CN1080119C - 含有质子泵抑制剂的药物组合物 - Google Patents

含有质子泵抑制剂的药物组合物 Download PDF

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CN1080119C
CN1080119C CN96194084A CN96194084A CN1080119C CN 1080119 C CN1080119 C CN 1080119C CN 96194084 A CN96194084 A CN 96194084A CN 96194084 A CN96194084 A CN 96194084A CN 1080119 C CN1080119 C CN 1080119C
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K·J·戴夫
J·B·威廉斯
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Abstract

本发明涉及一种口服药物制剂，其含有一种质子泵抑制剂(PPI)，该质子泵抑制剂适合于治疗人和动物与胃酸相关的疾病。更具体地说，本发明组合物是一种糊剂，特别适合于对马运送质子泵抑制剂。

Description

含有质子泵抑制剂的药物组合物
发明概要
本发明提供一种含有一种质子泵抑制剂为活性成分的糊剂形式的稳定的口服药物组合物。该组合物用于给难以吞咽下固体剂量形式如片剂和胶囊的动物，尤其是马，和人运送对酸不稳定的药物。
发明背景
质子泵抑制剂(PPI)是通过抑制H+K+-ATP酶而抑制胃酸分泌的有效抑制剂，所述酶在壁细胞氢离子产生的最后步骤中涉及。因此，PPI已被用于治疗人的与胃酸有关的疾病。这样的疾病包括胃溃疡和十二指肠溃疡。消化道溃疡也常发生于一些动物尤其是马身上。尽管马的胃-十二指肠溃疡病因学尚未确认，但显示出应激反应在某些情况下起重要作用。
PPI是高度酸不稳定的，因此口服制剂是肠溶包衣的。肠溶包衣制剂贵而且制造费时，且需要复杂的技术和设备。肠溶包衣剂的另一个缺点是其对潮湿的敏感性。
WO 94/25070公开了以肠溶包衣干颗粒与干凝胶剂混合的形式的含质子泵抑制剂的口服组合物，然后该混合物可以制成象糊状的凝胶体后给药。因此，该组合物需要肠溶包衣，具有与这种制剂有关的上述缺点。而且，因为这样一种湿凝胶在室温下长期储存不稳定，因此不能以即用制剂制备和出售，而一定要在给药时现制备，使其用起来不方便。
本发明所述的制剂是一种稳定的即用型半固体糊剂，其中含有一种质子泵抑制剂，适于对难以吞咽固体剂量形式如片剂和胶囊的动物，如马，牛，猪等，和人给药。本发明药剂容易对马给药，且容易被这些动物接受。本发明制剂在室温下长期储存时稳定。
发明的详细说明
本发明提供一种稳定的即用的PPI口服药物糊剂组合物，其容易对动物如马给药。更具体地说，本发明组合物含有：一种或几种质子泵抑制剂，一种疏水油性液体载体，一种碱化剂，和一种增稠剂。
本发明中使用的质子泵抑制剂是下面通式化合物：
Figure C9619408400051
其中Ra是
Figure C9619408400052
或
Figure C9619408400053
R1和R3独立地选自氢，低级烷基，低级烷氧基和卤素，R2选自氢，低级烷基，低级烷氧基，低级烷氧基-低级烷氧基，低级氟代烷氧基，和R4和R5独立地选自低级烷基，A是
Figure C9619408400055
或
Figure C9619408400056
R6和R7独立地选自氢，低级烷基，低级烷氧基，低级氟代烷氧基，低级氟代烷基，卤素，
Figure C9619408400057
在其中R8是低级烷基或低级烷氧基。
根据式I的质子泵抑制剂的例子是
Figure C9619408400061
奥美拉唑                兰索拉唑
Figure C9619408400063
泮托拉唑
Figure C9619408400064
       E—3810
Figure C9619408400071
  兰明拉唑
Figure C9619408400072
  S—4216
本发明中使用的优选的质子泵抑制剂是已知为奥美拉唑的化合物。本发明中使用的质子泵抑制剂是本领域已知的化合物，其制备方法可以参见文献。例如奥美拉唑公开于EP 5129，兰索拉唑公开于EP174726，泮托拉唑公开于EP166287，以及兰明拉唑公开于GB 2163747。
疏水油性液体载体可以是任何不溶或几乎不溶于水的可药用油；例子包括矿物油，杏仁油，棉花籽油，油酸乙酯，十四烷酸异丙酯，十六烷酸异丙酯，十四醇，十八醇，橄榄油，花生油，红花油，芝麻油，豆油和角鲨烯。优选的疏水油性液体是一种或几种C6-C18羧酸甘油三酯；优选的甘油三酯是癸酸甘油三酯或辛酸甘油三酯，或其混合物，例如商品名为Miglyol 810(Hu1s America，Inc.，New Jersey)的产品。
增稠剂可以是任何不溶或几乎不溶于水的可药用的增稠剂；例子包括二氧化硅，蜡例如蓖麻蜡或氢化蓖麻油，石蜡，鲸蜡硬脂醇等等。优选的疏水性增稠剂是氢化蓖麻油。
合适的碱化剂是例如可药用的胺碱，例如三乙醇胺，或羧酸的盐，如乙酸钠，柠檬酸钠，山梨酸钾，等等。优选的碱化剂是山梨酸钾。
本发明组合物可以包括通常用于人的制剂和兽药的附加成分。例如可以加入调味剂如焦糖，胡萝卜，苹果，香肠调味剂；着色剂，如氧化铁，二氧化钛，铝色淀；甜味剂，如糖，钠糖精；防腐剂，例如对羟基苯甲酸酯类；抗氧化剂如BHT，BHA和粘度调节剂如白蜡或合成蜡，例如三山萮酸甘油酯，三-十四酸甘油酯，氢化的可可甘油酯。
本发明组合物可以通过将粉末形式的活性成分，质子泵抑制剂分散于含有除增稠剂之外任何其它赋形剂的疏水性液体载体中而制备。然后向混合物中加入增稠剂并混合，得到需要的稠度。这样得到的糊剂可以用来装入针管，该针管直接用来将活性药给与需要治疗的动物。
质子泵抑制剂的量可以在最终组合物中自1至35％W/W变化，优选自大约1至大约25％W/W。增稠剂占最终组合物的大约2至9％W/W，优选大约5至7％W/W。疏水性载体以大约60至95％存在，取决于糊剂中其它赋形剂的量。使用的碱化剂量是足以为酸不稳定的质子泵抑制剂提供非酸性环境；一般情况下，碱化剂的量是大约0.01至大约2％W/W，而0.1％一般就足够了。
该制剂中加入酸不稳定药物使糊剂口服口感好且药学稳定。本发明和药物活性成分保持稳定。
本发明组合物用于治疗人或动物消化道溃疡疾病，其可用来将酸不稳定药物口服送给动物以提供全身活性。本发明组合物还可以用来在难以吞咽固体剂量形式如肠溶包衣片剂和胶囊的人体内运送酸不稳定药物。该组合物可直接经口对需要抗溃疡治疗的动物如马给药；优选使用糊剂给药注射器以有利于给药。糊剂的稠度达到一定程度使其不容易滴落，或者其一旦弄到了动物舌头的背面也可清理出来。本发明糊剂实际上没有气泡，这增强了剂量的准确度。本发明制剂的另一个优点是可以单剂量给药。
要服用的组合物的量可以根据要治疗的具体动物种类，组合物中具体活性成分，疾病的严重程度，有病动物的身体条件和其它因素而不同。溃疡治疗领域熟练的医生或兽医容易确定对于治疗的具体宿主的合适剂量。一般情况下，可以使用的剂量范围自约0.2mg/kg至约20mg/kg。
提供下面的实施例以更全面详细说明本发明，但不应理解为在任何方面限制本发明的范围。
实施例1
奥美拉唑粉末         25.0g
癸酸/辛酸甘油三酯    67.9g
山梨酸钾             0.1g
氢化蓖麻油           7.0g
一边混合一边向癸酸/辛酸甘油三酯(Miglyol 810)中加入山梨酸钾(如果需要，同时加入其它赋形剂，但不加入药物或增稠剂)。然后一边混合一边加入奥美拉唑粉末。最后加入氢化蓖麻油，继续混合大约30分钟。
实施例2
奥美拉唑粉末          25.0g
癸酸/辛酸甘油三酯     67.8g
Mapico黄              0.1g
山梨酸钾              0.1g
氢化蓖麻油            7.0g
按照实施例1的方法，制备上述组合物的奥美拉唑糊剂。
实施例3
奥美拉唑粉末         25.0g
癸酸/辛酸甘油三酯    67.8g
Mapico红             0.1g
山梨酸钾             0.1g
氢化蓖麻油           7.0g
按照实施例1的方法，制备上述组合物的奥美拉唑糊剂。
实施例4
奥美拉唑粉末         10.0g
癸酸/辛酸甘油三酯    84.0g
三乙醇胺             1.0g
二氧化硅             5.0g
按照实施例1的方法，制备上述组合物的奥美拉唑糊剂。
实施例5
奥美拉唑粉末         22.0g
癸酸/辛酸甘油三酯    67.8g
BHT                  0.01g
Mapico黄             0.1g
山梨酸钾             0.1g
氢化蓖麻油           7.0g
按照实施例1的方法，制备上述组合物的奥美拉唑糊剂。

