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CN1071571C - 含有反胺苯环醇物质和乙酰氨基苯的组合物及其应用 - Google Patents

含有反胺苯环醇物质和乙酰氨基苯的组合物及其应用 Download PDF

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CN1071571C
CN1071571C CN92112594A CN92112594A CN1071571C CN 1071571 C CN1071571 C CN 1071571C CN 92112594 A CN92112594 A CN 92112594A CN 92112594 A CN92112594 A CN 92112594A CN 1071571 C CN1071571 C CN 1071571C
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CN1086133A (zh
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R·B·拉发
J·L·沃特
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Janssen Pharmaceuticals Inc
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Abstract

本发明涉及一种包括反胺苯环醇和乙酰氨基苯的组合物及其应用。所用的反胺苯环醇涉及各类反胺苯环醇。该组合物可用来治疗药理学上的疼痛和咳嗽引起的症状。所述组合物很少有类鸦片的副作用，例如滥用性、耐受性、便秘和呼吸抑制。此外，组合物的各组分在一定比例范围内，该组合物的药物效果是超相加的(增效的)。

Description

含有反胺苯环醇物质和乙酰 氨基苯的组合物及其应用
美国专利3652589号公开了一类镇痛的环烷醇取代的苯酚酯，在环烷环中具有碱性胺基团。其中具体介绍了化合物(1RS,2RS)-[(二甲氨基)甲基]-1-(3-甲氧苯基)环己醇，一般称为反胺苯环醇。有关反胺苯环醇的药理、毒理和临床研究的一系列论文参见Arzneim Forsch(Drug Res.),28(1),114(1978)。Driessen等在Arcb.Pharmacol.,341,R104(1990)中公开了反胺苯环醇产生其镇痛作用的机理既不完全象类鸦片，也不象非类鸦片的作用机理。关于疼痛的第Ⅵ次世界会议(1990年4月1日-6日)摘要介绍了反胺苯环醇盐酸盐是一种口服活性纯兴奋的类鸦片镇痛剂。然而，临床实践表明反胺苯环醇缺少许多类鸦片兴奋剂的典型副作用，例如呼吸抑制[见W.Vogel et al.,Arzneim.Forsch(Drug Res),28(1).183(1978)]、便秘[见I.Arend el al.Arzneim.Forsch.(Drug Res.),28(1).199(1978)]、耐受性[见L.Flohe et al.,Arzneim.Forsch.(Drug Res.),28(1),213(1978)]和滥用倾向[见T.Yanagita,Arzneim.Forsch.(Drug Res),28(1),158(1978)]。当快速静脉注射剂量为50mg反胺苯环醇时，会产生一定的副作用，这只有反胺苯环醇才有的使脸潮红和出汗。尽管有这些副作用，具有非类鸦片和类鸦片活性的反胺苯环醇仍是一个极独特的药物。GrumenthalGMH将反胺苯环醇作为镇痛剂广泛销售。
多年来，类鸦片一直作为镇痛剂用来治疗剧痛，但是，它们产生不希望的副作用，因此不能反复或以高剂量给药。所述副作用问题可由许多文献资料证明。例如参见J.Jaffe和Martion的“ThePharmacological Basis of Therapentics”一书第15章245页(编者L.Goodman和A.Gilman，第5版，1975)，其中，揭示了吗啡及其同类物质，例如可待因、氢化可待因酮和氧化可待因酮均是类鸦片兴奋镇痛剂，具有副作用，如呼吸抑制、便秘和滥用倾向。
作为使用类鸦片的代替物、非类鸦片例如乙酰氨基苯(APAP)和阿司匹灵都可用作镇痛剂。APAP，像阿司匹灵一样，它不会造成类鸦片镇痛剂的耐受性、成瘾和毒性。然而，APAP和阿司匹灵只用于减轻中度疼痛，而类鸦片镇痛剂用于减轻严重疼痛[参见：Woodbury,D.and Fingl,E.,“The Pharmacological Basis of Therapentics”,5th Ed；Goodman,L.and Gilman,A.,Chapter 15,Pages 325(1975)]。
