CN1150897C - 非甾体抗炎药物的可注射药物组合物 - Google Patents
非甾体抗炎药物的可注射药物组合物Info
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Abstract
本发明公开了一种非甾体抗炎药物的非胃肠道的能与水混合的无强烈外观变化的可注射组合物。本发明包括利用增溶技术来达到足够高的尼美舒利浓度以合适的小体积释放治疗剂量,其中使用实质上为油性的基质而没有使用水性的也没有使用尼美舒利的任何盐形式或复合物。
Description
本发明涉及非甾体抗炎药物的新的治疗性的无强烈外观变化的能与水混合的可注射镇痛药物组合物及其制备方法。在哺乳动物特别是人的急性疼痛疾病(如手术后外伤、与癌症有关的疼痛、运动损伤、偏头痛、神经痛、与坐骨神经和脊椎炎有关的疼痛)治疗中,可注射的镇痛组合物是非常有用的,对于这些适应症,也可有某些改进的给药途径。
非甾体抗炎药物如环氧化酶(cyclo-oxygenase)-2抑制剂类在药物(包括尼美舒利)是高度疏水的化合物并且甚至在少量水存在时都容易产生沉淀。
所以,配制属于环氧化酶抑制剂的非甾体抗炎药物的肌内或静脉内使用的注射剂是非常困难的。
过去,已进行了努力来制备尼美舒利的可注射组合物。
在现有技术的PCT专利号WO95/34533中已报道了尼美舒利可注射制剂,其中使用尼美舒利与L-赖氨酸的盐的形式,然后进一步与环糊精复合形成可溶于水的物质而获得可注射制剂。报告称该可注射的组合物所达到的最大溶解度为2.4mg/ml,这样的溶解度不足以用于肌内给药,因为需要非常大的体积来给予治疗剂量。而且,制备尼美舒利的盐的形式并与环糊精结合不仅使方法烦琐而且也增加了制剂的成本。
另一文献(Daffonchio.L等Inflammatory Research 45:259-264;1995)中,是将尼美舒利溶于盐水并在动物实验研究中用于静脉给药,其中也仅仅描述了非常稀的不能在人体中释放治疗剂量的溶液。
本发明的发明人在美国专利5688829(相应于南朝鲜专利申请号96-48013、澳大利亚申请号67993/96和日本专利申请号8-290585,均为悬而未决的)描述的发明克服了WO95/34533中的缺陷和与之相关的问题。
本发明利用增溶技术达到足够高的尼美舒利浓度以适于合适的小体积释放治疗剂量,其中使用实质上为油性的基质而没有使用水性的也没有使用尼美舒利的任何盐形式或复合物。
本发明包含一种组合物,其中基质的所有组分均为亲水性的。这种亲水性基质具有与体液更好的混合性、更快的药物分布和与组织环境更好的相容性的优点。
本发明的一个目的是提供一种非甾体抗炎药物的可注射的镇痛的亲水性组合物,该组合物没有强烈的外观变化并具有与体液较好的混合性。本文所描述的这种亲水性组合物除通过肌内给药外,还可通过静脉内途径给药。
本发明的另一目的是提供一种新的制备NSAID(非甾体抗炎药物)非胃肠道的可注射的亲水性组合物的方法。
本发明包括一种环氧化酶-2抑制剂如尼美舒利的新的能与水混合的可注射组合物,它包括:
1、环氧化酶抑制剂
2、烷基酰胺/烷基亚砜或吡咯烷酮
3、二元醇
4、0-20%的水。
属于NSAID类的环氧化酶-2抑制剂选自尼美舒利、萘丁美酮、塔帕沙林(Tapoxalin)和氟舒利(flosulide)及其衍生物。
本发明的烷基酰胺/烷基亚砜或吡咯烷酮选自二甲基乙酰胺、二甲基甲酰胺和二甲基亚砜或N-甲基吡咯烷酮。
本发明的二元醇选自分子量为200-6000的聚乙二醇、丙二醇、己二醇、丁二醇和二元醇衍生物如硬脂酸聚乙二醇660羟基酯(商业上可购得Solutrol HS15)。
除此之外,组合物也可包含下列合适的附加组分:表面活性剂、亲水性聚合物、增溶剂,即甘油、各种级别的聚环氧乙烷、β-环糊精如硫代丁基醚-β-环糊精、Transcutol和四氢呋喃聚乙二醇醚(Glycofurol)、张力调节剂、局麻药、pH调节剂和缓冲剂。
优选地,属于环氧化酶-2抑制剂类的非甾体抗炎药物是尼美舒利及其衍生物并以占组合物的0.1-10%w/v的含量存在。
更优选地,尼美舒利以0.5-8%w/v的含量存在。
特别优选的是尼美舒利以1.2-4.8%w/v的含量存在。
优选地,本发明组合物含有2.0%-95%w/v的烷基酰胺/烷基亚砜或吡咯烷酮。
更优选地,组合物含有5%-9()%的烷基酰胺/烷基亚砜或吡咯烷酮。
特另优选的是烷基酰胺/烷基亚砜或吡咯烷酮以10%-20%w/v存在。
优选地,二元醇以组合物的0.1%-95%w/v存在。
在本发明优选的实施方案中,描述一种尼美舒利的可注射的能与水混合的无强烈外观变化的镇痛药物组合物,它含有:
尼美舒利:0.1-10%w/v
二甲基乙酰胺:2.0-90%w/v
聚乙二醇:0.1-95%w/v
水:0-20%w/v
在优选的实施方案中,将药物溶于油相并在使用包括卵磷脂的表面活性剂的水相中乳化而产生适于静脉内使用的微乳剂或乳剂。
本发明也描述一种新的制备NSAID的可注射的可与水混合的镇痛药物组合物的方法。
所述方法包括:
