CN1171738A - 药物组合物 - Google Patents
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Abstract
一种用于治疗急性疼痛和炎症的口服给药的药物组合物,其中含有一种非类固醇消炎药或其可药用盐与环糊精的包合配合物及一种生理上可接受的碱性试剂,该碱性试剂选自碱和碱土金属的碳酸盐、碳酸氢盐、磷酸盐和氢氧化物以及水溶性胺类,其数量相当于2—30摩尔当量的非类固醇消炎药,该碱性试剂能在胃肠道内形成包围该组合物的碱性扩散层。
Description
本发明涉及一种用于口服给药的药物组合物,其中含有一种非类固醇消炎药(NSAID)与环糊精的包合配合物及一种碱性试剂。
使用非类固醇消炎药进行口服治疗的缺点是有胃肠副作用,特别是局部的胃刺激作用。NSAID与粘膜之间的接触据信是胃刺激发病机理的一个重要因素〔Bianchi,P.G.等,“非类固醇消炎药为何在消化道溃疡形成中重要?”,营养药理学和治疗学(Alimentary Pharmacology andTherapeutics),1987,1,5405-5475〕。口服用的NSAID商品制剂包括包有肠溶衣的片剂,它在十二指肠中释放出药物,以便避免局部的胃刺激作用。但是这样作的缺点是药物的峰值血浆要在服用该包肠溶衣的片剂1-4小时后达到。
NSAID的一个实例是双氯高灭酸,它是苯基乙酸型NSAID,具有有效的消炎和止痛作用,广泛用于治疗急性和慢性疼痛,尤其是与炎症有关的疼痛,例如手术后疼痛、风湿病、关节炎、痛风、肌肉骨骼损伤和创伤。为了减小与包有肠溶衣的双氯高灭酸片剂有关的时间滞后,近来一种不包肠溶衣的片剂和可分散的剂型已经商品化,它适应急性炎症的短期治疗,但是胃肠副作用经常发生,尤其是局部胃刺激作用〔Martindale特级药典,第30版〕。
因此,需要能迅速吸收并且胃肠刺激作用极小的NSAID(例如双氯高灭酸)口服药物组合物。
环糊精和许多包合配合物的性质是众所周知的,并且已有详细的评论〔Szejtli,J.环糊精工艺(Cyclodextrin Technology),1988,Kluwer科学出版社,Dordrecht〕。
根据溶剂情况,溶解的包合配合物在未配合的主体和客体与配合的主体/客体之间存在着平衡。口服的环糊精-药物包合配合物通常由于环糊精的促进造成药物被迅速吸收,但环糊精无明显吸收。另外,某些药物的环糊精包合配合物显示出胃肠副作用减小〔Frmming,K-H &Szejtli,J.“药学中的环糊精”(Cyclodextrins in Pharmacy)1994,Kluwer科学出版社〕。因此,环糊精具有理想的药物载体性质。环糊精及其包合配合物显示出便于药片压制的有利的流动、粘合及压实性质。
关于双氯高灭酸与β-环糊精的配合物的可扩散性已有报道〔NSAIDH β-环糊精包合配合物的可用性,Orienti,I.,Cavallari,C.和Zecchi,V.药物文献(Arch,Pharm)(weinheim),1989,322,207-211〕。发现该配合物在pH2时溶解性差。
已知向几乎不溶的酸性药物(如利尿磺胺)的片剂和胶囊剂的制剂中加入缓冲剂能提高药物在胃介质中的溶解速度〔Marais,A.F.和vander Watt J.G.“扩散层的pH和利尿磺胺的溶解速度之间的关系”;药物发展和工业药学(Drug Development and Industrial Pharmacy)1991,17,1715-1720〕。
以Smithklne Beecham PLC名义申请的南非专利94/5930公开了一种用来以水溶液形式口服的药物组合物,该组合物含有药物/β-环糊精配合物,其中该组合物内还含有一种可药用的酸-碱对,其数量足以在组合物与冷水混合时使该药物/β-环糊精配合物溶解,形成带有酸性或中性pH值的溶液。对于这种药物组合物,必须含有一对酸和碱的组合,它可以产生或者不产生泡腾作用。
