成分。延长作用主要由活性成分(氧化氮供体)在载体内的溶解度控制。
本发明还提供如下制备的包衣粒,将纤维素材料与聚乙二醇、填料、粘合剂等其他赋型剂混合,将氧化氮供体或其他药物或药物组合物吸收到该纤维素材料上。然后通过挤塑或球化(即制成球形的过程)将所得的基质制成小球。然后在球粒上包以适当厚度的一种或多种合适的材料,例如甲基丙烯酸-丙烯酸聚合物,聚氨基甲酸酯,乙烯乙酸乙烯酯共聚物,聚酯,硅橡胶等。球粒上的包衣层起着控速膜的作用,调节药物从芯粒中释放的速度。
口服制剂
另一实施例中,本发明提供了适合口服的单位剂型的药物组合物,每单位剂量包含磷酸二酯酶抑制剂、环核苷酸模拟物或β-肾上腺素能激动剂,和药学上认可的载体。这样的组合物可用于前文所述的肛门直肠病等疾病。
要向颊粘膜传递,通常使用锭剂、片剂或胶囊等口服制剂。此类制剂的制备方法是本领域所熟知的,包括但不限于:将药物加入预制片剂;对惰性填料、粘合剂和药物或含药物的物质进行低温压缩(例如美国专利4,806,356所述);胶囊化。另一种是可与纤维素衍生物、羟丙基纤维素粘合剂联合用于口腔粘膜的口服制剂,例如美国专利4,940,587。此类颊粘性制剂在用于颊粘膜后,可使药物有控地释放入口腔并透过颊粘膜。此类制剂中还可加入本发明的消炎药。
喷雾剂
要向鼻腔或支气管粘膜传递药物,通常可使用喷雾剂。“喷雾剂”包括各种气载的悬浮药物,可被吸入支气管或鼻腔通道。具体地说,喷雾剂包括气载的本发明化合物微滴悬浮剂,可将其装入有剂量刻度的吸入器或喷雾器中,或装在喷雾器中。喷雾剂还包含药物悬浮在空气或其他载体气体中形成的干燥粉末组合物,这样的组合物可由(例如)吸入装置吹入给予。就用于制造喷雾剂的溶液而言,药物的优选浓度是0.1-100mg/ml,以0.1-30mg/ml为佳,1-10mg/ml最好。通常,以磷酸盐或碳酸盐种类生理相容性缓冲剂对溶液进行缓冲。通常的pH为5-9,以6.5-7.8为佳,7.0-7.6更好。通常加入氯化钠将渗透压调节到生理范围,以10%等渗压为宜。有关此类用于制造喷雾吸入剂的溶液可参见Remingtong药物科学,还可参见Ganderton和Jones的向呼吸道的药物传递,Ellis Horwood(1987);Gonda(1990)有关治疗药载体系统的重要评论6:273-313;和Raeburn等(1992),药物,毒性及方法杂志27:143-159。
用各种已知的喷雾吸入剂制造方法都可将药物的溶液转化为喷雾剂。这样的方法一般包括:将溶液压缩在容器中,这通常用惰性气体进行,让压缩气体通过一喷口,由此将溶液液滴带入动物的口腔和气管。一般在喷口的外部装有管嘴,方便药物加入口腔和气管。
非肠胃制剂
另一实施例中,本发明提供适合非肠胃给药的单位剂量形式的药物组合物,其中每单位剂量包含有磷酸二酯酶抑制剂,环核苷酸模拟物,或β-肾上腺素能激动剂,以及药学上认可的载体。这样的组合物可用于治疗前文所述的肛门直肠病。
局用全身性制剂
药物透过角膜或结膜后仍必须在眼表明上保持活性,给予这样的药物最常用的形式是溶液或水性悬浮液。为了提高药物的生物利用度,延长治疗效果,提高患者的顺应性,多年来曾开发了多种剂型。其中包括可溶性植入体(会逐步溶解或发生表面溶蚀),不可溶植入体(含药物的隐形眼镜,例如Ocusert等),凝胶(例如Gelrite),脂质体和通过纳米颗粒传递的药物(乳液,悬浮液等)和膏剂(参见,眼药传递使用的生物药理学,CRC Press,1993)。
治疗肛门直肠病的方法
本发明还提供了治疗肛门直肠病的方法,包括:向患者的相应肛门区或患病肛门组织(例如外肛或内肛组织或肛道)给予有效量的上述各种组合物。用本发明方法可缓解肛门直肠过度紧张和/或痉挛,并改善与肛门直肠病相关的表现和症状,例如肛裂,肛门溃疡和痔疮,以及疼痛。本发明方法还可用于治疗复发性肛门疾病,还可用于松弛肛门括约肌,减轻(患者或健康人)肛门直肠检查过程中,尤其是将仪器置入肛门时的疼痛。
