CN1081614A - 具有抑制胃酸分泌作用的物质与可被酸降解的抗生素的协同组合物 - Google Patents
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Abstract
本发明涉及一种升高胃内pH值的物质和一种
可被酸降解的抗菌化合物的组合物。通过用该组合
的产品,能够使可被酸降解的抗生素发挥最大的局部
抗菌作用,而且能提高活性抗生素的生物利用度,由
于弱碱的分泌作用,因而使活性抗生素在胃粘膜的含
量提高。两种药理作用都对提高可被酸降解抗生素
的抗菌能力具有显著作用,该抗生素被用于治疗引起
胃炎和/或消化道溃疡的胃肠道局部感染。本发明
还涉及所述组合物的应用及其制备方法。
Description
本发明涉及一种胃酸分泌抑制剂-一种能升高胃内pH值的物质,如氢离子泵抑制剂、H2-组胺阻断剂、酸中和剂同一种或多种可被酸降解的抗菌化合物的协同组合物。
目前,对消化性溃疡的治疗目标是减少胃酸分泌,从而使胃肠道的损伤减轻。胃酸分泌抑制剂,尤其是氢离子泵抑制剂能很快缓解疼痛和其它与溃疡病有关的症状。但是,此病的复发是已确证的事实。由于抑制胃酸分泌物治疗只能减少主要组织刺激因子-胃酸的含量(胃酸被认为是一种可能的致病原因),所以旋门螺旋杆菌基本未受影响。(幽门螺旋杆菌以前叫做幽门弯曲杆菌)。
体外和体内的结果证实幽门螺旋杆菌受某些抗生素的影响,如大环内酯类和青霉素类。但是,这些抗生素在胃酸存在时被分解成无抗菌效果的产物,这样就明显减低了它们的抗菌效果。
鉴于在治疗感染性疾病时或为其它目的而广泛应用抗生素,由此而出现耐药菌株和因正常菌群紊乱而导致的细菌替代症的发生增高,感染的特点也在发生变化等等,所以需要不断发展新的抗生素或对它们进行联合应用。
按本发明应用的氢离子抑制剂如奥美拉唑(omeprazole)和其药学上可接受的盐是已知化合物(如EP5129和EP124495),而且能用已知方法制得。从U.S.5093 342中还知道奥美拉唑可被用于治疗螺旋杆菌感染。而且早在WO 92/04898中就已推荐使用一种对胃酸稳定的特别抗生素-羟氨苄青霉素(amoxycillin)与奥美拉唑合用,以治疗十二指肠溃疡。但在所述文献中没有具体的实验数据。
从文献中(如Science,March 22,1946,P359-361)得知如果口服能被酸降解的青霉素,它们会被胃中所含的酸破坏掉。
再有,Eur.J.Clin.Microbiol.Infect.Dis.August 1988,P.566-569中叙述到某些可被酸降解的抗生素在体外具有抗幽门螺旋杆菌的作用。
现在已经意外地发现:将一种具有抑制胃酸分泌作用的物质(该物质能升高胃内的pH值,如氢离子泵抑制剂、H2-组胺阻断剂、酸中和剂)与一种能被酸降解的具有抗菌作用的化合物联合应用,在口服时能使该抗生素的血浆浓度达到高水平。
通过减低胃的酸度,有可能大幅度提供易被酸降解的抗生素的生物利用度,因此使所给的药物更多地在局部发挥抗菌作用,并被吸收。由于窄谱抗菌素如苄青霉素几乎没有什么副作用,所以选用这类抗菌素是有利的。由于弱碱如奥美拉唑的一些通常已知的理化特性,所以选用一些弱碱如红霉素有利于使该抗生素在胃壁和胃陷凹中蓄积,这些地方是细菌如幽门螺旋杆菌的寄居处。
因此,通过把本发明的各成分结合在一起作用,使抗生素的抗菌作用增效,从而产生改进的疗效。
本新发明的新组合物尤其针对治疗胃病,如由幽门螺旋杆菌诱发的感染。幽门螺旋杆菌是一种革兰氏阴性的螺菌形细菌,它们在胃粘膜形成菌落。单独应用普通能被酸降解的抗生素进行治疗效果不明显。将5-甲氧基-2-{[4-甲氧基-3,5-二甲基-2-吡啶基)甲基]亚磺酰基}-1H-苯并咪唑(俗名:奥美拉唑)或其药学上可接受的盐与一种酸可降解的抗生素联合应用,口服后能达到很高的血浆浓度。
按照本发明,奥美拉唑的盐是一种药学上可接受的碱性盐。这些盐的实例包括:无机盐,如碱金属盐(如钠盐、钾盐等),碱土金属盐(如钙盐、镁盐等),铵盐;有机盐,如有机胺盐(如三甲基胺盐、三乙基胺盐、吡啶盐、普鲁卡因盐、甲基吡啶盐、二环己基胺盐、N,N-二苄基乙二胺盐、N-甲基葡糖胺盐、二乙醇胺盐、三乙醇胺盐、三(羟甲基氨基)甲烷盐、苯乙基苄胺盐、二苄基乙二胺盐。