发明概要
根据本发明,提供了一种用于口服给药的药物组合物,其中含有一种非类固醇消炎药或其可药用的盐与环糊精的包合配合物,以及一种生理上可接受的碱性溶剂,该碱性试剂选自碱和碱土金属的碳酸盐、碳酸氢盐、磷酸盐和氢氧化物以及水溶性的胺类,其数量相当于非类固醇消炎药物的2-30摩尔当量,该碱性试剂能在胃肠道中形成包围组合物的碱性扩散层。
NSAID可以是任何合适的NSAID,例如双氯高灭酸、消炎痛、甲氧萘丙酸、异丁苯丙酸、甲灭酸、吡氧噻嗪、替诺昔康、芬诺昔康(Lornoxicam)或它们的可药用的盐。
环糊精可以是任何合适的环糊精,但是优选的β-环糊精,它可以被例如甲基或羟丙基取代,或者最好是未取代的β-环糊精。但是,对于替诺昔康和芬诺昔康,环糊精最好是α-环糊精。
碱性试剂若是一种胺,则可以选自氢氧化铵、三(羟甲基)氨基甲烷、乙醇胺和二乙醇胺。
碱性试剂最好是碳酸氢钠,或三(羟甲基)氨基乙烷,也称作缓血酸胺。
药物组合物优选配制成片剂或胶囊。
药物组合物中也可以含有常规的赋形剂,包括粘合剂,如淀粉和微晶纤维素;稀释剂,如乳糖;崩解剂,如羧甲基纤维素钠;以及润滑剂。
NAISD:环糊精包合配合物中的NSAID:环糊精的质量比优选为1∶0.85-1∶5,更为优选的是1∶1-1∶2.5。
活性组分最好是双氯高灭酸与未取代的β-环糊精的包合配合物,双氯高灭酸可任选地采用可药用的盐的形式,例如双氯高灭酸钠或双氯高灭酸钾。双氯高灭酸与β-环糊精的质量比优选1∶1.8-1∶9,更优选1∶3-1∶5。配合物的单位剂量可以是相当于10-100mg双氯高灭酸,但最好是20-60mg双氯高灭酸。
活性组分也可以是芬诺昔康与α-环糊精的包合配合物。芬诺昔康与α-环糊精的质量比优选为1∶2.6-1∶13。配合物的单位剂量可以相当于2-10mg芬诺昔康,但最好是4-8mg芬诺昔康。
这种药物组合物还可以含有至少一种其它活性组分,例如吗啡、可待因、丙氧芬或扑热息痛或氨甲丙二酯。
本发明的药物组合物可用于治疗急性疼痛和炎症。
附图简介
图1是实施例3中的血浆浓度随时间变化图;
图2是实施例5的片剂平均溶解速度图。
实施方案的说明
本发明涉及一种用于口服给药的药物组合物,其中含有一种NSAID或其可药用盐与环糊精的包合配合物,以及一种生理上可接受的碱性试剂,该碱性试剂选自碱和碱土金属的碳酸盐、碳酸氢盐、磷酸盐和氢氧化物以及水溶性的胺类,其数量相当于NSAID的2-30摩尔当量,该碱性试剂能在胃肠道中形成包围该组合物的碱性扩散层。
应当指出,本发明的药物组合物必须不含任何能与碱性试剂形成酸-碱对的另外的酸性试剂,或该碱性试剂不能在胃肠道中形成包围组合物的碱性扩散层。
在NSAID-环糊精配合物制剂中掺加碱性试剂改进了NSAID在胃介质内自配合物中的释放。
碱的另外的功能是中和在胃肠道中(特别是胃中)崩解的药片周围的微环境,形成碱性的扩散层。在对键康的志愿人员用药时,本发明的含有双氯高灭酸但不包肠溶衣的二氯高灭酸钠-β-环糊精片剂与作为参照产品的不包肠溶衣的双氯高灭酸片剂商品相比,根据数据曲线下面积(AUDC)参数测定显示出优越的吸收范围。与参照产品相比,变量Cmax扩展到更高的生物等效值范围边界,而Tmax变量缩短约50%。本发明的含双氯高灭酸的片剂因此显示出吸收速度比参照产品提高。吸收速度的提高大概会减少双氯高灭酸和肠粘膜的接触时间,从而减小胃刺激作用的可能性。另外,对于胃粘膜以包合配合物形式存在的药物可以进一步减小胃刺激作用。同样的作用也适用于其它的NSAID。
用于本发明药物组合物中的包合配合物可以制备如下:
(1)将所所需比例的预先过筛的NSAID与环糊精预混合;
(2)转移到合适的混合容器中;
(3)在激烈混合下逐渐加入去离子的纯化水,直到达到糊状的稠度;
(4)将糊状物揉捏一段时间,例如0.25-1小时,如有必要,不时再加入一些去离子纯化水以便保持糊状稠度,直到形成包含配合物;
