CN1093254A - 含有麦角溴烟酯的控释药物组合物 - Google Patents
含有麦角溴烟酯的控释药物组合物 Download PDFInfo
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Abstract
含有作为活性成分的麦角溴烟酯或其药用盐的
口服控释药物组合物,包括负载有麦角溴烟酯或其
盐,并用下列物质组成的膜包衣的微粒混合物:
——100—97%的由丙烯酸乙酯和甲基丙烯酸
甲酯组成的平均分子量为800,000的中性共聚物;
——0—3%的水溶性物质。
Description
本发明是关于以麦角溴烟酯为主要活性成分的口服控释药物配方。麦角溴烟酯或8-β-1,6-二甲基-〔(5-溴烟酰氧基)甲基〕-10α-甲氧基麦角灵是麦角灵的半合成衍生物。
麦角溴烟酯和它的活性代谢物主要影响脑血液动力学和代谢。这些活性是由于它的α-阻滞和肌肉溶解及增加葡萄糖和氧的消耗的活性。这种药物还有抗血小板凝集活性。
麦角溴烟酯被吸附在肠道中,并经水解、去甲基化和/或与葡糖醛酸连结而迅速代谢。它主要经肾脏排泄,在每种动物(小鼠、狗、猴、人)中的排泄方式非常相似。在人体中,给药剂量以代谢物的形式3-4天内排泄出,主要在尿中,少量(10%)在粪便中。麦角溴烟酯在临床上主要由于动脉硬化、血栓形成、脑栓塞和短时的脑局部缺血引起的急性和慢性脑血管代谢疾病。
一般的口服配方要求每天给药两次或多次。每天一次的缓释配方对改善病情的同时方便病人明显有利。而且从治疗学的角度来看,控释配方更能维持血药浓度恒定,减小可能的副作用。
根据本发明,发现可以通过包含载有麦角溴烟酯或其盐并由下列物质组成的膜包衣的微粒的药物组合物,得到麦角溴烟酯或它的药用盐的有效的缓释效果:
-100-97%的由丙烯酸乙酯和甲基丙烯酸甲酯组成的、平均分子量为800,000的中性共聚物;
-0-3%的水溶性物质。
本发明的多组分控释配方使一次口服日剂量的麦角溴烟酯,日剂量为20-100mg,优选为40-80mg。
麦角溴烟酯优选以与药用有机酸如酒石酸或琥珀酸的盐的形式载于微粒上。麦角溴烟酯和有机酸的比例为1∶0.5到1∶3(mol∶mol),优选化学计量比。
负载介质优选水相的及可能含有连结剂、润湿剂、抗粘剂和抑泡剂。将负载悬浮液施于由淀粉和蔗糖组成的惰性微粒上,其大小为0.4-1.4mm,优选0.6-0.9mm。
麦角溴烟酯从负载微粒上的释放是由丙烯酸共聚物膜的包衣来控制的,共聚物膜以商标Eudragit Ne在市场上可得到。
由这种聚合物制得的膜不溶于水和胃肠内的流体,对水相介质可渗透,并可膨胀。这些独特的特征使这种聚合物特别适合于制造麦角溴烟酯“库”-微粒制剂,这种制剂能够控制通过扩散穿过包衣的释放。当增加聚合物膜的厚度时,麦角溴烟酯透过膜的释放减少,因此可能通过增厚包衣来减低释放速度。
施于载有麦角溴烟酯的微粒上的聚合物包衣的量为4-20%,优选6-16%(w/w)。包衣聚合物的水相悬浮液中也可以含有抗粘剂和抑泡剂。
另外,通过增加惰性微粒的大小,从0.4到1.4mm,可以减低活性成份的释放速度。
根据本发明的另一个目的,控制麦角溴烟酯释放的包衣膜由丙烯酸乙酯和甲基丙烯酸甲酯共聚物与适当的水溶性物质的混合物组成,以形成微孔包衣膜。在这样的体系中,当膜与胃肠中流体接触时,可溶性物质被溶解后在膜上形成孔,活性成分主要从这些孔中释放。膜孔是由水溶性物质/共聚物的比例来决定的;此比例越高,相等膜厚度下麦角溴烟酯的释放越快。
