CN1293576A - 胃和/或十二指肠粘附性药物组合物 - Google Patents
胃和/或十二指肠粘附性药物组合物 Download PDFInfo
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- CN1293576A CN1293576A CN99804193A CN99804193A CN1293576A CN 1293576 A CN1293576 A CN 1293576A CN 99804193 A CN99804193 A CN 99804193A CN 99804193 A CN99804193 A CN 99804193A CN 1293576 A CN1293576 A CN 1293576A
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- preparation
- stomach
- polymer
- medicine
- adhesiveness
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Abstract
粘附胃/十二指肠的医药组合物,其特征在于是通过在一种组合物上用一种聚合物包衣而得到的,该组合物含有作用于胃和/或十二指肠的药物和选自水不溶性聚合物、聚甘油脂肪酸酯、脂类和蜡类的成分,该聚合物在酸性条件下能够粘附消化道粘膜表面,但在中性或碱性条件下是可从该表面剥离的。利用这些专门粘附胃及十二对肠粘膜的组合物使在长时间释放药物成为可能,由此以较少剂量即可达到充分的药物作用。
Description
技术领域
本发明涉及药物组合物，该药物组合物仅粘附胃粘膜和十二指肠粘膜，并且其药物是控制释放的。
背景技术
考虑药物的有效利用，药物的控释制剂、特别是缓释制剂具有重要的优点，例如减少给药频率、使血液水平维持预定时间等，这是因为它能够连续释放药物长达几个小时。因此已经对缓释制剂进行了各方面的研究。
由于缓释制剂的药物主要是在肠被吸收的，很多制剂尽管通过整个消化道，也被设计成逐渐地释放药物。相反，被设计成不是在被肠吸收以后、而是在胃或十二指肠局部发挥其功效的制剂还没有那么多。
作为打算使药物在胃中起效的制剂，据报道通过赋予制剂以浮动性，从而提高其胃内保留性(Daviss SS等《药学研究》208-213(1996))，还有通过增加制剂的比重，从而提高其与粘膜表面的接触比(Devereux JE等《药理学》42，500-501(1990))等。不过，这些制剂在保留性上还是不够的。
另外，有人已经提出了通过聚合物与水的胶凝作用粘附在消化道粘膜上的制剂，该聚合物是已经加入到制剂中的(日本专利申请未审公开平5-132416)。不过，这种制剂对有意粘附的消化道缺乏粘附选择性，因此这种制剂不可能仅粘附胃与十二指肠粘膜。
因此本发明的一个目的是提供仅粘附胃与十二指肠粘膜的制剂，其药物是控制释放的，并且选择性地对胃与十二指肠具有优异的药理学作用。
发明的公开
鉴于前述，本发明人进行了广泛研究。结果发现，通过利用一种成分控制药物的释放，该成分选自水不溶性聚合物、聚甘油脂肪酸酯、脂类和蜡类；并利用一种聚合物赋予该药物以仅针对胃与十二指肠粘膜的选择性粘附能力，该聚合物在酸性条件下粘附消化道粘膜表面，但在中性或碱性条件下不粘附，使该药物作用于胃与十二指肠粘膜长达几个小时，但又快速地从肠中排泄，这样可以提供以低药物浓度发挥高效药理作用的制剂，从而完成了本发明。
因此本发明提供了胃和／或十二指肠粘附性药物组合物，该药物组合物是通过在一种组合物上用一种聚合物包衣而得到的，该组合物含有在胃和／或十二指肠中发挥作用的药物和一种选自水不溶性聚合物、聚甘油脂肪酸酯、脂类和蜡类的成分，该聚合物在酸性条件下对消化道粘膜表面具有粘附能力，但在中性或碱性条件下从消化道粘膜上分离。
附图的简要说明
图1阐述制剂的粒径与其对细胞的粘附比之间的关系。图2阐述pH与粘附之间的关系。图3阐述药物向明胶的转移。图4阐述杀灭作用。图5阐述不同释放时间的制剂的杀灭作用。
实施发明的最佳方式
尽管对在酸性条件下对胃和／或十二指肠粘膜表面具有粘附能力而在中性或碱性条件下从消化道粘膜上分离的聚合物(所述聚合物以下将称为“依赖于pH的粘附性聚合物”)没有强加特别的限制，不过优选在至少pH4的溶液中是可溶性的并且具有一个阴离子基团的聚合物。这样的依赖于pH的粘附性聚合物的实例包括：
(1)天然聚合物：纯化的虫胶和白虫胶；和
(2)合成聚合物：
纤维素衍生物聚合物：
羟丙基甲基纤维素邻苯二甲酸酯、乙酸羟丙基甲基纤维素琥珀酸酯、羧甲基乙基纤维素、乙酸纤维素苯三酸酯、乙酸纤维素邻苯二甲酸酯等，
丙烯酸类聚合物：
从丙烯酸和／或甲基丙烯酸得到的聚合物、从丙烯酸和／或甲基丙烯酸和一种羧酸酯得到的聚合物等，和
聚乙烯醇型聚合物：
乙酸聚乙烯邻苯二甲酸酯等。
