CN1291092A - 含有曲马朵的药物组合物 - Google Patents
含有曲马朵的药物组合物 Download PDFInfo
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- CN1291092A CN1291092A CN99803122A CN99803122A CN1291092A CN 1291092 A CN1291092 A CN 1291092A CN 99803122 A CN99803122 A CN 99803122A CN 99803122 A CN99803122 A CN 99803122A CN 1291092 A CN1291092 A CN 1291092A
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- migraine
- tramadol
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Abstract
本发明涉及药物组合物,其含有作为活性成分的曲马朵或其一种对映体或其一种药用盐和灭吐灵,哌双咪酮或具有促动力学和止吐作用的其它物质或它们的一种药用盐。所述组合物用于治疗偏头痛,类偏头痛及伴随呕吐和/或恶心(如在化疗中)和/或延迟胃排空(如在糖尿病胃轻瘫中)的疼痛。
Description
本发明涉及药物组合物的用途，该药物组合物可以用于治疗偏头痛或类偏头痛以及伴随有恶心和／或呕吐(例如在化疗情况下)和／或胃排空延迟(例如术后的糖尿病性胃轻瘫)等症状的疼痛状态，其含有作为活性成分的曲马朵或其一种对映体或其一种药用盐以及灭吐灵、哌双咪酮或其它前动力学和止吐活性物质或它们的一种药用盐。
偏头痛是一种反复发作的头痛，其可以持续4-72小时。偏头痛发作主要是单侧的，最初为迟钝性的，然后发展为中等至严重程度的博动性头痛。偏头痛所伴发的典型症状为对光和噪音的高度敏感，面部苍白，在先兆阶段带有和不带有神经性病灶缺陷的恶心和呕吐。
没有先兆的偏头痛(常见型)有别于带有先兆的偏头痛(传统型)，后者在每次发作时均以出现闪光盲点开始。如果这种视觉失调持续数天或有视网膜、基底、眼肌麻痹、失语或偏瘫性头痛等已知特定形式的其它神经病灶症状出现的话，则为复合型偏头痛。
有关偏头痛的致病机理存在各种观点。早期的血液动力学观点认为，最初的神经缺陷是由颅内区域血管收缩引起的，随后的博动性头痛是由经眼神经和三叉神经疼痛传导的颅外血管舒张引起的，这一观点对偏头痛的解释是不充分的。
在带有先兆的偏头痛发作时，大脑区域血流在枕骨部降低，伴有个体动脉供应范围过度射出的皮质血量减少的慢发作偏头痛使得我们有理由相信其涉及的不仅是血管舒缩，还有对应于所谓的“扩散性抑郁”的电生理现象(Spierings ELH(1988)；在偏头痛理解方面的最新进展，头痛28：655-658)。
其它发现使得我们有理由相信伴发的头痛不仅颅外血管舒张引起，还可由疼痛域值的中心降低引起，即由有害刺激之后，在脊柱索细胞和脑干细胞中被活化的所谓的直接早期基因(immediate early genes)(IEGs)引起(Zimmermann，M．(1995)；Neurobiologie desSchmerzsystems[疼痛系统的神经生物学]Neuroforum 1／95：34-45)。
另一个理论“神经原性炎症模型”提供了解释偏头痛发作期间血流改变和血管疼痛敏感性增加的可能性。因此，疼痛敏感性增加是由三叉神经血管系统的感觉血管周纤维的敏感性增加引起的。由于这种敏感性增加，通常不能诱导疼痛感觉的血管博动成为一种强疼痛刺激，并引起随脉搏搏动的偏头痛。神经原性炎症是由脑(脊)膜血管的血管周神经纤维的有害刺激引起的。从神经末端(其可能为同时的伤害感受器)分泌出可以诱导神经原性炎症的神经肽，例如P物质，神经激肽A以及CGRP(与降钙素基因有关的肽类)。CGRP还可被检出用于指示偏头痛发作时头部静脉血的增加程度。
神经肽分泌的结果是建立一个动态的恶性循环：肽释放-血管舒张以及毛细血管渗透性增加-对伤害感受器的刺激增加-肽释放增加。活性化合物及舒马曲坦和麦角生物碱抑制神经肽的释放，因此干扰了疼痛诱导循环(Zimmermann，M．：Chronische Schmerzen und ihre Ursachen[慢性疼用及其原因]，Deutsches Arzteblatt 93，43号，1996：A-2749-2752)。
其它发现支持初级神经原性下丘脑功能失调的说法，在偏头痛发作期间，来自脑干Raphe’s核的分泌量有所减少的血管活性5-羟色胺具有关键的作用(Ferrari MD等人，(1989)：偏头痛中的5-羟色胺代谢，神经病学39：1239-1242；Pramod R．，等人(1989)：5-HT1-样受体激动剂以及偏头痛的病理生理学，药理学趋势10，200-204)。