为减少类鸦片的副作用问题，已将类鸦片与其它包括非类鸦片镇痛剂的药物结合，可降低产生相当镇痛程度所需的鸦片用量。其中某些组合物产品还具有产生协同镇痛效果的优点，已要求权利保护。例如，A.Takemori,Annals New York Acad.Sci.,281,262(1976)公开了类鸦片镇痛剂与非镇痛剂药物结合的组合物呈现多种作用，即亚相加(抑制)、相加或超相加镇痛作用。R.Taber et al.,J.Pharm.Expt.Thera.,169(1),29(1969)公开了吗啡和美沙酮、及另一个类鸦片镇痛剂的结合呈现相加作用。美国专利4571400号揭示二氢可待因、类鸦片镇痛剂、布洛芬、非类鸦片镇痛剂等组分按一定比例结合时，能提供超相加作用。A.Pircio et al.,Arch.Int.Pharmacodyn.,235,116(1978)报导环丁甲二羟吗喃、另一个类鸦片镇痛剂和乙酰氨基苯(APAP)、非类鸦片镇痛剂以1∶125的混合物显示出超相加镇痛作用，而以1∶10的混合物则显示不出任何统计学上有意义的超相加镇痛作用。
同样，已制备一些非类鸦片镇痛剂的组合物，以避免类鸦片伴生的副作用，特别注意到这些组合物具有只需较少的每种组分而产生超相加作用的优点。G.Stacher et.al.,Int.J.Clin.Pharmacol.Biopharmacy,17,250(1979)报导了非类鸦片镇痛剂即甲苯酰吡酸和APAP的结合可以明显减少产生镇痛作用所需甲苯酰吡酸的量。此外，美国专利4260629号公开了对哺乳动物口服给以按特定重量比范围的APAP和氯苯酰二甲基吡咯乙酸、一种非类鸦片镇痛剂的组合物，能产生超相加作用减轻疼痛。另外，美国专利4132788号公开了当5-芳酰基-1-(低级)烷基吡咯-2-乙酸衍生物，非类鸦片镇痛剂与APAP或阿司匹灵结合时，能呈现超相加抗关节炎活性。但是，警告每天不能大剂量或长时期服用非类鸦片镇痛剂混合物以及单一的非类鸦片镇痛剂(参见D.Woodbary和E.Fingl at page 349)。
然而，现有技术并没有公开反胺苯环醇，一种“非典型”的类鸦片镇痛剂，它能够或可以与另一种镇痛剂结合，致使减少各自的副作用，或产生含有反胺苯环醇物质和另一种镇痛剂的组合物，该组合物呈现超相加镇痛作用。
业已发现反胺苯环醇，包括下文定义的各种形式的反胺苯环醇，可以与APAP结合，产生镇痛作用。所述结合，使反胺苯环醇和APAP两者的用量均少于它们单独使用产生同一镇痛效果所需要的量。由于这两种药物用量均较少，各自伴生的副作用在数量和程度上也都减少。意想不到地发现由反胺苯环醇和APAP按一定比例结合生成的组合物会呈现出镇痛增效作用。本发明的组合物还可用于治疗咳嗽病症。
附图是均等兴奋图，它表示反胺苯环醇盐酸盐和乙酰氨基苯组合物对乙酰胆碱诱发的小鼠腹收缩的镇痛效果。
本发明提供含有反胺苯环醇物质和乙酰氨基苯的组合物。所述反胺苯环醇物质是(1S,2S或1S,2S)-(二甲氨基甲基)-1-(3-甲氧苯基)-环己醇(反胺苯环醇)、它的N-氧化物衍生物(“反胺苯环醇-N-氧化物”)的任何一种或其混合物。而且还包括反胺苯环醇物质的单个的立体异构体、立体异构体混合物(包括外消旋物)、药学上可接受的胺盐(例如盐酸盐)、溶剂化物和多晶型物。所述反胺苯环醇可购自Grunenthal公司或按照作为参考文献并入本文的美国专利3652589号介绍的方法制备。
反胺苯环醇-N-氧化物可通过下述方法制备，即在有机溶剂例如甲醇或异丙醇中，反胺苯环醇游离碱用氧化剂例如过氧化氢(30％)在加热下(最好不加热)处理(参见“Reagents For OrganicSynthesis”,L,471,Fieser 8 Fieser eds.,Wiley N.Y.,(1987),B.Kelentey etal Arzneim.forsch.,7594(1957)。加热反应约需1小时，而不加热反应需3天左右。氧化后，所述混合物用试剂(例如PtO2或优选Pt/C)处理约1天，消除过量的过氧化氢。该混合物过滤，接着滤液蒸发，残留物用有机溶剂混合物(例如二氯甲烷/乙酸乙酯)重结晶。
O-去甲基反胺苯环醇可通过下述方法制备，即反胺苯环醇游离碱，在O-去甲基化反应条件下，例如它与强碱(如NaOH或KH苯硫酚)和二甘醇(DEG)反应，同时加热回流[(参见Wildes et al.,J.Org.Chem.,36,721(1971)]。该反应进行1小时左右，接着冷却，然后用水处理该反应混合物，酸化，用有机溶剂如乙醚提取，碱化，用有机卤代溶剂如二氯甲烷提取，提取物干燥，溶剂蒸发，得O-去甲基产品，然后经短程蒸馏并转化成相应的盐(例如用酸化溶液，HCl乙醇处理)，于有机溶剂混合物(例如乙醇/乙醚)中重结晶。
乙酰氨基苯的药物学评述参见B.Ameer et al.,Ann.Int.Med.,87,202(1977)；乙酰氨基苯的制备参见美国专利2998450号，它作为参考文献并入本文。
APAP和反胺苯环醇物质通常以反胺苯环醇对APAP的重量比约为1∶1至1∶1600存在，某些比率导致组合物呈现镇痛增效作用。例如，含有一种反胺苯环醇物质和APAP的组合物，所述反胺苯环醇物质：APAP的比例优选约1∶5至1∶1600，更优选约1∶19至1∶800。
