CN102481317A - 活性炭对达比加群酯过量给药的紧急干预 - Google Patents
活性炭对达比加群酯过量给药的紧急干预 Download PDFInfo
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Abstract
本发明涉及一种处理式I的活性物质达比加群酯过量给药的方法,所述达比加群酯任选地为其药学上可接受的盐的形式,该方法包括给药有效量的炭。
Description
本发明涉及一种处理式I的活性物质达比加群酯(Dabigatran etexilate)过量给药(overdosing)的方法
所述达比加群酯任选地为其药学上可接受的盐的形式,该方法包括给药有效量的炭。
发明背景
现有技术已知式I化合物,其首次公开于专利WO98/37075中。它是一种强效的凝血酶抑制剂,可例如用于手术后预防深静脉血栓和预防中风,尤其是预防心房纤维颤动患者的中风。专利WO 03/074056公开了达比加群酯与甲磺酸的加成盐(即达比加群酯甲磺酸盐)尤其有用。
该化合物通常口服给药。尤其是,可以使用所谓的弹丸剂(pelletformulation),如例如专利WO 03/074056所公开。这些制剂是如下的组合物,其中将含粘合剂和任选地隔离剂的活性物质层涂敷于含药学上可接受的有机酸(或由其组成)的基本上为球形的核心材料上。所述核心层和活性物质层彼此通过所谓的隔离层(isolating layer)而分开。此类活性物质制剂的结构的示意图参见专利WO 03/074056的图1。
达比加群酯(I)是一种前药,其在体内迅速地转化为活性部分达比加群(dabigatran,式II的化合物),其为强效的直接凝血酶抑制剂。即,达比加群酯仅在体内转化为实际上有效的化合物达比加群。
该药物目前正在进行心房纤维颤动患者中的中风预防(SPAF)试验,并且在这些患者中长期给药以替代华法林。由于长期抗凝血治疗中出血并发症的风险,因此可能存在紧急中和这种药物的需求。
本发明的目的在于提供一种紧急中和达比加群酯的合适的方法,特别是在过量给药的情况下。
发明详述
本发明涉及上述问题的一种可行的解决方案。
本发明涉及一种处理式I的活性物质达比加群酯过量给药的方法所述达比加群酯任选地为其药学上可接受的盐的形式,
该方法包括给药有效量的炭。
本发明涉及一种在患者的胃中中和达比加群酯的方法,其中将有效量的活性炭口服给予有需要的患者。所述活性炭的有效量通常在20-130g的范围,优选在50-100g的范围。所用炭的量取决于过量给药的程度。
达比加群酯I是达比加群(式(II)的化合物)的双前药,即达比加群酯I仅在体内转化为实际上有效的化合物达比加群II。
在另一实施方案中,本发明涉及一种在血浆中中和达比加群II的方法,该方法包括用活性炭纯化患者的血浆。通过用炭过滤器进行血液灌流而从血浆中吸附过量给药的达比加群II。
炭对达比加群酯和达比加群惊人的高度吸附,在下述的实验中得以证实。这些实验中,在水中达比加群酯与活性炭的结合模拟了在胃液中新近大量摄入(2-5小时,优选2-3小时)达比加群酯的情形。在血浆中达比加群与活性炭的结合模拟了达比加群在摄入后被吸收并且以高浓度存在于血浆中的情形。
下面的部分公开了达比加群剂型的制备方法以及由此得到的剂型。
制备所述临床试验中所用的药物组合物的方法,特征在于一系列分步步骤。首先,由药学上可接受的有机酸制备核心1。在本发明的范围内,用酒石酸制备核心1。然后通过喷射隔离混悬液2将由此得到的核心材料1转化为所谓的经隔离的酒石酸核心3。在包衣方法的一个或多个操作步骤中,将随后制备的达比加群混悬液4喷射于这些包衣的核心3上。最终,将由此得到的活性物质弹丸剂5填充于合适的胶囊中。
通过空气喷射筛选确定酒石酸的粒径
测量装置和设置:
测量装置:空气喷射筛(Air jet screen),例如Alpine A200 LS
筛: 根据需要
放入重量:10g/筛
持续时间:1分钟/筛,然后每1分钟至多减重0.1g。
样品制备/产品提供:
将物质转移至研钵中,且用力将所有结块捣碎。将具有胶塞和盖的筛置于天平上,调零,于筛上称重10.0g捣碎的物质。
将筛与其内容物、胶塞和盖子一起置于装置上。计时器设置为1分钟,在该时间内经空气喷射筛选处理所述材料。然后将残余物称重并记录。重复该方法,直至空气喷射筛选后减重<0.1g。
实施例1-起始弹丸剂的制备
