CN102176902B - 有机溶剂在莫西沙星湿法造粒中的应用 - Google Patents

有机溶剂在莫西沙星湿法造粒中的应用 Download PDF

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CN102176902B
CN102176902B CN200880131455XA CN200880131455A CN102176902B CN 102176902 B CN102176902 B CN 102176902B CN 200880131455X A CN200880131455X A CN 200880131455XA CN 200880131455 A CN200880131455 A CN 200880131455A CN 102176902 B CN102176902 B CN 102176902B
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法哈德·法什
莱赛普·阿夫奇
菲克莱特·科克
赛尔达·索伊莱麦斯
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Abstract

本发明包括通过采用有机溶剂或有机溶剂混合物的湿法造粒，获得非转化型无水莫西沙星固体药物制剂。

Description

有机溶剂在莫西沙星湿法造粒中的应用
EP0350733描述莫西沙星作为抗感染剂。 
US6610327(TR0101310)公开了一种药物组合物包括莫西沙星或者其盐和/或水合物，至少一种干式粘合剂，至少一种崩解剂，至少一种润滑剂和2.5％～25％的乳糖。该专利的主旨为提供一种药物制剂，可用于制备具有足够硬度或崩解载荷的片剂，同时具有良好的释放性能。该目的通过使用2.5wt％到25wt％范围内的一定量的乳糖而实现。 
EP0780390(TR0970481)请求保护莫西沙星盐酸盐一水合物的晶型。 包括如专利EP0780390中所公开的莫西沙星盐酸盐一水合物，且X-射线粉末衍射图可见(图1)。 
无水莫西沙星盐酸盐比莫西沙星盐酸盐一水合物更适合获得可溶的药物组合物。晶体中出现水更易于降解，由此无水莫西沙星盐酸盐更加优选。 
在药物制剂中使用无水莫西沙星盐酸盐，其X-射线粉末衍射图可见(图2)，提供了合适的稳定性，因此比莫西沙星盐酸盐一水合物更加优选。但是在造粒阶段，如果润湿剂是水而不是有机溶剂或者有机溶剂的混合物，则无水莫西沙星盐酸盐立刻转化为莫西沙星盐酸盐一水合物。这是不希望发生和应该避免的。 
本发明的目的是通过采用有机溶剂或有机溶剂混合物的湿法造粒法得到非转化型无水莫西沙星固体药物制剂。在特定条件下，希望在湿法造粒后，无水莫西沙星盐酸盐应该永久具有其自身形式的性质，而不会转化为EP0 780 390所提到的形式，并且成为药物剂型。无水莫西沙星盐酸盐，而不是EP0 780 390中的形式，应该在制剂的制备和储存过程中永久保持其性质。因此，应当获得非转化型制剂和其制备方法。由此，技术问题为转化成莫西沙星一水合物和万灵药(panacea)通过在湿法造粒中使用有机溶剂或者有机溶剂混合物，用于阻碍转化。 
根据本发明的药物组合物，包括无水莫西沙星盐酸盐，微晶纤维素，聚乙烯吡咯烷酮，甘露醇，交联羧甲纤维素钠，硬脂酸镁和其它适当的赋形剂。并不限于上述赋形剂，且可期冀其它与所述赋形剂具有类同的或同样性质的赋形剂。术语莫西沙星采用其最广的含义且包括其所有的盐，碱和其它衍生物和形式。 
采用有机溶剂或有机溶剂混合物的湿法造粒方法选自异丙醇（IPA），丙酮，乙醇，二氯甲烷或它们的混合物的组。有机溶剂或有机溶剂混合物是优选的，因为湿法造粒采用水导致从无水莫西沙星盐酸盐向莫西沙星一水合物的转化（图3）。不希望被转化，因此造粒不应采用水或水混合物来进行。无水莫西沙星盐酸盐在制备过程中不应暴露于水中。在湿法造粒方法中有机溶剂选自异丙醇（IPA），丙酮，乙醇，二氯甲烷或它们的混合物的组，由此得到非转化型制剂（分别参见图4，图5，图6，图7）。 
具体实施方式
实施例1 
将聚维酮K30加入到异丙醇并混合直到聚维酮K-30完全溶解（步骤1）。将无水莫西沙星盐酸盐和微晶纤维素转移至造粒机并混合（步骤2）。将步骤1中得到的造粒溶液加入到步骤2得到的粉末混合物中并混合。将湿颗粒从所述造粒机中取出置于烤箱中并干燥。颗粒过筛。将甘露醇SD200，交联羧甲纤维素钠转移至容器内的混合物中并且混合。将硬脂酸镁过筛并加入到容器内的混合物中并过筛。根据规格用适当的冲头将所述掺和物制成片剂。用异丙醇处理的X-射线粉末衍射图可见图4。如图4所示，没有发生转化。如果同样的造粒过程，不用异丙醇，而采用丙酮（图5），乙醇（图6），二氯甲烷（图7），也没有发生转化为莫西沙星一水合物的现象。 