Claims (7)

1.一种口服药物组合物，其含有下面通式(I)的质子泵抑制剂，增稠剂，碱化剂，和疏水性油性液体载体，其中所述质子泵抑制剂是1至35％重量，增稠剂是2至9％重量，
Figure C9619408400021
其中Ra是或
Figure C9619408400023
R1和R3独立地选自氢，低级烷基，低级烷氧基和卤素，R2选自氢，低级烷基，低级烷氧基，低级烷氧基-低级烷氧基，低级氟代烷氧基，和R4和R5独立地选自低级烷基，A是
Figure C9619408400031
或
Figure C9619408400032
R6和R7独立地选自氢，低级烷基，低级烷氧基，低级氟代烷氧基，低级氟代烷基，卤素，其中R8是低级烷基或低级烷氧基。
2.权利要求1的组合物，其中所述质子泵抑制剂是奥美拉唑。
3.权利要求1的组合物，其中所述增稠剂是氢化蓖麻油。
4.权利要求1的组合物，其中所述疏水性液体载体是癸酸/辛酸甘油三酯。
5.权利要求2的组合物，其中所述碱化剂是山梨酸钾。
6.权利要求1的组合物，其中所述质子泵抑制剂是奥美拉唑，增稠剂是氢化蓖麻油，疏水性液体载体是癸酸/辛酸甘油三酯。
7.权利要求1的组合物，其中所述质子泵抑制剂是奥美拉唑，所述增稠剂是氢化蓖麻油，所述疏水性油是癸酸/辛酸甘油三酯，所述碱化剂是山梨酸钾。
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