作为用于本发明的依赖于pH的粘附性聚合物，特别优选具有一个羧基的那些，更优选从丙烯酸和／或甲基丙烯酸得到的那些，进而更优选从丙烯酸和／或甲基丙烯酸和一种羧酸酯得到的那些。这里所用羧酸酯的实例包括丙烯酸酯和甲基丙烯酸酯，例如丙烯酸甲酯、丙烯酸乙酯、丙烯酸正丙酯、丙烯酸异丙酯、丙烯酸正丁酯、丙烯酸异丁酯、丙烯酸叔丁酯、2-羟乙基丙烯酸酯、2-羟丙基丙烯酸酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、甲基丙烯酸正丙酯、甲基丙烯酸异丙酯、2-羟乙基甲基丙烯酸酯、2-羟丙基甲基丙烯酸酯、甲基丙烯酸正丁酯、甲基丙烯酸异丁酯和甲基丙烯酸叔丁酯。
其中，优选甲基丙烯酸-甲基丙烯酸酯共聚物，特别优选甲基丙烯酸含量为20至60％者，例如Eudragit L100或S100。
这些依赖于pH的粘附性聚合物可以单独或者组合使用。
本发明中，选自水不溶性聚合物、聚甘油脂肪酸酯、脂类和蜡类的成分(以下可以称为“水不溶性成分”)是一种用于控制活性成分释放的成分。
对用于本发明的水不溶性聚合物没有强加特别的限制，只要它们是制剂中常用的缓释基质。这些聚合物可以单独或者组合使用。作为这样的聚合物，可以举出下列实例。
纤维素型聚合物：晶性纤维素、乙基纤维素、羟甲基纤维素邻苯二甲酸酯、乙酸羟甲基纤维素琥珀酸酯、羧甲基乙基纤维素、乙酸纤维素邻苯二甲酸酯等。其中，特别优选乙基纤维素。
对用于本发明的聚甘油脂肪酸酯没有强加特别的限制，可以使用的聚甘油的脂肪酸酯例如二甘油、三甘油或高级甘油。作为聚甘油脂肪酸酯的脂肪酸部分，优选C8-30脂肪酸，而作为聚甘油部分，优选二甘油至二十甘油。
聚甘油脂肪酸酯的具体实例包括二甘油单硬脂酸酯、四甘油单硬脂酸酯、六甘油单硬脂酸酯、十甘油单硬脂酸酯、四甘油三硬脂酸酯、十甘油三硬脂酸酯、四甘油五硬脂酸酯、六甘油五硬脂酸酯、六甘油单油酸酯、十甘油单油酸酯、三甘油二油酸酯、四甘油二油酸酯、四甘油五油酸酯、六甘油五油酸酯、三甘油二亚油酸酯、四甘油二亚油酸酯、六甘油二亚油酸酯、四甘油单棕榈酸酯、六甘油单棕榈酸酯、十甘油单棕榈酸酯、四甘油三棕榈酸酯和六甘油三棕榈酸酯。
用于本发明的脂类实例包括高级脂肪酸及其盐、高级醇和脂肪酸甘油酯，蜡类实例包括蜡和烃。高级饱和脂肪酸或其盐的实例包括C8-30脂肪酸及其盐，例如硬脂酸、硬脂酸镁和硬脂酸铝。高级醇的实例包括C10-24脂族醇，例如硬脂醇和鲸蜡醇。作为脂肪酸甘油酯，不仅可以使用脂肪酸的三甘油酯，而且可以使用它的单甘油酯和二甘油酯。蜡的实例包括巴西棕榈蜡和蜂蜡，烃的实例包括微晶蜡和石蜡。
上述水不溶性成分、即水不溶性聚合物、聚甘油脂肪酸酯、脂类和蜡类，可以单独或者组合使用。
鉴于自由控制药物从制剂中的释放能力，可以向上述水不溶性成分中加入任意比例的水溶性聚合物。这样的聚合物的实例包括聚乙二醇、羟乙基纤维素、羟丙基纤维素、氨基烷基甲基丙烯酸酯共聚物和聚乙烯缩醛二乙氨基乙酸酯。
本发明中为了自由地控制释放能力，优选向上述水不溶性成分中加入0．1至60wt％的水溶性聚合物。
作为用于本发明的药物，在胃或十二指肠中起效的药物是适合的。这样的药物实例包括抗酸剂、胃粘膜保护剂、H2阻滞剂、质子泵抑制剂(PPI)、抗生素和脲酶抑制剂。
用于本发明的抗酸剂实例包括氢氧化镁和硅酸镁铝。
用于本发明的胃粘膜保护剂实例包括甲基甲硫氨酸磺酰氯(MMSC)、依卡倍特钠、硫糖铝和盐酸西曲酸酯。
用于本发明的H2阻滞剂实例包括法莫替丁、西咪替丁、乙酸罗沙替丁和雷尼替丁。
用于本发明的PPI实例包括奥美拉唑和兰索拉唑。
用于本发明的脲酶抑制剂实例包括乙酰氧肟酸和辛酰氧肟酸。
用于本发明的抗生素实例包括抗幽门螺杆菌活性物质、铋盐和喹诺酮型化合物，其中优选抗幽门螺杆菌活性物质。抗幽门螺杆菌活性物质的实例包括青霉素型抗生素(例如阿莫西林和氨苄西林)、大环内酯(例如红霉素和克红霉素)和四环素型抗生素(例如四环素、米诺环素和链霉素)。在这些抗生素中，优选青霉素型抗生素，特别优选对幽门螺杆菌具有高抗菌性的阿莫西林(以下将简称为“AMOX”)。
本发明的组合物中，药物的含量可以酌情根据药物或制剂的性质加以确定。通常，优选0．01至95wt％左右的含量，特别优选0．1至90wt％的范围。水不溶性成分的用量可以根据成分的性质、药物的释放时间等加以确定。不过，优选在组合物中加入0．1至95wt％，特别优选1至60wt％。优选在组合物中加入0．1至95wt％依赖于pH的粘附性聚合物，特别优选1至50wt％。
向本发明的组合物中可以加入固体药物制剂中常用的添加剂。实例包括如下：
(1)赋形剂：乳糖、玉米淀粉、滑石、绵白糖、轻质无水硅酸、碳酸钙、碳酸镁等。
(2)粘合剂：淀粉、蔗糖、明胶、阿拉伯胶粉、羧甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、支链淀粉、糊精等。
(3)增塑剂：聚乙二醇、柠檬酸三乙酯等。
另外，可以使用着色剂、矫味剂、吸附剂、防腐剂、湿润剂和抗静电剂作为添加剂。这样一种添加剂的量可以酌情加以确定，但要在既不影响依赖于pH的对胃粘膜的粘附性、对药物释放能力也不具有副作用的程度内。