Claims (3)

1.一种通过湿法造粒制备无水莫西沙星或其盐的药物制剂的方法，包括如下步骤：
（a）将聚维酮K-30加入到润湿剂中并混合直至聚维酮K-30完全溶解，其中所述润湿剂选自异丙醇，丙酮，乙醇，二氯甲烷或它们的混合物的组；
（b）将无水莫西沙星或其盐和微晶纤维素转移至造粒机并混合；
（c）将步骤（a）得到的造粒溶液加入到步骤（b）得到的粉末混合物中并混合；
（d）将湿颗粒从所述造粒机中取出置于烤箱中干燥并过筛；
（e）将甘露醇SD200，交联羧甲纤维素钠转移至容器内的混合物中并且混合；
（f）将硬脂酸镁过筛并加入到容器内的混合物中并过筛；
（g）根据规格用适当的冲头将掺和物制成片剂。
2.如权利要求1所述的方法，包括如下步骤：
（a）将聚维酮K-30加入到异丙醇中并混合直至聚维酮K-30完全溶解；
（b）将无水莫西沙星盐酸盐和微晶纤维素转移至造粒机并混合；
（c）将步骤（a）得到的造粒溶液加入到步骤（b）得到的粉末混合物中并混合；
（d）将湿颗粒从所述造粒机中取出置于烤箱中干燥并过筛；
（e）将甘露醇SD200，交联羧甲纤维素钠转移至容器内的混合物中并且混合；
（f）将硬脂酸镁过筛并加入到容器内的混合物中并过筛；
（g）根据规格用适当的冲头将掺和物制成片剂。
3.如权利要求1所述的方法，其中无水莫西沙星盐为盐酸盐。
CN200880131455XA 2008-10-09 2008-10-09 有机溶剂在莫西沙星湿法造粒中的应用 Expired - Fee Related CN102176902B (zh)

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TR200907227A2 (tr) * 2009-09-18 2011-04-21 Bi̇lgi̇ç Mahmut Çözünürlüğü yüksek stabil mikronize granüller.
EP2491921A1 (en) * 2011-02-25 2012-08-29 Deva Holding Anonim Sirketi Conservation of anhydrous form of gemifloxacin
CN102204911B (zh) * 2011-03-25 2013-04-17 华润赛科药业有限责任公司 一种盐酸莫西沙星药物组合物及其制备方法
BRPI1106900A2 (pt) * 2011-12-26 2013-11-05 Ems Sa Composição farmacêutica sólida compreendendo antibótico da familia das quinolonas e processo de sua obtenção
FR2992218B1 (fr) * 2012-06-22 2015-01-23 Rivopharm Sa Composition pharmaceutique de chlorhydrate de moxifloxacine et procede de preparation
IL315294A (en) * 2015-03-03 2024-10-01 Pharmacyclics Llc Pharmaceutical formulations of proton tyrosine kinase inhibitor

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US20050031683A1 (en) * 2003-08-04 2005-02-10 Ashish Kapoor Solid pharmaceutical composition
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WO2007148137A1 (en) * 2006-06-23 2007-12-27 Generics [Uk] Limited Novel hydrate form of moxifloxacin monohydrochloride

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BR9915208A (pt) 1998-11-10 2001-07-31 Bayer Ag Preparado farmacêutico de moxifloxacina
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WO1996009056A1 (en) * 1994-09-22 1996-03-28 Akzo Nobel N.V. Process of making dosage units by wet granulation
US20050137227A1 (en) * 2003-04-09 2005-06-23 Dr. Reddy's Laboratories Limited Crystalline form III of anhydrous moxifloxacin hydrochloride and a process for preparation thereof
US20050031683A1 (en) * 2003-08-04 2005-02-10 Ashish Kapoor Solid pharmaceutical composition
WO2007148137A1 (en) * 2006-06-23 2007-12-27 Generics [Uk] Limited Novel hydrate form of moxifloxacin monohydrochloride

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