a)将尼美舒利溶于二甲基乙酰胺中,然后加到新蒸馏苯甲醇中并搅拌。随后将聚乙二醇400溶液加到上述溶液中并混合。搅拌下,将所得溶液缓慢地加到盐酸溶液中并加到丙二醇中使体积达到最终实际体积的95%。
该溶液pH介于2.0-3.0之间。若pH不能在此范围内,则需要用氢氧化钠(10%w/v)溶液或盐酸溶液调节,再用聚乙二醇调至最终的体积。
b)使用6微米的玻璃纤维预-滤器将所得溶液自0.45微米的尼龙膜滤器过滤。将过滤的溶液收集在清洁的无纤维的容器中。将溶液填充在无纤维的无菌2毫升琥珀色USP1型玻璃安瓿中,在填充前后都用氮气冲洗。
c)经热压器处理灭菌安瓿。光学检查所有安瓿并经质量控制部门弃去不合格的产品后,标记合格的产品。
现通过下列NSAID可注射镇痛组合物的实施例来描述本发明。
实施例1
尼美舒利 | %w/v |
2% | |
二甲基乙酰胺 | 10% |
水 | 1% |
苯甲醇 | 4% |
BHA(丁基化的羟基茴香醚) | 0.1% |
聚乙二醇300 | 适量到100% |
实施例2
氟舒利(Flosulide) | %w/v |
1% | |
N-甲基吡咯烷酮 | 5% |
二甲基乙酰胺 | 5% |
聚乙二醇400 | 30% |
水 | 5% |
苯甲醇 | 2% |
α-生育乙酸酯 | 0.05 |
丙二醇 | 适量到100% |
实施例3
尼美舒利 | %w/v |
1.2% | |
二甲基乙酰胺 | 1 0% |
苯甲醇 | 4% |
丙二醇 | 适量到100% |
实施例4
尼美舒利 | %w/v |
10% | |
苯甲醇 | 2% |
二甲基乙酰胺 | 适量到100% |
该类型的组合物在用前必需使用合适的稀释剂进行稀释。
实施例5
尼美舒利 | %w/v |
0.5% | |
苯甲醇 | 2% |
卵磷脂(Lipoid E-80) | 1% |
二甲基乙酰胺 | 10% |
水 | 2% |
聚乙二醇300 | 适量到100% |
以Balb/C小鼠通过腹腔途径来研究对急性毒性的影响时,发现小鼠的LD50为160mg/kg,ED50=3mg/kg,治疗指数=53.3。表明本发明的高安全性。在初步的动物实验和临床前期实验中,表明本发明可注射镇痛组合物具有明显的镇痛活性。而且,已经发现甚至在相同部位反复使用也没有毒性。
没有观察到发生组织坏死或任何其它副作用。镇痛剂量范围为0.1mg/kg-8.4mg/kg。
因为在不脱离本发明的主旨和范围的情况下,本发明可有许多明显不同的实施方案,无论如何本发明都将说明书仅仅解释为说明性的而不使其以任何方式限制本发明的范围。
Claims (9)
1、一种属于环氧化酶-2抑制剂类的非甾体抗炎药物的非胃肠道的可与水混合的无强烈外观变化的可注射组合物,该组合物包括:
a)至少一种选自尼美舒利、萘丁美酮和氟舒利及其衍生物的环氧化酶-2抑制剂类的非甾体抗炎药物
b)烷基酰胺或烷基亚砜或吡咯烷酮
c)二元醇及其衍生物
d)0-20%的水。
2、权利要求1的可注射组合物,其中所述的属于环氧化酶-2抑制剂类的NSAID选自尼美舒利和氟舒利及其衍生物。
3、权利要求2的可注射组合物,其中所述的NSAID为尼美舒利并且在组合物中以0.1-10%w/v的含量存在。
4、权利要求1的可注射组合物,其中所述的烷基亚砜或烷基酰胺或吡咯烷酮选自二甲基乙酰胺、二甲基甲酰胺、二甲基亚砜或N-甲基吡咯烷酮。
5、权利要求1的可注射组合物,其中所述的烷基亚砜或烷基酰胺或吡咯烷酮是二甲基乙酰胺并且在组合物中以2-90%的含量存在。
6、权利要求1的可注射组合物,其中所述二元醇选自分子量为200-6000的聚乙二醇、聚丙二醇、己二醇、丁二醇和作为二元醇衍生物的硬脂酸聚乙二醇660羟基酯。
7、权利要求6的可注射组合物,其中所述的二元醇为聚乙二醇300并且在组合物中以0.1-95%的含量存在。
8、权利要求1的可注射组合物,它含有:
尼美舒利:0.1-10%w/v
二甲基乙酰胺:2.0-90%w/v
聚乙二醇300:0.1-95%w/v
水:0-20%w/v。
9、一种制备NSAID的非胃肠道的可与水混合的无强烈外观变化的可注射组合物的方法,所述方法包括:
i)将0.1-10%w/v尼美舒利溶于2-90%w/v二甲基乙酰胺中形成溶液,
ii)在搅拌下将上述第i)步所得的溶液加到苯甲醇中,
iii)将0.1-60%w/v聚乙二醇加到上述第ii)步所得的溶液中,
iv)将一定体积的盐酸溶液缓慢地加到上述第iii)步所得的溶液中,
v)将一定体积的丙二醇加到上述第iv)步所得的溶液中,
vi)过滤上述第v)步所得的溶液并将该溶液填充到合适的容器中,然后进行灭菌。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU73089/98A AU718356B2 (en) | 1998-01-12 | 1998-06-22 | A parenteral water-miscible non-intensely coloured injectable composition of non-steroidal anit-inflammatory drugs |