本发明组合物包含药物，必要的话还包含添加剂和上述不溶性成分，它用依赖于pH的粘附性聚合物包衣。这里，包含药物、必要的添加剂和上述水不溶性成分的组合物可以是在药物或添加了药物的混合物上用上述水不溶性成分包衣的组合物，或者是含有药物、必要的添加剂和上述水不溶性成分混合物的基质。不过前者是优选的。本文所用的术语“包衣”不仅指整个颗粒表面的均匀包衣，而且指颗粒表面的部分包衣。
尽管药物从制剂中的释放时间可以鉴于所选择的药物性质等自由地加以确定，仍然需要连续的和更长的释放时间，目的是完全发挥制剂的性质，也就是粘附在胃粘膜上，使药物直接作用于此。另外，在制剂仍然粘附和留存在胃粘膜上时，药物的释放需是完全的。胃液、胃上皮细胞的代谢、膳食等的影响当然也必须加以考虑。由上述因素判断，药物从制剂中的释放时间需要2至8小时。释放时间可以用一定比例的水不溶性成分与水溶性聚合物、水不溶性成分的量等加以控制。
有鉴于对胃和／或十二指肠粘膜的粘附性，本发明药物组合物的粒径优选在30至300μm的范围内，特别优选75至300μm、进而100至250μm的范围。
在本发明药物组合物是用上述水不溶性成分包衣的制剂的情况下，它例如是通过用常用造粒机等形成含有药物的颗粒，然后将颗粒用上述水不溶性成分和依赖于pH的粘附性聚合物顺续包衣加以制备的。对造粒来说，可以适用流化床造粒、高剪切造粒、挤出造粒等。对包衣来说，可以适用常用方法，例如锅包衣或流化床包衣。对含有水或有机溶剂的溶液或分散系形式的包衣剂来说，也可以适用喷雾包衣。
在含有药物和上述水不溶性成分的组合物是基质形式的情况下，它可以通过将上述水不溶性成分溶解在适当的有机溶剂中，将所得溶液与药物捏合，然后干燥并粉碎捏合物加以制备，或者通过将含有药物的上述水不溶性成分溶解在适当的溶剂中，将所得溶液分散在与该溶剂不可混溶的溶液中，然后加热蒸发溶剂以形成颗粒，然后将颗粒用依赖于pH的粘附性聚合物包衣加以制备。
对有机溶剂的性质没有强加特别的限制。实例包括醇类、例如甲醇、乙醇和异丙醇，酮类、例如丙酮，和卤代烃类、例如氯仿和二氯甲烷。在包衣剂或基质中，可以加入上述添加剂等。
实施例
以下将通过实施例和试验对本发明作更具体地描述。不过应当牢记，本发明不受这些实施例所限。
实施例1
按照表1所示配方，利用流化床包衣机制备胃和／或十二指肠粘膜粘附性制剂。也就是说，向3000g无水磷酸氢钙(平均粒径：150μm)中喷入75g磷酸核黄素的3升水溶液，干燥，然后用400g乙基纤维素的4升乙醇溶液喷雾包衣。干燥后，喷入500g甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”)与50g柠檬酸三乙酯的5升乙醇溶液进行包衣，由此制得黄色胃和／或十二指肠粘膜粘附性制剂1。
对比例1
以类似于实施例1的方式，向3000g无水磷酸氢钙(平均粒径：150μm)中喷入75g磷酸核黄素的3升水溶液，干燥，然后仅用400g乙基纤维素的4升乙醇溶液包衣，由此得到对比制剂1。表1
| 粘附性制剂1 | 对比制剂1 | |
| 无水磷酸氢钙(商品名“Fujikarin SG”)磷酸核黄素乙基纤维素甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”)柠檬酸三乙酯 | 3000g75g400g500g50g | 3000g75g400g-- |
参照例1
按照表2所示配方，制备胃和／或十二指肠粘膜粘附性组合物。也就是说，将20g甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”)与2g柠檬酸三乙酯溶解在50ml乙醇中，然后加入25g药物和75g赋形剂。所得混合物加热至60℃使充分混合，然后干燥。将干燥后的混合物粉碎，然后分级，由此分别得到平均粒径分别为约30、70、100、150、200、270、325、350和400μm的制剂。表2
| 硫酸钡玉米淀粉甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”)柠檬酸三乙酯(乙醇) | 25g75g20g2g50ml |
实施例2
在流化床造粒机中装入250g AMOX和250g赋形剂，成分出于表3所示，然后向其中喷入40g乙基纤维素的400ml乙醇溶液，造粒。然后，将所得颗粒用150g乙基纤维素的1．5升乙醇溶液包衣，然后用125g甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”)与25g柠檬酸三乙酯的1．5升乙醇溶液包衣，由此得到制剂。将所得制剂分级，由此得到球状微颗粒，不可通过150目筛但可通过80目筛(以下将简称为“80／150目”)，为制剂(1)。其次，将41．9g AMOX和458．1g赋形剂装入流化床造粒机，然后造粒。所得颗粒以类似于制剂(1)所述方式包衣，由此得到制剂(2)。第三，将41．9g AMOX和458．