本发明还提供将上述组合物与局部麻醉剂(例如利多卡因,普鲁卡因等)一起使用的方法。通常上述各种组合物都以药学上认可的剂量形式提供,作为治疗各种疾病的有效方法,所述疾病包括痔疮疼痛,括约肌(包括内肛括约肌,食管末端括约肌,幽门括约肌,Oddi括约肌,回肠括约肌)痉挛和/或过度紧张。上述药物组合物还可用于治疗因肛门直肠区括约肌痉挛和/或过度紧张引起的病情,包括肛裂,术后直肠痛,幽门增生性狭窄和胰腺炎,以及一般性消化道肌肉痉挛,如Zenker憩室,驰缓不能,食管痉挛(核桃夹食管),应激性肠病和先天性巨结肠(肠梗阻)等引起的病情。另一方面,本发明提供如下治疗肛门疾病的方法,其中将有效量的上述组合物与局部麻醉剂一起给予患者。所述的组合物可以口服,局部或非肠胃给予。
同样,本发明还提供将上述组合物与萘普生、吡罗昔康等局部消炎药一起使用的方法,它们呈药学上认可的剂型,可有效治疗痔疮疼痛,内肛括约肌、食管末端括约肌、幽门括约肌、Oddi括约肌、回肠括约肌等括约肌过度紧张和/或痉挛。上述药物组合物还可用于治疗因肛门直肠区括约肌痉挛和/或过度紧张引起的病情,包括肛裂,术后直肠痛,幽门增生性狭窄和胰腺炎,以及一般性消化道肌肉痉挛,如Zenker憩室,驰缓不能,食管痉挛(核桃夹食管),应激性肠病和先天性巨结肠(肠梗阻)等引起的病情。另一方面,本发明提供治疗肛门疾病的方法,其中将有效量的上述组合物与局部麻醉剂一起给予患者。所述的组合物可以口服,局部或非肠胃给予。
本发明的其他方法中,将两种或两种以上药物同时或先后给予,从而增强治疗效果,所述的药物选自NO供体,V、II型磷酸二酯酶抑制剂,非特异性PDE抑制剂,β-肾上腺素能激动剂,cAMP依赖性蛋白质激酶活化剂,α1-肾上腺素能拮抗剂,超氧化物(O2 -)清除剂,ATP-敏感性K+通道活化剂,雌激素或雌激素模拟物,或平滑肌松弛剂。具体地说,NO供体和上述第二药物联用可减少和减轻单用NO要获得相当效果时的副作用。更具体地说,NO供体与第二药物联用可减少为获得与单用时相同效果的NO供体用量,从而显著减少头痛的发生率,并缩短发作期。
实施例
实施例1
该实施例用大鼠内肛括约肌(IAS)松弛模型说明cGMP单用,和与NO供体联用时的作用。
用开他敏(90mg/kg)将雌性Sprague-Dawley大鼠(300-400g)麻醉,肌内注射甲苯噻嗪(9mg/kg),根据需要补给1/3剂量。在实验过程中,将大鼠松弛地仰面束缚在温热的手术台(Harvard Apparatus)上。在腹膜内插入24号血管插管(VWR,SanFrancisco,CA),通过生理盐水补水来抵消麻醉剂的利尿效果。收缩/松弛测定组件包括:Millar插管/传感器(直径1.67mm),连到一Digi-Med低压分析仪(Micro-Med)上,其量程为-50-150mmHg。用Digi-Med系统积分软件进行数据积分,并转化为波形。用动脉插管/传感器和以DMSI软件工作的Digi-Med血压分析仪来监测血液变化。用汞张力计/传感器围绕大鼠的肋廓,然后连到以DMSI软件工作的Digi-Med同类信号分析仪上,如此来监测呼吸变化。用PE10管,靠近插管传感器,通过两根没有死空隙(dead space)的Hamilton针筒给药。一般在读数达到稳定基线水平后不久给药。虽然有其他实验使用不麻醉的被束缚大鼠,但发现麻醉后静息肛门压没有改变;因此,本发明的实验在将大鼠麻醉后进行,避免对动物造成的不适。
该模型中,典型的内肛括约肌静息压(IASP)在30-60mmHg之间。Millar插管传感器可准确分别测定IAS。图1是一张典型的波形图,说明静息对IASP几乎没有影响。硝化甘油处理后10分钟的情况显示在图2中。
用同样的实验方案研究了一种cGMP模拟物,二丁酰基-cGMP的作用。图3显示,将20μl二丁酰基-cGMP在盐水中的10%溶液用于肛道,2.5小时后,IASP下降45%。实验结束前1小时内,平均IASP总共下降60%。
次日早晨显示IASP下降仍达34%,说明药物效力被延长。继续给予1%硝化甘油,30分钟的IASP下降为24%,前10分钟的为71%。在IASP回到处理前的基线后,再次给予二丁酰基-cGMP,发现在其后的3小时又10分钟中使IASP降低了15%(见图4)。
以上结果支持这样的观点,cGMP模拟物具有松弛肛门括约肌的作用,更重要的是,因为NO供体起效快,cGMP模拟物产生的松弛作用持续时间延长,由此提示了NO供体与cGMP模拟物联用的潜在优越性。
实施例2
本实施例用大鼠内肛括约肌松弛模型说明磷酸二酯酶抑制剂的作用。
