CN1174503A - 固体活性化合物制剂 - Google Patents
固体活性化合物制剂 Download PDFInfo
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- CN1174503A CN1174503A CN96191928A CN96191928A CN1174503A CN 1174503 A CN1174503 A CN 1174503A CN 96191928 A CN96191928 A CN 96191928A CN 96191928 A CN96191928 A CN 96191928A CN 1174503 A CN1174503 A CN 1174503A
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- reactive compound
- melt
- hydroxypropyl cellulose
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Abstract
一种固体制剂,通过同时熔融挤出如下组分制得:A)至少一种活性化合物,B)一种如下组分的混合物:B1)10至90wt%的一种热塑性水溶性聚合物,和B2)10至90wt%的低取代羟丙基纤维素,和C)0至50wt%的惯用药物助剂(按制剂总重量计)。
Description
本发明涉及固体制剂,通过同时熔融挤出如下组分制得:A)一种或多种活性化合物,B)一种如下组分的混合物:
B1)10至90wt%的至少一种热塑性可加工水溶性聚合物,和
B2)10至90wt%的低取代的水不溶性羟丙基纤维素,和C)0至50wt%的一种或多种药物助剂(按制剂总重量计)。
本发明进一步涉及生产这些制剂的方法,和其作为药物的用途。
通过熔融挤出生产的含活性化合物的制剂通常是已知的。
挤出含活性化合物的水溶性聚合物(优选乙烯基吡咯烷酮共聚物)熔体描述于EP-A240904和EP-A240906中。
JP-A58-192817和JP-A58-79915公开了熔融挤出基于热塑性聚合物如羟丙基纤维素作为粘合剂的含活性化合物的制剂。
通过纤维素与环氧丙烷部分醚化制备的低取代羟丙基纤维素(L-HPC)不溶于水,但与水接触时溶涨。考虑到这种溶涨性,L-HPC被用作崩解剂以加速片剂的崩解。L-HPC还可用作片剂的粘合剂以提高片剂的硬度。
Kawashima等人(药物化学公报,41(1993),1827-31)描述了在将L-HPC粒子用于压片时一方面非常取决于L-HPC的颗粒尺寸,另一方面活性化合物的释放特性非常受压实过程中压力的影响。
然而,与具有高取代度的羟丙基纤维素相比,L-HPC不显示可热塑加工性。
本发明的一个目的是发现可通过聚合物-活性化合物熔融挤出生产活性化合物制剂并可具体调节活性化合物的释放。
我们已发现,本发明目的可通过开始定义的制剂、其生产方法和其作为药物的用途实现。
适合作为组分A)的活性化合物是在熔融挤出过程中的加工条件下不分解的那些化合物。
合适的活性化合物是,例如:
醋丁酰心安、乙酰半光氨酸、乙酰水杨酸、开糖环乌苷、三唑安定、白蛋白、1α-羟维生素D3、尿囊素、别嘌呤醇、溴环己胺醇、丁胺卡那霉素、氨氯吡脒、氨基乙酸、乙胺碘呋酮、阿米替林、amlodipine、羟氨基苄青霉素、氨苄青霉素、抗坏血酸、天冬酰苯丙氨酸甲酯、苄苯哌咪唑、氨酰心安、氯地米松、羟苄丝肼、氢氧化苄烷铵、苯佐卡因、苯甲酸、倍他米松、降脂苯酰、生物素、双环哌丙醇、bisoprolol、溴吡二氮卓、溴己胺、溴麦角环肽、丁地去炎松、丁苯乙肟、甲氧吡丁苯、丁螺旋酮、咖啡因、樟脑、巯甲丙脯酸、氨甲酰氮卓、甲基多巴肼、carboplatin、头孢氯、头孢氨苄、头孢羟氨苄、头孢唑啉、cefixime、头孢氨噻、ceftazidine、头孢三嗪噻肟、头孢氨呋肟axetil、氯霉素、洗必太、氯苯吡胺、氯噻酮、胆碱、ciclosporin、cilastatin、甲氰咪胍、ciprofloxacin、cisapride、顺氯氨铂、clarithromycin、棒酸、氯丙咪嗪、氯硝安定、氯压定、克霉唑、氯氮平、可待因、消胆胺、色甘酸、维生素B12、去乙酰环丙氯地孕酮、甲烯甲炔诺、地塞米松、泛醇、右甲吗喃、右旋丙氧芬(dextroproxiphene)、安定、双氯高灭酸、地高辛、二氢可待因、二氢麦角胺、硫氮卓酮、苯海拉明、潘生丁、安乃近、双异丙吡胺、哌双咪酮、多巴胺、enalapril、麻黄碱、肾上腺素、维生素D2、麦角胺、红霉素、雌二醇、炔雌烯醇、鬼臼乙叉甙、桉叶球剂、famotidine、felodipine、降脂异丙酯、酚丙喘宁、芬太尼、盐酸吖啶黄单苷酸、fluconazole、氟苯桂嗪、氟尿嘧啶、氟苯氧丙胺、氟联苯丙酸、亚叶酸、速尿、二甲苯氧庚酸、庆大霉素、Ginkgo