尽管存在许多假设和复杂的模型想象，偏头痛的发病机理至今仍未搞清。偏头痛的发生是由多因素造成的，其带有遗传性，并有外部(例如酒精)和内部(例如激素)的触发机制。
尽管心理因素可以诱发偏头痛，但其不属于身心失调。
已知大量含有单个活性化合物或一些以固定组合存在的活性化合物的制剂可以用于偏头痛的治疗。
通常，推荐使用象灭吐灵或哌双咪酮本身或与非鸦片类止痛剂(例如乙酰水杨酸、扑热息痛、布洛芬或萘普生)相结合的止吐剂来治疗偏头痛发作。在中等严重至严重的偏头痛发作时，选择与麦角生物碱(例如麦角胺或二氢麦角胺或舒马曲坦)组合的止吐剂。
麦角胺或二氢麦角胺常见的副作用是恶心、干呕、呕吐、头痛、肌肉疼痛以及通常的发冷，因此在偏头痛继续发作的错误假设下，可以导致重复使用这类制剂，并引起药物过量。经常使用的结果是继续出现头痛，该结果导致了麦角胺的滥用。可能会出现的严重副作用是循环失调、冠心病(CHD)、动脉闭合疾病(AOD)、高血压以及咽痛症状。麦角生物碱不能用于怀孕和泌乳期间的妇女及12岁以下的儿童。
舒马曲坦及其衍生物(阿莫曲坦、依莱曲坦、纳雷曲坦、利托曲坦、佐咪曲坦)是有效的偏头痛治疗剂，当采用口服给药时，它们的效果要优于麦角胺、乙酰水杨酸或扑热息痛等单个物质。儿童、怀孕和泌乳期间的妇女、65岁以上的老年人及有冠心病的病人禁用舒马曲坦。可能发生的副作用有压迫感和发热感、感觉身体虚弱、胸部紧张、高血压、冠心痛(CHD)、心肌梗死以及心绞痛。
由于在偏头痛期间，胃排空被抑制或速度相当慢，因与小肠相比，胃的吸收面积相对较小并且血管化程度也明显偏小，故作为药物的吸收部位，胃具有次级重要性，所以在偏头痛发作时，出现了止痛药物的吸收不足或被高度延迟。
借助灭吐灵和哌双咪酮的动力学，可以加速胃排空及对止痛剂的吸收。
在偏头痛治疗中，灭吐灵和哌双咪酮具有它们的有效性，然而，这不仅仅是因为它们的动力学作用，还因为它们抵抗诸如恶心和呕吐症状的作用，这些症状是偏头痛发作时经常伴发的。
偏头痛的药物治疗只能缓解症状，但不能治愈。不主张使用非鸦片类止痛剂的混合制剂及麦角生物碱类的混合制剂，因为当需要长期使用，尤其是需要每日使用时，它们反过来可以产生头痛。另外，长期使用止痛剂组合物的结果是可能导致肝和肾损伤，例如所谓的止痛剂肾病。
通常，由于鸦片类止痛剂的滥用和依赖性，它们不适于治疗偏头痛。
下列特定组合是从治疗偏头痛的专利文献中得到的：-扑热息痛和灭吐灵(EP 011 489，EP 011 490，US 5 437 874，EP 695546，EP 774 253)-乙酰水杨酸或其L-赖氨酸乙酰水杨酸酯和甲氧氯普胺(EP 606 031)-止痛剂(例如乙酰水杨酸)，止吐剂(例如灭吐灵)以及蚁酸(CA 20 20018)
上述专利文献中的止痛结合通常用于治疗偏头痛发作。但它们不适于治疗中等至严重程度的偏头痛。在严重的偏头痛发作时，一般采用麦角生物碱与止吐剂或舒马曲坦的结合。
在用麦角生物碱或舒马曲坦进行治疗时，一个不利的方面是在一些情况下会出现严重的心血管副作用，例如心绞痛，冠心病(CHD)，高血压以及心肌梗死。
因此开发可以有效作用于中等严重至严重程度偏头痛发作且具有较少副作用的可靠止痛剂的需求依然存在。
因此本发明的目标是提供对中等严重至严重程度偏头痛发作具有改善疗效的药物。
因此本发明涉及专利权利要求中所要求的主题内容。
曲马朵(1RS，2RS)-2[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己醇是可以用于治疗中等严重至严重程度疼痛发作的有效止痛剂。
曲马朵属于弱活性鸦片类物质。曲马朵区别于其它鸦片类物质的一个特点是就止痛作用而言它的耐药性发展很慢，并缺少鸦片类物质典型的副作用，并且具有极低的依赖性。
曲马朵的止痛作用包括鸦片类物质和非鸦片类物质，后者可以使5-羟色胺的释放并对中枢神经系统(CNS)内的5-羟色胺(5-HT)和去甲肾上腺素的再摄取具有抑制作用。
非鸦片类活性成分对于曲马朵的止痛作用具有显著的贡献。
去甲肾上腺素的再摄取主要被(-)-对映体所抑制，5-羟色胺的释放以及对突触间隙中5-羟色胺再摄取的抑制决定性地由(+)-对映体引起。两种对映体均对人体的止痛作用有所贡献。
在用曲马朵的治疗时，偶尔出现恶心、呕吐、出汗、口干、眩晕以及光-头痛。胃肠道症状或不同的心理副作用很少见到。
以灭吐灵和哌双咪酮为代表的助动力学活性化合物可以提高较低的食管括约肌的紧张性并加速胃排空和通过小肠的速度。
同时，这些活性化合物可以用作止吐剂，用来抑制恶心、干呕、呕吐等症状。
灭吐灵和哌双咪酮被指定用于胃轻瘫，其通常发生在术后和一些常见失调中(例如其中包括糖尿病)。在功能性的消化不良时也可以给予此药，因为怀疑该病是由于胃肠道动力原因引起的。
另外，上述药物也可以用于偏头痛以及其它伴随有胃肠道排空失调的疼痛状态。
令人惊奇的是我们发现通过联合给予曲马朵及促动力学活性止痛剂，尤其是在治疗中等严重至严重程度的偏头痛发作时，获得了改善的治疗制剂。