用以上实验方法,使用20μl以1-甲基-2-吡咯烷酮配制的5%扎普司特溶液与仅用载体相比,在32分钟后使平均IASP降低了21%。极小量的NO供体,例如硝化甘油,即可进一步增强磷酸二酯酶抑制剂的作用,硝化甘油可加快起效,保持括约肌松弛,但不引起高剂量NO供体单用时出现的头痛等副作用。
实施例3
本实施例用大鼠内肛括约肌松弛模型说明钾通道开放剂(米诺地尔)的作用。
用以上实验方法,一次使用20μl以62.5%丙二醇配制的4%米诺地尔溶液在2.5小时后使IASP降低了64%。单纯载体对IASP几乎没有作用(图5)。
实施例4
本实施例说明一种治疗肛门直肠病的方法,其中使用磷酸二酯酶抑制剂和其他药物来减轻与急性和慢性肛裂等疾病相关的痛症。
用以下药物治疗严重肛门痛症(特别是在排便时和排便后)患者:扎普司特,扎普司特和硝化甘油,米诺地尔,硝化甘油和cGMP模拟物,异丙基肾上腺素或sildenafil,每日1-3次,或根据需要,只要能有效减轻肛门直肠疼痛。评定疼痛的减轻(表现为平时疼痛和/或排便疼痛的减轻),并测定时间与疼痛减轻之间的关系。可有效缓解肛门疼痛的治疗方法最后有效治愈了相关的肛门直肠病。此外,极具治疗意义的是可避免疾病复发,但几乎不引起诸如头痛、恶心和低压等副作用的药物。
实施例5
本实施例治疗肛门疾病的方法用磷酸二酯酶抑制剂和其他药物促进急性和慢性肛裂的愈合。
可用以下药物治疗肛裂患者:扎普司特,扎普司特和硝化甘油,米诺地尔,硝化甘油和cGMP模拟物,异丙基肾上腺素或sildenafil,每日1-3次,或根据需要,只要能有效促进愈创。愈合表现为裂口的上皮再生,并可结合完全愈合所需的时间进行评定。可有效愈合肛裂的治疗方法最后有效治愈了相关的肛门直肠病。此外,具有重要治疗意义的是可避免疾病复发,但几乎没有头痛等副作用的药物。
实施例6
本实施例说明减轻痔疮症状或疾病患者出血的方法。
可用以下药物治疗痔疮患者:扎普司特,扎普司特和硝化甘油,米诺地尔,硝化甘油和cGMP模拟物,异丙基肾上腺素或sildenafil,每日1-3次,或根据需要,只要能有效减少出血并促进愈创。疾病的痊愈表现为出血减少和/或不再疼痛,并可结合完全愈合所需的时间进行评定。可有效改善痔疮症状的治疗方法最后有效治愈了相关的肛门直肠病。此外,具有重要治疗意义的是可避免疾病复发,但几乎没有副作用的药物。
实施例7
一种基质凝胶组合物,含有1.0g沙丁醇胺,0.6g聚羧乙烯(Carbopol)1342USP,35.44g丙二醇,15.16g无水乙醇USP,15.16g异丙醇USP,2.5%油酸,用1N的三乙醇胺HCl将pH调节至6.0-7.0,0.05g丁基化羟基甲苯NF,和29.72g纯化水USP。为获得治疗效果,可在相同的凝胶基质中加入其他浓度的沙丁醇胺;这也可以通过用油酸等凝胶基质赋型剂调节β激动剂浓度来做到。
实施例8
局用组合物实施例之一含0.05-1%sildenafil,75%(w/w)白凡士林USP,4%(w/x)石蜡USP/NF,羊毛脂14%(w/w),2%脱水山梨醇倍半油酸酯NF,4%(w/w)丙二醇USP,以治疗有效剂量给予肛门直肠区。通常,要减轻与肛门直肠病(例如肛裂、肛门溃疡和痔疮等)相关的症状,可将50-600mg sildenafil药膏用于肛门直肠区。sildenafil或其他磷酸二酯酶抑制剂的浓度可通过改变其与赋型剂之间的比例来调节,赋型剂的作用是使sildenafil附着于局部组织,或增强患病组织对药物吸收。
另一局用实施例含0.1%硝化甘油和0.1%sildenafil,同样配制在上述油膏基质中。可从一有刻度的给药装置中取用50mg-1.5g该组合物,将其用于患病的肛门直肠部位,以获得所需的治疗效果。
另一种治疗方法是给肛门直肠病患者使用口服sildenafil的同时局部使用硝化甘油药膏。这两种剂型可联合使用,从而获得获得最佳的效力和患者顺应性。
实施例9
一种氨茶碱局用喷雾剂组合物含0.1-0.5%(w/w)氨茶碱,乙酰化羊毛酯醇,芦荟,丁烷,乙酸十六烷酯,氢氟烃,对羟基苯甲酸甲酯,PEG-8月桂酸酯和聚山梨醇酯80,装在2盎司的喷雾瓶中。氨茶碱或其他非特异性磷酸二酯酶抑制剂的浓度可以是0.5-5%。也可使用其他非氢氟烃推进剂。可将该组合物直接喷在病患组织上,每日4次,以缓解肛门直肠病的相关症状。该组合物还可以包含孟醇和苯唑卡因,用以即时缓解局部疼痛以及起舒缓作用,而其中的氨茶碱则提供较为持久的肛门括约肌松弛作用。