1g赋形剂装入流化床造粒机，以类似于制剂(2)所述方式造粒，然后用112g乙基纤维素与38g聚乙二醇6000的1．5升乙醇溶液包衣，用于控制释放能力。以类似于制剂(1)或(2)所述方式将甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”)包衣，由此得到制剂(3)。第四，将250g AMOX和250g赋形剂装入流化床造粒机，然后以类似于(1)的方式造粒。将所得颗粒用乙基纤维素包衣，然后用甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”93．7g；商品名“Eudragit S100”31．3g)与25g柠檬酸三乙酯的1．5升乙醇溶液包衣，由此得到制剂(4)。表3
| (1) | (2) | (3) | (4) | |
| AMOX玉米淀粉甘露糖醇乙基纤维素PEG6000甲基丙烯酸-甲基丙烯酸甲酯共聚物：(商品名“Eudragit L100”)(商品名“Eudragit S100”)柠檬酸三乙酯 | 250g250g-190g-125g-25g | 41．9g250g208．1g190g-125g-25g | 41．9g250g208．1g152g38g125g-25g | 250g250g-190g-93．7g31．3g25g |
| 释放时间(小时) | 6 | 6 | 2 | 6 |
对比例2
利用一种与水形成凝胶的聚合物，所述聚合物描述在日本专利申请未审公开平5-132416，制备粘附在消化道粘膜上的制剂。具体来说，在70℃下将85g硬脂酸溶解，然后加入15g丙烯酸型聚合物(商品名“Hibiswako 104”)。彻底混合10分钟后，所得混合物冷却，固化。对所得固体进行粉碎和分级，由此制得粒径约为150μm的制剂。
试验1
由依赖于pH的粘附性聚合物引起的胃内保留性的研究
将实施例1和对比例1中得到的制剂各自悬浮在JP第一液体中，浓度为10％(W／V)。将2ml所得悬浮液对禁食24小时的大鼠(SD大鼠，8周龄)给药。各在给药后一小时和三小时，摘出胃，研究胃中制剂的保留性。结果，胃中实施例1的黄色制剂的保留性在给药后各一小时和三小时得以确认，而对比例1的黄色制剂的保留性在给药后一小时得不到确认。从这些结果可以确认，加入甲基丙烯酸-甲基丙烯酸甲酯共聚物对胃粘膜中制剂的保留性来说是必要的。
试验2
依赖于粒径的粘附性研究
将参照例1中得到的不同粒径的制剂各自悬浮在JP第一液体中，浓度为10％(W／V)。将2ml所得悬浮液对人成纤维细胞给药，该细胞已经在塑料条上培养，直到融合状态。静置一分钟，使制剂粘附在细胞上。粘附后，将塑料条在JP第一液体中洗涤。然后，测量塑料条上残留的制剂重量，计算所粘附的制剂的量。另外，从所粘附的量，按照下式计算制剂所覆盖的面积，作为制剂对细胞的粘附性指征。
计算公式
粒径：r，制剂比重：d，所粘附的量：W
每粒重量：w=4／3xπx(r／2)3xd
所粘附的颗粒数：N=W／w
每粒所覆盖的面积：s=πx(r／2)2
总覆盖面积：S=Nxs
结果如图1所示。从结果可知，关于制剂对细胞的粘附性，粒径最高为200μm的颗粒的粘附性没有改变，粒径超过200μm的颗粒的粘附性逐渐衰退，粒径为350μm或以上的颗粒没有粘附性。从上述发现确认，制剂的依赖于pH的粘附性发生在粒径小于300μm左右的范围内，当粒径最高为200μm左右时可得到恒定的高粘附性。
试验3
利用含有甲基丙烯酸-甲基丙烯酸甲酯共聚物并且具有150μm粒径的参照例1制剂和含有丙烯酸型聚合物并且在对比例2中制备的对比制剂，研究了在pH各不相同的溶液中对人成纤维细胞的粘附性。结果如图2所示。
从结果观察到，含有甲基丙烯酸-甲基丙烯酸甲酯共聚物的制剂在JP1(pH1．2)中表现良好的粘附性，但在pH调为6的生理盐水中没有粘附性。另一方面，含有丙烯酸型聚合物的对比制剂在粘附性上没有表现出因pH而异的差别。从上述发现可知，由甲基丙烯酸-甲基丙烯酸甲酯共聚物带来的粘附性因pH而异，并且具有较高的局部选择性。
试验4
药物因粘膜粘附性而发生的过渡
将固化的20％明胶置于溶液中，作为胃粘膜模型。向明胶中各自给以50mg(折合1mg磷酸核黄素)实施例1中制备的胃和／或十二指肠粘膜粘附性制剂和1mg磷酸核黄素，然后在25rpm下搅拌，以除去浓度梯度。1小时和3小时后分别测量药物转移给明胶的量。结果如图3所示。
从结果确认，用胃和／或十二指肠粘膜粘附性制剂给药的明胶与用溶液给药的明胶相比，转移性更高，说明通过使制剂直接粘附在胃和／或十二指肠上并且使药物从制剂中释放，可以达到更有效的药理作用，并且可以减少剂量。
试验5
含有AMOX的胃和／或十二指肠粘膜粘附性制剂的作用
