CN1102385C - 反胺苯环醇或反胺苯环醇盐的一种快速崩解药物剂型 - Google Patents
反胺苯环醇或反胺苯环醇盐的一种快速崩解药物剂型 Download PDFInfo
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Abstract
本发明描述了不含粘合剂的反胺苯环醇或反胺苯环醇盐口服片剂。
Description
本发明涉及口服反胺苯环醇或反胺苯环醇盐的不含粘合剂片剂。
为了获得药物的固体剂型如片剂中有效成分尽可能快速良好的释放,必须使药物剂型在释放介质中很快崩解。崩解,也就是片剂分解为粒状物的单独颗粒,它受很多因素影响:粘合剂(成粒剂)、润滑剂和填充剂且尤其是填充剂的溶解性可以显著地降低崩解速率,而且颗粒的大小和形状以及片剂的硬度对崩解速率有很大影响。片剂的硬度取决于生产中用的压力。在许多情况下,在一给定的片剂硬度以上,崩解时间显著增加。
片剂的崩解速率可以通过应用崩解剂来增加。崩解剂是一些当片剂同水、缓冲液或消化液接触时可以加速片剂崩解的物质。已知的崩解剂的实例包括淀粉、低度取代的羧甲基纤维素钠、低度取代的羟丙基纤维素、羧甲基纤维素钙、海藻酸、交联羧甲基纤维素和交联聚乙烯吡咯烷酮。
崩解剂的作用和片剂的崩解可受辅料和/或水中易溶的活性成分的强烈影响也是人们周知的,因为片剂的崩解由于辅料溶解过程中片剂体积的减小而受到阻碍。此外水溶性物质在一定程度上显示了粘合剂的性质并且片剂中的毛吸管由于高浓度扩散界面层的快速形成而关闭。因此WO 87/01936提出可选择水溶性的甘露醇同崩解剂熔合在一起随后粉碎用于具有在水中难溶的活性成分的片剂。这样制成的较粗颗粒的优选粒径在0.1~0.6mm之间,同未经处理的甘露醇相比在水中的溶解度降低。具有在水中难溶的活性成分并与经熔化粉碎的甘露醇共同压制的片剂在水中能十分迅速地崩解。
由欧洲专利申请EP 124027也得知难溶性活性成分可以制成速溶片。这些片剂含有以限定粒径分布的活性成分,并含有微晶纤维素和淀粉。
根据德国专利DE 16 17 343,为获得良好的崩解剂作用,可将粘合剂和辅料混悬在一起,然后喷雾干燥。辅料的喷雾干燥混合物有助于片剂快速崩解。由欧洲专利申请EP 130683也可知喷雾干燥片,它含有N-乙酰基-对氨基苯酚作为活性成分,还有部分胶凝化的淀粉,可任选地含有微晶纤维素作为辅助崩解剂。然而这些具有在药学上可以被接受的硬度的喷雾干燥片的崩解时间为3-5分钟,被归为中等一类。
由US 3,181,998得知所压制品由于粘合剂引起的崩解时间的延长可以通过将干燥状态的酶加至该药物制剂中而克服。酶在同水或消化液接触时被激活,通过切断作为粘合剂应用的淀粉、纤维素衍生物或明胶而加速片剂崩解。
另一个影响片剂崩解速率的因素为片剂的硬度。制片过程中高的压力导致高的片剂硬度,也就是压缩制品内部高的结合力使片剂同水性介质接触时崩解更加困难。为了解决这一问题US 5.254.355尝试将干燥混合物压成小于35N的极低硬度的片剂,随后通过磨光片剂表面使硬度至少增加10N。结果表明片剂内部结合力仍保持较低而可能良好崩解。
由专利申请DE 39 09 520知柠檬片可以通过使用接触水可产生CO2的辅料来促进片剂迅速崩解。
盐酸反胺苯环醇-(1RS;2RS)-2-[(二甲氨基)甲基]-1-(3-甲氧苯基)环己醇盐酸盐是一种对剧痛和中强度疼痛有效的止痛剂。然而迄今为止这种活性成分非常好的水溶性阻止成功地开发在水中迅速崩解的片剂。例如,若将反胺苯环醇同不溶性辅料如磷酸二氢钙和超崩解剂如KollidonCL混合制粒得到硬度为80N的片剂,完全崩解需要5分钟,即使增加崩解剂的量也不能加速崩解。然而对在水中应迅速崩解并迅速释放活性成分的片剂,5分钟的崩解速率是不能接受的。因此本发明的目的在于开发一种能在水中迅速崩解并迅速释放有效成分的含有反胺苯环醇或反胺苯环醇盐的片剂,从而能得到含有活性成分的混悬液并可立即饮服。
已经发现可以通过将反胺苯环醇或反胺苯环醇盐以一定重量比同微晶纤维素结合制得不含粘合剂的片剂而满足药物制剂的要求。
因此,本发明涉及口服用不含粘合剂的片剂,它含有重量比至少为2∶1的微晶纤维素与反胺苯环醇或反胺苯环醇盐。
不含粘合剂的片剂中微晶纤维素同反胺苯环醇或反胺苯环醇盐的重量比最好为至少3∶1,特别是至少为4∶1。
按照本发明的片剂能在水中非常迅速地崩解并能非常迅速地释放反胺苯环醇或反胺苯环醇盐,因此按照本发明的片剂在同水接触后可立即产生含有活性成分可以饮服的混悬液。按照本发明的片剂在服用前以固体形式存在,具有诸如剂量准确、良好贮存期、可卫生包装及不需防腐剂的有利特性,而服用时以液体形式存在有例如易于吞服、活性成分快速进入血液的有利特性。
含有淀粉且淀粉与反胺苯环醇或反胺苯环醇盐的重量比为1∶1的按照本发明的片剂是特别优选的。在这些片剂中,片剂的硬度对崩解速率的影响显著降低。而不含淀粉的按照本发明的片剂(实施例1)硬度由80N增至100N时,崩解时间由30秒增至120秒。相反,含有淀粉的按照本发明的片剂(实施例2)硬度由80N增至100N时,崩解时间由30秒增至55秒。而且,据本发明含有淀粉的片剂也显示出活性成分的释放加速。