实施例10
一种霜剂含有2g盐酸哌唑嗪(2.0%,w/w),54.3g纯水USP,2gSepigel305,4.5g Crodamol,5.0g甘油,6.0g芝麻油,15.0g白凡士林USP,2.0g羊毛脂USP,7.0g 1,3-丁二醇,0.2g对羟基苯甲酸甲酯和2.0g硅HL88。
该霜剂的制备为:先将霜剂的各组分分别配制成水相和非水相(即油相)。待含盐酸哌唑嗪的水相成分混匀后,将融合的油相缓慢加入水相,同时搅拌,形成均一的霜剂。
实施例11
sildenafil是一种V型磷酸二酯酶特异性抑制剂,可以片剂形式口服,非肠胃给药或局部使用,用于诊断为急性或慢性肛裂或其他肛门直肠病的患者。sildenafil可每日给予1-3次,持续8周,尤其适用于患慢性肛裂的患者,可缓解与此相关的症状。
就局部使用而言,可用一有刻度的给药装置量取约50-900mg含0.02-5%sildenafil的该霜剂,用涂药器或手指涂在肛门直肠患区,每日1-4次,可获得所需的效果。此外,可同时采用口服和局用治疗,可获得最佳的治疗效果。
实施例12
磷酸二酯酶抑制剂,例如氨茶碱,可以片剂形式口服,非肠胃给药,或以霜剂等局用剂型外用于诊断为急性或慢性肛裂或其他肛门直肠病的患者。就局用而言,可用一有刻度的给药装置量取约50-900mg霜剂,用涂药器或手指涂在肛门直肠患区,可获得所需的治疗效果。
实施例13
β-肾上腺素能激动剂,例如沙丁胺醇,可以栓剂的形式或霜剂等局用形式用于治疗诊断为急性或慢性肛裂或其他肛门直肠病的患者。就栓剂而言,可用给药器或手指将约300mg-3g的栓剂用到肛门直肠患区,每日1-4次。待栓剂在肛道中融合后,沙丁胺醇就从中释放出来,从而获得所需的治疗效果。
实施例14
α-肾上腺素能拮抗剂,例如哌唑嗪,可以局用喷雾剂的形式用于痔疮患者,它可以单用,也可以与立多卡因等局部麻醉剂,或混合的β2-、β3-肾上腺素能激动剂(例如沙丁醇胺),或PDE IV抑制剂(例如ariflo(SB207499),RP73401,CDP840,咯利普兰和LAS31025联用。可借助推进剂将哌唑嗪直接喷在患区,用于缓解疼痛,并舒缓肛门括约肌的过度紧张。最后,哌唑嗪可使痔疮痊愈。
以上实施例仅用来说明本发明,本领域技术人员可以看出,根据以上所述可进行多种修改,这些都包涵在后文权利要求的范围内。文中对所引用的各出版物、专利和专利申请进行了全面的参考。
Claims (16)
1.ATP-敏感性钾通道开放剂用以制造治疗肛门直肠病并控制相关痛症的药物的用途。
2.如权利要求1所述的用途,所述ATP-敏感性钾通道开放剂的用量为舒解肛门括约肌过度紧张的有效量。
3.如权利要求2所述的用途,所述药物为局部使用剂型。
4.如权利要求3所述的用途,所述药物含0.01-7.5wt%ATP-敏感性钾通道开放剂。
5.如权利要求1所述的用途,所述ATP-敏感性钾通道开放剂选自米诺地尔,硫酸米诺地尔,哌诺地尔,二氮嗪,levcromokalim,PCO400或cromokalim。
6.如权利要求4所述的用途,所述ATP-敏感性钾通道开放剂选自米诺地尔,硫酸米诺地尔,哌诺地尔,二氮嗪,levcromokalim,PCO400或cromokalim。
7.如权利要求6所述的用途,所述钾通道开放剂是米诺地尔或硫酸米诺地尔。
8.如权利要求1所述的用途,所述肛门直肠病选自急性或慢性肛裂,内部或外部血栓性痔疮,痔疮性疾病,与内痔粘连相关的疾病,提肌痉挛,便秘,以及肛门括约肌过度紧张或痉挛引起的疾病。
9.如权利要求1所述的用途,所述药物还含有cAMP依赖性蛋白质激酶活化剂,雌激素,α1-肾上腺素能拮抗剂,L型Ca2+通道阻滞剂或平滑肌松弛剂。
10.如权利要求1所述的用途,所述药物的剂型为栓剂。
11.如权利要求3所述的用途,所述药物的形式为膏剂、霜剂或凝胶剂。
12.一种治疗肛门直肠病并控制相关痛症的局部使用型药物,包含ATP-敏感性钾通道开放剂和药学上认可的载体。
13.如权利要求12所述的药物,还包含cAMP依赖性蛋白质激酶活化剂,雌激素,α1-肾上腺素能拮抗剂,L型Ca2+通道阻滞剂或平滑肌松弛剂。
14.如权利要求12所述的药物,含0.01-7.5wt%ATP-敏感性钾通道开放剂。