鸦片类物质通常不适合于治疗偏头痛，因为它通常带来大量的副作用，并可以引起生理和机体的依赖性。
此外，由于偏头痛而导致的胃动力缺乏增加以及随之而来的止痛剂的吸收和发挥作用推迟，因而鸦片类物质经常产生便秘作用。
在鸦片类止痛剂中有一个例外是曲马朵，其不显示那些在鸦片类物质使用过程中经常看到的严重副作用。
令人惊奇的是我们发现本发明中所述的联合给予的曲马朵和(特别是)灭吐灵可以有效地阻断偏头痛发作，并可以避免恶心和呕吐等症状的出现。
这便是更令人惊奇的，因为曲马朵本身可以诱导恶心和呕吐，或者可以增强偏头痛的这些伴随症状。
通过与灭吐灵的联合使用，使得曲马朵更加容易利用，其在偏头痛的治疗中对中等严重至严重的疼痛具有高度的有效性。
正如安慰剂控制研究证实的，由于灭吐灵本身在偏头痛中具有止痛作用，因此可以假设当同时给予曲马朵和灭吐灵时，同样也可以出现协同止痛作用。
进一步地，通过固定的组合以及曲马朵在胃肠道中的吸收加速，可以改善曲马朵的耐受性，并且还可以防止偏头痛伴随症状如恶心、呕吐等的发生。就曲马朵以及灭吐灵和哌双咪酮的药物动力学性质来说，它们也适合在一个固定的药物制剂中作为配伍。曲马朵的止痛作用持续时间约为4-7小时，最终的消除半衰期约为5-6小时。灭吐灵和哌双咪酮前动力学作用的持续时间约为1-2小时，止吐作用的持续时间约为3-5小时。半衰期约为4-6小时。
在本发明的进一步的实施例中，该组合可以另外含有非甾体抗炎剂(NSAID)，例如乙酰水杨酸，布洛芬，萘普生或扑热息痛。
结果，一方面，这项研究成果使得我们可以利用各种止痛机理(曲马朵的中枢作用以及非甾体抗炎剂的外周和中枢止痛和抗炎作用)来治疗中等严重至严重程度的偏头痛发作，这对那些对治疗具有抵抗作用类型的偏头痛是很有价值的。另一方面，由于在疼痛发作期间具有同等的或改进的作用，通过使用具有合适配伍的组合物，可以降低曲马朵或其它止痛活性配伍的总剂量，并且可以降低或避免副作用(例如NSAIDs的胃肠道症状)。
所列明的组合特别适合治疗中等至严重程度的偏头痛或类偏头痛样的头痛。
进一步地，这些组合适合于治疗：
-伴随有恶心和／或呕吐(例如由化疗引起的呕吐)的中等至严重程度的急性和慢性疼痛
-同时存在胃肠道排空失调(例如除了别的之外，术后或糖尿病性胃轻瘫)的中等至严重程度的急性和慢性疼痛，以及
-在曲马朵治疗中出现的恶心和呕吐。
采用临床实验，以曲马朵和灭吐灵的组合作为实例，可以更详细地说明本发明所要求的组合治疗偏头痛的活性。
将患有中等至严重程度头痛的8名患者(他们不能再用弱的止痛剂进行治疗了，弱止痛剂包括乙酰水杨酸，布洛芬或扑热息痛)作为研究对象。
记录治疗开始前偏头痛的强度以及伴发症状的特征，在接下来的治疗过程中由患者评价治疗的效果。
分别在0，30min，1h，2h，4h，6h以及12h等时间点，用长度为100mm的VAS尺度法对给药前后的头痛强度进行测定。用多水平口头等级尺度法记录偏头痛伴随症状的特征以及它们在给药后的变化。进一步地，要求患者以概括的方式评价有效性和适用性。
8名接受治疗的患者中有7名女性，1名男性。患者的平均年龄为44．7岁(35-63岁)。平均身高和体重相应为169．3cm(159-186cm)和70．4kg(55-103kg)。
所有的患者符合用于诊断偏头痛的IHS操作诊断标准，并且在4-72小时内至少已经有5次偏头痛发作。头痛严格地限制在头部一侧，肌体的活动可以增加头痛的强度。
在头痛发作期间，所有的患者同时伴有恶心并对噪音敏感，28％的患者还有呕吐症状，43％的患者对光敏感。平均头痛史15．3年(2-38年)；平均发作频率为每月4．1天(2-8天／月)。
在研究期间，患者遭受11次急性头痛发作，用曲马朵和灭吐灵的自由组合进行治疗。
所有的患者同时摄入单一口服剂量的100mg曲马朵(2个曲马朵AWD胶囊，每个中含有50mg曲马朵盐酸盐)和10mg灭吐灵溶液(30滴5mg的灭吐灵Temmler溶液)。
在进行方案治疗之前，先由患有强至非常强头痛的患者陈述偏头痛的情况。平均来说，原疼痛用VAS尺度法来衡量的话为75±7mm(62-83mm)之间。
在治疗中有两名治疗了两次偏头痛发作的患者声称疼痛没有任何改善，将这些患者宣布为非反应者并排除在分析之外。
保留六名治疗了7次偏头痛发作的患者。在这项研究在中，采用了在其它疼痛研究中常用的长度为100mm的VAS尺度法来对头痛定量：0mm (无头痛，0级)，1-30mm (轻微头痛，1级)，31-60mm (中等头痛，2级)，61-100mm (强至非常强的头痛，3级)。
在大多数研究中，通常成功的标准是在规定的时间内(大多数情况是2-4小时后)，能够感觉到头痛强度从3或2级改善为1或0级的患者百分比。表1：曲马朵／灭吐灵反应者：头痛强度与原疼痛之间的差别(单位为mmVAS)(括号中的值为疼痛强度改变的百分比)