(5)将步骤(4)的产物干燥;和
(6)将步骤(5)的产物过筛。
为了形成本发明的药物组合物,将包合配合物与碱性试剂及合适的赋形剂掺混,然后形成合适的口服剂型,例如片剂或胶囊。
本发明药物组合物的优选的活性组分是双氯高灭酸或其可药用的盐与未取代的β-环糊精或者芬诺昔康或其可药用的盐与α-环糊精的包合配合物。现在给出使用这类包合配合物的各实施例。
实施例1
将6.6g双氯高灭酸钠和23.4g β-环糊精过筛(30目)亚翻滚混合。将混合物转移到研钵中。在激烈混合下逐渐加入10-15ml去离子水以便形成均匀的糊状物。继续激烈搅拌0.5小时,在整个操作中保持均匀的糊状体稠度。将混合物在烘箱中于40℃干燥。将干燥过的物质粉碎,过30目筛。将粉末在粉末混合器中均化10分钟。用HPLC测得产物中含21%(m/m)的双氯高灭酸钠。用Karl Fisher滴定法测得产物的水含量为9-11%(m/m)。因此产物的分子组成相当于1分子双氯高灭酸钠、1分子β-环糊精和7-10水分子。产物的粒子大小经光学显微镜测定有90%在30μm以下。配合物的形貌类似于破碎得很细的晶体颗粒。
实施例2
将实施例1中得到的β-环糊精-双氯高灭酸钠包合配合物配制成具有以下单位组成的片剂:
双氯高灭酸钠-β-环糊精配合物
(相当于50mg双氯高灭酸钠) 220mg
碳酸氢钠 200mg
微晶纤维素 130mg
淀粉 44mg
硬脂酸镁 6mg
600mg
将碳酸氢钠、微晶纤维素和淀粉等在混合机中预混合。向此混合物中加入双氯高灭酸钠-β-环糊精配合物并掺混之。将硬脂酸镁筛入并进行掺混。用大约100N的压力将混合物压制成片。可以任选地将片剂膜包衣。
实施例3
以没有肠溶包衣的双氯高灭酸钾50mg商品的药片作为参照产品,在一项双盲交叉试验中使6名健康的志愿人员施用按照实施例2制备的片剂。每名候选人接受2×50mg双氯高灭酸产品,按20分钟的间隔测定血浆中双氯高灭酸的浓度。药物动力学数据总结在表1中,血浆浓度随时间的变化曲线出示于图1(数据得自生物等效值研究FARMOVS20/94)。
表1 二氯高灭酸的药物动力学数据总结(n=6)
参照产品剂量:2×[50mg双氯高灭酸钾药片] | 试验产品剂量:2×[相当于50mg双氯高灭酸钠的双氯高灭酸/β-环糊精药片] | |||||
变量 | 单位 | 几何 标准平均值 偏差 | 范围 | 几何 标准平均值 偏差 | 范围 | |
Cmax | (ng/ml) | 3050 | 1.22 | 2253-3825 | 3992 1.46 | 2440-6260 |
Tmax | 小时 | 0.67 | 0.33-0.67 | 0.33 | 0.33-0.67 | |
AUDC | (nghr/ml) | 2827 | 1.77 | 2423-3631 | 3047 1.24 | 2230-3898 |
Cmax=达到的最大血浆浓度
Tmax=达到Cmax的时间
AUDC=数据曲线下的面积
试验产品能被令人满意地忍受,无不利作用的报道。在大约20分钟内(平均Tmax=0.33小时)或无肠溶包衣的双氯高灭酸商品制剂所需的一半时间内,由β-环糊精配合物放出的双氯高灭酸达到峰值血浆浓度。由于达到十二指肠的时间滞后,常规的带有肠溶包衣的双氯高灭酸的Tmax要长得多(1小时或更长)。对于试验产物的变量Cmax平均值,90%置信区间扩展到比参照产品更高的生物等效值范围边界,而AUDC值则处在常规的生物等效值范围的80-125%之内。试验产品在双氯高灭酸的吸收程度方面与参照产品生物上等效,而且看来吸收速度比试验产品更高。因此,本发明的制剂以比常规的包和不包肠溶衣的双氯高灭酸制剂吸收明显更快的形式提供双氯高灭酸,而又不影响吸收的程度。于是本发明具有在相对较短的时间内达到治疗用的血浆中双氯高灭酸含量的优点,从而能迅速地发挥药理作用。除了环糊精包合配合物产生的潜在的胃保护剂作用之外,吸收速度的明显提高大概会减少双氯高灭酸与胃肠粘膜的接触时间,结果使与口服双氯高灭酸治疗有关的局部胃刺激的程度减弱。
