CN113456639A - 一种抗心律失常的药物组合物及制备方法 - Google Patents
一种抗心律失常的药物组合物及制备方法 Download PDFInfo
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Abstract
本发明公开了一种抗心律失常的药物组合物,其特征在于,所述药物组合物包括:活性成分,包括1‑(3‑甲磺酰胺基苄基)‑6‑甲氧基,7‑苄氧基‑1,2,3,4‑四氢异喹啉或其药学上可接受的盐;辅料,包括基于组合物总重量的30%~80%的乳糖、微晶纤维素和预胶化淀粉。该组合物具备良好的溶出特效,稳定性优异,可以更好地应用于临床。
Description
技术领域
本发明属于药物制剂领域,更具体地说,涉及一种抗心律失常的药物组合物及制备方法。
背景技术
突发性心脏死亡(SCD)是心血管疾病死亡的主要原因之一。SCD产生是由于心肌电生理不稳定而导致有规律的心律消失,最严重的是持续室速(VT,ventriculartachycardia)和室颤(VF,vetricalar fibrillation)。
专利ZL200710181295.7公开了1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉(以下简称化合物A)或其盐,已知其为III类抗心律失常药物,具有延长动作电位时程,对室速和室颤有效。
发明内容
本发明的目的在于提供一种稳定性良好同时溶出迅速的抗心律失常药物组合物及其制备方法。具体地,本发明提出的药物组合物包括:
活性成分,包括1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉或其药学上可接受的盐;
辅料,包括基于组合物总重量的30%~80%的乳糖、微晶纤维素和预胶化淀粉。
进一步地,所述乳糖、微晶纤维素和预胶化淀粉占组合物总重量的40%~60%。
优选地,所述乳糖、微晶纤维素和预胶化淀粉的重量比为1:1.8~2.2:0.9~1.1。优选1:1.9~2.1:0.9~1.1。更优选1:2:1。
进一步地,所述药物组合物还包括崩解剂;其中,所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素及交联聚维酮中的至少一种。
进一步地,所述崩解剂含量选自基于组合物的总重量的1-30%,优选2~20wt%,更优选2.5~4%。
进一步地,所述药物组合物还包括润滑剂;其中,
所述润滑剂选自硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、微粉硅胶、滑石粉、胶态二氧化硅中的至少一种,优选硬脂酸镁和胶态二氧化硅中的至少一种。
具体地,所述润滑剂含量选自基于组合物的总重量的0.5%~5%,优选0.7%。
具体地,所述药物组合物可以是由所述活性成分和所述辅料经过包括混合制粒和干燥工序后得到的颗粒剂、片剂或胶囊剂。
进一步地,所述活性成分的含量为基于组合物总重量的5%~70%,优选10%~50%,更优选20~45%;所述药物组合物为片剂时,每片活性成分含量具体重量为0.1~1000mg,优选10~500mg,再优选50~300mg,更优选100mg。
进一步地,所述药学上可接受盐可以是盐酸盐或磷酸盐。
进一步地,所述的药物组合物还包括粘合剂,其中,
所述粘合剂选自羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮,甲基纤维素中的至少一种;所述粘合剂含量选自基于组合物的总重量的0.5-10%,优选0.9%。
更优选地,所述的药物组合物的处方重量比如下:
其中,化合物B为化合物A的磷酸盐。
本发明还提出了一种如前任一所述的药物组合物在抗心律失常的中的用途。
本发明还提出了一种制备如前所述的药物组合物的方法,该方法包括:
e)将活性成分与乳糖、微晶纤维素和预胶化淀粉混合过筛;
f)进行湿法制粒;
g)干燥;
h)整粒,总混。
具体地,所述干燥选采用静态干燥或流化干燥。
具体地,所述制粒方式采用高速剪切制粒法或流化床喷雾制粒法。
进一步地,所述药物组合物选自片剂时,该方法包括:
按重量比43.6:13.2:26.4:13.2份称取1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉磷酸盐、乳糖、微晶纤维素和预胶化淀粉混匀后过80目筛;
加入3%的羟丙甲纤维素的75%乙醇溶液制软材,过20目筛制粒;
采用热风循环烘箱,50℃鼓风干燥;
采用20目筛整粒;
将整粒后的干颗粒,加入交联羧甲基纤维素钠2.9份和硬脂酸镁0.7份混合;
压片。
本发明对各辅料的种类和用量配比进行了筛选,最终得到具有溶出迅速、稳定性良好特点的药物组合物。0.01mol/L盐酸溶液介质条件下,所述药物组合物中活性成分的溶出度(%),30min达到80%或更高。且该药物组合物制备工艺简单,更适合工艺化大生产。
