CN101352412A - 肠溶性非甾体解热镇痛抗炎药及其制备 - Google Patents
肠溶性非甾体解热镇痛抗炎药及其制备 Download PDFInfo
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- CN101352412A CN101352412A CNA2008102120962A CN200810212096A CN101352412A CN 101352412 A CN101352412 A CN 101352412A CN A2008102120962 A CNA2008102120962 A CN A2008102120962A CN 200810212096 A CN200810212096 A CN 200810212096A CN 101352412 A CN101352412 A CN 101352412A
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- inflammatory agent
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Abstract
本发明涉及肠溶性非甾体解热镇痛抗炎药及其制备，经包衣的非甾体解热镇痛抗炎药经口服给药时可避免它们对人和动物胃肠道造成的众所周知的副作用，如：恶心、呕吐、胃溃疡、穿孔、出血和水肿等。
Description
技术领域
本发明涉及非甾体解热镇痛抗炎药肠溶制剂的制备方法。
背景技术
非甾体类抗炎药(nonsteroidal antiinflammatory drugs，NSAIDs)是临床上常用的解热镇痛抗炎药，广泛应用于风湿性疾病、慢性炎性关节炎以及各种原因导致的发热、疼痛性疾病。
自从阿司匹林于1898年上市以来的一个多世纪里，非甾体类镇痛消炎药(nonsteroidal antiinflam-matory drugs，NSAIDs)已增至百余个品种，按化学结构可分为甲酸类也称水杨酸类(代表药物阿司匹林、双氯尼柳等)；乙酸类(代表药物双氯芬酸、吲哚美辛、舒林酸和依托芬那酯)；丙酸类(代表药物布洛芬、酮基布洛芬、芬布芬、奈普生、奥沙普秦和恶丙嗪等)；昔康类也叫苯并噻嗪类(代表药物美洛昔康、罗诺昔康、吡罗西康、替诺昔康等)；昔布类(代表药物罗非昔布、塞来昔布)；吡唑酮类(代表药物安乃近、氨基比林、保泰松、羟基布他酮)；非酸类(萘丁美酮、尼美舒利)；免疫抑制剂类(来氟米特)等，这些药物已成为全球最畅销的药品。
所有的非甾体抗炎药(non-steroidal anti-inflammatory drug，NSAID)的化学结构虽然差别很大，但他们的作用机制主要都是通过抑制PGs环氧化酶(COX)，阻止花生四烯酸转化为PGs而发挥镇痛、消炎和解热作用。COX有两个亚型，即COX-1(体内平衡的常态)和诱导形式(导致受损的)被归为COX-2。COX-1出现在胃(肠)壁、肾脏和血小板中，在细胞内维持机体正常的生理功能，由它催化合前列腺素E2(Prostaglandin E2，PGE2)和前列腺素I2(Prostaglandin I2，PGI2)具有稳定细胞功能和保护细胞的作用。前列腺素在胃肠道和肾中产生维持胃肠道黏膜的完整性，和肾充满。COX-2在正常细胞中较少，但当单核细胞、巨噬细胞、纤维母细胞、血管平滑肌或内皮细胞等细胞接触到内毒素、脂多糖、IL-1等致炎因子或细胞因子后，这些细胞经诱导可产生大量的COX-2，由它催化合成的PGE2和PGI2是原炎性前列腺素，它们具有强的致炎、致痛作用。
非甾体抗炎药(non-steroidal anti-inflammatory drug，NSAID)在人临床上的使用情况经过一个多世纪的不断研究和临床使用发现大多数解热镇痛抗炎药对COX-1及COX-2没有选择性，只是不同的药物在COX-1和COX-2选择效果上的不同。因此在使用NSAIDs类药物时，在对COX-2产生抑制的同时也对COX-1产生抑制作用，因此在使用NSAIDs药物时常因COX-1被抑制而出现胃、肾和血小板功能的障碍，发生胃部不适、恶心、呕吐、血液不易凝结、胃溃疡、穿孔、出血、水肿、电解质紊乱、一过性肾功能不全等不良反应。为了在口服使用过程中减少对胃部的副作用，对该类产品进行肠溶性材料的包被处理，使药物在经过胃部时不发生崩解，仍然完整的通过胃部，而在药物到达肠部时又能迅速崩解，同时被吸收利用。