CNB981033008A CN1150897C (zh) | 1998-01-12 | 1998-07-07 | 非甾体抗炎药物的可注射药物组合物 |
EP98308779A EP1002531B1 (en) | 1998-01-12 | 1998-10-27 | A water-miscible composition of nimesulide |
JP33771698A JP3242622B2 (ja) | 1998-01-12 | 1998-11-27 | 非ステロイド系抗炎症薬の非経口で水混和性の非濃色注射可能組成物 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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IN56DE1998 IN187306B (zh) | 1998-01-12 | 1998-01-12 | |
CNB981033008A CN1150897C (zh) | 1998-01-12 | 1998-07-07 | 非甾体抗炎药物的可注射药物组合物 |
EP98308779A EP1002531B1 (en) | 1998-01-12 | 1998-10-27 | A water-miscible composition of nimesulide |
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Publication Number | Publication Date |
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CN1240646A CN1240646A (zh) | 2000-01-12 |
CN1150897C true CN1150897C (zh) | 2004-05-26 |
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CNB981033008A Expired - Fee Related CN1150897C (zh) | 1998-01-12 | 1998-07-07 | 非甾体抗炎药物的可注射药物组合物 |
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Country | Link |
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EP (1) | EP1002531B1 (zh) |
JP (1) | JP3242622B2 (zh) |
CN (1) | CN1150897C (zh) |
AU (1) | AU718356B2 (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001078724A1 (en) * | 2000-04-18 | 2001-10-25 | Pharmacia Corporation | Rapid-onset formulation of a selective cyclooxigenase-2 |
CA2432037C (en) * | 2000-12-22 | 2008-08-12 | Yamanouchi Pharmaceutical Co., Ltd. | Famotidine injection solution |
GR1003969B (el) * | 2001-02-05 | 2002-08-14 | U��-Pharma ����� ������ ������������ ���������� ���� | Σταθερα φαρμακευτικα διαλυματα νιμεσουλιδης. |
US20030105144A1 (en) * | 2001-04-17 | 2003-06-05 | Ping Gao | Stabilized oral pharmaceutical composition |
WO2003035063A1 (en) * | 2001-10-25 | 2003-05-01 | Dinesh Shantilal Patel | Novel preparation of selective cyclooxygenase ii inhibitors |
CN100346785C (zh) * | 2001-10-25 | 2007-11-07 | 迪内希尚蒂拉尔·帕特尔 | 选择性环氧化酶ⅱ抑制剂的新型制剂 |
AU2003100262B4 (en) * | 2003-04-07 | 2003-09-18 | Jurox Pty Ltd | Stable carprofen composition |