附图说明
图1为本发明药物组合物以水为溶出介质的溶出曲线。
图2为本发明药物组合物以0.01mol/L盐酸为溶出介质的溶出曲线。
图3为本发明药物组合物以pH4.0醋酸缓冲盐为溶出介质的溶出曲线。
图4为本发明药物组合物以pH6.8磷酸缓冲盐为溶出介质的溶出曲线。
具体实施方式
研究发现,在将化合物A及其盐制备成药物组合物时,在湿、热存在的条件下,药物发生分解,同时药物组合物吸湿造成药物溶出度下降,给制剂工业化大生产造成困难。本发明据此提供了一种稳定性良好同时溶出迅速的抗心律失常药物组合物及其制备方法。
通过以下实施例和试验例进一步详细说明本发明。这些实施例和试验例仅用与说明性目的,而并不用于限制本发明的范围。
1、填充剂种类选择
将化合物A的磷酸盐(以下简称化合物B)、乳糖、微晶纤维素、预胶化淀粉按照表1中的比例,采用湿法制粒,以3%羟丙甲纤维素(50cp)60%乙醇溶液为粘合剂,进行制粒、干燥处理,然后将干颗粒(水分小于3%)进行整粒,再加入处方量的交联羧甲基纤维素钠和硬脂酸镁,进行混合,混匀后,压片,按照每片含化合物B 100mg的标准压片,即得。其中,溶出度为根据中国药典2015版四部附录0931溶出度测定第二法(浆法)使用1000ml的0.01mol/L盐酸溶液进行溶出度测定(下同)。
表1填充剂种类考察
结论:处方1-6中,乳糖-微晶颗粒与乳糖-预胶化淀粉制粒过硬,颗粒细粉量少,影响片剂外观;乳糖-微晶颗粒崩解较快溶出度较好,但粘冲;乳糖-预胶化淀粉颗粒崩解慢,随着乳糖用量增加溶出度增加,但粘冲;处方7-9:微晶-预胶化淀粉崩解较快,不粘冲,但细粉量多。故接下来考察乳糖、微晶纤维素和预胶化淀粉不同比例对片剂成型性及溶出度的影响。
2、填充剂比例选择
将化合物B、乳糖、微晶纤维素、预胶化淀粉按照表2中的比例,采用湿法制粒,以3%羟丙甲纤维素(50cp)60%乙醇溶液为粘合剂,进行制粒、干燥处理,然后将干颗粒(水分小于3%)进行整粒,再加入处方量的交联羧甲基纤维素钠和硬脂酸镁,进行混合,混匀后,压片,按照每片含化合物A100mg的标准压片,即得。
表2填充剂不同比例考察
结论:处方10和11乳糖含量高,制得颗粒较硬,片面粗糙,处方12-13颗粒均匀,片面平整光滑,处方12溶出度较高,预胶化淀粉比例大影响崩解和溶出,因此优选处方12。
3、崩解剂种类考察
将化合物B、乳糖、微晶纤维素、预胶化淀粉按照表3中的比例,采用湿法制粒,以3%羟丙甲纤维素(50cp)75%乙醇溶液为粘合剂,进行制粒、干燥处理,然后将干颗粒(水分小于3%)进行整粒,再加入表3中的交联羧甲基纤维素钠/羧甲基淀粉钠/交联聚维酮和硬脂酸镁,进行混合,混匀后,按照每片含化合物A100mg的标准压片。
表3崩解剂考察
结论:从颗粒性状、溶出现象及溶出度结果看,优选处方14。在确定崩解剂的基础上,进一步筛选填充剂的用量。
4、填充剂用量选择
将化合物B、乳糖、微晶纤维素、预胶化淀粉按照表4中的比例,采用湿法制粒,以3%羟丙甲纤维素(50cp)75%乙醇溶液为粘合剂,进行制粒、干燥处理,然后将干颗粒(水分小于3%)进行整粒,再加入交联羧甲基纤维素钠和硬脂酸镁,进行混合,混匀后,按照每片含化合物A 100mg的标准压片。
表4填充剂用量选择
结果:从颗粒性状、溶出现象及溶出度结果看,优选处方14。
按照处方14、和19分别制备2批样品,每批500片,在高温(60℃)、高湿(75%RH)和光照(4500Lx)条件下放置30天,影响因素试验试验结果表明:在高温和光照条件下,处方14和19溶出度、有关物质和含量无明显变化,但在高湿条件下,处方19片较处方14外观略有膨胀,溶出度明显降低。
结论:通过上述处方筛选及影响因素试验,处方14颗粒流动性、片剂外观、溶出现象、溶出度及稳定性较好,故确定处方14为优选处方。
按照初步确定的处方14,制备三批化合物B片,批号:批次A、批次B、批次C,每批3000片,进行质量研究。完成制剂质量研究后,接着制备三批化合物B片,批号:批次1、批次2、批次3,每批10000片,进行稳定性研究。
5、处方及制备工艺
处方:
单位:质量%
制备工艺:
①预处理
将化合物B、乳糖、微晶纤维素和预胶化淀粉混匀后过80目筛,备用。
②制粒
将经预处理的原辅料加入3%的羟丙甲纤维素(50cp)的75%乙醇溶液制软材,过20目筛制粒。
③干燥
采用热风循环烘箱,50℃鼓风干燥,每半小时翻一次颗粒。用快速水分测定仪测定颗粒水分,当水分在2.0%~3.0%时,干燥结束,收料。
④整粒
采用20目筛整粒。
⑤总混
将整粒后的干颗粒,加入交联羧甲基纤维素钠和硬脂酸镁于物料袋中混合5分钟。
⑥压片
用13mm×6.5mm椭圆形模具压片机,片重控制:重量差异应控制在±5.0%,脆碎度:应小于0.7%。
