CN100473379C - 替硝唑结肠定位肠溶片 - Google Patents
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Abstract
本发明涉及一种结肠定位肠溶片的处方组成，制备工艺和体外溶出测定方法，该片剂的有效成分为替硝唑。其特征在于通过包衣的方法，实现结肠定位释药的目的，临床上主要用于治疗结肠炎症。
Description
发明领域
本发明涉及一种口服定位释药范畴的药物制剂，特别涉及一种替硝唑结肠定位肠溶片及其处方和制备工艺。
该制剂的有效成分为2-甲基-1-[2-(乙基磺酰基)乙基]-5-硝基-1H咪唑，通用名为替硝唑(tinidazole)。
研究背景
本发明所涉及的替硝唑最早由美国辉瑞公司60年代开发上市并在国外广泛应用。替硝唑片剂和注射剂已被中国药典2000年版收载。
替硝唑为目前常用的抗厌氧菌及抗原虫药甲硝唑的衍生物。替硝唑对革兰氏阳性菌和阴性菌有强力抗菌作用，临床主要用于治疗厌氧菌感染引起的肺炎、腹膜内感染、皮肤软组织感染、牙周炎、慢性结肠炎、手术后厌氧菌感染等。
替硝唑片剂和栓剂的结肠炎临床治疗研究表明，普通片剂口服后易于吸收，口服1小时后吸收80％以上，且进食与空腹服用生物利用度无明显差异，一次口服替硝唑500mg后，1.6小时达血药浓度约10.1μg/ml，消除半衰期12-13小时；替硝唑栓剂给药1.0g后，3.4±0.9小时血药浓度达峰值，峰浓度平均为7.9±1.8μg/ml，半衰期为14.2±1.1小时。口服普通片剂时，药物主要在胃和小肠被吸收，到达结肠的药物很少，因而对结肠炎治疗的效果较差；使用栓剂可以增加药物的局部浓度，提高治疗效果，但使用不方便；如果提高药物剂量，会增加药物不良反应的发生率，包括恶心、呕吐、腹泻、腹胀、白细胞减少、头痛、多发性神经炎等。
使用聚丙烯酸肠溶树脂，对颗粒、小丸、片剂进行包衣，可以使制剂通过胃和小肠上段时不释放药物，当达到回肠或结肠时才逐渐释药。在美国专利US5401512，US5422121，US5171580，US4968508中均使用了聚丙烯酸肠溶树脂使制剂具有定位释药的特性，本发明参照以上专利研制了替硝唑结肠定位肠溶片，其具有独特的靶向释药特性，能够通过胃和小肠而不被吸收，当到达结肠时药物才逐渐释放出来，使药物能够直接作用于病变部位，增加药物在结肠局部的浓度，提高治疗效果。与普通口服片剂相比，在相同剂量下可以增加疗效，减少不良发应发生率，与直肠栓剂和灌肠剂相比，病人有更好的耐受性。因此，替硝唑结肠定位肠溶片在治疗各种类型的结肠炎症上具有明显的优势。经专利及文献检索，未见替硝唑结肠定位肠溶片研制报道，且国内外均无产品上市。
发明目的
研制了一种替硝唑结肠定位肠溶片的处方组成和制备工艺，并优选出替硝唑结肠定位肠溶片的体外溶出度测定方法.
技术方案
本发明提供了一种涉及如下成分的片剂：
a.主药为替硝唑。
b.片芯辅料包括稀释用辅料、粘合用辅料、崩解用辅料、润滑
用辅料等。
c.包衣材料包括结肠溶丙烯酸树脂、增塑用辅料、润滑用辅料、遮光用辅料等。
替硝唑结肠定位肠溶片的关键是片芯的组成以及包衣处方的选择。
片芯的组成主要包括主药、稀释用辅料、粘合用辅料、崩解用辅料、润滑用辅料等，替硝唑为水略溶性药物，所以选择的片芯辅料要能够促进药物的溶出。
片芯中稀释用辅料常选如乳糖、蔗糖、甘露醇、微晶纤维素、糊精、淀粉、磷酸氢钙等，本发明优选乳糖、微晶纤维素和淀粉，更优选乳糖和微晶纤维素；
片芯中粘合用辅料常选如聚乙烯吡咯烷酮、聚乙二醇、甲基纤维素、羟丙甲纤维素、羟丙基纤维素及可压性淀粉等，本发明优选羟丙甲纤维素、聚乙烯吡咯烷酮和可压性淀粉，更优选羟丙甲纤维素；
片芯中崩解用辅料常选如羧甲基淀粉钠、淀粉、微晶纤维素、交联聚乙烯吡咯烷酮、低取代羟丙纤维素等，本发明优选羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素，更优选羧甲基淀粉钠；
片芯中润滑用辅料可选用如硬脂酸、硬脂酸镁、氢化植物油、滑石粉、聚乙二醇等，本发明优选硬脂酸镁。
包衣处方中包括结肠溶高分子材料、增塑用辅料、润滑用辅料、遮光用辅料等。