将实施例2中制备的含有AMOX的胃和／或十二指肠粘膜粘附性组合物(表3中的(1)、(2)和(4))各自悬浮在0．1％黄蓍胶溶液中，用作制剂给药溶液。在类似的黄蓍胶溶液中悬浮AMOX粉末，用作给药溶液。用幽门螺杆菌ATCC 43504(以下将简称为“HP”，109活菌计数x3／小鼠)经口和胃内感染禁食24小时的ddY小鼠。27天后，将各制剂溶液和溶液调至AMOX的含量为0．1mg／kg(制剂(2))和1mg／kg(制剂(1)和(4))，然后连续5天口服给药。最后一次给药后24小时切除小鼠的胃，将破裂后的胃的溶液接种在HP选择性培养基上。在微需氧条件下培养8天后，测量活菌计数。HP的活菌计数如图4所示。从结果可确认，与用给药溶液给药的组相比，用含有AMOX的胃和／或十二指肠粘附性制剂给药的组表现出更高的杀灭作用。
试验6
含有AMOX的胃和／或十二指肠粘膜粘附性制剂因释放时间而异的杀灭作用
将实施例2中制备的含有AMOX的胃和／或十二指肠粘膜粘附性制剂(表3中的(2)和(3))各自悬浮在0．1％黄蓍胶溶液中。将所得悬浮液调至含有0．1mg／kg的AMOX，然后连续5天对以类似于试验4的方式用HP感染的ddY小鼠给药。如试验5测量活菌计数，结果如图5所示。从结果可知，两种含有AMOX的胃和／或十二指肠粘膜粘附性制剂比溶液具有更高的杀灭作用。而且，具有较长AMOX释放时间(6小时)的制剂(2)比具有较短AMOX释放时间(2小时)的制剂(3)具有更高的杀灭作用。从上述发现可知，通过药物的控制释放，可以实现有效的杀灭作用。
实施例3
在20ml乙醇中加入6g甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”)和1．2g柠檬酸三乙酯，充分溶解之。向所得溶液中加入8g四甘油单硬脂酸酯。干燥后，所得混合物进行造粒和分级，由此得到平均粒径为150μm的制剂。
实施例4
在20ml乙醇中加入6g甲基丙烯酸-甲基丙烯酸甲酯共聚物(商品名“Eudragit L100”)和1．2g柠檬酸三乙酯，充分溶解之。将所得溶液与8g硬脂酸混合。干燥后，将混合物造粒和分级，由此得到平均粒径为150μm的制剂。
以类似于试验3的方式测试了实施例3和4中得到的制剂的粘附性。结果可知，这些制剂的粘附性取决于pH，并且具有较高的局部选择性。
工业上开发的能力
根据本发明的胃和／或十二指肠粘膜粘附性药物组合物表现出它的依赖于pH的粘附性，因此它在酸性条件下直接粘附在消化道粘膜上，在消化道内具有较高的保留性，这使药物从制剂中直接释放到胃和／或十二指肠粘膜上成为可能；它也表现出控释特性，这使药物连续释放和活性成分有效转移到胃和／或十二指肠粘膜中成为可行。通过较小的剂量可以达到充分的作用，因此制剂具有较高的安全性，使活性成分的有效利用成为可行。
Claims (4)
1、胃和／或十二指肠粘附性药物组合物，该药物组合物是通过在一种组合物上用一种聚合物包衣而得到的，该组合物包含作用于胃和／或十二指肠的药物和一种或多种选自水不溶性聚合物、聚甘油脂肪酸酯、脂类和蜡类的成分，该聚合物在酸性条件下对消化道粘膜表面具有粘附能力，而在中性或碱性条件下从消化道粘膜上分离。
2、根据权利要求1的药物组合物，其中该药物已经用一种或多种选自水不溶性聚合物、聚甘油脂肪酸酯、脂类和蜡类的成分包衣。
3、根据权利要求1或2的药物组合物，其中在酸性条件下对消化道粘膜表面具有粘附能力、而在中性或碱性条件下从消化道粘膜上分离的该聚合物可溶于pH至少为4的溶液，并且具有一个阴离子基团。
4、根据权利要求1至3任意一项的药物组合物，其中该药物选自抗酸剂、胃粘膜保护剂、H2阻滞剂、质子泵抑制剂、抗生素和脲酶抑制剂。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP72098/1998 | 1998-03-20 | ||
| JP7209898 | 1998-03-20 | ||
| JP10072099A JPH11269064A (ja) | 1998-03-20 | 1998-03-20 | 胃・十二指腸付着性医薬組成物 |
| JP72099/1998 | 1998-03-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1293576A true CN1293576A (zh) | 2001-05-02 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99804193A Pending CN1293576A (zh) | 1998-03-20 | 1999-03-17 | 胃和/或十二指肠粘附性药物组合物 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6582720B1 (zh) |
| EP (1) | EP1062955A1 (zh) |
| KR (1) | KR20010041019A (zh) |
| CN (1) | CN1293576A (zh) |
| AU (1) | AU748299B2 (zh) |
| BR (1) | BR9908616A (zh) |