⑦包衣
包衣增重约3%。
⑧白塑瓶包装
电磁感应铝箔封口机封口,铝封严密,外表整洁。
6、质量检验数据
按照上述工艺制备3批中试规模样品,每批1万片,主要项目检测见表5。
表5化合物B片主要项目检测结果
从3批样品检测主要项目结果看,本品工艺较为稳定。
7、制剂的相关特性
(1)溶出曲线
根据中国药典2015版四部附录0931溶出度测定第二法(浆法)进行溶出度测定,分别使用1000ml的0.01mol/L盐酸溶液,pH4.0醋酸缓冲盐,pH6.8磷酸缓冲盐和水作为溶出介质,并在37.0±0.5℃下以50rpm的桨速进行溶出试验。比较4批制剂在不同溶出介质中的溶出曲线。
4种溶出介质的溶出曲线图附后。本品以0.01mol/L盐酸溶液、pH4.0醋酸缓冲盐和pH6.8磷酸缓冲盐为溶出介质,15分钟溶出85%以上,以水为溶出介质15分钟溶出接近85%。
(2)有关物质
3批有关物质检测结果见表6。
表6 3批化合物B片有关物质测定结果
本品原料性质较稳定,制剂中原辅料相容性较好,单个杂质未超过0.1%,3批制剂有关物质均符合规定。
(3)稳定性
①影响因素试验
批号:批次1;批量:1万片;规格:0.1g;包装:口服固体药用高密度聚乙烯瓶;
表7影响因素考察结果
结论:化合物B片在高温、高湿、光照条件下0、5、10、30天试验结果:样品性状、有关物质、溶出度、含量与0天相比无显著变化。
②加速试验
批号:批次1;批量:1万片;规格:0.1g;包装:口服固体药用高密度聚乙烯瓶;考察条件:40℃±2℃,RH75%±5%。
表8加速稳定性考察-批次1
批号:批次2;批量:1万片;规格:0.1g;包装:口服固体药用高密度聚乙烯瓶;考察条件:40℃±2℃,RH75%±5%
表9加速稳定性考察-批次2
批号:批次3;批量:1万片;规格:0.1g;包装:口服固体药用高密度聚乙烯瓶;考察条件:40℃±2℃,RH75%±5%
表10加速稳定性考察-批次3
小结:化合物B片的3个批次样品加速6个月稳定性试验结果表明:本品性状、有关物质、溶出度及含量与0月相比,各项检测指标均未见明显变化,提示本品加速稳定性试验结果良好。
③长期试验
批号:批次1;批量:1万片;规格:0.1g;包装:口服固体药用高密度聚乙烯瓶;考察条件:30℃±2℃,RH65%±5%
表11长期稳定性考察-批次1
批号:批次2;批量:1万片;规格:0.1g;包装:口服固体药用高密度聚乙烯瓶;考察条件:30℃±2℃,RH65%±5%
表12长期稳定性考察-批次2
批号:批次3;批量:1万片;规格:0.1g;包装:口服固体药用高密度聚乙烯瓶;考察条件:30℃±2℃,RH65%±5%
表13长期稳定性考察-批次3
小结:化合物B片3个批次样品长期12个月稳定性试验结果表明:本品性状、有关物质、溶出度及含量与0月相比,各项检测指标均未见明显变化,提示本品长期稳定性试验结果良好。
结论:本发明的化合物B片3个批次样品通过加速6个月及长期12个月稳定性试验表明:本品在拟定的包装条件下(口服固体药用高密度聚乙烯瓶)密封保存,可以保证样品稳定性良好。
需要指出的是,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。
Claims (10)
1.一种抗心律失常的药物组合物,其特征在于,所述药物组合物包括:
活性成分,包括1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉或其药学上可接受的盐;
辅料,包括基于组合物总重量的30%~80%的乳糖、微晶纤维素和预胶化淀粉。
2.根据权利要求1所述的药物组合物,其特征在于,所述乳糖、微晶纤维素和预胶化淀粉占组合物总重量的40%~60%。
3.根据权利要求1所述的药物组合物,其特征在于,所述乳糖、微晶纤维素和预胶化淀粉的重量比为1:1.8~2.2:0.9~1.1。
4.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物还包括崩解剂;其中,
所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素及交联聚维酮中的至少一种。
5.根据权利要求1所述的药物组合物,其特征在于,所述崩解剂含量选自基于组合物的总重量的1-30%,优选2.5~4%。
6.根据权利要求1所述的药物组合物,其特征在于,所述的药物组合物还包括润滑剂;其中,
所述润滑剂选自硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、微粉硅胶、滑石粉、胶态二氧化硅中的至少一种,优选硬脂酸镁和胶态二氧化硅中的至少一种;
所述润滑剂含量选自基于组合物的总重量的0.5%~5%,优选0.7%。