另外，接着上述用于偏头痛药物成功或有效的评估惯例，在表2中我们另外通过头痛程度有所改善的患者百分比(这些患者的头痛程度从3或2级降至1或0级)说明了治疗的成功(包括非反应者在内)。
*未测到值表2：口服给予100mg曲马朵胶囊以及10mg灭吐灵溶液后，作为时间函数的头痛程度从3或2级降至1或0级的改善情况。
| 患者 | 0h | 0.5h | 1h | 2h | 4h | 6h | 12h | ||||||
| mm | mm | ％ | mm | ％ | mm | ％ | mm | ％ | mm | ％ | mm | ％ | |
| 1 | 62 | -2 | (-3.2) | -14 | (-22.6) | -24 | (-38.7) | -27 | (-43.6) | -28 | (-45.2) | -62 | (-100) |
| 2 | 83 | -19 | (-22.9) | -42 | (-50.26) | -60 | (-72.3) | -61 | (-73.5) | -45 | (-54.2) | -43 | (-51.8) |
| 3 | 81 | 2 | (-2.5) | -9 | (-11.1) | -21 | (-25.9) | -37 | (-45.7) | -81 | (-100) | -81 | (-100) |
| 4 | 70 | -37 | (52.9) | -37 | (-52.9) | -38 | (-54.3) | -30 | (-42.9) | -30 | (-42.9) | -29 | (-41.4) |
| 5 | 72 | -6 | (-8.3) | -32 | (-44.4) | -67 | (-93.1) | -70 | (-97.2) | -72 | (-100) | -72 | (-100) |
| 6 | 80 | -70 | (-87.5) | -65 | (-81.3) | -59 | (-73.8) | -45 | (-56.3) | -80 | (-100) | -80 | (-100) |
| 7 | 77 | 2 | (-2.6) | 1 | (1.3) | * | * | -77 | (-100) | -77 | (-100) | -77 | (-100) |
| 平均值 | 75 | -18.57 | (-24.25) | -28.29 | (-37.36) | -38.43 | (-51.15) | -49.57 | (-65.58) | -59 | (-77.46) | -63.43 | (-84.75) |
| 标准差 | 7 | 26.66 | (34.04) | -22.58 | (28.27) | 24.81 | (31.97) | 19.88 | (25.94) | 23.86 | (28.32) | 20.19 | (26.22) |
| 时间 | 患者数(n=8) | 从3-2级降至1-0级的改善情况(患者％) |
| 0.5h1h2h4h6h12h | 256666 | 256275757575 |
平均来讲，在反应者组中，以原发的疼痛作为基础，给予自由组合的曲马朵和灭吐灵后，甚至在30min内头痛程度就可以有24．3％的改善，2h后，有51．1％的改善。4和6小时后，相应的疼痛降低程度平均为65．6％和77．5％(参见表1)。
对于整个的治疗患者组来说(包括非反应者在内)，我们发现在给药30min后出现25％的有效性(头痛从强或中等程度变为轻微或不头痛)，2h后，出现75％的有效性(参见表2)。
为了概述以上内容，还可以从现有的数据中推断出给药剂量的曲马朵和灭吐灵的组合物是一种市场上现售用于偏头痛药物的具有保证性的替代品，其可以用来治疗中等强度到强的急性偏头痛。
这些组合物可以片剂、泡腾片、胶囊、颗粒、粉末、缓释药片，缓释胶囊(单或多剂量单位配方)、静脉和肌内注射用安瓿以及灌输溶液、悬浮液、栓剂或其它合适的药物剂型进行给药。
缓释药物剂型可含有以完全或部分缓释剂型存在的活性化合物，它们带有或不带有初始剂量的内含物。
可以采取一起或彼此部分或完全分开的配方来提供活性化合物，以便有可能进行分别给药或从时间方面来说进行逐步给药。
如果存在这种完全分开的配方，它们彼此之间相互协调，并含有以剂量单位形式存在的相应活性化合物，它们具有相同的量和相应的重量比，在其中活性成分以合并混合物的形式存在。
在这些药物组合物中，活性化合物还可以其制药学上可利用的盐类形式存在。
包含所列组合的口服药物组合物是优选的。
为了制备含有这些组合的药物制剂，按照需要的方式，将活性成分按照指定量与生理上可耐受的赋形剂和／或稀释剂和／或辅助剂进行配制。
