CN1413110A - 药物组合物 - Google Patents

药物组合物 Download PDF

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CN1413110A
CN1413110A CN00815918A CN00815918A CN1413110A CN 1413110 A CN1413110 A CN 1413110A CN 00815918 A CN00815918 A CN 00815918A CN 00815918 A CN00815918 A CN 00815918A CN 1413110 A CN1413110 A CN 1413110A
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克利斯托弗·波恩·夏普利奥
基思·麦考马克
尼古拉斯·卡尔弗特·维尔利
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Abstract

肠胃外单位剂型或者适合于经由黏膜释放的单位剂型的镇痛组合物，包含一定量的丁丙诺啡，少于减轻疼痛所需的临床剂量，和一定量的纳络酮，以便丁丙诺啡与纳络酮的重量比在12.5∶1至27.5∶1的范围内，或一定量的纳曲酮或纳美芬，以便丁丙诺啡与纳曲酮或纳美芬的重量比在12.5∶1至22.5∶1的范围内。

Description

药物组合物
本发明涉及含有丁丙诺啡的镇痛组合物，确切地涉及含有亚临床镇痛剂量水平的丁丙诺啡与纳络酮、纳曲酮或纳美芬的组合。
丁丙诺啡(N-环丙基甲基-7α-[1-(S)-羟基-1，2，2-三甲基丙基]-6，14-内桥亚乙基-6，7，8，14-四氢-降东罂粟碱的国际非专利名称)已经在临床试用中显示是一种强大的鸦片部分激动性镇痛药，缺乏在其他鸦片镇痛药中所发现的拟精神病作用。按0.1mg或以上剂量肠胃外或舌下给药的丁丙诺啡有效地减轻中度至重度疼痛。关于单一剂量的最佳治疗范围，通过注射是0.3mg-0.6mg，舌下片是0.2mg-0.8mg。
在动物试验和人体试验中，丁丙诺啡已经显示既具有激动剂(吗啡样)又具有拮抗剂的性质。不过从对动物和人所进行的直接依赖性研究得出结论，丁丙诺啡不产生显著的身体依赖，动物的自我给药研究和成瘾后令人欣快的作用测量都说明了这一点。不过，丁丙诺啡面临典型鸦片激动剂的副作用，例如有些患者的恶心与呕吐、便秘和呼吸抑制，尽管作为其部分激动剂性质的直接结果，它对呼吸抑制的作用是有限的。
纳络酮(1-N-烯丙基-14-羟基降氢吗啡酮的国际非专利名称)是一种麻醉性拮抗剂，已被掺入到各种鸦片类口服与舌下制剂中，目的是保护制剂不被肠胃外滥用，同时保持鸦片类的镇痛作用。
GB-A-2150832描述了舌下或肠胃外剂型的镇痛组合物，包含有效剂量的丁丙诺啡和一定量的纳络酮，通过肠胃外给药足以证实与麻醉成瘾相反，但是不足以危及丁丙诺啡的镇痛作用。优选地，肠胃外剂型含有纳络酮与丁丙诺啡的重量比为1∶3至1∶1，舌下剂型为1∶2至2∶1。
纳曲酮(1-N-环丙基甲基-14-羟基降二氢吗啡酮的国际非专利名称)是一种纯的鸦片拮抗剂，当用于对鸦片成瘾的维持药物口服给药(50mg/天)时，阻断自我给药的鸦片的作用，这归因于消除了对药物的渴望。
纳美芬((5α)-17-(环丙基甲基)-4，5-环氧-6-亚甲基吗啡烷-3，14-二醇的国际非专利名称)是一种具有鸦片拮抗剂活性的纳曲酮结构类似物。
GB-A-2167633描述了肠胃外或舌下单位剂型的镇痛组合物，包含有效剂量的丁丙诺啡和一定量的纳曲酮，通过肠胃外给药足以证实与麻醉成瘾相反，但是不足以危及丁丙诺啡的镇痛作用，其中丁丙诺啡在肠胃外剂型中的剂量从约0.3mg至约0.6mg，在舌下剂型中的剂量从约0.1mg至约0.4mg，丁丙诺啡与纳曲酮的重量比对于肠胃外剂型为12∶1至3∶1，对于舌下剂型为4∶1至1∶1。
