CN1610551A - 用作止痛剂的6－羟基羟吗啡酮的肠胃外给药 - Google Patents

用作止痛剂的6－羟基羟吗啡酮的肠胃外给药 Download PDF

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CN1610551A
CN1610551A CNA028153243A CN02815324A CN1610551A CN 1610551 A CN1610551 A CN 1610551A CN A028153243 A CNA028153243 A CN A028153243A CN 02815324 A CN02815324 A CN 02815324A CN 1610551 A CN1610551 A CN 1610551A
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oxymorphone
hydroxy
pharmaceutical composition
blood plasma
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H－H·考
R·史密斯-卡里斯
T·麦克卡尔
D·李
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Abstract

在治疗疼痛的方法中，以足以诱导止痛的量向患者给以6－羟基羟吗啡酮的药物组合物。在一种实施方式中，药物组合物是肠胃外给药的，优选地借助注射和静脉内滴注。为了达到所需的止痛效果，6－羟基羟吗啡酮的血浆水平在治疗期间被提升至至少大约0.05ng/ml。以足以诱导止痛的量给以含有6－羟基羟吗啡酮和一种或多种载体、稀释剂和赋形剂的组合物也涵盖其中。

Description

用作止痛剂的6-羟基羟吗啡酮的肠胃外给药
本申请涉及下列临时专利申请：2001年10月15日提交的60/329,445、2001年10月15日提交的60/329,432、2001年7月6日提交的60/303,357和2001年10月15日提交的60/329,444。
背景
发明领域
本发明涉及减轻疼痛的方法。更确切地，本发明涉及通过给以6-羟基羟吗啡酮来减轻疼痛的方法。最确切地，本发明涉及通过增加6-羟基羟吗啡酮的血浆水平来诱导止痛的方法。
发明概述
本发明提供治疗疼痛的方法，该方法以足以诱导止痛的量给以包含6-羟基羟吗啡酮的药物组合物。在一种实施方式中，药物组合物是肠胃外给药的，优选地借助注射和静脉内滴注。为了达到所需的止痛效果，6-羟基羟吗啡酮的血浆水平被提升至至少大约0.05ng/ml。还提供了以足以诱导止痛的量给以组合物的方法，该组合物包含6-羟基羟吗啡酮和一种或多种载体、稀释剂和赋形剂。
附图的简要说明
图1是6-羟基羟吗啡酮的药动学曲线和PID得分。
图2是羟吗啡酮的药动学曲线和PID得分。
图3是6-羟基羟吗啡酮的药动学曲线和绝对疼痛得分。
图4是羟吗啡酮的药动学曲线和绝对疼痛得分。
详细说明
本文所述方法为含有6-羟基羟吗啡酮作为活性成分的药物组合物提供直接给药。在优选的实施方式中，组合物包含单独的6-羟基羟吗啡酮(当然除了载体、稀释剂和其他赋形剂以外)。在其他实施方式中，6-羟基羟吗啡酮可以与其他阿片类或其他药物成分组合。例如，组合物包含6-羟基羟吗啡酮和它的母体、即羟吗啡酮。
在分开的研究中，历经12小时记录血浆水平和疼痛缓解的指征。图1-4显示联合两项研究所得数据的图示，以便可以评价血浆水平对疼痛的影响。
羟吗啡酮的给药产生羟吗啡酮及其代谢产物之一6-羟基羟吗啡酮的血浆水平。羟吗啡酮在2小时内达到峰值，缓慢下降至坪值。有趣的是，该水平在给药后4-6小时再次形成峰。这之后，羟吗啡酮水平再次下落，最终下降至接近先前坪值的水平。
象羟吗啡酮一样，6-羟基羟吗啡酮血浆水平在给药后2小时内达到峰值。不过在最初的峰之后，观察到6-羟基羟吗啡酮血浆水平的或多或少稳态衰退。
比较这些水平与疼痛曲线，可以见到在6-羟基羟吗啡酮血浆水平与疼痛缓解之间存在相互关系.疼痛水平几乎反映6-羟基羟吗啡酮水平，峰形附近缓解的实质性上升与羟吗啡酮血液水平有关。因而，疼痛缓解可以通过6-羟基羟吗啡酮的单独给药而实现。
除了药动学研究以外，还已进行了结合研究，以比较6-羟基羟吗啡酮的结合亲合性与羟吗啡酮的结合亲合性。结果报告在表1中。这些结果清楚地表明，6-羟基羟吗啡酮对δ、κ和μ受体部位具有很大的结合亲合性，与其母体的结合亲合性相当。发明人相信，凭借这种结合亲合性，6-羟基羟吗啡酮具有与其母体羟吗啡酮相似的止痛效果。
表1：测定报告
       6-羟基羟吗啡酮            羟吗啡酮
  10nm1.0 E-8   10μm1.0 E-5   10nm1.0 E-8   10μm1.0 E-5
阿片δ1   -4.12％   90.48％   -18.26％   89.03％
阿片δ2(人重组体)   7.19％   55.45％   7.76％   72.74％
阿片κ(人重组体)   2.45％   62.47％   10.35％   89.41％
阿片μ(人重组体)   63.16％   99.91％   85.42％   100.39％
因此，已经开发了直接给以代谢产物6-羟基羟吗啡酮的方法。据信β异构体在疼痛治疗上具有更大的功效，但是这种揭示并不限于该异构体的单独使用。含有6-α-羟基羟吗啡酮、6-β-羟基羟吗啡酮或其混合物的药物组合物都可以用在本发明中。
6-羟基羟吗啡酮的肠胃外给药确保了向血流中的立即释放和最快的疼痛缓解途径。含有6-羟基羟吗啡酮的组合物的注射、IV滴注或其他手段给药是最有效的。与实际给药途径无关，都将提供足以诱导止痛的6-羟基羟吗啡酮量。6-羟基羟吗啡酮的血浆水平必须提升至足以诱导所需止痛水平的水平。
给药量将依赖于正常的标准，例如患者体重、疼痛强度和其他因素。基于药动学研究，在至少0.05ng/ml左右的血浆水平将提供一定的止痛效果。血浆水平上限最终将出于安全性的考虑加以确立。任何阿片类、包括6-羟基羟吗啡酮的超剂量服用可以引起呼吸衰竭和其他不可取的副作用，甚至可能导致死亡。优选地，6-羟基羟吗啡酮的血浆水平将被提升至至少0.075ng/ml。可能需要随后的剂量维持在这些血液水平上。
6-羟基羟吗啡酮的优选给药方式是与适当的载体和赋形剂一起给药，这对本领域技术人员而言将是显而易见的。这些优选的给药方式中所得血浆将因此基本上不含羟吗啡酮。
上述说明涵盖本发明的一些优选实施方式。这种揭示仅供例证，不打算限制下列权利要求。