赋形剂和辅助剂的实施例有明胶，天然糖，例如甘蔗糖或乳糖，卵磷脂，果胶，淀粉(例如玉米淀粉或直链淀粉)，环糊精和环糊精衍生物，葡聚糖，聚乙烯吡咯烷酮，聚乙烯乙酸酯，阿拉伯胶，藻酸，纤基乙酸钠，滑石，石松，硅酸，磷酸氢钙，纤维素，纤维素衍生物，例如甲氧丙基纤维素，甲基纤维素，羟丙基甲基纤维素，羟丙基甲基纤维素邻苯二甲酸，具有12-22个碳原子的脂肪酸，乳化剂，油和脂肪，特别是植物甘油酯和饱和脂肪酸的多聚甘油酯，单-或多羟基醇以及多二元醇，例如聚乙二醇，具有2-22个碳原子的脂肪族饱和或不饱和脂肪酸[裂孔]与具有1-20个碳原子的单羟基脂肪醇[裂孔]或多羟基醇(例如甘醇，甘油，二甘醇，1，2-丙二醇，山梨醇，甘露糖醇)形成的酯。
进一步合适的辅助剂是那些可以引起崩解的物质(所谓的崩解剂)，交联聚乙烯吡咯烷酮，羧甲基淀粉钠，羧甲基纤维素钠，微晶纤维素。可以使用已知的包衣物质，它们是丙烯酸和／或异丁烯酸和／或它们的酯类的聚合物和共聚物，玉米醇溶蛋白，乙基纤维素，琥珀酸乙基纤维素，紫胶片。
用于包衣物质的合适的增塑剂有：柠檬酸和酒石酸酯，甘油和甘油酯，各种链长的聚乙二醇。水或生理上可耐受的有机溶剂例如醇和脂肪醇适合于溶液或悬浮液的制备。
对于液体制剂，防腐剂例如山梨酸钾，4-羟基苯甲酸甲酯或4-羟基苯甲酸丙酯，或抗氧剂例如抗坏血酸以及调味增强剂例如薄荷油的使用是必需的。
在制备制剂中，可以使用已知和常规的助溶剂或乳化剂，例如聚乙烯吡咯烷酮和聚山梨醇酯80。
进一步合适的赋形剂和辅助剂的实例可以参见Dr．H．P．Fiedler“Lexikon der Hilfsstoffew Fur Pharmazie，Kosmetik undangrenzende Gebiete”[用于药品、化妆品和相关领域的辅助剂百科全书]。
在含有助动力学活性止吐剂和曲马朵的药物制剂中，二者的比例应为1∶4-1∶10。作为单独的剂量来说，这些药物制剂通常含有5-80mg的止吐剂或其一种盐类以及50-400mg的曲马朵其一种盐类。在这种情况下，优选的每日剂量应含有20-80mg止吐剂以及200-400mg曲马朵。
根据治疗的症状，上述每日剂量既可以采取整个剂量一次给药也可以分成2-4份多次给药。通常，每日给药2-4次是优选的。
下列实施例意在更详细地说明本发明，因此并不是一个结论性的罗列。实施例1灭吐灵溶液的制备
将802．4g纯水导入合适的容器中，搅拌下，将4．7g灭吐灵盐酸盐单水合物，0．1g抗坏血酸，170．1g山梨醇，2．8g山梨酸钾以及18．9g 96％乙醇(v／v)的预备溶液，0．7g 4-羟基苯甲酸甲酯和0．3g 4-羟基苯甲酸丙酯加入其中，继续搅拌混合物，直至所有的成分全部溶解。此溶液用合适的滤器进行过滤。
| 配方 | 重量份(％) |
| 灭吐灵盐酸盐单水合物抗坏血酸山梨醇山梨酸钾96％乙醇(v／v)4-羟基苯甲酸甲酯4-羟基苯甲酸丙酯纯水 | 0.470.0117.010.281.890.070.0380.24 |
溶液的填充：
将此溶液用合适的填充机填充至合适的滴瓶中。实施例2灭吐灵溶液的制备
将484．2g纯水导入合适的容器中，搅拌下，将100．0g灭吐灵盐酸盐，1．5g山梨酸钾，161．8g 96％乙醇(v／v)，124．5g 1，2-丙二醇，200．0g粒化糖，1．0g多聚山梨醇酯80以及1．0g薄荷油加入其中，继续搅拌混合物，直至所有的成分全部溶解。此溶液用合适的滤器进行过滤。
| 配方 | 重量比(％) |
| 灭吐灵盐酸盐山梨酸钾96％乙醇(v／v)1，2-丙二醇粒化糖多聚山梨醇酯80薄荷油纯水 | 9.30.117.111.618.60.10.145.1 |
溶液的填充：
将此溶液用合适的填充机填充至合适的滴瓶中。实施例3曲马朵-灭吐灵缓释药丸含活性化合物核的制备
在包衣锅，采用约2200g 15％乙基纤维素／紫胶片(6∶4)的约96％(v／v)乙醇-水混合物的浓溶液，将4824g曲马朵盐酸盐-灭吐灵盐酸盐单水合物-Aerosil_200混合物加到1000g大小合适(例如直径在0．5-0．6mm之间)的中性药丸上。将所得到的核进行干燥和过筛(0．8-1．4mm)。膜的应用
将膜应用到6．15kg含活性化合物的核上，上述含活性化合物的核是通过加入470g 15％乙基纤维素／紫胶片(6∶4)的约96％(v／v)乙醇-水混合物的浓溶液制备得到的。将700g滑石以粉末形式导入其中作为释放剂。
活性化合物释放
| 配方 | 重量比(％) |
| 曲马朵盐酸盐灭吐灵盐酸盐单水合物中性丸乙基纤维素紫胶片Aerosil 200滑石约96％(v／v)乙醇／水混合物 | 57.811.614.43.52.30.310.1适量 |
按照USP 23／NF方法，在仪器3上可以测定曲马朵盐酸盐在体外从实施例3缓释药丸中的释放情况。释放介质的温度为37℃，样品管揉动的速率为20次／分钟，每次考察(测定)的受试溶液量为175ml。
在测定开始时，采用pH1．5的受试溶液，一小时后，将带有样品的转子转移到175ml pH 4．5的受试溶液中，第二个小时后，转移到175mlpH 6．9的受试溶液中，第四个小时后，转移到新的175ml pH 6．9的受试溶液中，第六个小时后，转移到175ml pH 7．2的受试溶液中，第八个小时后，转移到175ml pH 7．5的受试溶液中。采用分光光度法测定上述时间点溶液介质中所发现的活性化合物的量。下表给出了测定得到的曲马朵盐酸盐的释放速率：