水溶性物质的例子包括:聚乙烯基吡咯烷酮、聚乙二醇、羟丙基甲基纤维素、乳糖、蔗糖或它们的混合物,优选与聚合物的百分比为1-3%(w/w)的羟丙基甲基纤维素。
当膜由水溶性物质和共聚物组成时,将膜以10-30%(w/w)的量施于麦角溴烟酯微粒上。包衣悬浮液中可以加入增塑剂、抗粘剂和抑泡剂。
本发明的第三个目的是通过不同比例地混合具有不同活性成分释放速度的微粒,来设计麦角溴烟酯的释放。这使得此多成分配方具有明显的灵活性,以得到最适的释放方式。
例如,无包衣的载有5-25mg麦角溴烟酯的快速释放微粒,可
与根据本发明前两个目的得到的控释微粒混合,后者载有15-75mg的麦角溴烟酯。
用微粒装载麦角溴烟酯、用聚合物膜包衣及干燥的操作可用流式床或旋转平锅设备来完成。
然后,微粒可以装入胶囊中或用于形成片剂。
下列实施例进一步说明本发明。
实施例1
含60mg麦角溴烟酯的明胶胶囊。
每个胶囊含有:
麦角溴烟酯 60mg
蔗糖 130.1mg
滑石 58.4mg
玉米淀粉 21.2mg
丙烯酸乙酯/甲基丙烯酸甲酯共聚物 26mg
酒石酸 18.6mg
胶态二氧化硅 8.5mg
聚乙烯基吡咯烷酮 3.75mg
吐温80 1.25mg
Simethicone乳剂 0.20mg。
(二甲基聚硅氧烷和硅胶的混合物)
70℃下,将600g麦角溴烟酯和186g酒石酸溶解在1700g纯化
水中。
将37.5g聚乙烯吡咯烷酮和12.5g吐温80加入此溶液中,搅拌直到彻底溶解。然后,加入6.25g 16%的Simethicone乳剂、225g滑石和25g胶态二氧化硅,用汽轮搅拌器分散均匀。
将所得悬浮液在流式床设备中喷雾到1513g 0.6-0.85mm大小的惰性淀粉和蔗糖微粒上,然后微粒在静电炉中40℃干燥过夜。
为了包衣微粒,将339g滑石、6.25g 16%的Simethicone乳剂和40g胶态二氧化硅用汽轮搅拌器分散在1900g纯化水中。将此悬浮液脱气,并在不断搅拌下加入867g 30%的丙烯酸乙酯/甲基丙烯酸甲酯共聚物悬浮液。
将此悬浮液在流式床设备中喷雾到事先负载有麦角溴烟酯的微粒上。
包衣微粒在静电炉中40℃干燥过夜。
包衣微粒与20g胶态二氧化硅和20g滑石混合,并装入胶囊中,剂量为328mg/胶囊。
实施例2
含有60mg麦角溴烟酯的明胶胶囊。
每个胶囊含有:
麦角溴烟酯 60mg
蔗糖 115.1mg
滑石 58.4mg
玉米淀粉 36.2mg
丙烯酸乙酯/甲基丙烯酸甲酯共聚物 26mg
酒石酸 18.6mg
胶态二氧化硅 8.5mg
聚乙烯基吡咯烷酮 3.75mg
吐温80 1.25mg
Simethicone乳剂 0.20mg。
用实施例1同样方法制备,只是使用比实施例1中较大的惰性微粒,大小为0.95-1.2mm。
将微粒装入胶囊中,剂量为328mg/胶囊。
实施例3:
含有60mg麦角溴烟酯的明胶胶囊。
每个胶囊含有:
麦角溴烟酯 60mg
蔗糖 115.1mg
滑石 38.46mg
玉米淀粉 36.2mg
丙烯酸乙酯/甲基丙烯酸甲酯共聚物 10.4mg
酒石酸 18.6mg
胶态二氧化硅 6.1mg
聚乙烯基吡咯烷酮 3.75mg
吐温80 1.25mg
Simethicone乳剂 0.14mg。
用实施例2中相同方法制备,只是用厚度较小的聚合物膜。将微粒装入胶囊中,剂量为290mg/胶囊。
实施例4
含有60mg麦角溴烟酯的明胶胶囊。
每个胶囊含有:
麦角溴烟酯 60mg
蔗糖 130.1mg
滑石 90.32mg
丙烯酸乙酯/甲基丙烯酸甲酯共聚物 52mg
玉米淀粉 21.2mg
酒石酸 18.6mg
胶态二氧化硅 12.2mg
聚乙烯基吡咯烷酮 3.75mg