biloba、优降糖吡磺环己脉、光果甘草、愈创木酚甘油醚、氟哌啶醇、肝素、玻璃[糖醛]酸、双氢氯噻嗪、二氢可待因酮、氢化可的松、二氢吗啡酮、氢化异丙托品、异丁苯丙酸、imipenem、消炎痛、碘酞六醇、碘异酞醇、异山梨醇二硝酸酯、异山梨醇一硝酸酯、13-顺维生素A酸、甲哌噻庚酮、酮哌恶咪唑、苯酮苯丙酸、ketorolac、柳胺心定、乳果糖、卵磷脂、左旋肉碱(levocarnitine)、左旋多巴、左旋谷酰胺、左旋18-甲基炔诺酮、左旋甲状腺素、利多卡因、脂肪酶、lisinopril、氯苯哌酰胺、氯羟去甲安定、lovastatin、6α-甲-17-羟孕酮、薄荷醇、甲氨喋呤、甲基多巴、甲强龙、灭吐灵、甲氧乙心安、双氯苯并唑、咪唑二氮、二甲胺四环素、长压定、misoprostol、吗啡、多种维生素和矿物质(mineral)、制霉菌素、N-甲基麻黄碱、萘呋胺酯(naftidrofuril)、甲氮萘丙酸、新霉素、硝吡胺甲酯、麦角溴烟酯、烟酰胺、烟碱、烟酸、硝苯吡啶、硝苯吡酯、硝吡乙甲酯、nizatidine、炔诺酮、norfloxacin、右旋甲基炔诺酮、去甲替林、ofloxacin、omeprazole、ondansetron、胰酶、泛醇、泛酸、扑热息痛、青霉素G、青霉素V、苯巴比妥、己酮可可碱、苯福林、苯丙醇胺、phenytoin、吡氧噻嗪、多粘菌素B、聚烯吡酮碘、prarastatin、哌唑嗪、强的松龙、苯丙酰苯心安、萘心胺、假麻黄素、吡哆醇、奎尼丁、ramipril、糖硝烯二胺、利血平、维生素A、核黄素、利福平、芦丁、糖精、舒喘宁、salcatonin、水杨酸、丙炔苯丙胺、simvastatin、somatropin、甲磺胺心定、安宁舒通、硫糖铝、sulbactam、磺胺甲基异噁唑、止呕灵、三苯氧胺、呋氟尿嘧啶、teprenone、terazosin、叔丁喘宁、丁苯哌丁醇、茶碱、硫胺、氯卡噻啶、噻吗心定、凝血酸、全反维生素A酸、丙炎松、氨苯喋啶、甲氧卡氨嘧啶、维生素P4、尿嘧啶、丙戊酸、万古霉素、戊脉安、维生素E、zidovudine。
此外,合适的活性化合物还可以为维生素,如维生素C、β-胡萝卜素和其它类胡萝卜素或作物保护剂。
活性化合物A优选以固体溶液形式存在,即以分子分散形式分布于基体中,或以固体分散体形式存在。
活性化合物组分A)在总的制剂中的量可根据活性和释放速率在宽范围内变化。因此活性化合物的含量可为0.1至90wt%,优选0.5至60wt%(按制剂总量计)。唯一的条件是制剂仍可热塑加工。
作为聚合物组分B),本发明的制剂可含有如下组分的混合物:B1)10至90wt%,优选20至80wt%水可溶热塑性聚合物,和B2)10至90wt%,优选20至80wt%水不溶低取代羟丙基纤维
素,用量数据按B1)和B2)的总重量计。
可提及的水溶性聚合物B1)是:- 烷基纤维素,如甲基纤维素,- 羟烷基纤维素,如羟甲基-、羟乙基-、羟丙基-和羟丁基纤维
素,- 羟烷基烷基纤维素,如羟乙基甲基-和羟丙基甲基纤维素,- 聚乙烯基吡咯烷酮,- N-乙烯基吡咯烷酮与乙酸乙烯酯的共聚物(含至多50wt%
乙酸乙烯酯),- 羧烷基纤维素,如羧甲基纤维素,- 多糖类,如藻酸和其碱金属和铵盐,及这些水溶性聚合物的混合物。
在所有组分的总混合物中的组分B1)应在50至180℃,优选60至150℃范围内软化或熔化,这样物料是可挤出的。因此聚合物的玻璃转化温度应低于180℃。
水溶性是指至少0.5g,优选至少2g聚合物溶于100g 20℃的水中,若合适甚至为胶体形式。
所用的聚合物组分A)优选为摩尔取代度3.0至4.4的羟丙基纤维素。