Claims (7)

1、治疗疼痛的方法，包含：
以足以诱导止痛的量向患者肠胃外给以包含6-羟基羟吗啡酮的药物组合物。
2、权利要求1的方法，其中所述药物组合物是借助注射或IV滴注给药的。
3、权利要求1的方法，其中所述给药足以提升6-羟基羟吗啡酮的血浆水平至至少约0.05ng/ml。
4、权利要求1的方法，其中所述给药足以提升6-羟基羟吗啡酮的血浆水平至至少约0.075ng/ml。
5、治疗疼痛的方法，包含以足以诱导止痛的量向患者肠胃外给以药物组合物，该组合物包含6-羟基羟吗啡酮和一种或多种载体、稀释剂和赋形剂。
6、药物，包含6-羟基羟吗啡酮溶液，用于向动物、包括人类的肠胃外释放。
7、治疗疼痛的方法，包含：
以足以诱导止痛的量向患者肠胃外给以包含6-羟基羟吗啡酮和羟吗啡酮的药物组合物。
CNA028153243A 2001-07-06 2002-07-03 用作止痛剂的6－羟基羟吗啡酮的肠胃外给药 Pending CN1610551A (zh)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US30335701P 2001-07-06 2001-07-06
US60/303,357 2001-07-06
US32943201P 2001-10-15 2001-10-15
US32944401P 2001-10-15 2001-10-15
US32944501P 2001-10-15 2001-10-15
US60/329,445 2001-10-15
US60/329,444 2001-10-15
US60/329,432 2001-10-15

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CN1610551A true CN1610551A (zh) 2005-04-27

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CNA028153243A Pending CN1610551A (zh) 2001-07-06 2002-07-03 用作止痛剂的6－羟基羟吗啡酮的肠胃外给药
CNA028172361A Pending CN1551770A (zh) 2001-07-06 2002-07-03 羟吗啡酮控释制剂

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US20140134250A1 (en) 2014-05-15
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US20070098793A1 (en) 2007-05-03
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