CN1283112A - 包含三种不同类型聚合物的持续释放制剂及由其制备的片剂 - Google Patents
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Abstract
储存药物制剂包含药物本身和控制释放速度的三组分基质组合物。所述基质组合物的三个组分是(1)与pH有关的胶凝聚合物如藻酸盐组分;(2)肠溶性聚合物如
Description
有关申请的交叉参考
该申请是1995年3月1日提出的在先的同时待批的申请08／395，565的部分继续，特别将该公开全文引入本文供参考。
本发明领域
本发明涉及用于制备以控制速度将所述药物释放到宿主的胃和／或胃肠道中的持续释放药物形式的制剂。尤其，本发明涉及一种用于制备持续释放片剂的改善的储存药物形式。
本发明背景
在临床应用中，有时需要从其控制释放剂量形式的药物的零级释放速度。用于配制零级释放剂量形式的技术是公知的。将药物包埋在基质中是配制具有零级释放速度的持续释放片剂的一般方法。
已经有人报道，可通过单独使用藻酸盐(参见美国专利5，132，295)，使用藻酸盐和聚丙烯酸酯(参见美国专利5，230，901)以及使用藻酸盐和与pH无关的碳氢化合物胶凝剂如羟丙基甲基纤维素(参见美国专利4，792，452)制备用于控制药物释放的储存药物剂量。也已知单独使用藻酸盐通常存在压片、膜包衣和贮存困难。
将聚丙烯酸酯加到所述藻酸盐制剂中可将这些困难克服到某种程度，然而，用藻酸盐和聚丙烯酸酯制备的片剂通常具有与pH有关的溶出速度。在低pH环境下，藻酸盐和聚丙烯酸酯不适当地溶胀和／或溶解。这导致药物按照扩散机制通过非粘性毛细血管释放，产生与高pH环境下不同的溶出速度。另一方面，在高pH环境下，藻酸盐溶胀并成为可溶的，而聚丙烯酸酯可能这样或不这样。这导致药物以不同于低pH下释放速度的速度通过溶蚀和扩散释放。
在包含藻酸盐和与pH无关的胶凝聚合物如羟丙基甲基纤维素的制剂中，在低pH下，所述聚合物水合产生用于药物释放的粘性凝胶层。然而，在高pH下，在药物释放过程中，由于聚合物的溶蚀，片剂变得越来越小，这导致表面积减小，因此可影响溶出速度。
本发明概要
本发明的新颖性在于它提供一种减少并且也许完全消除这些问题的持续释放制剂。尤其，本发明提供一种控制释放的药物制剂，包含1)与pH有关的胶凝聚合物如藻酸盐物质、羧基乙烯基聚合物或羧甲基纤维素钠，2)肠溶性聚合物如醋酸邻苯二甲酸纤维素、邻苯二甲酸纤维素羟丙基甲基醚、聚醋酸乙烯邻苯二甲酸酯、醋酸琥珀酸羟丙基甲基纤维素、1，2，4-苯三酸醋酸纤维素、紫胶或聚丙烯酸酯物质如Eudragit，L或EudragitS，和3)与pH无关的胶凝聚合物如羟丙基甲基纤维素、羟丙基乙基纤维素、羟丙基纤维素、羟乙基纤维素、甲基纤维素、黄原胶或聚氧化乙烯。所述组分的组合有利于生产操作并改善药物溶出速度。
在本发明制剂中，与pH有关的胶凝聚合物提供良好的约束性和控释性，因此有利于生产操作。在溶出过程中，与pH无关的胶凝聚合物在低pH下水合形成控制药物释放的凝胶层。在高pH下，肠溶性聚合物增加溶蚀速度以便于保持恒定的溶出速度，与片剂的大小无关。所以减小片剂的大小不降低释放速度。因此，与上述现有技术的制剂相比，本发明制剂提供改善的药物释放速度。
优选实施方案的详细描述
本发明提供用药物组合物、与pH有关的胶凝聚合物、肠溶性聚合物和与pH无关的胶凝聚合物的混合物配制的持续释放片剂，其中所述药物组合物可以以控制的速度从所述片剂中释放。在特别优选的本发明剂型中，所述制剂可用于提供控制释放含维拉帕米的药物组合物的储存药物形式。然而，所述制剂也可以与其它各种药物或活性组合物包括水溶性组合物、水微溶性组合物和水不溶性组合物一起使用，因此认为，本发明不受在控制条件下从中释放的确切组合物和／或药物或其它活性组合物特性的限制。