已经指出,在实施例1的片剂于胃内被稀释时,形成了由碱产生的碱性扩散层。配合物在扩散层内迅速溶解,然后扩散到体相流体中并被稀释,随后发生游离的二氯高灭酸的解离和吸收。
实施例4
将3.71g芬诺昔康和24.30g α环糊精过筛(30目)并且翻滚混合。将该混合物转移到研钵中。在激烈混合下逐渐加入10-15ml去离子水以形成均匀的糊状物。继续激烈搅拌1小时。将混合物在40℃真空干燥、将干燥过的物质粉碎并通过30目的筛。粉末在翻滚混合器中均化10分钟。产品中含13%重量的芬诺昔康。
实施例5
将实施例4中得到的α-环糊精-芬诺昔康包合配合物配制成具有以下单位组成的片剂;
芬诺昔康-α-环糊精复合物 30.2mg
(相当于4mg芬诺昔康)
三甲醇氨基甲烷 30.0mg
微晶纤维素 26.2mg
淀粉 12.4mg
硬脂酸镁 1.2mg
总计 100mg
片剂按实施例2中所述制备。
图2是根据实施例5制备的6片芬诺昔康-α-环糊精药片的平均溶解速度。在浆片速度50rpm下纯水(pH~6.5,温度37℃)中的溶解速度表明在30分钟内有80%溶解。芬诺昔康自体系中的释放速度与对于高度可溶性药物的药典规格(例如在45分钟内80%溶解)相等,表明按照本发明制备的片剂的溶解潜力。
本发明药物组合物优选用于治疗急性疼痛和炎症。
Claims (15)
1.一种用于口服给药的药物组合物,其中含有一种非类固醇消炎药或其可药用盐与环糊精的包合配合物及一种生理上可接受的碱性试剂,该碱性试剂选自碱和碱土金属的碳酸盐、碳酸氢盐、磷酸盐和氢氧化物以及水溶性胺类,其数量相当于非类固醇消炎药物的2-30摩尔当量,该碱性试剂能在胃肠道中形成包围该组合物的碱性扩散层。
2.权利要求1的一种药物组合物,其中的非类固醇消炎药或其可药用盐选自双氯高灭酸、消炎痛、甲氧萘丙酸、异丁苯丙酸、甲灭酸、吡氯噻嗪、替诺昔康、芬诺昔康及它们的可药用的盐。
3.权利要求1或2的药物组合物,其中环糊精选自α-环糊精、未取代的β-环糊精和取代的β-环糊精。
4.权利要求1至3中任一项的药物组合物,其中的碱性试剂是碳酸氢钠。
5.权利要求1至3中任一项的药物组合物,其中的碱性试剂是缓血酸胺。
6.权利要求1至5中任一项的一药物组合物,其中包合配合物内的非类固醇消炎药与环糊精的质量比1∶0.85-1∶5。
7.权利要求6的一种药物组合物,其中在包合配合物内的非类固醇消炎药与环糊精的质量比1∶1-1∶2.5。
8.权利要求1的一种药物组合物,其中的包合配合物是双氯高灭酸或其可药用的盐与未取代的β-环糊精的包合配合物。
9.权利要求8的药物组合物,其中双氯高灭酸与β-环糊精的质量比为1∶1.8-1∶9,配合物的单位剂量相当于10-100mg双氯高灭酸。
10.权利要求9的药物组合物,其中双氯高灭酸与β-环糊精的质量比为1∶3-1∶5,配合物的单位剂量相当于20-60mg双氯高灭酸。
11.权利要求1的一种药物组合物,其中包合配合物是芬诺昔康与α-环糊精的包合配合物。
12.权利要求11的一种药物组合物,其中芬诺昔康与α-环糊精的质量比为1∶2.6-1∶1 3,配合物的单位剂量相当于2-10mg芬诺昔康。
13.权利要求1-12中任一项的药物组合物,它还含有选自吗啡、可待因、丙氧芬、扑热息痛和氨甲丙二酯的另一种活性组分。
14.权利要求1-13中任一项的药物组合物,其中含有一种或多种常规赋形剂。
15.权利要求1-14中任一项的药物组合物,其形式为药片或胶囊。
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ZA949055 | 1994-11-15 | ||
ZA94/9055 | 1994-11-15 |