根据本发明,组分B2)为摩尔取代度0.5至2,优选1.5至1.8的低取代羟丙基纤维素,如在美国药典/NF XVII和日本药典JP XL.中描述的羟丙基纤维素(L-HPC)。这种L-HPC是水不溶的,但在水中溶涨,并且不具有热塑性。
在上述范围内,所用组分B2)的量优选取决于活性化合物所需的释放速率。在快速释放的情况下,推荐使用较少的量,例如5至30wt%,而在需要活性化合物缓慢释放的情况下,推荐使用30至90wt%的B2)。
根据本发明,所用L-HPC的颗粒尺寸并不重要。
对于组分C),本发明的制剂可含有惯用药物助剂,如填料、润滑剂、脱模剂、流动调节剂、成形剂、着色剂和稳定剂,其用至多约50wt%。这些用量和下面给出的用量都按制剂的总重量计(=100%)。
可提及的填料是,例如镁、铝、硅和钛的氧化物以及乳糖、甘露糖醇、山梨糖醇、木糖醇、季戊四醇和其衍生物,填料的用量为约0.02至约50,优选0.2至约20wt%。
可提及的流动调节剂为,例如长链脂肪酸如C12-、C14-、C16-和C18-脂肪酸的单、二和三甘油酯,石蜡如巴西棕榈蜡以及卵磷脂,其用量为约0.1至约30,优选0.1至约5wt%。
可提及的成形剂是,例如,除低分子量聚烯化氧如聚乙二醇、聚丙二醇和聚亚乙基丙二醇外,还有多元醇如丙二醇、甘油、季戊四醇和山梨糖醇以及二乙基硫代丁二酸钠、甘油的单-、二-和三乙酸酯和聚乙二醇硬脂酸酯。在这种情况下成形剂的用量为约0.5至约15,优选0.5至约5wt%。
可提及的润滑剂为,例如铝或钙的硬脂酸盐以及滑石和硅油,其用量为约0.1至5,优选0.1至3wt%。
可提及的稳定剂为,例如光稳定剂、抗氧剂、游离基清除剂和抗微生物进攻的稳定剂,其用量优选为约0.01至0.05wt%。
为了生产本发明的制剂,可将活性化合物直接以物理混合物形式与聚合物B熔融或与已存在的聚合物熔体混合。
此外,组分A)与熔体的混合可按本身已知的方式在挤出机,优选单或双螺杆挤出机中在温度50至200℃下进行。为得到本发明的制剂,可(例如)通过按照EP-A240906中描述的方法压延挤出物,并根据DE-A3830355中公开的方法用旋转刀将挤出物切成仍可形变的具有固化表面的等体积片状物,随后在惯用的制片机中压成片剂的方式,进行含活性化合物的聚合物熔体的成型。
可将助剂混入活性化合物和聚合物B的熔体或溶液中。还可将助剂与活性化合物一起加入聚合物熔体中。此外,也可将助剂、活性化合物和聚合物B的混合物直接熔化。通常,一般都是将助剂、活性化合物和聚合物B的物理混合物一起熔化。
本发明的制剂可用作药物,并可以片剂、药丸、药粒或胶囊形式使用。优选用本发明的制剂生产缓释活性化合物的药物形式。
若需要,还可在固体药物形式上提供惯用的包衣以改进其外观和/或味道(包衣片剂)或起到辅助缓释活性化合物的作用。对于具有缓释活性化合物性能的口服片剂,为使其浮在胃里并使残余物停留时间更长,若按照一种已知工艺生产闭壳多孔形式的片剂,则是有利的。
本发明可以简单形式具体调节本发明的固态药物形式,特别是生产的具有缓释药物活性化合物性能的固态药物形式的活性化合物释放过程。令人吃惊的是,这种调节与L-HPC的颗粒尺寸和成型过程中的方法参数无关。
实施例1至3
将表中所给量的活性化合物及聚合物B1)和B2)混合,加入双螺杆挤出机(ZSK 30,Werner&Pfleiderer公司)并经5个温度段中挤出。每一情况下各温度段的温度(1-5组)在表I中给出。将经挤出机喷嘴边缘挤出的熔融挤出物用切刀辊造粒机通过空气冷却降热造粒。
借助搅拌浆方法(按照USP XXI,美国药典的桨叶方法)测量活性化合物的释放。用这种在玻璃试管内的方法测定含活性化合物的成型制品(如片剂、药丸等)的溶解速率。
为此,将900ml pH为6.8的磷酸盐缓冲剂与1升圆底容器中的0.1wt%月桂基硫酸钠控温至37℃并加入300g颗粒尺寸1.25至1.60mm的药丸。在每一情况下经1、2、3、4、5、6、7和8小时后在桨叶旋转速度100转/分钟下用UV光谱测定从药丸中释放出的活性化合物。
此试验的结果示于表II中。表I
1)摩尔取代度3.0至4.4的羟丙基纤维素(Klucel EF,Hercules,USA)2)摩尔取代度1.5至1.8的羟丙基纤维素(LH31,Shin-Etsu ChemicalComp.Ltd.,Japan)表II
实施例 | 硝苯吡啶wt% | 聚合物B1)1)wt% | 聚合物B2)2)wt% | 温度1-5组 |