根据本发明,还可应用其它的氢离子泵抑制剂如兰索拉唑(Lansoprazole)。
联合应用的抗生素必须是这类抗生菌,即通过提高胃内pH值能提高其生物利用度的抗生素。同时,它还应该是一种具有很窄抗菌谱的抗菌化合物如苄青霉素。
其它实例是可被酸降解的和对酸半稳定的大环内酯类如红霉素碱如克来索霉素(Clarithromycin)(Nakagawa et al.,Chem.Pharm.Bull.,1992,40,725-28)。另外的实例是经制药加工成能抵御酸破坏的抗生素和/或其盐,如包肠溶衣(如Erymax)。
在体外培养基中MIC-值(最小抑菌浓度)表明大环内酯类对幽门螺旋杆菌的抗菌活力随pH值的增加而明显减低。
依照本发明的组合形式可以用一种包含两种活性成分的药物制剂,或用两种片剂、胶囊、粉剂、混合剂、泡腾片剂或溶液等形式。
按照本发明,把活性成分做成一种药物制剂来通过口服或非肠道途径给药,该药物制剂含有活性成分(如游离红霉素碱)或活性成分的盐(如奥美拉唑),及药学上可接受的载体。上述载体可以是固体、半固体、液体稀释剂或胶囊。能够应用的剂型包括各种形式的片剂、胶囊、颗粒、粉剂、口服剂、针剂等。整个组合物中活性组分通常为0.1-100%(重量),最好为0.1-95%(重量)。
在制备口服的药物制剂时,可以把活性成分与一种固体粒状载体,如乳糖、蔗糖、山梨糖醇、甘露醇、淀粉、支链淀粉、纤维素衍生物或明胶等相混合,同时还可加入润滑剂如硬脂酸镁、硬脂酸钙、聚乙二醇蜡。将所得组合物压成片。用粘稠的蔗粉溶液或者由挥发性有机溶剂或混合溶剂制得的硝基纤维素溶液将制得的片心包衣,可制得包衣片或糖衣片,该蔗糖溶液含有阿拉伯胶、明胶、滑石、二氧化钛等。
软明胶胶囊的生产方法是把含有活性组分和一种已知的植物油的组合物填入胶囊中。硬明胶胶囊的生产方法是把含有活性成分和一种固体颗粒载体的组合物填入胶囊中,所述载体的实例是乳糖、蔗糖、山梨糖醇、甘露醇、土豆淀粉、玉米淀粉、支链淀粉、纤维素衍生物或明胶。
奥美拉唑或其盐和抗生素的剂量随个体条件(如病人状况、体重、年龄、性别等)和给药方法而变化。一般而论,成年人的日口服剂量是:奥美拉唑1-200mg,可被酸降解的抗生素可多达10g。可一次将苄青霉素分别单独和与奥美拉唑合用给予八名健康志愿者,并测定了他们血浆的药物浓度。当单独应用苄青霉素时血浆药物浓度不足以达到治疗效果(表1)。当把苄青霉素与奥美拉唑合用时血浆药物浓度达到了有效的治疗水平(表2)。当分别在奥美拉唑引起的人的胃酸分泌减少前和减少后口服红霉素乳糖酸盐时也得到了类似的结果(表3和表4)。在胃酸分泌减少后抗生素的血浆浓度很高是所用抗生素在胃中降解明显下降的证据。这就使胃腔中活性抗生素的含量升高,因此局部抗菌效果增强。它还能使更多的抗生素被吸收,从而引起该抗生素在血浆和组织中的浓度升高(生物利用度升高)。目前,应用本发明的最好方式是持续应用奥美拉唑和红霉素。
表4
8位健康志愿者分别在用和不用奥美拉唑时口服红霉素乳糖醛酸盐的动力学数据。交叉试验。
本发明联合用药的优点是将一种能升高胃内pH值的化合物(如奥美拉唑)与一种可被酸降解的抗生素相组合,从而使该抗生素的生物利用度提高,结果使其血浆浓度达到治疗水平。另一优点是胃腔中该抗生素的含量升高。
由于苄青霉素的抗菌谱很窄故对肠道正常菌群的影响非常有限,所以它是有意义的。
通过减少胃酸分泌或中和胃酸使胃内pH值升高。由于周围的酸度减弱从而使口服的可被酸降解的抗生素的分解减少,所以能在局部发挥抗菌作用。另一个优点是使达到小肠的抗生素量增加,它们在小肠以生物活性形式被吸收。体外实验证实提高胃内pH值对抗生素发挥效力有利。如果幽门螺旋杆菌的体外培养基的pH值降至7以下的不同值,则抗菌作用很快下降。
具有弱碱性的那些抗生素(如大环内酯类)由于它们具有与其它已知的弱碱如尼石丁,氨基嘌呤,奥美拉唑相同的理化特性,能通过胃壁分泌入胃(Larsson et al.,Scand.J,Gastroenterol.,1983,85,900-7)。因此,该弱碱抗生素被生物学作用浓集在胃壁,该处是细菌(如幽门螺刻杆菌)的寄居处。
Claims (13)
1、一种具有抑制胃酸分泌作用、升高胃内pH值的物质与一种可被酸降解的抗菌化合物的组合物。
