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CN1134258C - 含有阿莫西林和棒酸盐的聚合物包衣片 - Google Patents

含有阿莫西林和棒酸盐的聚合物包衣片 Download PDF

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CN1134258C
CN1134258C CNB951934023A CN95193402A CN1134258C CN 1134258 C CN1134258 C CN 1134258C CN B951934023 A CNB951934023 A CN B951934023A CN 95193402 A CN95193402 A CN 95193402A CN 1134258 C CN1134258 C CN 1134258C
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C·P·康尼
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N·P·M·戴维森
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Abstract

一种口服给药治疗细菌感染的药物片剂，该片剂包括750-950毫克阿莫西林和一定量棒酸盐的致密混合物，阿莫西林和棒酸盐的重量比为6∶1至8∶1，并且该片剂具有可通过含水薄膜包衣技术使用的聚合物薄膜衣。

Description

含有阿莫西林和棒酸盐的聚合物包衣片
本发明涉及治疗细菌感染的口服药物，该药物包括阿莫西林和棒酸盐。
阿莫西林及其衍生物，例如三水合阿莫西林是已知用于治疗革兰氏阴性和革兰氏阳性细菌感染的抗菌药(例如GB 1241844)。棒酸及其衍生物，例如棒酸钾是已知的β-内酰胺酶抑制剂(例如GB1508977)，其可抑制细菌产生的β-内酰胺酶的活性并且可通过破坏β-内酰胺类抗生素(如阿莫西林)而具有抗生素抗性。本文所用术语“阿莫西林”和“棒酸盐”除非另外说明即包括二者的游离母体酸及衍生物如它们的盐。将棒酸盐与阿莫西林联合使用即可增强阿莫西林的活性。
GB 2005538中描述了棒酸钾和三水合阿莫西林的联合使用，二者比例为阿莫西林∶棒酸为1∶1至6∶1(以母体化合物阿莫西林或棒酸的重量表示，该表示法除非另外说明即用于本说明书全文)。棒酸钾是一个极其难制备的物质，它极易吸湿并对潮湿敏感。在水及含水介质存在下易于发生降解。
阿莫西林和棒酸盐的已知剂型为每日三次给药(即“tid”剂量)。如果将这些剂型制成每日两次给药(即“bd”剂量)则合乎患者便利性和依从性的需要。同样也非常需要这些制剂的活性成分-棒酸盐和阿莫西林具有稳定的生物利用率。
已制备出可每日两次给药的阿莫西林/棒酸盐制剂，而且其具有意想不到极稳定的生物利用率，特别是棒酸盐的生物利用率。在某些情况下，该制剂也可显示出提高的生物利用率。
因此，本发明提供了一种片剂，其为可口服给药治疗细菌感染的药物，该片剂含有750-950毫克阿莫西林和一定数量棒酸盐的致密混合物，阿莫西林与棒酸盐的重量比为6∶1至8∶1(含端点)，并且其具有一层可通过含水薄膜包衣技术使用的聚合物包衣。
适当的阿莫西林衍生物有三水合阿莫西林、无水阿莫西林和阿莫西林的碱金属盐，例如阿莫西林钠。适当的棒酸衍生物有棒酸的碱金属盐，例如棒酸钾。优选使用三水合阿莫西林和棒酸钾联合用于本发明含有两者的片剂，这种联合使用已获得标准许可并且其具有特别的优越性。
适当的片剂含有875毫克阿莫西林±10％和125毫克棒酸盐±10％，即阿莫西林与棒酸盐的比为7∶1。本发明的片剂可适当含有50重量％或更多，例如约65-75重量％的阿莫西林和棒酸盐联合，例如一般为70重量％±2重量％。
本发明的片剂可用于治疗细菌感染，例如一种或多种上呼吸道感染、下呼吸道感染、生殖泌尿道感染及皮肤和软组织感染。本发明的片剂通常适用于治疗对β-内酰胺类抗生素敏感的微生物感染，也对一些耐青霉素微生物有效。