| 小时数 | 释放重量百分比(％) |
| 1246812 | 395770788493 |
图1给出了缓释药丸的体外释放曲线。
实施例4曲马朵-灭吐灵胶囊
胶囊填充物质的制备
将323g曲马朵盐酸盐，6．5g灭吐灵盐酸盐单水合物，597g磷酸氢钙盐酸盐单水合物，0．5g Aerosil_200以及1．0g硬脂酸镁进行过筛并在合适的混合器中混合。
| 配方 | 重量比(％) |
| 曲马朵盐酸盐灭吐灵盐酸盐单水合物磷酸氢钙Aerosil _00硬脂酸镁 | 32.76.559.70.51.0 |
胶囊的制备
采用合适的胶囊填充机，将胶囊填充物质填充到合适大小的硬胶囊中，填充量为155mg。实施例5曲马朵-灭吐灵可溶性片剂
粉末状混合物的制备：
将251g曲马朵盐酸盐，25g灭吐灵盐酸盐一水合物，4g Aerosil_200，50g Aspartam_，100g交联聚乙烯吡咯烷酮，700g微晶纤维素，819．5g乳糖单水合物，37．5g调味剂(例如草莓)，10g十二烷基硫酸钠以及3g硬脂酸镁进行过筛并在合适的混合器中混合。
| 配方 | 重量比(％) |
| 曲马朵盐酸盐灭叶灵盐酸盐一水合物Aerosil _200Aspartam交联聚乙烯吡咯烷酮微晶纤维素乳糖芳香剂十二烷基硫酸钠硬脂酸镁 | 12.551.250.202.505.0035.0040.981.880.500.15 |
片剂的制备：
用合适的压片机对粉末状混合物进行压片(名义重量400mg)。
Claims (11)
1．含有至少一种促动力学活性止吐剂或其药用盐类及曲马朵，其对映体或药用盐类的药物组合物用于制备治疗偏头痛或类偏头痛药物的用途。
2．含有至少一种促动力学活性止吐剂或其药用盐类及曲马朵，其对映体药用盐类的药物组合物用于制备治疗伴随有恶心或呕吐和／或胃排空延迟等症状的疼痛状态药物的用途。
3．权利要求1或2中所述的用途，其特征是药物组合物含有灭吐灵，哌双咪酮或5-HT3拮抗剂作为止吐剂。
4．权利要求1或2中所述的用途，其特征是药物组合物含有5-80mg止吐剂或其一种盐类以及50-400mg曲马朵或其一种盐类。
5．权利要求1或2中所述的用途，其特征在于优选的是通过口服途径给予药物组合物。
6．含有至少一种促动力学活性止吐剂或其药用盐类及曲马朵，其对映体或药用盐类以及非甾体抗炎剂(NSAID)或扑热息痛的药物组合物。
7．权利要求6中所述的药物组合物，其特征在于所用的NSAID优选的是为乙酰水杨酸，布洛芬或萘普生。
8．权利要求6中所述的药物组合物用于制备治疗偏头痛或类偏头痛药物的用途。
9．权利要求6中所述的药物组合物用于制备治疗伴随有恶心或呕吐和／或胃排空延迟等症状的疼痛状态药物的用途。
10．含有权利要求6中所述的药物组合物，以及(如果合适)药用合适的赋形剂和／或辅助剂的药物。
11．制备权利要求10中所述药物的方法，其特征在于使用赋形剂和／或辅助剂对权利要求6中所述的药物组合物进行加工。
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| Application Number | Priority Date | Filing Date | Title |
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| DE19807535A DE19807535A1 (de) | 1998-02-21 | 1998-02-21 | Pharmazeutische Kombinationen mit Tramadol |
| DE19807535.9 | 1998-02-21 |
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| JP (1) | JP2002503689A (zh) |
| KR (1) | KR100567154B1 (zh) |
| CN (1) | CN1141937C (zh) |
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| AU (1) | AU748993B2 (zh) |
| BG (1) | BG64888B1 (zh) |
| BR (1) | BR9909211A (zh) |
| CZ (1) | CZ291941B6 (zh) |
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| DK (1) | DK1056448T3 (zh) |