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CN95197252A Pending CN1171738A (zh) | 1994-11-15 | 1995-11-14 | 药物组合物 |
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US (1) | US5854226A (zh) |
EP (1) | EP0792147B1 (zh) |
JP (1) | JPH10508835A (zh) |
CN (1) | CN1171738A (zh) |
AT (1) | ATE261301T1 (zh) |
AU (1) | AU694577B2 (zh) |
DE (1) | DE69532678D1 (zh) |
WO (1) | WO1996014839A1 (zh) |
ZA (1) | ZA959469B (zh) |
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-
1995
- 1995-11-08 ZA ZA959469A patent/ZA959469B/xx unknown
- 1995-11-14 AU AU38538/95A patent/AU694577B2/en not_active Ceased
- 1995-11-14 AT AT95936694T patent/ATE261301T1/de not_active IP Right Cessation
- 1995-11-14 WO PCT/GB1995/002679 patent/WO1996014839A1/en active IP Right Grant
- 1995-11-14 US US08/849,059 patent/US5854226A/en not_active Expired - Lifetime
- 1995-11-14 EP EP95936694A patent/EP0792147B1/en not_active Expired - Lifetime
- 1995-11-14 JP JP8515851A patent/JPH10508835A/ja active Pending
- 1995-11-14 DE DE69532678T patent/DE69532678D1/de not_active Expired - Lifetime
- 1995-11-14 CN CN95197252A patent/CN1171738A/zh active Pending
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Publication number | Publication date |
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ATE261301T1 (de) | 2004-03-15 |
JPH10508835A (ja) | 1998-09-02 |
US5854226A (en) | 1998-12-29 |
EP0792147B1 (en) | 2004-03-10 |
WO1996014839A1 (en) | 1996-05-23 |
EP0792147A1 (en) | 1997-09-03 |
AU694577B2 (en) | 1998-07-23 |
ZA959469B (en) | 1996-05-15 |
AU3853895A (en) | 1996-06-06 |
DE69532678D1 (de) | 2004-04-15 |
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