本发明的片剂可包括一种或多种另外的常规用于制剂的赋形剂等。例如片剂可包含一种或多种的常规稀释剂，例如微晶纤维素(其也有利于压片)，如每片含有约20-35重量％(如25-30重量％)；崩解剂如羟基乙酸淀粉钠，例如每片含有0.5-3.5重量％(如1.75-2.25重量％)；润滑剂如硬脂酸镁，例如每片含有0.5-1.5重量％(如0.75-1.25重量％)；以及助流剂如胶态二氧化硅，例如每片含有0.25-1.0重量％(如0.5-0.9重量％)。尽管以上所列各组实例赋形剂与活性成分一起即可组成100％未包衣重量的片芯，但是片剂可另外含有常规用于制剂的矫味剂、着色剂、防腐剂、干燥剂等而组成100％未包衣重量的片芯。
本发明的片剂可通过常规的片剂生产方法而制备，例如混合各成分，然后干压、制粒，接着挤压颗粒形成致密的片芯。通过诸如腾涌或滚压而制备适当的颗粒。
滚压通常包括过筛步骤，该步骤可使粒度分布较均匀，几乎没有极限两端的颗粒。滚压也可适用于大规模及连续生产形成本发明片剂的颗粒，因为尽管在药学上一般认为腾涌和滚压是完全等效的，但是对本发明的片剂而言，发现滚压可意外增加生物利用率的稳定性，因此优选滚压。滚压适当的方法是通过使用已知的“Chilsonator”滚压机。这种滚压机的说明包括在如“The Theory and Practice of IndustrialPharmacy”Lachan等，第3版，Lea & Febiger(1986)，第318-320页。同样优选在低湿度环境下制备本发明制剂，例如低于30％RH，更适合在低于20％RH，理论上湿度尽可能低以保护对湿度高度敏感的棒酸盐，特别是棒酸钾。
可用含水薄膜包衣的聚合物可有利于通过含水薄膜包衣技术包衣薄膜，从而避免使用有机溶剂。适当的聚合物包括羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素(例如胶乳组合物中的乙基纤维素，由FMC公司提供，商标名为“Aqua-Coat”)、甲基羟乙基纤维素、聚乙烯吡咯烷酮(“PVP”，例如以商标名Povidone提供)、羧甲基纤维素钠和丙烯酸聚合物(例如已知的丙烯酸酯，  以商标名“Eudragit”提供)。
优选的聚合物是羟丙基甲基纤维素(“HPMC”)与聚乙二醇(“PEG”)的适当结合。低分子量(200至600系列)的PEG在室温下是液体，可用作增塑剂。高分子量(900至8000)的PEG在室温下是蜡状固体，与低分子量的PEG及其它聚合物如HPMC联合使用可改善薄膜的性质及片剂光泽。
可用于含水薄膜包衣技术的优选聚合物是与一种或多种PEG结合的一种或多种羟丙基甲基纤维素。HPMC聚合物具有溶于生理液及水，不干扰片剂的崩解、溶解度或药物的利用度，可形成韧性薄膜，无不良味道或气味，对热、光、空气、湿度稳定，与稳定剂、着色剂、不透光剂等配伍以及具有光泽等优越性。该羟丙基甲基纤维素用作薄膜形成剂，及聚乙二醇官能用作增塑剂。薄膜包衣中羟丙基甲基纤维素与聚乙二醇的比适合在7.5∶1至5.5∶1至，例如约6.5∶1±10％。适宜羟丙基甲基纤维素以羟丙基甲基纤维素6cps和15cps的混合物形式使用，比例为约2∶1至4∶1，如约3∶1±10％。适宜聚乙二醇以聚乙二醇4000*和6000*的混合物形式使用，比例为约1∶2至2∶1，如约1∶1(*在美国这些物质是分别以聚乙二醇3350和6000*供给的)。薄膜衣也可适当包括一种不透光剂，例如二氧化钛(白色)。薄膜衣中不透光剂与羟丙基甲基纤维素的比适宜为1∶1±10％。
薄膜衣材料优选通过含水薄膜包衣方法施用，因为按此法施用可形成自然薄膜，认为这样也有利于改善生物利用率的稳定性。含水薄膜衣中的适当固体约为10-30％w/v，一般为10-20％，如15％±2％。
所用薄膜衣适宜为干燥薄膜材料的重量相当是总包衣片重的1.0-4.0重量％。
优选本发明药物的剂型包装在一种可防止大气潮气进入的容器中，例如本领域常规的泡囊或密闭瓶等。优选药瓶还含有保护棒酸盐的干燥剂材料。
本发明药物的单位剂量可适宜为口服给药，例如6小时或更长的给药间隔，例如8或更长的给药间隔，如达约12小时的给药间隔。尽管本发明的片剂特别适用每日两次给药，但是根据适当说明并在允许的剂量范围内其也可以较多的频率给药，例如每日三次给药。
阿莫西林每日适当的总剂量为每日900-1800毫克，优选每日1000-1 750毫克(含端点)。棒酸每日适当的总剂量为每日200-300毫克，优选每日250±10毫克。在上述每日总剂量的范围内，对于每日两次口服给药而言，本发明片剂可以约8-12小时的间隔口服给药。