包衣处方中结肠溶高分子材料选用聚丙烯酸树脂类，本发明优选聚丙烯酸树脂II、聚丙烯酸树脂III、EudragitR、EudragitS等；更优选聚丙烯酸树脂III和EudragitS。
包衣处方中增塑用辅料常选如邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、甘油三醋酸酯、蓖麻油、柠檬酸三乙酯等，本发明优选邻苯二甲酸二丁酯和柠檬酸三乙酯，更优选邻苯二甲酸二丁酯。
包衣处方中润滑用辅料常选滑石粉、硬脂酸镁、微粉硅胶等，本发明优选滑石粉。
包衣处方中遮光用辅料优选二氧化钛和黄色色淀。
包衣处方中溶媒常选水、乙醇、乙醇水溶液，本发明优选80％-95％得乙醇水溶液。
优选的处方及工艺如下：
片芯处方：
包衣液处方：
聚丙烯酸树脂III 35.0g
邻苯二甲酸二丁酯 3.5g
钛白粉 8.0g
黄色色淀 3.0g
滑石粉 8.0g
80％乙醇溶液 650.0g
制备工艺
取处方量的替硝唑、乳糖、微晶纤维素和羧甲淀粉钠，分别过80目筛混匀，加入羟丙甲纤维素RT15的乙醇水溶液制软材，过18目尼龙筛制粒，湿颗粒放入烘箱中于50℃通风烘干，过16目尼龙筛网整粒，加入处方量的硬脂酸镁混匀，压制片芯。
将聚丙烯酸树脂III粉碎后与处方量的滑石粉、钛白粉和色淀混匀。将邻苯二甲酸二丁酯加入到80％的乙醇水溶液中，然后在搅拌下缓慢加入上述混合物，继续搅拌1小时，得包衣溶液。用配制的包衣液在连续搅拌下对片芯进行喷雾包衣，包衣增重为片芯的6-7％。包衣时进风温度控制在40-50℃，片床温度控制在25-35℃，雾化压力为1bar。
体外溶出度的测定方法
采用中国药典2000年版二部附录XC第一法篮法进行溶出度的测定，试验条件如下：
溶出介质：盐酸溶液(9→1000)；pH6.8的磷酸盐缓冲；pH7.8的磷酸盐缓冲液。
介质体积：900ml
温度：37℃
转速：100rpm
先以稀盐酸溶液(9→1000)为溶出介质，二小时内包衣膜应完好，片子不崩解；然后转移至pH6.8的磷酸盐缓冲液中，三小时内包衣膜应完好，片子不崩解；最后转移至pH7.8的磷酸盐缓冲液中，60分钟时测定溶出度。
用以上处方和工艺制备三批样品的溶出结果见图1至图3。
图1为000410批的溶出结果。
图2为000412批的溶出结果。
图3为000414批的溶出结果。
Claims (2)
1.一种用于治疗结肠炎的替硝唑结肠定位肠溶片，其特征在于由片芯和包衣层组成，片芯由替硝唑、稀释用辅料、粘合用辅料和崩解用辅料组成，包衣层由丙烯酸树脂、增塑用辅料、润滑用辅料和遮光用辅料组成；所述稀释用辅料选自乳糖、微晶纤维素、淀粉或由其组成的混合物；所述粘合性辅料选自羟丙甲纤维素、聚乙烯吡咯烷酮、可压性淀粉或由其组成的混合物；所述崩解用辅料，选自羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素或由其组成的混合物；所述丙烯酸树脂选自丙烯酸树脂II、丙烯酸树脂III、Eudragit R、Eudragit S或由其组成的混合物；所述增塑用辅料选自邻苯二甲酸二乙酯、邻苯二甲酸二丁酯或柠檬酸三乙酯；所述润滑用辅料选自滑石粉、硬脂酸镁或微粉硅胶；所述遮光用辅料选自二氧化钛或色淀。
2.根据权利要求1所述的定位肠溶片，片芯中含有100—500mg的替硝唑。
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| CN101934079B (zh) * | 2010-08-20 | 2013-03-13 | 温州小伦包衣技术有限公司 | pH依赖型口服结肠定位释药薄膜包衣预混辅料及其制备方法 |
| CN104784217A (zh) * | 2015-05-08 | 2015-07-22 | 广西大学 | 一种肠溶包衣蟾酥微丸预混剂及其制备方法 |
| CN112007002B (zh) * | 2020-08-05 | 2022-08-12 | 河北君临药业有限公司 | 一种质量稳定的甲硝唑片剂组合物及其制备方法 |
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