15.如权利要求12所述的药物,所述ATP-敏感性钾通道开放剂选自米诺地尔,硫酸米诺地尔,哌诺地尔,二氮嗪,levcromokalim,PCO400或cromokalim。
16.如权利要求12所述的药物,所述钾通道开放剂是米诺地尔或硫酸米诺地尔。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11232598P | 1998-12-14 | 1998-12-14 | |
US60/112,325 | 1998-12-14 | ||
US13991699P | 1999-06-17 | 1999-06-17 | |
US60/139,916 | 1999-06-17 | ||
US60/155,318 | 1999-09-12 | ||
US15531899P | 1999-09-21 | 1999-09-21 |
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CNB998144304A Division CN1149983C (zh) | 1998-12-14 | 1999-12-13 | 用于治疗肛门直肠病的组合物和方法 |
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CNA200410008292XA Pending CN1526448A (zh) | 1998-12-14 | 1999-12-13 | 用于治疗肛门直肠病的药物和方法 |
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CNB998144304A Expired - Fee Related CN1149983C (zh) | 1998-12-14 | 1999-12-13 | 用于治疗肛门直肠病的组合物和方法 |
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US (2) | US6395736B1 (zh) |
EP (1) | EP1143956A3 (zh) |
JP (1) | JP2002542147A (zh) |
KR (1) | KR20010093828A (zh) |
CN (2) | CN1149983C (zh) |
AU (1) | AU764921B2 (zh) |
BR (1) | BR9916162A (zh) |
CA (1) | CA2354543A1 (zh) |
CZ (1) | CZ20012113A3 (zh) |
HU (1) | HUP0104676A3 (zh) |
IL (1) | IL143726A0 (zh) |
NO (1) | NO20012916L (zh) |
PL (1) | PL348817A1 (zh) |
WO (1) | WO2000035434A2 (zh) |
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-
1999
- 1999-12-13 PL PL99348817A patent/PL348817A1/xx unknown
- 1999-12-13 EP EP99966154A patent/EP1143956A3/en not_active Withdrawn
- 1999-12-13 CZ CZ20012113A patent/CZ20012113A3/cs unknown
- 1999-12-13 WO PCT/US1999/029459 patent/WO2000035434A2/en not_active Application Discontinuation
- 1999-12-13 JP JP2000587755A patent/JP2002542147A/ja active Pending
- 1999-12-13 HU HU0104676A patent/HUP0104676A3/hu unknown
- 1999-12-13 KR KR1020017007394A patent/KR20010093828A/ko not_active Application Discontinuation