本发明另外提供了一种治疗人或动物细菌感染的方法，包括每日最多两次口服给予所需治疗的人或动物上述药物。
本发明还提供了一种制备用于口服给药治疗细菌感染的药物片剂的方法，包括将750-950毫克阿莫西林和一定量的棒酸盐混合物压片，阿莫西林和棒酸盐的重量比为6∶1至8∶1(含端点)，然后用含有羟丙基甲基纤维素和聚乙二醇的薄膜衣包衣。
该方法适当的及优选的方式如上所述，参照片剂mutatesmutandis。
本发明还提供了上述用作活性治疗物质的片剂。
本发明还提供了上述用于治疗细菌感染的片剂。
本发明还提供了上述片剂在生产用于治疗细菌感染药物中的应用。
本发明还提供了一种治疗患者被细菌感染的方法，包括给予有效量的阿莫西林和棒酸盐(包含在上述片剂中)给药步骤。
本发明仅通过实施例方式描述。
实施例1
制备含有下列组分的片剂：
组分 (mg) 重量％ 作用 参考标准
活性成分1三水合阿莫西林(等价于阿莫西林) 1017.4875.00 70.2 活性成分 EP
棒酸钾(等价于棒酸)其它成分：硬脂酸镁羟基乙酸淀粉钠胶态二氧化硅微晶纤维素片芯重薄膜衣2纯水Opadry WhiteYS-1-7700Opadry WhiteYS-1-7700可分解如下：二氧化钛羟丙基甲基纤维素6cps羟丙基甲基纤维素15cps聚乙二醇33503聚乙二醇88003纯水4包衣片剂重量： 152.45125.014.5029.0010.0226.651450.00NA32.013.7610.563.522.082.08NA1482.00 10.51.002.000.7015.6100.00NA2.243.033.011.06.56.5NA 活性成分润滑剂崩解剂助流剂助压片剂及稀释剂溶剂薄膜衣不透光剂薄膜形成剂薄膜形成剂增塑剂增塑剂溶剂4 G319NFNFNFNFUSPNAEPJPUSNFUSNF X VIIUSP
1所有重量都取决于所用活性成分的强度，以86％的阿莫西林和82％的棒酸钾(41％的棒酸钾与微晶纤维素1∶1混合)为基础。根据活性成分的强度调节微晶纤维素的含量而维持恒定片重。2薄膜衣各成分可以用干粉混合器施用，如美国的Colorcon，OpadryWhite YS-1-7700或欧洲的Opadry White OY-S-7300。薄膜衣各组分的重量％以Opadry薄膜的重量百分比表示。3聚乙二醇3350和8000在欧洲分别以聚乙二醇4000和6000供给。4纯水在操作过程中除去。薄膜衣用于100％的片芯重量。
通过将阿莫西林、棒酸钾和一些微晶纤维素和硬脂酸镁混合，滚压此混合物，然后在常规压片机上压片及包衣前再与其它组分混合而制备片剂。具体方法如下所述。
将所有组分通过装备有4目筛的振动喂料器或通过14目混合筛及磨(除非另外说明)筛到或装入混合器中。在1500rpm操作磨，刀向前，带有0.093英寸的多孔板。
将大约2/3的微晶纤维素装入适当混合器中。将约1/5的三水合阿莫西林装入该混合器中。通过14目筛将一半硬脂酸镁装入该混合器中。混合2分钟。将另外2/5三水合阿莫西林和1/2棒酸钾和微晶纤维素的混合物装入该混合器中。混合3分钟。然后将剩余的三水合阿莫西林和棒酸钾及微晶纤维素混合物装入该混合器中。混合5分钟。
将混合后的组分通过适当容积的Chilsonator，压力为1000psi，然后通过Fitzmill(在1800rpm操作，刀向前，带有0.079”-0.109”的多孔板)，然后经摇摆筛(装备有一个14目的上部筛和一个18目的下部筛)过筛，重复并将过大及过小的颗粒反复挤压直至98％的颗粒都能过适当的筛。
将大约10％的颗粒装入混合器中，过磨。将胶态二氧化硅、羟基乙酸淀粉钠和剩余部分的硬脂酸镁及微晶纤维素装入该混合器中，混合5分钟。将剩余的颗粒装入混合器中，过磨，混合15分钟。
用适当压片机(装备有0.3937”×0.8465”胶囊形状的冲头)挤压混合物形成重量为1.450克的片剂，其硬度和厚度值都达到了生成药用片剂的指标。
然后用含水薄膜衣在60”(150cm)包衣锅中以300Kg批量的规模将片芯包衣。优选的包衣过程需要在足够的温度导入干燥空气以使喷雾过程中的相对湿度低于12％。
在临床试验中，实施例1的片剂个体差异低。尽管实施例1的片剂为典型，但是这种效果也可在药学上等同的片剂(组合物中各成分的比例在例如+10％范围内变化，例如实施例1中的+5％)中观察到。