在常规的具有盘形底和搅拌器的混合容器中,将480kg水加热至50℃并伴随搅拌加入120kg阿拉伯胶。在恒定温度持续搅拌直至得到澄清溶液。一旦形成澄清溶液(通常在1至2小时后),伴随搅拌加入600kg酒石酸。在恒定温度并伴随持续搅拌加入酒石酸。添加结束后,再搅拌该混合物约5至6小时。
将1000kg酒石酸加入缓慢旋转(3转/分)的未打孔的水平盘中,该水平盘具有喷射和粉末涂敷单元(例如Driamat 2000/2.5)。喷射开始前,取酸的样品用于筛选分析。该酸为酒石酸颗粒,其具有的粒径范围为0.4-0.6mm。
将上述方法得到的酸的胶溶液喷射于由此得到的酒石酸颗粒上。喷射过程中,将空气供给量调节至1000m3/小时和35°-75℃。分压为2毫巴,且盘的转速为9转/分钟。喷嘴应安排在距填料350-450mm处。
通过交替使用下列步骤喷射该酸的胶溶液。在将约4.8kg酸的胶溶液喷射于酒石酸颗粒(粒径0.4-0.6mm)上并分配该溶液后,将约3.2kg酒石酸粉末喷洒在潮湿的酒石酸颗粒上。所述酒石酸粉末含酒石酸微粒,其粒径<50微米。总计需要800kg酒石酸粉末。喷洒和分散所述酒石酸粉末后,干燥喷洒材料直至产物温度达到约40℃。在其随后依次进行酸的胶溶液的喷射。
重复这一循环,直至酸的胶溶液用尽。一旦方法结束,将所述酸弹丸剂在3rpm的盘中干燥240分钟。为防止干燥结束后结块,每小时以3rpm进行3分钟的间隔操作。在本案中,这是指,每隔1小时将该盘以3rpm旋转3分钟,然后将其保持静止。然后将该酸弹丸剂转移至干燥器中。然后在60℃将其干燥48小时。最终,通过筛选分析测定粒径分布。直径为0.6-0.8mm的粒径符合产品的要求。这一部分应占>85%。
实施例2-起始弹丸剂的隔离
为了制备隔离混悬液,将666.1(347.5)kg乙醇置于混合容器中,将羟丙基甲基纤维素(33.1(17.3)kg)在约600rpm搅拌下加入并溶解。然后在相同条件下加入0.6(0.3)kg二甲硅油。临近使用前,在搅拌下加入滑石(33.1(17.3)kg)并使之混悬。
将酸弹丸剂1200(600)kg倾倒至包衣装置(例如GS-Coater Mod.600/Mod.1200)中,并通过持续数小时的喷射操作以32kg/小时(对于1200kg混合物)或21kg/小时(对于600kg混合物)的喷射速率向其中的旋转盘中喷射上述隔离混悬液。所述弹丸剂还在最高70℃通过空气供给持续干燥。
当GS-Coater清空后,经隔离的起始弹丸剂通过筛选分级。将直径≤1.0mm的级分储存并进一步使用。
实施例3-达比加群酯混悬液的制备
在配有旋桨式搅拌器的1200升混合容器中,将26.5kg羟丙基纤维素加入720kg异丙醇,并搅拌该混合物直至完全溶解(约12-60小时;大约500rpm)。一旦溶液澄清,在搅拌(400rpm)下加入132.3kg达比加群酯甲磺酸盐(多晶型I),并且再搅拌该混合物约20-30分钟。然后在恒定搅拌速率下加入21.15kg滑石,并以相同的速率再持续搅拌约10-15分钟。上述步骤优选在氮气氛下进行。
通过使用UltraTurrax搅拌器(约60-200分钟)均质化将形成的任何团块打碎。在整个制备方法中,混悬液温度不应超过30℃。
搅拌该混悬液直至可以进行其他操作,以确保无沉降发生(在大约400rpm)。
若混悬液储存于30℃以下,其应在最多48小时内进一步操作。若(例如)该混悬液在22℃制备和储存,其可在60小时之内进一步操作。若该混悬液在35℃制备和储存,其可在最多24小时之内进一步操作。
实施例4-达比加群酯活性物质弹丸剂的制备
使用具有未打孔的容器的水平盘(GS Coater Mod.600)。与流化床(fluidised bed)方法不同,通过″顶端喷射(top spray)″方法将该混悬液喷射在旋转盘中弹丸剂的流化床上。其通过直径为1.4mm的喷嘴喷射。干燥空气通过所谓的浸没刀片(immersion blades)通入弹丸剂床,并通过包衣器后壁的开口排出。
在水平盘中装入320kg根据实施例2得到的酒石酸弹丸剂,并加热弹丸剂床。一旦产物温度达到43℃,则开始喷射。喷射根据实施例3预先制备的900kg混悬液,首先以20kg/小时的喷射速率喷射2小时,然后为24kg/小时,且喷射压力为0.8巴。不断搅拌混悬液。供给空气的温度最高为75℃。供给空气的量为约1900m3/小时。
然后在水平盘(5转/分)中经约1-2小时的时间将该弹丸剂干燥,空气流入温度为最低30℃、最高50℃,且空气流入量为500m3/小时。