吐温80 1.25mg
羟丙基甲基纤维素 1.07mg
Simethicone乳剂 0.3mg
聚乙二醇6000 0.21mg。
同实施例1负载麦角溴烟酯。
为了用微孔聚合物膜包衣微粒,在剧烈搅拌下,将2.1g聚乙二
醇6000和10.7g羟丙基甲基纤维素溶解在3760g 90℃纯化水中。将12.5g 16%的Simethicone乳剂、82g胶态二氧化硅和663g滑石加入到此溶液中,用汽轮搅拌分散均匀。冷却混合物,在不断搅拌下加入1733g 30%丙烯酸乙酯/甲基丙烯酸甲酯共聚物悬浮液。
将所得的溶液在流式床设备中喷雾到事先负载好麦角溴烟酯的微粒上。
在此负载微粒上再覆以15g胶态二氧化硅和15g滑石,并装入胶囊中,剂量为391mg/胶囊。
实施例5
含有60mg麦角溴烟酯的明胶胶囊。
每个胶囊含有:
麦角溴烟酯 60mg
蔗糖 130.1mg
滑石 49.42mg
玉米淀粉 21.2mg
丙烯酸乙酯/甲基丙烯酸甲酯共聚物 19.5mg
酒石酸 18.6mg
胶态二氧化硅 7mg
聚乙烯基吡咯烷酮 3.75mg
吐温80 1.25mg
Simethicone乳剂 0.18mg。
同实施例1负载麦角溴烟酯。
为了包衣微粒,将254.2g滑石、5g 16%的Simethicone乳剂和30g胶态二氧化硅,用汽轮搅拌器分散在1420g纯化水中。将该悬浮液脱气,并在持续搅拌下加入650g 30%的丙烯酸乙酯/甲基丙烯酸甲酯共聚物悬浮液。将所得悬浮液在流式床设备中喷雾在事先负载好麦角溴烟酯的微粒上。将此包衣微粒在静电炉中40℃干燥过夜。将650g无包衣微粒(相当于150g麦角溴烟酯)与2430g包衣微粒(相当于450g麦角溴烟酯)混合,再加入15g胶态二氧化硅和15g滑石。将此微粒混合物装入胶囊中,剂量为311mg/胶囊。
实施例6
含有60mg麦角溴烟酯的明胶胶囊。(参考制剂)
每个胶囊含有:
麦角溴烟酯 60mg
蔗糖 128mg
滑石 36.44mg
玉米淀粉 20.9mg
酒石酸 18.6mg
甲基丙烯酸铵盐共聚物,B型 18mg
胶态二氧化硅 4mg
柠檬酸三乙酯 4mg
聚乙烯基吡咯烷酮 3.75mg
甲基丙烯酸铵盐共聚物,A型 2mg
吐温80 1.25mg
Simethicone乳剂 0.06mg。
70℃下,将37.5g聚乙烯基吡咯烷酮和12.5吐温80加入到含600g麦角溴烟酯、186g酒石酸和1490g纯化水的溶液中,将150g滑石和25g胶态二氧化硅分散在其中。将所得悬浮液在流式床设备中喷雾到惰性淀粉和蔗糖微粒上(大小为0.6-0.85mm),最后在40℃炉中干燥过夜。
另外,将40g柠檬酸三乙酯溶解在70℃ 1300g纯化水中,然后分散4g Simethicone乳剂(16%)和199.4g滑石。冷却混合物,持续搅拌下加入66.8g 30%的甲基丙烯酸铵盐共聚物A型的悬浮液和600g 30%的甲基丙烯酸铵盐共聚物B型的悬浮液。所得溶液在流式床设备中喷雾到事先负载好麦角溴烟酯的微粒上。包衣微粒在静电炉中40℃干燥过夜,再与15g胶态二氧化硅及15g滑石混合,然后装入胶囊中,剂量为297mg/胶囊。
用阳离子共聚物混合物代替中性共聚物来包衣微粒,含有这种微粒的明胶胶囊配方在溶解作用实验中用作对比。
实施例1-6的配方的释放特性用溶解作用实验来评价,此实验用装有桨式搅拌器的根据Ph.Eur.Ⅱ的仪器来进行。用人造胃液(pH1.2)作为开始2小时的溶解介质,然后用磷酸缓冲液将pH升至6.5。
溶解作用实验结果表示在表1中,用释放出的麦角溴烟酯占胶囊中原含量的百分比表示,结构表明:
一用中性丙烯酸共聚物作为包衣膜(实施例1-4)可延长活性成分的释放,但用阳离子丙烯酸共聚物(实施例6)则无效;
-或用不同厚度的聚合物膜(实施例2和3)或用不同大小的惰性微粒(实施例1和2)均可调节释放;
-掺入适当水溶性物质(实施例4对照实施例1)形成多孔包衣膜,也可以加快释放;
-最后,可混合例如具有不同释放速度的微粒(实施例5对照实施例1)来适当设计释放或使释放持久。
实施例1-5的配方的溶解作用实验结果证实了用适当的中性丙烯酸共聚物包衣,来延长麦角溴烟酯的释放和/或使其释放持久的可能性。
经三名26-35岁健康的志愿者“交叉”服用实施例5配方的药剂,与市售的传统30mg片剂对比,进行药代动力学评价。先给每位实验对象空腹服用传统片剂,一天二次(上午9点和下午4点),然后在一周排泄完毕后,再服用一粒实施例5的胶囊(上午9点)。在0时(服药前)和0.5、1、2、3、5、8、9、10、11、13、24小时采集血样,放入含肝素钠的试管中,将样品立即在4℃,3500rpm离心10分钟。所得血浆用丙酮/冰冷冻,-20℃保存、直到分析时为止。因为麦角溴烟酯的半衰期很短,所以用特异的HPLC方法检测它的主要代谢物-10α-甲氧基二氢麦角醇(M2),HPLC使用反相柱,事先在Extrelut萃取柱上萃取及用溶剂萃取来纯化。
结果(表2)表明实施例5的配方(一天服用一次)提供活性代谢物M2的血浆水平达24小时,与此相对比,传统配方需一天服用2次。另外,由于一天只服用一次,使病人更方便,本发明的配方使峰浓度减低,因此减低了麦角溴烟酯的副作用,如高血压和头晕、胃失调、热潮红和皮肤发红。
Claims (12)
1、含有作为活性成分的麦角溴烟酯或其药用盐的口服控释药物组合物,包括负载有麦角溴烟酯或其盐、并用下列物质组成的膜包衣的微粒混合物:
--100-97%的由丙烯酸乙酯和甲基丙烯酸甲酯组成的平均分子量为800,000的中性共聚物;
--0-3%的水溶性物质。
2、根据权利要求1的组合物,其中负载麦角溴烟酯或其盐的惰性微粒为0.4-1.4mm大小的淀粉和蔗糖微粒。
3、根据权利要求2的组合物,其中微粒大小为0.6-0.9mm。
4、根据权利要求1-3任一项的组合物,含有不同大小和包衣的微粒,以控制活性成分的释放速度。
5、根据权利要求1-4任一项的组合物,其中膜由100%的分子量为800,000的丙烯酸乙酯/甲基丙烯酸甲酯共聚物组成。
6、根据权利要求5的组合物,其中膜的量为组合物的4-20%w/w。
7、根据权利要求1-4任一项的组合物,其中膜由97-99%的丙烯酸乙酯/甲基丙烯酸甲酯中性共聚物及1-3%的水溶性物质组成。
8、根据权利要求7的组合物,其中水溶性物质选自聚乙烯基吡咯烷酮、聚乙二醇、羟丙基甲基纤维素、乳糖、蔗糖或它们的混合物。
9、根据权利要求7或8的组合物,其中膜为组合物的10-30%w/w。
10、组合物,其含有根据权利要求1-9的包衣微粒与负载有麦角溴烟酯或其盐的无包衣微粒的适当混合物。
11、根据上述任一项权利要求的组合物,其中含有20-100mg麦角溴烟酯。
12、含有根据权利要求1-11任一项的微粒的胶囊或片剂。
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CN102228450A (zh) * | 2011-06-28 | 2011-11-02 | 重庆市庆余堂制药有限公司 | 尼麦角林胶囊及其生产方法 |
CN111904938A (zh) * | 2020-05-15 | 2020-11-10 | 山东方明药业集团股份有限公司 | 一种尼麦角林片剂的制备方法 |