1 | 20 | 50 | 30 | 70,120,110,100,100 |
2 | 20 | 40 | 40 | 60,120,120,110,120 |
3 | 20 | 30 | 50 | 60,120,120,120,130 |
实施例 | 在如下小时后的释放% | |||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |
1 | 32 | 70 | 91 | 99 | 100 | 100 | 100 | 100 |
2 | 31 | 60 | 77 | 89 | 96 | 100 | 100 | 100 |
3 | 24 | 43 | 57 | 69 | 75 | 81 | 87 | 91 |
Claims (6)
1.一种固体制剂,通过同时熔融挤出如下组分制得:A)一种或多种活性化合物,B)一种如下组分的混合物:
B1)10至90wt%的至少一种热塑性可加工水溶性聚合物,和
B2)10至90wt%的低取代的水不溶性羟丙基纤维素,和C)0至50wt%的一种或多种药物助剂(按制剂总重量计)。
2.如权利要求1的制剂,含有摩尔取代度为1.5至1.8的羟丙基纤维素作为组分B2)。
3.如权利要求1或2的制剂,含有水溶性羟丙基纤维素作为组分B1)。
4.一种生产如权利要求1至3的制剂的方法,包括将活性化合物A)与聚合物组分B)和若合适助剂C)一起加工为熔体,挤出该熔体和成型加工。
5.如权利要求1至3的制剂作为药物的用途。
6.一种由权利要求1至3的制剂制备的固体药物形式。
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1995
- 1995-02-14 DE DE19504832A patent/DE19504832A1/de not_active Withdrawn
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1996
- 1996-02-01 AU AU47860/96A patent/AU4786096A/en not_active Abandoned
- 1996-02-01 CZ CZ972394A patent/CZ239497A3/cs unknown
- 1996-02-01 PT PT96903958T patent/PT809488E/pt unknown
- 1996-02-01 EP EP96903958A patent/EP0809488B1/de not_active Expired - Lifetime
- 1996-02-01 HU HU9702424A patent/HUP9702424A3/hu unknown
- 1996-02-01 DK DK96903958T patent/DK0809488T3/da active
- 1996-02-01 CN CNB961919280A patent/CN1177584C/zh not_active Expired - Lifetime
- 1996-02-01 WO PCT/EP1996/000417 patent/WO1996025151A1/de active IP Right Grant
- 1996-02-01 ES ES96903958T patent/ES2180738T3/es not_active Expired - Lifetime
- 1996-02-01 NZ NZ302243A patent/NZ302243A/xx unknown
- 1996-02-01 KR KR1019970705588A patent/KR19980702193A/ko not_active Application Discontinuation
- 1996-02-01 JP JP52461596A patent/JP4049810B2/ja not_active Expired - Fee Related
- 1996-02-01 TR TR97/00786T patent/TR199700786T1/xx unknown
- 1996-02-01 AT AT96903958T patent/ATE220541T1/de active