最优选的比例为约1∶19至1∶50。在这些重量比范围内的反胺苯环醇物质和APAP的组合物已呈现出镇痛增效作用。此外，各组分的比例为约1∶1和约1∶5的具体组合物包括在本发明范围内。
根据常规药物配制技术可以制备含有作为活性成分充分混合的反胺苯环醇物质和乙酰氨基苯及药物载体的药用组合物。所述载体的种类繁多，这取决于给药要求的制剂形式，例如静脉注射、口服或非肠道给药。所述组合物还可用喷雾方式给药。就制备口服剂型组合物而言，可以使用常用的任何药用介质，例如，制备口服液体制剂(如混悬液、酏剂和溶液)时，可以使用水、乙二醇类、油类、醇类、调味剂、防腐剂、着色剂等。制备口服固体制剂(例如粉剂、胶囊和片剂)时，可以使用的载体如淀粉、糖、稀释剂、制粒剂、润滑剂、粘合剂、崩解剂等。由于片剂和胶囊易于给药，它们是最具优点的口服剂量单元剂型，在此情况下，显然使用固体药用载体。必要时，片剂可按标准技术包覆糖衣或肠衣。对于非肠道给药，载体通常包括无菌水，尽管可以包括其它成分，例如帮助溶解或防腐的成分。也可制备注射混悬液，在此情况下，可以使用适宜的液体载体、混悬剂等。所述药用组合物一般呈剂量单元形式，例如片剂、胶囊、粉剂、注射剂、冲剂等，所含活性成分为0.1至约800mg/Kg，优选约0.3至200mg/Kg。
下述实施例更具体阐述本发明，但并非限制本发明。实施例1：反胺苯环醇和APAP结合剂量的制备
不同比例的反胺苯环醇/APAP结合的制剂通过下述方法制备，首先制备某一浓度的反胺苯环醇储液(浓度以每10ml蒸馏水含药物的毫克数表示)，例如3mg反胺苯环醇作为游离碱溶解于10ml水中，得到高剂量反胺苯环醇储液，然后，所述反胺苯环醇储液用足够的蒸馏水稀释，制备每10ml蒸馏水含较低剂量反胺苯环醇的溶液，然后将每10ml稀释溶液加到适当毫克数的APAP中，使之混合，以达到反胺苯环醇比APAP的要求比例。就1∶50的实例而言：400mg APAP游离碱混悬于10ml含8mg反胺苯环醇的溶液和2滴吐温80(由Fisher科学公司生产的药用分散剂)中，形成1∶50比例，即每10ml水中结合(8mg∶400mg)。以类似方法分别制备每一种比例的药剂，对每只小鼠以10ml/Kg体重的量注射。实施例2：反胺苯环醇-N-氧化物和APAP结合剂量的制剂
首先制备反胺苯环醇-N-氧化物，如下所述：将反胺苯环醇盐酸盐(0.5摩尔)在碱化水(PH＞9)中转化成游离碱，然后用醚提取。蒸发醚，得反胺苯环醇的结晶状水合物，该固体在高真空度下用蒸汽加热，尽可能除去多的水分，得131.5g产物，该产物溶解于甲醇(500ml)中，加入65g 30％H2O2，搅拌3小时，再加入65g 30％H2O2，该反应液在室温下搅拌2.5天，加入约10mgPtO2/C催化剂，很缓和地起泡，另加10mg PtO2(建议使用Pt/C，易于去除)，反应混合物搅拌过夜，然后通过助滤器过滤，真空浓缩滤液，＜40℃温度加热，残留物溶于二氯甲烷，由于二氯甲烷溶液含有某些胶态铂，故用乙酸乙酯稀释该溶液至1L，通过尼龙滤膜(孔径为0.45μ)过滤，得无色澄清滤液，该滤液浓缩至600ml，然后连续加入乙酸乙酯，维持80ml体积，同时加热该溶液，直至蒸汽温度达74℃，然后冷却至室温，过滤收集固体，用乙酸乙酯洗涤，真空干燥，得126.6g反胺苯环醇-N-氧化物(mp.159.5-160℃)。
    C16H25NO3
    理论值：C,68.78；H,9.27；N,5.01
    实测值：C,68.65；H,9.22；N,4.99
反胺苯环醇-N-氧化物/APAP不同比例结合的制剂通过下述方法制备。首无制备以每10ml蒸馏水含mg药物表示的某一浓度的反胺苯环醇-N-氧化物储液，例如8mg反胺苯环醇-N-氧化物游离碱溶解于10ml水中，生成高剂量反胺苯环醇储液，然后，所述反胺苯环醇-N-氧化物储液用足够的蒸馏水稀释，制备每10ml蒸馏水含较低浓度的反胺苯环醇-N-氧化物溶液，然后将每10ml稀释的溶液加到适当mgAPAP中，使之结合，以达到反胺苯环醇-N-氧化物比APAP的要求比例。就1∶50的实例而言：400mgAPAP游离碱混悬于10ml含8mg反胺苯环醇-N-氧化物的溶液和2滴吐温80(由Fisher科学公司生产的药用分散剂)中，形成1∶50比例，即每10ml水中结合(8mg∶400mg)。以类似方法分别制备每一种比例的药剂，对每只小鼠以10ml/Kg体重剂量注射。实施例3：O-去甲基反胺苯环醇(-)和(+)对映体：它们的合成以及O-去甲基反胺基苯环醇与APAP结合制剂。