CN113398089A (zh) * | 2021-06-29 | 2021-09-17 | 海南通用三洋药业有限公司 | 一种尼麦角林胶囊的制备方法和尼麦角林胶囊 |
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FR2786100B1 (fr) * | 1998-11-24 | 2002-03-01 | Aventis Laboratoire | Nouvelle application therapeutique de la nicergoline |
FR2786101B1 (fr) | 1998-11-24 | 2002-07-05 | Aventis Laboratoire | Utilisation de la nicergoline dans le traitement de la spasticite |
JP3718398B2 (ja) * | 2000-01-11 | 2005-11-24 | 信越化学工業株式会社 | フィルムコーティング剤及び経口固形製剤 |
JP5228359B2 (ja) * | 2007-04-12 | 2013-07-03 | ニプロ株式会社 | 主薬粒子及びその製造方法ならびに口腔内崩壊錠 |
CN106333927A (zh) | 2015-07-08 | 2017-01-18 | 昆山龙灯瑞迪制药有限公司 | 修饰释放的尼麦角林组合物 |
CN113081993A (zh) * | 2021-04-15 | 2021-07-09 | 海南通用三洋药业有限公司 | 一种尼麦角林片剂的制备方法 |
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CN102228450A (zh) * | 2011-06-28 | 2011-11-02 | 重庆市庆余堂制药有限公司 | 尼麦角林胶囊及其生产方法 |
CN102228450B (zh) * | 2011-06-28 | 2012-10-31 | 重庆市庆余堂制药有限公司 | 尼麦角林胶囊及其生产方法 |
CN111904938A (zh) * | 2020-05-15 | 2020-11-10 | 山东方明药业集团股份有限公司 | 一种尼麦角林片剂的制备方法 |
CN113398089A (zh) * | 2021-06-29 | 2021-09-17 | 海南通用三洋药业有限公司 | 一种尼麦角林胶囊的制备方法和尼麦角林胶囊 |
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ITMI922885A1 (it) | 1994-06-18 |
HU9303633D0 (en) | 1994-04-28 |
HUT66371A (en) | 1994-11-28 |
ITMI922885A0 (it) | 1992-12-18 |
EP0602619A1 (en) | 1994-06-22 |
JPH0748256A (ja) | 1995-02-21 |
PL301513A1 (en) | 1994-06-27 |
KR950016748A (ko) | 1995-07-20 |
CZ277593A3 (en) | 1994-07-13 |
IT1256743B (it) | 1995-12-15 |
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