我们现已惊讶地发现，低剂量纳络酮或纳曲酮或纳美芬加强和提高了丁丙诺啡的亚临床剂量水平。药物之间的相互作用是协同性相互作用，且更强于单独药物实体的加合效应。
因此，本发明在其最广泛的方面提供肠胃外单位剂型或者适合于经由黏膜释放的单位剂型的镇痛组合物，包含一定量的丁丙诺啡，起少于减轻疼痛所需的临床剂量，和
(i)一定量的纳络酮，使丁丙诺啡与纳络酮的重量比在12.5∶1至27.5∶1的范围内，或
(ii)一定量的纳曲酮或纳美芬，使丁丙诺啡与纳曲酮或纳美芬的重量比在12.5∶1至22.5∶1的范围内。
由此，丁丙诺啡的镇痛作用借助低剂量纳络酮、纳曲酮或纳美芬被加强。
本发明在第一方面提供肠胃外或舌下单位剂型或者适合于经由黏膜释放的单位剂型的镇痛组合物，每单位剂量包含15μg至200μg丁丙诺啡和
(i)一定量的纳络酮，使丁丙诺啡与纳络酮的重量比在12.5∶1至27.5∶1的范围内，或
(ii)一定量的纳曲酮或纳美芬，使丁丙诺啡与纳曲酮或纳美芬的重量比在12.5∶1至22.5∶1的范围内。
不言而喻的是，本文所用的术语丁丙诺啡、纳络酮、纳曲酮和纳美芬表示不仅涵盖碱，而且涵盖它们的药学上可接受的盐。特别优选的盐是盐酸盐。
优选的是配制单位剂型的组合物，也就是物理上不连续的单位，含有适量的丁丙诺啡和纳络酮、纳曲酮或纳美芬，以及药学上可接受的稀释剂和/或载体。这类单位剂型对于肠胃外给药适合为安瓿的形式，对于经由黏膜释放例如舌下给药可以是片剂的形式。
术语肠胃外意欲涵盖组合物通过除食道以外的所有方式给药。
术语黏膜意欲涵盖任意的黏膜，包括口腔黏膜、直肠黏膜、阴道黏膜和鼻黏膜。
用于肠胃外给药的组合物包含丁丙诺啡和纳络酮、纳曲酮或纳美芬在无菌水中的等渗溶液。适宜的话，利用葡萄糖使溶液等渗，通过高压灭菌法或膜过滤法灭菌。组合物可以通过肌内、皮内、腹膜内、静脉内、动脉内、皮下或硬膜外途径给药。组合物还可以透皮给药。
舌下片形式的组合物含有可溶性赋形剂，例如乳糖、甘露糖醇、葡萄糖、蔗糖或其混合物。它们还将含有造粒与崩解剂，例如淀粉，黏合剂，例如聚烯吡酮或羟丙基甲基纤维素，和润滑剂，例如硬脂酸镁。
用于肠胃外给药或经由黏膜释放、例如上述通过舌下给药的组合物可以通过本领域技术人员熟知的生产工艺加以制备。
本发明的单位剂型组合物优选含有纳络酮、纳曲酮或纳美芬的量在使丁丙诺啡与纳络酮、纳曲酮或纳美芬的重量比在15∶1至20∶1的范围内。
本发明组合物含有丁丙诺啡的量低于减轻疼痛所需的单位剂量。对人类来说，在没有加强作用的存在下，令人满意地减轻疼痛需要约40μg丁丙诺啡每千克体重的剂量。因而关于50至80kg的典型体重，剂量将为2000μg至3200μg、即2mg至3.2mg丁丙诺啡每天。这将适宜分4个单位剂量给药。丁丙诺啡在本发明中有效的量低于在没有纳络酮、纳曲酮或纳美芬的加强作用的存在下有效的量。
本发明在第二方面提供人或动物患者疼痛的治疗方法，该方法包含通过肠胃外或经由黏膜途径对人或动物给以1.25μg至10μg每千克体重的丁丙诺啡每天和
(i)一定量的纳络酮，使丁丙诺啡与纳络酮给药的重量比在12.5∶1至27.5∶1的范围内，或
(ii)一定量的纳曲酮或纳美芬，使丁丙诺啡与纳曲酮或纳美芬给药的重量比在12.5∶1至22.5∶1的范围内。
本发明在第三方面提供纳络酮、纳曲酮或纳美芬在药物生产中的用途，该药物用于治疗疼痛，包含亚临床量的丁丙诺啡，其中丁丙诺啡与纳络酮的重量比在12.5∶1至27.5∶1的范围内，或者丁丙诺啡与纳曲酮或纳美芬的重量比在12.5∶1至22.5∶1的范围内。
按照Hargreaves，K.M.，Dubner，R.，Brown，F.，Flores，C.和Joris，J.：ANew and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia.Pain 32：77-88，1988的爪缩回法，由UniversityDepartment of Anaesthesia，Addenbrookes Hospital，Cambridge测定低剂量鸦片拮抗剂对丁丙诺啡的亚临床剂量的加强比例。这种方法能够使研究人员洞悉由药物所导致的无限制大鼠对外周介导的热刺激的反应。