| CA (1) | CA2320387A1 (zh) |
| EA (1) | EA003512B1 (zh) |
| HU (1) | HUP0101248A2 (zh) |
| ID (1) | ID26247A (zh) |
| MY (1) | MY120798A (zh) |
| NO (1) | NO20004049L (zh) |
| NZ (1) | NZ506280A (zh) |
| PL (1) | PL342971A1 (zh) |
| TR (1) | TR200002465T2 (zh) |
| TW (1) | TW585770B (zh) |
| YU (1) | YU51300A (zh) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE300285T1 (de) * | 1999-06-07 | 2005-08-15 | Altana Pharma Ag | Neue zubereitung und darreichungsform enthaltend einen säurelabilen protonenpumpeninhibitor |
| US8101209B2 (en) | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
| ATE407674T1 (de) | 2002-04-09 | 2008-09-15 | Flamel Tech Sa | Orale pharmazeutische formulierung in form einer wässrigen suspension von mikrokapseln zur modifizierten freisetzung von amoxicillin |
| CN100553625C (zh) | 2002-04-09 | 2009-10-28 | 弗拉梅技术公司 | 活性成分微囊的口服混悬液 |
| US7670627B2 (en) * | 2002-12-09 | 2010-03-02 | Salvona Ip Llc | pH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients |
| EP1784160A1 (en) * | 2004-06-17 | 2007-05-16 | Amano Enzyme USA., Ltd. | Controlled release formulations of enzymes, microorganisms, and antibodies with mucoadhesive polymers |
| US8252333B2 (en) | 2006-01-26 | 2012-08-28 | Jorge Cueto-Garcia | Biodegradable, non-toxic biological adhesive for use in abdominal surgery |
| WO2007086078A2 (en) * | 2006-01-30 | 2007-08-02 | Panacea Biotec Ltd. | Novel pharmaceutical compositions and process of preparation thereof |
| US20080279921A1 (en) * | 2007-05-07 | 2008-11-13 | Ceramoptec Industries, Inc. | Gel-formulations of hydrophobic photosensitizers for mucosal applications |
| US8303573B2 (en) | 2007-10-17 | 2012-11-06 | The Invention Science Fund I, Llc | Medical or veterinary digestive tract utilization systems and methods |
| US20090105561A1 (en) * | 2007-10-17 | 2009-04-23 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Medical or veterinary digestive tract utilization systems and methods |
| US8789536B2 (en) | 2007-10-17 | 2014-07-29 | The Invention Science Fund I, Llc | Medical or veterinary digestive tract utilization systems and methods |