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| ES (1) | ES2212549T3 (zh) |
| HK (1) | HK1035143A1 (zh) |
| HU (1) | HU225656B1 (zh) |
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| NO (1) | NO327860B1 (zh) |
| NZ (1) | NZ506020A (zh) |
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| PT (1) | PT1056448E (zh) |
| SK (1) | SK284937B6 (zh) |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1917862B (zh) * | 2003-12-24 | 2011-08-03 | 格吕伦塔尔有限公司 | 防滥用给药形式的制备方法 |
| CN1980643B (zh) * | 2004-04-22 | 2012-05-30 | 格吕伦塔尔有限公司 | 制备防止滥用的固体剂型的方法 |
| CN106413717A (zh) * | 2014-04-10 | 2017-02-15 | 查尔斯顿实验室公司 | 药物组合物 |
| US10532030B2 (en) | 2009-07-08 | 2020-01-14 | Locl Pharma, Inc. | Pharmaceutical compositions for treating or preventing pain |
| US10772840B2 (en) | 2016-03-04 | 2020-09-15 | Charleston Laboratories, Inc. | Sumatriptan promethazine pharmaceutical compositions |
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| CN1329590A (zh) * | 1998-12-02 | 2002-01-02 | 达尔文发现有限公司 | 治疗产品及其应用 |
| DE19940944B4 (de) * | 1999-08-31 | 2006-10-12 | Grünenthal GmbH | Retardierte, orale, pharmazeutische Darreichungsformen |
| WO2001064202A2 (en) * | 2000-03-01 | 2001-09-07 | Euro-Celtique S.A. | Tramadol for the treatment of functional gastrointestinal disorders |
| US6451813B1 (en) | 2001-01-26 | 2002-09-17 | R. T. Alamo Ventures I, Llc | Treatment of gastroparesis in certain patient groups |
| DE10108122A1 (de) | 2001-02-21 | 2002-10-02 | Gruenenthal Gmbh | Arzneimittel auf Basis von Tramadol |
| US7553858B2 (en) * | 2003-12-17 | 2009-06-30 | Meda Pharma Gmbh & Co. Kg | Combination of flupirtine and tramadol |
| SI2124556T1 (sl) | 2006-10-09 | 2015-01-30 | Charleston Laboratories, Inc. | Farmacevtske sestave |
| EP3090743A1 (en) | 2008-01-09 | 2016-11-09 | Charleston Laboratories, Inc. | Pharmaceutical compositions for treating headache and eliminating nausea |
| EP2273880B1 (en) | 2008-04-28 | 2014-12-31 | Zogenix, Inc. | Novel formulations for treatment of migraine |
| US20130213393A1 (en) | 2009-12-22 | 2013-08-22 | Evoke Pharma, Inc. | Nasal formulations of metoclopramide |