发明内容
本发明提供一种非甾体解热镇痛抗炎药肠溶组合物，该组合物含有非甾体解热镇痛抗炎药和肠溶包衣材料，
两者的重量百分比为：
非甾体解热镇痛抗炎药70-93％
肠溶包衣材料7～30％。
本发明的肠溶组合物，必要时还可以加入其他材料，如药物学上可接受的辅料。
人和动物胃部的PH值通常＜4.0，肠道PH值通常＞5.0，据此我们选择的肠溶包衣材料必须是在PH＞5.0的溶液中可以快速崩解，而在＜5.0的溶液中不溶解。
本发明的肠溶包衣材料符合上述要求，选自：虫胶(PH＞7.0)、聚乙烯醇乙酸苯二甲酸酯(PVAP)(PH＞5.0)、丙烯酸树脂类(Eudragit L30D-55 PH＞5.5)、Eudragit L100(PH＞6.0)、Eudragit S100(PH＞7.0))、邻苯二甲酸乙酸纤维素(乙酸纤维素肽酸酯，CAP)(PH＞6.0)；1，2，4-苯三甲酸乙酸纤维素(乙酸纤维素苯三酸酯，CAT)(PH＞5.5)；羟丙甲纤维素肽酸酯(HPMCP，有HP50、HP55、HP55S三种规格)(PH＞5.5)；1，2，4-苯三甲酸羟丙基甲基纤维素(HPMCr)；琥珀酸乙酸纤维素(CAS)；琥珀酸乙酸羟丙基甲基纤维素(HPMCAS)(5.5-7.1)、欧巴代等，也可以是它们的混合物。
本发明的非甾体解热镇痛抗炎药选自：双氯芬酸钠、氟尼辛、阿司匹林、二氟尼柳、吲哚美辛、阿昔美辛、桂美辛、单(双)氯芬酸、噻洛芬酸、醋洛芬酸、甲洛芬那酸、甲芬那酸、托芬那酸、氯芬那敏、氟芬那敏、依洛芬那酯、夫洛非宁、舒林酸、丁苯羟酸、环氯茚酸、托美汀、酮咯酸、萘普生、布洛芬、酮洛芬、芬布芬、吡洛芬、阿明洛芬、氟比洛芬、卡洛芬、非诺洛芬、洛索洛芬、奥沙普秦、吡洛昔康、美洛昔康、氯诺昔康、塞来昔布、罗非昔布、尼美舒利、安乃近、保泰松、羟布宗、依匹唑、苄达明、非普拉宗、萘丁美酮、来氟米特、青藤碱、芬太尼、罗通定、麦角胺、布桂嗪等以及它们的衍生物或盐类。
本发明的肠溶包衣材料的用量为被包药物重量(药物组合物)的3～30％，优选为5～10％。
本发明的非甾体解热镇痛抗炎药优选为双氯芬酸钠，优选的肠溶包衣材料为羟丙甲纤维素肽酸酯，
本发明的优选的组合物，组成为双氯芬酸钠70-93％，羟丙甲纤维素肽酸酯7～30％。
本发明更优选的组合物，组成为双氯芬酸钠90-95％，羟丙甲纤维素肽酸酯5-10％。
本发明的组合物，其制备包括将肠溶包衣材料溶解，加入非甾体解热镇痛抗炎药，搅拌混合均匀，浓缩，冷却，烘干得到。
也可以将非甾体解热镇痛抗炎药制备成药物制剂，如片剂，颗粒剂，粉剂等，然后用溶解的肠溶包衣材料对这些制剂进行包衣。
本发明的组合物优选将肠溶包衣材料溶解，加入非甾体解热镇痛抗炎药混合的方法制备。
本发明的组合物，可以进一步加工成药物制剂，如片剂，胶囊，颗粒，混悬，等固体制剂，可以用制剂学的常规方法制备成制剂。
本发明的组合物及制剂，适合人和动物服用，不会发生胃部不适、恶心、呕吐、血液不易凝结、胃溃疡、穿孔、出血、水肿、电解质紊乱、一过性肾功能不全等不良反应，具有稳定，安全，吸收好等特点。
具体实施方式：
下面通过举例说明本发明肠溶药物的制备：
实施例1：先用1000ml(乙醇∶水＝80∶20)溶液加热溶解45g羟丙甲纤维素肽酸酯(HP55)，再加入150g双氯芬酸钠，加热搅拌至溶解澄明，边搅拌边浓缩至稠状，冷却，烘干得肠溶包衣物。包衣增重：22.98％。
包封率测定：根据包衣物在酸性介质中溶出度为0(在以下溶出度测定中可得出此结论)，可取包衣物在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，被包合药物不会溶解，而游离药物将溶解，可测出游离药物的量W游离，另外药物总量W总已知，根据包封率＝(W总-W游离)/W总×100％，计算得包封率为98.1％。