| US8707964B2 (en) * | 2007-10-31 | 2014-04-29 | The Invention Science Fund I, Llc | Medical or veterinary digestive tract utilization systems and methods |
| US8808276B2 (en) * | 2007-10-23 | 2014-08-19 | The Invention Science Fund I, Llc | Adaptive dispensation in a digestive tract |
| US20090163894A1 (en) * | 2007-10-31 | 2009-06-25 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Medical or veterinary digestive tract utilization systems and methods |
| US8109920B2 (en) * | 2007-10-31 | 2012-02-07 | The Invention Science Fund I, Llc | Medical or veterinary digestive tract utilization systems and methods |
| US8333754B2 (en) * | 2007-10-31 | 2012-12-18 | The Invention Science Fund I, Llc | Medical or veterinary digestive tract utilization systems and methods |
| US8808271B2 (en) * | 2007-10-31 | 2014-08-19 | The Invention Science Fund I, Llc | Medical or veterinary digestive tract utilization systems and methods |
| US20090137866A1 (en) * | 2007-11-28 | 2009-05-28 | Searete Llc, A Limited Liability Corporation Of The State Delaware | Medical or veterinary digestive tract utilization systems and methods |
| EP2255794A1 (en) * | 2009-05-29 | 2010-12-01 | H e x a l Aktiengesellschaft | Enteric coating |
| EP2480250B1 (en) | 2009-09-24 | 2014-04-16 | Allergan, Inc. | Compositions comprising botulinum toxin A or B for use in the treatment of osteoporosis |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5846019A (ja) * | 1981-09-14 | 1983-03-17 | Kanebo Ltd | 持続性ニフエジピン製剤 |
| DE4036757A1 (de) * | 1990-11-17 | 1992-05-21 | Bayer Ag | Antazida-zubereitung mit verlaengerter magenverweilzeit |
| TW209174B (zh) | 1991-04-19 | 1993-07-11 | Takeda Pharm Industry Co Ltd | |
| ES2145102T3 (es) | 1993-09-09 | 2000-07-01 | Takeda Chemical Industries Ltd | Formulacion que comprende una sustancia antibacteriana y una sustancia antiulcerosa. |
| JP4137179B2 (ja) * | 1994-03-30 | 2008-08-20 | ジーエス ディベロップメント エービー | 生物付着性物質としての脂肪酸エステルの使用 |
| JPH09104640A (ja) | 1995-08-04 | 1997-04-22 | Takeda Chem Ind Ltd | 胃粘膜付着性組成物 |
| EP0867191A4 (en) * | 1995-11-27 | 2000-01-05 | Yamanouchi Pharma Co Ltd | MEDICINE COMPOSITION |