在按照本发明的片剂中,微晶纤维素同反胺苯环醇/反胺苯环醇盐及淀粉的重量比至少为2∶1∶1。若微晶纤维素同反胺苯环醇/反胺苯环醇盐及淀粉的重量比小于该值,则片剂的崩解速率显著降低。此外用水溶性乳糖或水不溶性的磷酸氢钙代替微晶纤维素也导致崩解速率显著下降。
按照本发明的片剂每片含5-1000mg、最适为10-200mg的反胺苯环醇和/或反胺苯环醇盐尤其是盐酸反胺苯环醇。
按照本发明的片剂可含有作为选择性成份的重量为0.5-10%的至少一种崩解剂,如交联聚乙烯吡咯烷酮(PVP-CL),交联羧甲基纤维素和/或羧甲基淀粉钠和至多20%(重量)的矫味剂,如甜味剂象糖精钠、环己基氨基磺酸钠和/或天冬酰苯丙氨酸甲酯,以及调味剂象水果和/或植物调味剂。
按照本发明的片剂的生产最好通过将组分混合随后压制来进行。
实施例
片剂的硬度用Heberlen硬度测定装置(型号2E/205)测定。
实施例1
10,000g 盐酸反胺苯环醇
44,400g 微晶纤维素
2000g 糖精钠
1000g 薄荷矫味剂
2000g 茴香矫味剂
400g 微粒分散二氧化硅和
200g 硬脂酸镁
将上述成分在混合容器内混合生产200,000只片子。将混合物过0.6mm筛,再在混合容器内混合,随后在Fette P 2000压片机上制片,得到的片子直径为10mm,平均高度为3.2mm,平均重量300mg,硬度在60~80N之间。
实施例2
用实施例1所给的条件由下述配方生产200,000只片子:
10,000g 盐酸反胺苯环醇
48,400g 微晶纤维素
10,000g 米淀粉
2000g 糖精钠
1000g 薄荷矫味剂
2000g 茴香矫味剂
400g 微粒分散二氧化硅和
200g 硬脂酸镁。所得片子直径为10mm,平均高度为3.9mm,平均重量为370mg,硬度在60N~80N之间。
实施例3
用实施例1给定的条件由以下配方生产200,000只片子:
10,000g 盐酸反胺苯环醇
29,400g 微晶纤维素
10,000g 米淀粉
2000g 糖精钠
1000g 薄荷矫味剂
2000g 茴香矫味剂
400g 微粒分散二氧化硅和
200g 硬脂酸镁。所得片子直径为10mm,平均高度为3.9mm,平均重量为275mg,硬度在60N~80N之间。
实施例4
用实施例1给定的条件由下述配方生产200,000只片子:
10,000g 盐酸反胺苯环醇
20,400g 微晶纤维素
10,000g 米淀粉
2000g 糖精钠
1000g 薄荷矫味剂
2000g 茴香矫味剂
400g 微粒分散二氧化硅和
200g 硬脂酸镁。所得片子直径为10mm,平均高度为3.9mm,平均重量为230mg,硬度在60N~80N之间。
实施例5
用实施例1给定的条件由下述配方生产200,000只片子:
10,000g 盐酸反胺苯环醇
20,140g 微晶纤维素
10,000g 玉米淀粉
2000g 糖精钠
260g PVP-CL
1000g 薄荷矫味剂
2000g 茴香矫味剂
400g 微粒分散二氧化硅和
200g 硬脂酸镁。所得片子直径为10mm,平均高度为3.9mm,平均重量为230mg,硬度在60N~80N之间。
实施例6(比较)
用实施例1的条件由实施例2的配方生产200,000只片子,只是用水溶性乳糖代替微晶纤维素。
实施例7(比较)
用实施例1的条件由实施例2的配方生产200,000只片子,只是用不溶性的磷酸氢钙代替微晶纤维素。
含反胺苯环醇片剂的崩解时间和释放时间的测定
释放时间用Ph.Eur./DAB分光光度法在浆式搅拌装置中在600mlpH1.2的胃液中测定。释放介质的温度为37℃±0.5℃,搅拌速度为75rpm,崩解时间用Erweka崩解测试仪(Z T6-1-D)测定。
结果见下表:表:
1)sec代表秒;min代表分
根据实施例生产的片剂 | 崩解时间1) | 反胺苯环醇释放百分率1) | |||||
1min | 2min | 3min | 4min | 5min | 6min | ||
1 | 25-30sec | 2.5 | 65.8 | 94.1 | >99 | >99 | >99 |
2 | 25-30sec | 3.7 | >99 | >99 | >99 | >99 | >99 |
3 | 50-60sec | 2 | 78.9 | >99 | >99 | >99 | >99 |
4 | 100-110sec | 0.9 | 47.4 | 75.2 | 87.4 | 92.0 | >99 |
5 | 110sec | 1.2 | 62.0 | 97.8 | >99 | >99 | >99 |
6(比较) | >10min | 0.1 | 10.2 | 25.2 | 38.2 | 50.2 | 89.5 |
7(比较) | 360sec | 0.1 | 10.3 | 24.5 | 38.5 | 52.6 | 85.4 |
Claims (6)
1.不含粘合剂的反胺苯环醇或反胺苯环醇盐的口服片剂,含有微晶纤维素和反胺苯环醇或反胺苯环醇盐,其重量比为至少2∶1。
2.根据权利要求1的片剂,其特征在于微晶纤维素与反胺苯环醇或反胺苯环醇盐的重量比为至少3∶1。