溶出度测定：按照中国药典(2005版)附录XC溶出度测定法中第二法测定。将上述制备好的包衣物先在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，烘干。然后把处理后的包衣物分别加入到装有溶出介质的智能溶出仪中，加入量为：0.3g包衣物加至300ml溶出介质中。溶出介质为：0.1mol/L HCl溶液(PH＝1.0)和0.4mol/L KCl溶液(PH＝5.2)。控制溶出介质温度为37±0.5℃，搅拌速度为50r/min，分别在设定时间(0.5h、1.0h、1.5h、2.5h、4h)取样，同时补加同温等量溶出介质。经0.45μm微孔滤膜过滤，取澄清溶液，测定药物含量，计算出药物溶出度(即药物的溶出量占总量的百分比)。结果见表1
表1包衣物在不同溶出介质中的溶出度
| 时间(h) | 0.1mol/L HCl 溶液(PH＝1.0) | 0.4mol/L KCl 溶液(PH＝5.2) |
| 0.5 | 0 | 70.8％ |
| 1.0 | 0 | 72.6％ |
| 1.5 | 0 | 81.3％ |
| 2.5 | 0 | 85.2％ |
| 4.0 | 0 | 88.1％ |
实施例2：先用800ml(乙醇∶水＝80∶20)溶液加热溶解15g羟丙甲纤维素肽酸酯(HP55)，再加入150g双氯芬酸钠，加热搅拌至溶解澄明，边搅拌边浓缩至稠状，冷却，烘干得肠溶包衣物。包衣增重：9.0％。
包封率测定：根据包衣物在酸性介质中溶出度为0(在以下溶出度测定中可得出此结论)，可取包衣物在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，被包合药物不会溶解，而游离药物将溶解，可测出游离药物的量W游离，另外药物总量W总已知，根据包封率＝(W总-W游离)/W总×100％，计算得包封率为92.5％。
溶出度测定：按照中国药典(2005版)附录XC溶出度测定法中第二法测定。将上述制备好的包衣物先在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，烘干。然后把处理后的包衣物分别加入到装有溶出介质的智能溶出仪中，加入量为：0.3g包衣物加至300ml溶出介质中。溶出介质为：0.1mol/L HCl溶液(PH＝1.0)和0.4mol/L KCl溶液(PH＝5.2)。控制溶出介质温度为37±0.5℃，搅拌速度为50r/min，分别在设定时间(0.5h、1.0h、1.5h、2.5h、4h)取样，同时补加同温等量溶出介质。经0.45μm微孔滤膜过滤，取澄清溶液，测定药物含量，计算出药物溶出度(即药物的溶出量占总量的百分比)。结果见表2
表2包衣物在不同溶出介质中的溶出度
| 时间(h) | 0.1mol/L HCl 溶液(PH＝1.0) | 0.4mol/L KCl 溶液(PH＝5.2) |
| 0.5 | 0 | 88.7％ |
| 1.0 | 0 | 91.2％ |
| 1.5 | 0 | 95.3％ |
| 2.5 | 0 | 100％ |
| 4.0 | 0 | 100％ |
实施例3：先用500ml(乙醇∶水＝80∶20)溶液加热溶解5g羟丙甲纤维素肽酸酯(HP55)，再加入100g双氯芬酸钠，加热搅拌至溶解澄明，经喷雾干燥得肠溶包衣物。包衣增重：4.72％。
包封率测定：根据包衣物在酸性介质中溶出度为0(在以下溶出度测定中可得出此结论)，可取包衣物在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，被包合药物不会溶解，而游离药物将溶解，可测出游离药物的量W游离，另外药物总量W总已知，根据包封率＝(W总-W游离)/W总×100％，计算得包封率为90.7％。
溶出度测定：按照中国药典(2005版)附录XC溶出度测定法中第二法测定。将上述制备好的包衣物先在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，烘干。然后把处理后的包衣物分别加入到装有溶出介质的智能溶出仪中，加入量为：0.3g包衣物加至300ml溶出介质中。溶出介质为：0.1mol/L HCl溶液(PH＝1.0)和0.4mol/L KCl溶液(PH＝5.2)。控制溶出介质温度为37±0.5℃，搅拌速度为50r/min，分别在设定时间(0.5h、1.0h、1.5h、2.5h、4h)取样，同时补加同温等量溶出介质。经0.45μm微孔滤膜过滤，取澄清溶液，测定药物含量，计算出药物溶出度(即药物的溶出量占总量的百分比)。结果见表3