利用BASILE Plantar Test Device(Ugo Basile，Comerio-Italy)得到结果。它基本上由位于玻璃板下方的活动式I.R.(红外)发生器组成，操作者将大鼠放置在玻璃板上。塑胶围挡限定动物自由活动的空间。分成三个隔间，有助于操作者进行迅速的“筛选”工作：能够对至多三只大鼠进行试验，中间没有明显的耽搁。
操作者将I.R.发生器定位于大鼠后爪的正下方，同时激活I.R.光源和反应时间计数器。当大鼠感觉到疼痛并缩回爪子时，I.R.发生器自动关闭，计时器停止，测定缩回的潜伏期。
将三条绷带松散地系在成年大鼠普通坐骨神经周围，产生外周单神经病，测定不同剂量丁丙诺啡、不同剂量纳络酮、不同剂量纳曲酮和不同剂量丁丙诺啡与纳络酮或纳曲酮组合的作用。在手术操作后第八天进行试验。
为了测定基线水平以供对比，在皮下注射不同供试药物或药物组合之前对大鼠进行Hargreaves爪缩回试验。然后对大鼠皮下注射特定的供试药物或药物组合，记录大鼠因热刺激而缩回其爪子的时间相对基线水平的变化百分率，作为爪缩回潜伏期内的百分率。
提供下列实施例对发明作进一步描述。
方法
手术
将Lister Hooded大鼠(180-200g)用氟烷麻醉，将3条铬猫肠缝合线松散地系在左坐骨神经，诱导神经病。
手术后使大鼠恢复一周，再实施行为试验。
药物制备
药物(丁丙诺啡、纳络酮和纳曲酮)是新制备的，在水中的浓度是1mg/ml。然后将该储备溶液稀释在盐水中，得到用于研究的不同浓度。
将药物皮下注射至颈部折皱处。
试验
8天后，利用足跖试验(Ugo Basile，Comero，Italy)测量热痛域、即后爪缩回潜伏期。在试验之前，将大鼠放置在塑胶盒内适应5分钟。将热源定位在随机一只后爪跖面下，激活。该动作启动计时电路，测量施加光束与后爪缩回之间的时间间隔。该数值被指定为缩回潜伏期。
在注射之前和注射之后不同时间测定爪缩回潜伏期。每爪测量三次。
实施例1
在各种丁丙诺啡剂量下测定丁丙诺啡和重量比为20∶1与15∶1的丁丙诺啡/纳络酮的作用，以对大鼠皮下给药的μg/kg体重的药物表示(n＝3)。
图1给出这些试验的结果。从图1可以清楚地看出低剂量纳络酮对丁丙诺啡的亚临床剂量的加强作用。与在这些剂量水平下没有显著作用的单独的丁丙诺啡相比，两种重量比例的丁丙诺啡/纳络酮组合都明显地增加疼痛缩回潜伏期，其中丁丙诺啡的剂量为1.25μg和2.5μg。
实施例2
将丁丙诺啡按2.5μg/kg大鼠体重的剂量水平对大鼠给药(n＝6)。将丁丙诺啡与纳络酮或纳曲酮按5∶1至30∶1的各种重量比共同皮下给药。为了提供适当的基线点，还将单独的纳络酮和纳曲酮按与组合治疗所用相同的剂量水平对大鼠皮下给药。
图2给出结果，从中可以明显看出纳络酮或纳曲酮对丁丙诺啡的亚临床剂量的加强作用。
实施例3
为了研究若干比例(10∶1、15∶1和20∶1丁丙诺啡∶纳络酮，丁丙诺啡的剂量固定)的作用的持续时间，在皮下注射后的26小时内进行对PWL的作用。图3给出结果，从中可以看出该作用在40分钟后已经最大，然后在6小时内急剧降低。不过在26小时时，仍然可以见到残留的作用，尽管不是统计学上显著的。每种比例的最大作用(40min)与图2所示结果是一致的。在10∶1组合下观察到的结果不是统计学上显著的。
实施例4
具有下列组成的肠胃外制剂是这样制备的：
                                     mg/ml
          丁丙诺啡HCl                0.1
          纳络酮HCl                  0.0067
          无水葡萄糖                 50.0