3.根据权利要求2的片剂,其特征在于微晶纤维素与反胺苯环醇或反胺苯环醇盐的重量比为至少4∶1。
4.根据权利要求1或2的片剂,其特征在于所述片剂含有淀粉。
5.根据权利要求4的片剂,其特征在于淀粉与反胺苯环醇或反胺苯环醇盐的重量比为1∶1。
6.根据权利要求1、2、3和5中任一项的片剂,其特征在于含有0.5-10%(重量)的至少一种崩解剂作为可选择性组分。
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Application Number | Priority Date | Filing Date | Title |
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DE19530575A DE19530575A1 (de) | 1995-08-19 | 1995-08-19 | Schnell zerfallende Arzneiform von Tramadol oder einem Tramadolsalz |
DE19530575.2 | 1995-08-19 |
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CN1145780A CN1145780A (zh) | 1997-03-26 |
CN1102385C true CN1102385C (zh) | 2003-03-05 |
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CN100389752C (zh) * | 1978-04-21 | 2008-05-28 | 莱博法姆公司 | 控释组合物 |
CA2217238C (en) * | 1997-10-24 | 2005-09-20 | Louis Cartilier | Cross-linked cellulose as a tablet excipient |
AU741992B2 (en) * | 1998-03-06 | 2001-12-13 | Adare Pharmaceuticals S.R.L. | Fast disintegrating tablets |
SE9802973D0 (sv) * | 1998-09-03 | 1998-09-03 | Astra Ab | Immediate release tablet |
GB9904911D0 (en) * | 1999-03-03 | 1999-04-28 | Scherer Ltd R P | Pharmaceutical compositions |
DE19940740A1 (de) * | 1999-08-31 | 2001-03-01 | Gruenenthal Gmbh | Pharmazeutische Salze |
DE19940944B4 (de) | 1999-08-31 | 2006-10-12 | Grünenthal GmbH | Retardierte, orale, pharmazeutische Darreichungsformen |
CN1202815C (zh) * | 1999-08-31 | 2005-05-25 | 格吕伦塔尔有限公司 | 含有曲马朵糖精盐的持续释放给药剂型 |
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CN1942175B (zh) * | 2002-10-25 | 2010-05-26 | 莱博法姆公司 | 24小时有效的曲马多缓释制剂 |
TWI319713B (en) | 2002-10-25 | 2010-01-21 | Sustained-release tramadol formulations with 24-hour efficacy | |
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US8022053B2 (en) * | 2004-11-02 | 2011-09-20 | Bayer Schering Pharma Aktiengesellschaft | Oral solid dosage forms containing a low dose of estradiol |
CN101242856A (zh) | 2005-09-09 | 2008-08-13 | 莱博法姆公司 | 持续药物释放的组合物 |
US20090004248A1 (en) * | 2007-06-29 | 2009-01-01 | Frank Bunick | Dual portion dosage lozenge form |
ITMI20130210A1 (it) | 2013-02-14 | 2014-08-15 | Menarini Lab | Composizioni farmaceutiche contenenti dexketoprofene e tramadolo |