Claims (11)

1.一种制备片剂的方法，该片剂含有阿莫西林为750-950mg和阿莫西林与棒酸盐重量比为6∶1至8∶1的棒酸盐的致密混合物，并包括和具有聚合物薄膜包衣，该方法包括作为最后步骤，用在含水溶剂体系中配成的薄膜包衣材料包衣该片芯。
2.权利要求1的方法，其中含水包衣体系中的溶剂基本上由纯水组成。
3.权利要求1或2的方法，其中含水薄膜包衣材料中的固体填料是10-30％w/v。
4.前述任一权利要求的方法，其中薄膜包衣材料被施用以使沉积干膜材料重量相当于总包衣片剂重量的1.0-4.0％。
5.前述任一权利要求的方法，其中薄膜包衣材料包括羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基羟乙基纤维素、聚乙烯基吡咯烷酮、羧甲基纤维素钠或丙烯酸酯聚合物。
6.权利要求5的方法，其中薄膜包衣材料包括2∶1至4∶1的羟丙基甲基纤维素6cps和15cps。
7.权利要求5或6的方法，其中薄膜包衣材料包括与聚乙二醇结合的羟丙基甲基纤维素。
8.权利要求7的方法，其中聚乙二醇以1∶2至2∶1的聚乙二醇4000和6000的混合物形式使用。
9.前述任一权利要求的方法，其中该片剂含有875mg阿莫西林±10％和125mg棒酸盐±10％，阿莫西林∶棒酸盐为7∶1。
10.前述任一权利要求的方法，其中该片剂还含有该片剂20-35重量％的微晶纤维素，该片剂0.5-3.5重量％的羟基乙酸淀粉钠，该片剂0.5-1.5重量％的硬脂酸镁，该片剂0.25-1.0重量％的胶态二氧化硅，与活性成分一起组成100％未包衣片芯重。
11.前述任一权利要求的方法，还包括制备颗粒的预先步骤，该颗粒含有经滚压后的阿莫西林和棒酸盐的混合物，然后，该颗粒与赋形剂一起压成适宜包衣的片芯。
CNB951934023A 1994-04-23 1995-04-19 含有阿莫西林和棒酸盐的聚合物包衣片 Expired - Lifetime CN1134258C (zh)

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