2、按照权利要求1的组合物,其中所述的具有抑制胃酸分泌作用的物质是一种氢离子泵抑制剂。
3、按照权利要求2的组合物,其中所述的氢离子泵抑制剂是5-甲氧基-2-{[4-甲氧基-3,5-二甲基-2-吡啶基)甲基]-亚磺酰基-1H-苯并咪唑或其药学上可接受的盐。
4、根据权利要求1的组合物,它对细菌引起的胃炎和消化性溃疡有效。
5、根据权利要求1的组合物,它对由幽门螺旋杆菌引起的胃炎和消化性溃疡有效。
6、根据权利要求1的组合物,其特征在于:所述的可被酸降解的抗菌化合物是苄基青霉素。
7、根据权利要求1的组合物,其特征在于:所述的可被酸降解的抗菌化合物是弱碱抗生素。
8、根据权利要求7的组合物,其特征在于:所述的弱碱抗生素是红霉素碱。
9、根据权利要求7的组合物,其特征在于:所述的抗生素是克来索霉素(Clarit hromycin)。
10、根据权利要求1的组合物用于生产治疗由幽门螺旋杆菌引起的胃炎和消化性溃疡的药物。
11、治疗由幽门螺旋杆菌引起的胃炎和消化性溃疡的方法,该方法包括将一种具有抑制胃酸分泌、升高胃内pH值作用的物质与一种治疗所述感染足够量的可被酸降解的抗菌化合物一起给予患者。
12、用于治疗由幽门螺旋杆菌感染引起的胃炎和消化性溃疡的药物制剂,其中活性成分是一种具有抑制胃酸分泌作用、升高胃内pH值的物质和一种可被酸降解的抗菌化合物。
13、制备权利要求1的组合物的方法,该方法是将一种具有抑制胃酸分泌、升高胃内pH值作用的物质与一种可被酸降解的抗菌化合物掺入同一制剂中。
Applications Claiming Priority (4)
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SE9201297A SE9201297D0 (sv) | 1992-04-24 | 1992-04-24 | Synergistic combination |
SE9201297 | 1992-04-24 | ||
SE9300029A SE9300029D0 (sv) | 1993-01-08 | 1993-01-08 | Synergistic combination ii |
SE9300029 | 1993-01-08 |
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CN1081614A true CN1081614A (zh) | 1994-02-09 |
CN1041798C CN1041798C (zh) | 1999-01-27 |
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EP (2) | EP0637241B1 (zh) |
JP (1) | JPH07505901A (zh) |
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TN (1) | TNSN93040A1 (zh) |
TW (1) | TW276996B (zh) |
UA (1) | UA43830C2 (zh) |
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CN110799103A (zh) * | 2017-06-29 | 2020-02-14 | 爱惜康有限责任公司 | 具有横向针孔口的套管针闭塞器 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1061232C (zh) * | 1996-04-12 | 2001-01-31 | 马理国 | 一种治疗胃炎、溃疡的药物组合物 |
CN110799103A (zh) * | 2017-06-29 | 2020-02-14 | 爱惜康有限责任公司 | 具有横向针孔口的套管针闭塞器 |
CN110799103B (zh) * | 2017-06-29 | 2023-01-17 | 爱惜康有限责任公司 | 具有横向针孔口的套管针闭塞器 |
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