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1995
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1996
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- 1996-07-17 DE DE59607710T patent/DE59607710D1/de not_active Revoked
- 1996-07-17 SI SI9630318T patent/SI0759296T1/xx unknown
- 1996-07-17 DK DK96111483T patent/DK0759296T3/da active
- 1996-07-17 PT PT96111483T patent/PT759296E/pt unknown
- 1996-07-17 ES ES96111483T patent/ES2164198T3/es not_active Expired - Lifetime
- 1996-07-17 AT AT96111483T patent/ATE205708T1/de not_active IP Right Cessation
- 1996-07-17 EP EP96111483A patent/EP0759296B1/de not_active Revoked
- 1996-07-30 BR BR9604034A patent/BR9604034A/pt not_active Application Discontinuation
- 1996-08-06 AU AU61941/96A patent/AU703310B2/en not_active Ceased
- 1996-08-07 CN CN96110917A patent/CN1102385C/zh not_active Expired - Fee Related
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- 1996-08-09 PE PE1996000597A patent/PE8298A1/es not_active Application Discontinuation
- 1996-08-09 SK SK1042-96A patent/SK281779B6/sk not_active IP Right Cessation
- 1996-08-09 JP JP21122196A patent/JP4074675B2/ja not_active Expired - Fee Related
- 1996-08-09 CZ CZ19962359A patent/CZ289167B6/cs not_active IP Right Cessation
- 1996-08-12 AR ARP960103957A patent/AR003476A1/es not_active Application Discontinuation
- 1996-08-14 UY UY24308A patent/UY24308A1/es not_active IP Right Cessation
- 1996-08-14 PL PL96315749A patent/PL184785B1/pl not_active IP Right Cessation
- 1996-08-16 ZA ZA9606985A patent/ZA966985B/xx unknown
- 1996-08-16 HU HU9602266A patent/HU227360B1/hu not_active IP Right Cessation
- 1996-08-16 NO NO19963430A patent/NO313486B1/no not_active IP Right Cessation
- 1996-08-16 RU RU96116411/14A patent/RU2174837C2/ru not_active IP Right Cessation
- 1996-08-16 IL IL11908096A patent/IL119080A/en not_active IP Right Cessation
- 1996-08-19 UA UA96083292A patent/UA41392C2/uk unknown
- 1996-08-19 US US08/699,623 patent/US5776492A/en not_active Expired - Lifetime
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1998
- 1998-09-25 HK HK98110961A patent/HK1010100A1/xx not_active IP Right Cessation
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