由此获得的325kg弹丸剂再次装载于水平盘中,并加热至43℃。喷射900kg根据实施例3预先制备的混悬液,首先以20kg/小时的喷射速率喷射2小时,然后为24kg/小时,且喷射压力为0.8巴。不断搅拌混悬液。供给空气的温度最高为75℃。供给空气的量为约1900m3/小时。
然后在水平盘(5转/分)中经约1-2小时的时间将该弹丸剂干燥,空气流入温度为最低30℃、最高50℃,且空气流入量为500m3/小时。
然后将经干燥的弹丸剂通过振动筛(网目尺寸为1.6mm)并储存于带有干燥剂的容器中,直至需要用于其他操作。
下列胶囊基于根据上述方法制备的弹丸剂制备:
在下面的部分中,公开了支持炭惊人地高度吸附该药物的实验。
将5、10和20粒达比加群酯胶囊(150mg/胶囊)的内容物混悬于100ml水(约为胃体积,pH分别为2.7、2.5和2.4)。将每一混悬液等分成两份。向其中一份中加入刚刚制备的活性炭混悬液(125mg/ml,Merck)。过滤混悬液(有和无活性炭),并通过HPLC测定达比加群酯浓度。
通过HPLC测得未处理的水混悬液中达比加群酯浓度分别为8.3、15.6和29.6mg/ml。在活性炭处理的混悬液中,不再检测到达比加群酯的峰,这表明在所有三个测试浓度下,>99.9%的达比加群酯被活性炭吸附。
在血浆实验中,以470和940ng/ml的超过治疗的浓度,将达比加群加入血浆池中。然后将样品分成两份,并向其中一份中以生产商指定的浓度(125mg/ml)(或其1∶11稀释液)加入活性炭。通过经确证有效的LC-MS/MS方法测定达比加群的血浆水平。
将达比加群活性物质加入血浆后,未处理的血浆中测得浓度值为394±19.4和824±39.3ng/ml(平均值±SD)。在这两个浓度下添加活性炭,使达比加群水平减少至<1.01ng/ml(即,接近或低于分析的定量下限)。
Claims (11)
2.权利要求1的方法,其中所述炭以口服给药。
3.权利要求1或2的方法,其中口服给药的炭的量在20-130g的范围。
5.权利要求4的用途,其包括口服给药有效量的炭。
6.权利要求4或5的用途,其中所述炭的量在20-130g的范围。
8.权利要求7的炭,其中所述炭以口服给药。
9.权利要求7或8的炭,其中口服给药的炭的量在20-130g的范围。
11.权利要求10的方法,其中通过用炭过滤器进行血液灌流而从血浆中吸附达比加群II。
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Application Number | Priority Date | Filing Date | Title |
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US23632109P | 2009-08-24 | 2009-08-24 | |
US61/236,321 | 2009-08-24 | ||
PCT/EP2010/062229 WO2011023653A1 (en) | 2009-08-24 | 2010-08-23 | Emergency interventions of active charcoal with dabigatran etexilate overdosing |
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EA (1) | EA201200319A1 (zh) |
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IL (1) | IL216968A0 (zh) |
MX (1) | MX2012001767A (zh) |
NZ (1) | NZ597359A (zh) |
PL (1) | PL2470187T3 (zh) |
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CN114452839A (zh) * | 2022-02-10 | 2022-05-10 | 中南大学湘雅医院 | 一种抗凝抗栓血液净化膜及其制备方法 |
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AR079944A1 (es) | 2010-01-20 | 2012-02-29 | Boehringer Ingelheim Int | Anticuerpo neutralizante de la actividad de un anticoagulante |