| JPH10167985A (ja) | 1996-10-08 | 1998-06-23 | Takeda Chem Ind Ltd | 抗ヘリコバクター剤 |
| US6428813B1 (en) | 1997-03-25 | 2002-08-06 | Takeda Chemical Industries, Ltd. | Gastrointestinal mucosa-adherent pharmaceutical composition |
-
1999
- 1999-03-17 EP EP99909193A patent/EP1062955A1/en not_active Withdrawn
- 1999-03-17 CA CA002320387A patent/CA2320387A1/en not_active Abandoned
- 1999-03-17 TR TR2000/02465T patent/TR200002465T2/xx unknown
- 1999-03-17 YU YU51300A patent/YU51300A/sh unknown
- 1999-03-17 ID IDW20001880A patent/ID26247A/id unknown
- 1999-03-17 CN CN99804193A patent/CN1293576A/zh active Pending
- 1999-03-17 PL PL99342971A patent/PL342971A1/xx unknown
- 1999-03-17 BR BR9908616-6A patent/BR9908616A/pt not_active IP Right Cessation
- 1999-03-17 EA EA200000973A patent/EA003512B1/ru not_active IP Right Cessation
- 1999-03-17 TW TW088104140A patent/TW585770B/zh not_active IP Right Cessation
- 1999-03-17 NZ NZ506280A patent/NZ506280A/en unknown
- 1999-03-17 AU AU28524/99A patent/AU748299B2/en not_active Ceased
- 1999-03-17 HU HU0101248A patent/HUP0101248A2/hu unknown
- 1999-03-17 US US09/600,885 patent/US6582720B1/en not_active Expired - Fee Related
- 1999-03-17 KR KR1020007009050A patent/KR20010041019A/ko not_active Application Discontinuation
- 1999-03-19 MY MYPI99001044A patent/MY120798A/en unknown
-
2000
- 2000-08-11 NO NO20004049A patent/NO20004049L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| US6582720B1 (en) | 2003-06-24 |
| TR200002465T2 (tr) | 2000-12-21 |
| TW585770B (en) | 2004-05-01 |
| EP1062955A1 (en) | 2000-12-27 |
| AU2852499A (en) | 1999-10-18 |
| BR9908616A (pt) | 2000-10-31 |
| MY120798A (en) | 2005-11-30 |
| ID26247A (id) | 2000-12-07 |
| CA2320387A1 (en) | 1999-09-30 |
| EA003512B1 (ru) | 2003-06-26 |
| AU748299B2 (en) | 2002-05-30 |
| HUP0101248A2 (hu) | 2001-08-28 |
| NZ506280A (en) | 2001-08-31 |
| NO20004049D0 (no) | 2000-08-11 |
| PL342971A1 (en) | 2001-07-16 |
| EA200000973A1 (ru) | 2001-02-26 |
| NO20004049L (no) | 2000-10-03 |
| KR20010041019A (ko) | 2001-05-15 |
| YU51300A (sh) | 2002-09-19 |
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