AU2006271150A1 (en) * | 2005-07-20 | 2007-01-25 | Panacea Biotec Ltd. | Novel pharmaceutical modified release dosage form cyclooxygenase enzyme inhibitor |
GB0612749D0 (en) * | 2006-06-27 | 2006-08-09 | Univ College London Hospitals | Treatment and/or prevention of pain |
WO2009143558A1 (en) * | 2008-05-26 | 2009-12-03 | Silphion Pty Limited | Injectable formulations |
CN101716142B (zh) * | 2010-01-15 | 2011-07-13 | 西南大学 | 兽用尼美舒利注射液及其制备方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE1008307A3 (fr) * | 1994-06-16 | 1996-04-02 | Europharmaceuticals Sa | Sel de nimesulide hydrosoluble, solution aqueuse le contenant, sa preparation et son utilisation. |
HUP9601442A3 (en) * | 1995-07-25 | 1999-03-29 | Panacea Biotec Ltd | Nes antinflammatory and analgetic pharmaceutical compositions, containing nimesulid for transdermal use, and process for producing them |
IN186315B (zh) * | 1996-12-12 | 2001-08-04 | Panacea Biotec Ltd | |
IT1289973B1 (it) * | 1997-02-25 | 1998-10-19 | Helsinn Healthcare Sa | Sistemi gelificati di nimesulide per uso topico |
IT1289972B1 (it) * | 1997-02-25 | 1998-10-19 | Helsinn Healthcare Sa | Formulazioni topiche di nimesulide in forma di sistemi a cristalli liquidi |
IT1290448B1 (it) * | 1997-04-01 | 1998-12-03 | Schiena Michele Giuseppe Di | Nimesulide sale di colina,metodo di preparazione e composizioni farmaceutiche che lo contengono |
EP0868915A1 (en) * | 1997-04-02 | 1998-10-07 | Panacea Biotec Limited | An anti-spasmodic and antiinflammatory composition containing a NSAID, pentifenone and fenpiverinium |
-
1998
- 1998-06-22 AU AU73089/98A patent/AU718356B2/en not_active Ceased
- 1998-07-07 CN CNB981033008A patent/CN1150897C/zh not_active Expired - Fee Related
- 1998-10-27 EP EP98308779A patent/EP1002531B1/en not_active Expired - Lifetime
- 1998-11-27 JP JP33771698A patent/JP3242622B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JPH11228448A (ja) | 1999-08-24 |
EP1002531A1 (en) | 2000-05-24 |
JP3242622B2 (ja) | 2001-12-25 |
EP1002531B1 (en) | 2003-05-02 |
AU7308998A (en) | 1999-07-29 |
CN1240646A (zh) | 2000-01-12 |
AU718356B2 (en) | 2000-04-13 |
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