如下所述，首先制备O-去甲基反胺苯环醇：冷却下，将二甘醇(125ml)加到氢化钾(9.5g)中，温度维持在＜50℃，向该溶液加入苯硫酚(10ml)的二甘醇(25ml)溶液，然后加入(-)反胺苯环醇游离碱(9.3g)的二甘醇(50ml)溶液，最终的反应混合物缓慢加热回流45分钟，冷却，然后，倒入水中。PH值调至3左右，该混合物用乙醚提取，再调PH至8左右，所得混合物用二氯甲烷提取5次以上，提取液干燥，蒸发二氯甲烷，得4.6g油状标题化合物，将该油蒸馏(Kugeizohr)、并溶解于四氢呋喃，用乙醇/HCl溶液处理，得2.3g盐，该盐于乙醇/乙醚溶液中重结晶，干燥，得1.8g O-去甲基反胺苯环醇(-)对映体的盐(mp.242-3℃)[a]25 D=-32.9(c=1,EtOH)。
    C15H23NO2.HCl
    理论值：C,63.04；H,8.46；N,4.90
    实测值：C,63.00；H,8.51；N,4.94
为了制备标题化合物的(+)对映体，所述反应在相同条件下进行，所不同的是使用(+)反胺苯环醇游离碱取代(-)-反胺苯环醇，得2.8g O-去甲基反胺苯环醇的(+)对映体。
    C15H23NO2.HCl
    理论值：C,63.04；H,8.46；N,4.90
    实测值：C,63.14；H,8.49；N,4.86
O-去甲基反胺苯环醇/APAP不同比例结合的制剂通过下述方法制备：首先制备以每10ml蒸馏水含mg药物表示的一定浓度的O-去甲基反胺苯环醇储液，例如将8mg O-去甲基反胺苯环醇游离碱溶解于10ml水中，生成高剂量O-去甲基反胺苯环醇储液，然后，将所述O-去甲基反胺苯环醇储液用足够的蒸馏水稀释，制备每10ml蒸馏水含较低剂量O-去甲反胺苯环醇的溶液。将每10ml稀释溶液加到适当mg数的APAP中，使之结合，以达到反胺苯环醇比APAP的要求比例。就1∶50的实例而言：将400mg APAP游离碱混悬于10ml O-去甲基反胺苯环醇(8mg)溶液和2滴吐温80(由Fisher科学公司的药用分散剂)中，形成1∶50比例，即每10ml水中结合(8mg∶400mg)。以类似方法分别制备每一种比例的药剂，对每只小鼠以10ml/Kg体重的量注射。
实施例4：镇痛活性
利用CDI雄性小鼠(体重18-24g)测定有关本发明组合物的镇痛活性。小鼠全部口服完全溶于蒸馏水中的反胺苯环醇盐酸盐(按碱计)，和完全溶解于蒸馏水或含2％(体积)吐温80(含100％聚山梨酸酯80)的蒸馏水中的乙酰氨基苯(按碱计)。该剂量体积为10ml/Kg。
测定和比较不同种类镇痛药物的镇痛活性的方法是防止乙酰胆碱诱发的小鼠腹部收缩[H.Collier et al.,Br.J.Pharmacol.,32.295(1968)]，该方法与人类的效用高度相关。
喂小鼠的插管装有各种剂量的单一反胺苯环醇盐酸盐、单一乙酰氨基苯、反胺苯环醇盐酸盐和乙酰胺基苯的结合制剂，或载体，例如蒸馏水或含2％(体积)吐温80的蒸馏水，对小鼠腹膜内注射引起反应剂量的乙酰胆碱溴化物。该乙酰胆碱完全溶解于蒸馏水中，浓度为5.5mg/Kg，以0.20ml/20g比率注射。为便于评价，“腹部收缩”定义为伴随有背部拱起和四肢伸展的腹肌收缩。在小鼠接受乙酰胆碱剂量后，立而开始，观察小鼠10分钟是否存在腹部收缩反应，该时间正好是小鼠接受口服给予反胺苯环醇盐酸盐、乙酰氨基苯、反胺苯环醇和乙酰胺基苯结合制剂或赋形剂之后30分钟。每只小鼠仅使用一次。
按R.J.Tallarida et al.,Life Scj.,45,947(1989)介绍的方法测定分析每一固定比例的组合物可能产生的超相加性。该方法包括测定要求产生给定水平效果[例如50％(ED50mix)]的混合物总量，然后测定在简单相加性(ED50add)条件下所期望的相应总量。对于某一具体的固定比例而言，当ED50mix＜ED50add时，则具有超相加性。ED50mix和ED50add的量均为随机变量；ED50mix是由给定的固定比例剂量应答曲线计算的；ED50add是由在相加性条件下评价的两种药物的ED50加合而得的。然后，通过Student′s t-检验，将ED50mix与ED50add进行比较。单独的反胺苯环醇盐酸盐的ED50值是5.5(4.8-6.4)mg/Kg，单独的乙酰胺基苯的ED50值是164.3(122.7-219.9)mg/Kg。
在反胺苯环醇盐酸盐和乙酰氨基苯的精确剂量比例下，测定反胺苯环醇和乙酰氨基苯之间的相互影响。用能使试验的各独立剂量形式完全随机化的实验设计，研究了每一选择的结合的多种(一般4-6种)代码剂量在30分钟后的镇痛效果。
表Ⅰ数据说明反胺苯环醇盐酸盐和乙酰氨基苯对乙酰胆碱诱发的小鼠腹部收缩的相互影响，并以Loewe均等兴奋图示于图1中[参见S.Loewe,Pharm.Rev.9:237(1957)有关均等兴奋图的制作和基本原理]，如图1所示，连接两种给定药物的ED50值斜线分别表示在不同组分比例下时，效果的简单相加。靠近该斜线的两条点线确定了95％置信区间。落在曲线(在该ED50线和原点之间)下的ED50值表示超相加性，就是说，表示意想不到的增加效果。由座标原点向各方伸展的斜虚线表示小鼠接受药物结合制剂所用的APAP与反胺苯环醇的剂量比例。通过反胺苯环醇和APAP组合物的各ED50点的线表示ED50值的95％置信区间。如图1所示的试验数据表明反胺苯环醇与APAP的比例为1∶1至1∶1600(由曲线表示)的组合物给出意想不到的超相加效果，因为ED50mix小于EDadd。