在优选的形式中，本发明制剂可包含1)与pH有关的胶凝聚合物，如以水溶性藻酸盐形式存在的藻酸盐组分，以2％(重量)水溶液形式存在，在25℃下，当通过Brookfield LV粘度计测定时，其粘度范大约为60-10，000厘泊，并且优选大约为100-6，000厘泊；2)肠溶性聚合物的组合物组分如纤维素衍生物或甲基丙烯酸共聚物(优选Eudragit，L／S)；和3)与pH无关的胶凝聚合物组分，如纤维素衍生物或聚氧化乙烯，以2％(重量)水溶液形式存在，在20℃下，其粘度范围大约为10-100，000厘泊，并且优选大约为50-15，000厘泊。
在整个片剂中活性药物的含量可优选为大约0．5％-70％(重量)。在整个片剂中胶凝聚合物和肠溶性聚合物的总量优选为大约8％-65％(重量)。在整个片剂中与pH有关的胶凝聚合物的总量优选为大约2％-60％(重量)。在整个片剂中与pH无关的聚合物总量优选为大约2％-55％(重量)。优选地，在整个片剂中肠溶性聚合物的总量大约为1％-55％(重量)。
例如，在美国专利5，230，901中描述了适宜的肠溶性聚丙烯酸酯物质，将所述公开全文引入本文供参考。在这点上，本文所使用的术语聚丙烯酸酯包括在’901专利中公开的聚丙烯酸酯、聚甲基丙烯酸酯和丙烯酸与甲基丙烯酸的共聚物。例如，这些物质也在Houben-Weyl，Methoden derorganischen Chemie，Thieme-Verlag，Stutt，1961中描述。以Eudragit例如Eudragit L或EudragitS为商品名在市场上可得到的产品是特别适宜的。其它适宜的肠溶性聚合物包括，例如纤维素衍生物如邻苯二甲酸醋酸纤维素、邻苯二甲酸纤维素羟丙基甲基醚、乙酸琥珀酸羟丙基甲基纤维素、1，2，4-苯三酸醋酸纤维素、和如聚乙烯醋酸邻苯二甲酸酯、紫胶和聚甲基丙烯酸酯等的物质。
在本发明制剂中可包含或不包含的其它组分包括1)一种或多种粘合剂如聚烯吡酮(聚乙烯吡咯烷酮)、改性淀粉、低粘度羟丙基甲基纤维素等；2)一种或多种填充剂如微晶纤维素、乳糖、淀粉、硫酸钙等；3)一种或多种润滑剂，如硬脂酸镁、硬脂酸等；4)一种或多种包衣膜形成剂如Opadry(以羟丙基甲基纤维素为基础的包衣系统)；和5)一种或多种着色剂如FD&C绿色染料。粘合剂可以占整个制剂重量的大约10％并且润滑剂可以占整个制剂重量的大约0．1％-大约5．0％。
在下列阐述的具体实例中，举例说明本发明三个用于释放维拉帕米HCl的具体实施方案。这三个实例称为A、B和C。
优选实施方案的具体实例组分 各实例中组分的量
A B C1、维拉帕米HCl 240MG 120MG 240MG2、藻酸钠 250MG 80MG 200MG3、羟丙基甲基纤维素 50MG 15MG -4、聚氧化乙烯 - - 60MG5、甲基丙烯酸共聚物(EudragitL／S) 120MG 30MG 100MG6、聚烯吡酮 50MG 25MG 40MG7、微晶纤维素 60MG 80MG 80MG8、硬脂酸镁 5MG 2MG 5MG
将上述1-7项组分在混合器如高剪切混合器制粒机或行星式混合器中混合以便混合均匀。然后，将该混合物在水或其它适宜的制粒液体中制粒并在干燥器中干燥。然后，将干燥的颗粒物质碾磨并在碾磨过程中加入第8项组分(润滑剂)。然后，将润滑的颗粒物质用压片机压片。上述步骤是制片工业中使用的常规步骤。
在上述的优选实例中，本发明制剂尤其可用于制备持续释放的维拉帕米片剂。然而，本发明不仅仅局限于该药物的应用中。包含其它需要持续释放药物的片剂也在本发明范围内。期望本发明持续释放制剂可与水溶性、水微溶性或水不溶性药物一起使用。例如，在美国专利4，792，452中Howard等人列出了适宜的需要持续释放并因此包含在本发明范围内的药物，将该公开全文特别地引入本文供参考。
可与维拉帕米以外其它药物一起使用的本发明制剂的具体实例如下：组分 各实例中组分的量