          盐酸，至pH                 4.0
          注射用水，至               1.0ml
在搅拌下，将葡萄糖、盐酸丁丙诺啡和盐酸纳络酮按该顺序溶于约95％每批体积的注射用水。加入0.1M盐酸调节溶液的酸度至pH 4.0，用注射用水调节溶液的体积。将溶液通过0.22Φm膜滤器过滤，转移至已消毒的1ml或2ml玻璃安瓿内，其含有1ml或2ml该溶液。将安瓿密封，将产品经过高压灭菌消毒。
实施例5
使用0.005mg/ml盐酸纳络酮代替0.0067mg/ml，改变实施例4的制剂配方。
实施例6
用0.0067mg/ml盐酸纳曲酮取代实施例1的盐酸纳络酮，修改实施例4的制剂。
实施例7
用0.005mg/ml盐酸纳曲酮取代实施例1的盐酸纳络酮，修改实施例4的制剂。
实施例8
用0.0067mg/ml盐酸纳美芬取代实施例4的盐酸纳络酮，修改实施例4的制剂。
实施例9
用0.005mg/ml盐酸纳美芬取代实施例4的盐酸纳络酮，修改实施例4的制剂。
实施例10
具有下列组成的舌下片是这样制备的：
                               mg/片
      丁丙诺啡HCl              0.1
      纳络酮HCl                0.0067
      乳糖                     31.2433
      甘露糖醇                 18.0
      玉米淀粉                 9.0
      聚维酮                   1.2
      硬脂酸镁                 0.45
                               60.0
将除硬脂酸镁以外的全部原料通过750μm筛，混和在一起。然后对已混合的粉末进行湿法造粒，在50℃下干燥。使所得颗粒通过750μm筛，与硬脂酸镁(预先过500μm筛)混和。将颗粒压制成片，直径5.56mm，片重60mg。
实施例11
使用0.005mg/片的盐酸纳络酮并调节乳糖的重量，改变实施例10的制剂。
实施例12
用0.0067mg/片的盐酸纳曲酮取代实施例10的盐酸纳络酮，修改实施例10的制剂。
实施例13
用0.005mg/片的盐酸纳曲酮取代实施例10的盐酸纳络酮，修改实施例10的制剂。
实施例14
用0.0067mg/片的盐酸纳美芬取代实施例10的盐酸纳络酮，修改实施例10的制剂。
实施例15
用0.005mg/片的盐酸纳美芬取代实施例10的盐酸纳络酮，修改实施例10的制剂。
实施例16
具有下列组成的栓剂是这样制备的：
                                   mg/粒
     丁丙诺啡HCl                   0.1
     纳络酮HCl                     0.0067
     明胶                          200
     甘油                     700
     去离子水                 89.9
将各成分混合在一起，在60℃与70℃之间熔化。将已熔化的物质注入一次性塑料模具内，栓剂在其中成型，直至患者在使用时除去包装。
实施例17
使用0.005mg/粒的盐酸纳络酮，改变实施例16的制剂。
实施例18
用0.0067mg/粒的盐酸纳曲酮取代实施例16的盐酸纳络酮，修改实施例16的制剂。
实施例19
用0.005mg/粒的盐酸纳曲酮取代实施例16的盐酸纳络酮，修改实施例16的制剂。
实施例20
用0.0067mg/粒的盐酸纳美芬取代实施例16的盐酸纳络酮，修改实施例16的制剂。
实施例21
用0.005mg/粒的盐酸纳美芬取代实施例16的盐酸纳络酮，修改实施例16的制剂。