| US11517545B2 (en) | 2016-12-15 | 2022-12-06 | Evoke Pharma, Inc. | Treatment of moderate and severe gastroparesis |
| JP7195660B1 (ja) | 2021-09-09 | 2022-12-26 | 壽製薬株式会社 | 口腔内崩壊錠 |
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| US4309408A (en) * | 1978-11-16 | 1982-01-05 | Beecham Group Limited | Effervescent powders |
| AU528098B2 (en) * | 1978-11-16 | 1983-04-14 | Beecham Group Plc | Analgesic tablet |
| CA2020018A1 (en) * | 1990-06-27 | 1991-12-28 | Don L. Simmons | Method and composition for treating the migraine complex |
| GB9214184D0 (en) * | 1992-07-03 | 1992-08-12 | Smithkline Beecham Plc | Pharmaceuticals |
| FR2712809B1 (fr) * | 1993-11-26 | 1996-04-12 | Union Pharma Scient Appl | Nouvelle composition pharmaceutique destinée à la préparation d'une poudre stable contenant, à titre d'ingrédient actif, une association d'acide acétylsalicylique et de métoclopramide. |
| FR2720936B1 (fr) * | 1994-06-08 | 1997-04-30 | Synthelabo | Poudres à base de métoclopramide et de paracétamol ou de dérivés d'acide acétylsalicylique. |
| GB9523566D0 (en) * | 1995-11-17 | 1996-01-17 | Euro Celtique Sa | Pharmaceutical formulation |
| FR2741532B1 (fr) * | 1995-11-28 | 1998-08-21 | Bouchara Sa | Nouvelles compositions pharmaceutiques a action antimigraineuse et leur mode de preparation |
| GB2313309B (en) * | 1996-05-24 | 2000-01-26 | Ninh Thuy On | Pharmaceutical compositions comprising a nonsteroidal anti-inflammatory drug and domperidone in the treatment of migraine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1917862B (zh) * | 2003-12-24 | 2011-08-03 | 格吕伦塔尔有限公司 | 防滥用给药形式的制备方法 |
| CN1980643B (zh) * | 2004-04-22 | 2012-05-30 | 格吕伦塔尔有限公司 | 制备防止滥用的固体剂型的方法 |
| US10532030B2 (en) | 2009-07-08 | 2020-01-14 | Locl Pharma, Inc. | Pharmaceutical compositions for treating or preventing pain |
| CN106413717A (zh) * | 2014-04-10 | 2017-02-15 | 查尔斯顿实验室公司 | 药物组合物 |
| US10772840B2 (en) | 2016-03-04 | 2020-09-15 | Charleston Laboratories, Inc. | Sumatriptan promethazine pharmaceutical compositions |
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