- 1996-02-01 US US08/875,514 patent/US5939099A/en not_active Expired - Lifetime
- 1996-02-01 SK SK1043-97A patent/SK104397A3/sk unknown
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- 1996-02-01 BR BR9606957A patent/BR9606957A/pt not_active Application Discontinuation
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- 1996-02-12 IL IL11711296A patent/IL117112A0/xx unknown
- 1996-02-13 ZA ZA9601137A patent/ZA961137B/xx unknown
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1997
- 1997-07-17 BG BG101781A patent/BG101781A/xx unknown
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105744847A (zh) * | 2013-11-15 | 2016-07-06 | 帝斯曼知识产权资产管理有限公司 | 通过热熔挤出获得的略溶化合物的制剂 |
Also Published As
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PL321755A1 (en) | 1997-12-22 |
TR199700786T1 (xx) | 1998-02-21 |
DE59609451D1 (de) | 2002-08-22 |
NO973730L (no) | 1997-08-13 |
SK104397A3 (en) | 1998-04-08 |
FI973320A (fi) | 1997-10-13 |
FI973320A0 (fi) | 1997-08-13 |
NO973730D0 (no) | 1997-08-13 |
HUP9702424A2 (hu) | 1998-06-29 |
CZ239497A3 (cs) | 1998-01-14 |
CN1177584C (zh) | 2004-12-01 |
EP0809488B1 (de) | 2002-07-17 |
HUP9702424A3 (en) | 2001-03-28 |
KR19980702193A (ko) | 1998-07-15 |
EP0809488A1 (de) | 1997-12-03 |
WO1996025151A1 (de) | 1996-08-22 |
CA2211033C (en) | 2005-04-26 |
IL117112A0 (en) | 1996-06-18 |
ES2180738T3 (es) | 2003-02-16 |
NZ302243A (en) | 1999-01-28 |
US5939099A (en) | 1999-08-17 |
DK0809488T3 (da) | 2002-09-02 |
AU4786096A (en) | 1996-09-04 |
CA2211033A1 (en) | 1996-08-22 |
ATE220541T1 (de) | 2002-08-15 |
ZA961137B (en) | 1997-09-16 |
BG101781A (en) | 1998-03-31 |
DE19504832A1 (de) | 1996-08-22 |
JPH10513477A (ja) | 1998-12-22 |
JP4049810B2 (ja) | 2008-02-20 |
PT809488E (pt) | 2002-11-29 |
BR9606957A (pt) | 1997-10-28 |
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