7.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物为所述活性成分和所述辅料经过包括混合制粒和干燥工序后得到的颗粒剂、片剂或胶囊剂。
8.根据权利要求1所述的药物组合物,其特征在于,所述的药物组合物还包括粘合剂,其中,
所述粘合剂选自羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮,甲基纤维素中的至少一种;所述粘合剂含量选自基于组合物的总重量的0.5-10%,优选1.25%。
9.一种制备如权利要求1所述的药物组合物的方法,其特征在于,该方法包括:
a)将活性成分与乳糖、微晶纤维素和预胶化淀粉混合过筛;
b)进行湿法制粒;
c)动态干燥;
d)整粒,总混。
10.根据权利要求9所述的方法,其特征在于,所述药物组合物选自片剂时,该方法包括:
按重量比43.6:13.2:26.4:13.2份称取1-(3-甲磺酰胺基苄基)-6-甲氧基,7-苄氧基-1,2,3,4-四氢异喹啉磷酸盐、乳糖、微晶纤维素和预胶化淀粉混匀后过80目筛;
加入3%的羟丙甲纤维素的75%乙醇溶液制软材,过20目筛制粒;
采用热风循环烘箱,50℃鼓风干燥;
采用20目筛整粒;
将整粒后的干颗粒,加入交联羧甲基纤维素钠2.9份和硬脂酸镁0.7份混合;
压片。
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CN1566098A (zh) * | 2003-07-02 | 2005-01-19 | 上海医药工业研究院 | 一类异喹啉化合物及其盐的制备方法和应用 |
CN104693115A (zh) * | 2013-12-06 | 2015-06-10 | 上海医药工业研究院 | 手性四氢异喹啉的衍生物或其盐及其制备方法和用途 |
CN105362245A (zh) * | 2014-08-30 | 2016-03-02 | 山东中泰药业有限公司 | 含有索利那新的片剂组合物及其制备方法 |
US20170216209A1 (en) * | 2014-09-30 | 2017-08-03 | Molkerei Meggle Wasserburg Gmbh & Co. Kg | Direct compression excipient based on lactose, cellulose and starch |
CN107778232A (zh) * | 2016-08-31 | 2018-03-09 | 上海医药工业研究院 | 一种四氢异喹啉的盐衍生物及其晶体的制备方法和应用 |
CN107793356A (zh) * | 2016-08-31 | 2018-03-13 | 上海医药工业研究院 | 一种四氢异喹啉的盐衍生物及其晶体的制备方法和应用 |
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CN1566098A (zh) * | 2003-07-02 | 2005-01-19 | 上海医药工业研究院 | 一类异喹啉化合物及其盐的制备方法和应用 |
CN104693115A (zh) * | 2013-12-06 | 2015-06-10 | 上海医药工业研究院 | 手性四氢异喹啉的衍生物或其盐及其制备方法和用途 |
CN105362245A (zh) * | 2014-08-30 | 2016-03-02 | 山东中泰药业有限公司 | 含有索利那新的片剂组合物及其制备方法 |
US20170216209A1 (en) * | 2014-09-30 | 2017-08-03 | Molkerei Meggle Wasserburg Gmbh & Co. Kg | Direct compression excipient based on lactose, cellulose and starch |
CN107778232A (zh) * | 2016-08-31 | 2018-03-09 | 上海医药工业研究院 | 一种四氢异喹啉的盐衍生物及其晶体的制备方法和应用 |
CN107793356A (zh) * | 2016-08-31 | 2018-03-13 | 上海医药工业研究院 | 一种四氢异喹啉的盐衍生物及其晶体的制备方法和应用 |
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WO2021196982A1 (zh) | 2021-10-07 |
EP4129289A1 (en) | 2023-02-08 |
US20230135963A1 (en) | 2023-05-04 |
KR20220145878A (ko) | 2022-10-31 |
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