Claims (12)

1、肠胃外单位剂型或者适合于经由黏膜释放的单位剂型的镇痛组合物，包含一定量的丁丙诺啡，该含量少于减轻疼痛所需的临床剂量，和
(i)一定量的纳络酮，使丁丙诺啡与纳络酮的重量比在12.5∶1至27.5∶1的范围内，或
(ii)一定量的纳曲酮或纳美芬，使丁丙诺啡与纳曲酮或纳美芬的重量比在12.5∶1至22.5∶1的范围内，
由此，低剂量纳络酮、纳曲酮或纳美芬加强了丁丙诺啡的镇痛作用。
2、肠胃外或舌下单位剂型或者适合于经由黏膜释放的单位剂型的镇痛组合物，每单位剂量包含15μg至200μg丁丙诺啡和
(i)一定量的纳络酮，使丁丙诺啡与纳络酮的重量比在12.5∶1至27.5∶1的范围内，或
(ii)一定量的纳曲酮或纳美芬，使丁丙诺啡与纳曲酮或纳美芬的重量比在12.5∶1至22.5∶1的范围内。
3、如权利要求1或权利要求2所要求的组合物，其中该单位剂型含有纳络酮的量使丁丙诺啡与纳络酮的重量比在15∶1至20∶1的范围内。
4、如权利要求1或权利要求2所要求的组合物，其中该单位剂型含有纳曲酮或纳美芬的量使丁丙诺啡与纳曲酮或纳美芬的重量比在15∶1至20∶1的范围内。
5、人或动物患者疼痛的治疗方法，该方法包含通过肠胃外或经由黏膜途径对人或动物给以1.25μg至10μg每千克体重的丁丙诺啡每天和
(i)一定量的纳络酮，使给药的丁丙诺啡与纳络酮的重量比在12.5∶1至27.5∶1的范围内，或
(ii)一定量的纳曲酮或纳美芬，使给药的丁丙诺啡与纳曲酮或纳美芬的重量比在12.5∶1至22.5∶1的范围内。
6、如权利要求5所要求的方法，其中将丁丙诺啡对人或动物给药的量为1.25μg至5μg每千克体重。
7、如权利要求5或权利要求6的方法，其中丁丙诺啡与纳络酮、纳曲酮或纳美芬对人或动物给药的重量比在15∶1至20∶1的范围内。
8、纳络酮、纳曲酮或纳美芬在药物生产中的用途，该药物用于治疗疼痛，包含亚临床量的丁丙诺啡，其中丁丙诺啡与纳络酮的重量比在12.5∶1至27.5∶1的范围内，或者丁丙诺啡与纳曲酮或纳美芬的重量比在12.5∶1至22.5∶1的范围内。
9、如权利要求8所要求的用途，其中丁丙诺啡与纳络酮、纳曲酮或纳美芬的重量比在15∶1至20∶1的范围内。
10、根据本发明的镇痛组合物，基本上是如上文或实例所述的。
11、根据本发明的疼痛治疗方法，基本上是如上文或实例所述的。
12、如权利要求8或9之一所要求保护的用途，基本上是如上文或实例所述的。
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Patentee before: Reckitt & Benksl Health-Care (England) Ltd.

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20081112

Termination date: 20151117

CF01 Termination of patent right due to non-payment of annual fee