AP2013007046A0 (en) * | 2011-03-30 | 2013-08-31 | Boehringer Ingelheim Int | Anticoagulant antidotes |
GB201120693D0 (en) * | 2011-12-01 | 2012-01-11 | Convatec Technologies Inc | Wound dressing for use in vacuum therapy |
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PE121699A1 (es) | 1997-02-18 | 1999-12-08 | Boehringer Ingelheim Pharma | Heterociclos biciclicos disustituidos como inhibidores de la trombina |
EP1485094B2 (de) | 2002-03-07 | 2020-03-25 | Boehringer Ingelheim International GmbH | Oral zu applizierende darreichungsform für 3- [(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] -propionsäure-ethylester oder dessen salze |
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US5277820A (en) * | 1992-02-06 | 1994-01-11 | Hemocleanse, Inc. | Device and method for extracorporeal blood treatment |
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Cited By (1)
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CN114452839A (zh) * | 2022-02-10 | 2022-05-10 | 中南大学湘雅医院 | 一种抗凝抗栓血液净化膜及其制备方法 |
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Publication number | Publication date |
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EA201200319A1 (ru) | 2012-09-28 |
CA2767966A1 (en) | 2011-03-03 |
EP2470187B1 (en) | 2013-08-21 |
MX2012001767A (es) | 2012-02-29 |
CN102481317B (zh) | 2014-09-03 |
NZ597359A (en) | 2014-01-31 |
DK2470187T3 (da) | 2013-10-28 |
WO2011023653A1 (en) | 2011-03-03 |
PL2470187T3 (pl) | 2014-01-31 |
AU2010288601A1 (en) | 2012-02-02 |
IL216968A0 (en) | 2012-02-29 |
BR112012004169A2 (pt) | 2016-03-29 |
CL2012000488A1 (es) | 2012-08-31 |
US20110206656A1 (en) | 2011-08-25 |
ES2436076T3 (es) | 2013-12-26 |
AR077909A1 (es) | 2011-09-28 |
TW201124143A (en) | 2011-07-16 |
US20130302311A1 (en) | 2013-11-14 |
EP2470187A1 (en) | 2012-07-04 |
KR20120050457A (ko) | 2012-05-18 |
JP2013502449A (ja) | 2013-01-24 |
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