                           表1
                     反胺苯环醇：APAP药物组合物               剂量(mg/kg,p.o.)               30min.时的ED50(95％CI′s)(反胺苯环醇：APAP)      反胺苯环醇    APAP       镇痛      反胺苯环醇    APAP单一反胺苯环醇            2           0          3/15
                      3           0          4/15
                      4           0          14/45
                      6           0          20/45     5.5
                      8           0          40/60     (4.8-6.4)
                      10          0          15/15
                      16          0          14/151000∶1                  3.75        0.00375    1/13
                      7.5         0.0075     8/15      7.0           0.01
                      15          0.015      15/15     (5.7-8.4)     (0.1-0.1)100∶1                   1.875       0.01875    0/15
                      3.75        0.0375     4/15      6.9           0.1
                      7.5         0.075      5/15      (5.2-9.0)     (0.1-0.1)
                      15          0.15       15/1520∶1                    1.875       0.09375    0/15
                      3.75        0.1875     4/15      6.5           0.3
                      7.5         0.375      7/15      (5.1-8.3)     (0.3-0.4)
                      15          0.75       15/153∶1                     3.75        1.25       3/30
                      7.5         2.5        12/30     7.8            2.6
                      15          5          28/30     (6.6-9.1)     (2.2-3.0)1∶1                     0.94        0.94       3/15
                      1.875       1.875      8/30
                      3.75        3.75       14/30     3.8            3.8
                      5           5          12/28     (3.0-4.8)      (3.0-4.8)
                      7.5         7.5        24/30
                      15          15         15/151∶3                     3.75        11.25      7/30
                      5           15         7/15      4.7            14.2
                      7.5         22.5       29/30     (4.3-5.2)      (12.8-15.7)1∶5                     2.5         12.5       7/30