- 1999-12-13 AU AU21763/00A patent/AU764921B2/en not_active Ceased
- 1999-12-13 CA CA002354543A patent/CA2354543A1/en not_active Abandoned
- 1999-12-13 CN CNB998144304A patent/CN1149983C/zh not_active Expired - Fee Related
- 1999-12-13 CN CNA200410008292XA patent/CN1526448A/zh active Pending
- 1999-12-13 IL IL14372699A patent/IL143726A0/xx unknown
- 1999-12-13 US US09/460,306 patent/US6395736B1/en not_active Expired - Fee Related
- 1999-12-13 BR BR9916162-1A patent/BR9916162A/pt not_active Application Discontinuation
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2001
- 2001-01-23 US US09/769,621 patent/US20010012856A1/en not_active Abandoned
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101868239B (zh) * | 2006-01-05 | 2015-06-10 | 伊森舍丽斯有限公司 | 钾atp通道开放剂的盐及其用途 |
CN103393690A (zh) * | 2013-08-01 | 2013-11-20 | 南通大学附属医院 | Katp通道开放剂在制备治疗术后疼痛药物中的应用 |
CN103393690B (zh) * | 2013-08-01 | 2016-05-11 | 南通大学附属医院 | Katp通道开放剂在制备治疗术后疼痛药物中的应用 |
CN112423736A (zh) * | 2018-06-01 | 2021-02-26 | 塔凡塔医疗匈牙利公司 | 用于治疗肛门直肠疾病的局部氨氯地平盐 |
Also Published As
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NO20012916D0 (no) | 2001-06-13 |
CN1149983C (zh) | 2004-05-19 |
PL348817A1 (en) | 2002-06-17 |
US6395736B1 (en) | 2002-05-28 |
HUP0104676A3 (en) | 2005-12-28 |
WO2000035434A3 (en) | 2000-11-30 |
CZ20012113A3 (cs) | 2001-11-14 |
CN1330539A (zh) | 2002-01-09 |
WO2000035434A2 (en) | 2000-06-22 |
EP1143956A2 (en) | 2001-10-17 |
JP2002542147A (ja) | 2002-12-10 |
AU2176300A (en) | 2000-07-03 |
AU764921B2 (en) | 2003-09-04 |
KR20010093828A (ko) | 2001-10-29 |
EP1143956A3 (en) | 2001-12-12 |
CA2354543A1 (en) | 2000-06-22 |
HUP0104676A2 (en) | 2002-06-29 |
IL143726A0 (en) | 2002-04-21 |
US20010012856A1 (en) | 2001-08-09 |
NO20012916L (no) | 2001-08-14 |
BR9916162A (pt) | 2001-09-04 |
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