A B1、己酮可可碱 400MG 600MG2、藻酸钠 60MG 80MG3、羟丙基乙基纤维素 50MG 120MG4、EUDRAGIT 20MG 20MG5、聚烯吡酮 25MG 40MG6、微晶纤维素 42MG 55MG7、硬脂酸镁 3MG 5MG组分 各实例中组分的量
A B1、硝苯地平 90MG 60MG2、羧甲基纤维素钠 30MG 12MG3、羟丙基甲基纤维素 30MG 36MG4、邻苯二甲酸醋酸纤维素 10MG 12MG5、聚烯吡酮 16MG 14MG6、乳糖 12MG 74MG7、微晶纤维素 30MG 30MG8、硬脂酸镁 2MG 2MG
可利用与制备以混入维拉帕米的制剂为基础的片剂基本相同的方法来制备以上述混入己酮可可碱和硝苯地平的制剂为基础的片剂。
Claims (15)
1、一种持续释放药物的片剂，包含有效量以控制速度释放的药物和持续释放制剂，所述持续释放制剂包含至少三种不同类型的聚合物，其包括与pH有关的胶凝聚合物、与pH无关的胶凝聚合物和肠溶性聚合物。
2、权利要求1所阐述的片剂，其中所述与pH有关的胶凝聚合物包含一种或多种藻酸盐、羧基乙烯基聚合物和羧甲基纤维素的盐。
3、权利要求1所阐的片剂，其中所述与pH无关的胶凝聚合物包含一种或多种羟丙基甲基纤维素、羟丙基乙基纤维素、羟丙基纤维素、羟乙基纤维素、甲基纤维素、黄原胶或聚氧化乙烯。
4、权利要求1所阐述的片剂，其中所述肠溶性聚合物包含一种或多种聚丙烯酸酯物质、邻苯二甲酸醋酸纤维素、邻苯二甲酸纤维素羟丙基甲基醚、聚醋酸乙烯邻苯二甲酸酯、醋酸琥珀酸羟丙基甲基纤维素、1，2，4-苯三酸醋酸纤维素或紫胶。
5、权利要求4所阐述的片剂，其中所述聚丙烯酸酯物质包括甲基丙烯酸共聚物。
6、权利要求5所阐述的片剂，其中所述甲基丙烯酸共聚物是EudragitL。
7、权利要求5所阐述的片剂，其中所述甲基丙烯酸共聚物是EudragitS。
8、权利要求1所阐述的片剂，其中所述药物包含一种或多种水溶性、水微溶性或水不溶性活性物质。
9、权利要求1所阐述的片剂，其中所述药物在所述制剂中的含量为其重量的大约0．5-大约70％。
10、权利要求1所阐述的片剂，其中所述胶凝和肠溶性聚合物在所述制剂中的总含量为其重量的大约8％-大约65％。
11、权利要求1所阐述的片剂，其中所述与pH有关的胶凝聚合物在所述制剂中的含量为其重量的大约2％-大约60％。
12、权利要求1所阐述的片剂，其中所述与pH无关的的胶凝聚合物在所述制剂中的含量为其重量的大约2％-大约55％。
13、权利要求1所阐述的片剂，其中所述肠溶性聚合物在所述制剂中的含量为其重量的大约1％-大约55％。
14、一种包含持续释放制剂的用于持续释放活性物质的片剂，所述持续释放制剂包含至少三种不同类型的聚合物，包括与pH有关的胶凝聚合物、与pH无关的胶凝聚合物和肠溶性聚合物。
15、一种持续释放活性物质的制剂，所述持续释放制剂包含至少三种不同类型的聚合物，包括与pH有关的胶凝聚合物、与pH无关的胶凝聚合物和肠溶性聚合物。
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| EP1035840A4 (en) | 2007-05-02 |
| US6346268B1 (en) | 2002-02-12 |
| US6083532A (en) | 2000-07-04 |
| CA2312710A1 (en) | 1999-06-17 |
| AU1621899A (en) | 1999-06-28 |
| EP1035840A1 (en) | 2000-09-20 |
| WO1999029305A1 (en) | 1999-06-17 |
| JP2001525358A (ja) | 2001-12-11 |
| AU742301B2 (en) | 2001-12-20 |
| CA2312710C (en) | 2006-03-14 |
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