                      5           25         8/30      4.0            19.8
                      10          50         30/30     (3.3-4.7)      (16.7-23.4)药物组合物               剂量(mg/kg,p.o.)            30min时的ED50(95％CI′s)(反胺苯环醇：APAP)  反胺苯环醇    APAP      镇痛       反胺苯环醇        APAP1∶5.7               0.47        2.66      0/15
                  0.94        5.313     4/15
                  1.88        10.625    1/15        4.1              23.3
                  3.75        21.25     5/15        (3.0-5.7)        (16.8-32.3)
                  7.5         42.5      11/15
                  15          85        15/151∶19                0.94        17.813    4/30
                  1.88        36.625    10/28
                  3.75        71.25     21/30       2.5              47.3
                  5           95        22/30       (2.0-3.0)        (38.9-57.5)
                  7.5         142.5     29/30
                  15          285       15/151∶50                0.25        12.5      3/30
                  0.5         25        7/30
                  1           50        9/30        1.2              61.4
                  2           100       19/30       (1.0-1.5)        (49.0-77.1)
                  4           200       27/30
                  8           400       30/301∶100               0.25        25        3/60
                  0.5         50        12/60
                  1           100       19/60       1.1              111.3
                  2           200       51/60       (1.0-1.3)        (96.4-128.6)
                  4           400       55/60
                  8           800       30/301∶200               0.125       25        1/60
                  0.25        50        9/60
                  0.5         100       27/60       0.6              129.7
                  1           200       44/60       (0.6-0.8)        (110.4-152.4)
                  2           400       48/60
                  4           800       30/301∶400               0.0625      25        2/15
                  0.125       50        4/30
                  0.25        100       18/30       0.2              95.1