表3包衣物在不同溶出介质中的溶出度
| 时间(h) | 0.1mol/L HCl溶液(PH＝1.0) | 0.4mol/L KCl 溶液(PH＝5.2) |
| 0.5 | 0 | 95.8％ |
| 1.0 | 0 | 100％ |
| 1.5 | 0 | 100％ |
| 2.5 | 0 | 100％ |
| 4.0 | 0 | 100％ |
其它肠溶药物的制备：
实施例4：将20g聚丙烯酸树脂Eudragit L100边搅拌边加入到1000ml去离子水中，制成2％的水分散体系，在搅拌下将200g美洛昔康均匀分散于该水分散体系中，然后经喷雾干燥制得均匀包衣颗粒。包衣增重：6.86％。
实施例5：将20g聚乙烯醇乙酸苯二甲酸酯(PVAP)边搅拌边加入到1000ml(乙醇∶水＝50∶50)溶液中，制成2％的水分散体系，在搅拌下将150g托芬那酸均匀分散于该水分散体系中，然后经喷雾干燥制得均匀包衣颗粒。包衣增重：8.25％。
实施例6：先用500ml(乙醇∶水＝80∶20)溶液加热溶解5g琥珀酸乙酸羟丙基甲基纤维素(HPMCAS)，再加入100g酮洛芬，加热搅拌至溶解澄明，经喷雾干燥得肠溶包衣物。包衣增重：5.21％。
Claims (10)
1、一种非甾体解热镇痛抗炎药肠溶组合物，该组合物含有非甾体解热镇痛抗炎药和肠溶包衣材料。
2、权利要求1的组合物，其中非甾体解热镇痛抗炎药70-93％。肠溶包衣材料3～30％。
3、权利要求1的组合物，必要时还可以加入其他材料，如药物学上可接受的辅料。
4、权利要求1的组合物，其中肠溶包衣材料选自：虫胶(PH＞7.0)、聚乙烯醇乙酸苯二甲酸酯(PVAP)(PH＞5.0)、丙烯酸树脂类(Eudragit L30D-55 PH＞5.5)、Eudragit L100(PH＞6.0)、Eudragit S100(PH＞7.0))、邻苯二甲酸乙酸纤维素(乙酸纤维素肽酸酯，CAP)(PH＞6.0)；1，2，4-苯三甲酸乙酸纤维素(乙酸纤维素苯三酸酯，CAT)(PH＞5.5)；羟丙甲纤维素肽酸酯(HPMCP，有HP50、HP55、HP55S三种规格)(PH＞5.5)；1，2，4-苯三甲酸羟丙基甲基纤维素(HPMCr)；琥珀酸乙酸纤维素(CAS)；琥珀酸乙酸羟丙基甲基纤维素(HPMCAS)(5.5-7.1)、欧巴代、或是它们的混合物。
5、权利要求1的组合物，其中非甾体解热镇痛抗炎药选自：双氯芬酸钠、氟尼辛、阿司匹林、二氟尼柳、吲哚美辛、阿昔美辛、桂美辛、单(双)氯芬酸、噻洛芬酸、醋洛芬酸、甲洛芬那酸、甲芬那酸、托芬那酸、氯芬那敏、氟芬那敏、依洛芬那酯、夫洛非宁、舒林酸、丁苯羟酸、环氯茚酸、托美汀、酮咯酸、萘普生、布洛芬、酮洛芬、芬布芬、吡洛芬、阿明洛芬、氟比洛芬、卡洛芬、非诺洛芬、洛索洛芬、奥沙普秦、吡洛昔康、美洛昔康、氯诺昔康、塞来昔布、罗非昔布、尼美舒利、安乃近、保泰松、羟布宗、依匹唑、苄达明、非普拉宗、萘丁美酮、来氟米特、青藤碱、芬太尼、罗通定、麦角胺、布桂嗪等以及它们的衍生物或盐类。
6、权利要求1的组合物，组成为双氯芬酸钠70-93％，羟丙甲纤维素肽酸酯7～30％。
7、权利要求1的组合物，组成为双氯芬酸钠90-95％，羟丙甲纤维素肽酸酯5-10％。
8、权利要求1的组合物的制备方法，包括将肠溶包衣材料溶解，加入非甾体解热镇痛抗炎药，搅拌混合均匀，浓缩，冷却，烘干得到；或将非甾体解热镇痛抗炎药制备成药物制剂，如片剂，颗粒剂，粉剂等，然后用溶解的肠溶包衣材料对这些制剂进行包衣。
9、权利要求1所述的制备方法，其中溶解肠溶包衣材料的溶剂为水、甲醇、乙醇或它们的混合物。
10、用权利要求1的组合物，进一步加工成药物制剂，如片剂，胶囊，颗粒，混悬，等固体制剂，可以用制剂学的常规方法制备成制剂。
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