                  0.5         200       12/15       (0.2-0.3)        (75.4-119.8)
                  1           400       28/30
                  2           800       15/15药物组合物               剂量(mg/kg,p.o.)                   30min.时的ED50(95％CI′s)(反胺苯环醇：APAP)    反胺苯环醇   APAP       镇痛           反胺苯环醇         APAP1∶800               0.03125      25        254/30
                  0.0625       50        9/30
                  0.125        100       15/30             0.1              77.4
                  0.25         200       27/30             (0.1-0.1)        (62.9-95.2)
                  0.5          400       30/301∶1600              0.03125      50        2/30
                  0.0625       100       14/30
                  0.125        200       22/30             0.1              125.7
                  0.25         400       27/30             (0.1-0.1)        (102.7-153.8)
                  0.5          800       30/30单-APAP              0            30        2/15
                  0            40        12/43
                  0            50        1/15
                  0            60        8/30
                  0            80        23/60
                  0            100       13/30                              164.3
                  0            120       13/30                              (122.7-219.9)
                  0            160       10/30
                  0            200       13/25
                  0            240       14/25
                  0            400       12/15
                  0            800       13/15

Claims (10)

1．一种药用组合物的制备方法，该方法包含将反胺苯环醇物质和乙酰氨基苯混合，其中所述反胺苯环醇物质与乙酰氨基苯的重量比为1∶1至1∶1600。
2．按照权利要求1的方法，其中所述反胺苯环醇物质和乙酰氨基苯的配比的结合物是增效的药物组合物。
3．按照权利要求2的方法，其中所述反胺苯环醇物质是反胺苯环醇盐酸盐。
4．按照权利要求3的方法，其中所述反胺苯环醇盐酸盐是外消旋的。
5．按照权利要求1的方法，其中所述重量比为1∶1。
6．按照权利要求1的方法，其中所述重量比为1∶5至1∶1600。
7．按照权利要求6的方法，其中所述重量比为1∶5。
8．按照权利要求1的方法，其中所述重量比1∶19至1∶800。
9．按照权利要求8的方法，其中所述重量比为1∶19至1∶50。
10．按照权利要求1的方法，其中还包含作为有效成份的药用结合剂与药学上可接受的载体混合。
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US5336691A (en) 1994-08-09
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