CN102740853B - 可可碱的药物组合及其在治疗中的用途 - Google Patents
可可碱的药物组合及其在治疗中的用途 Download PDFInfo
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- CN102740853B CN102740853B CN201080051628.4A CN201080051628A CN102740853B CN 102740853 B CN102740853 B CN 102740853B CN 201080051628 A CN201080051628 A CN 201080051628A CN 102740853 B CN102740853 B CN 102740853B
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- theobromine
- codeine
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- cough
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Abstract
本发明涉及一种包含可可碱和阿片剂的试剂，其同时、连续或分别使用用于治疗。优选地，所述治疗是咳嗽治疗。
Description
技术领域
本发明涉及一种药物组合、其组成以及其在咳嗽治疗中的用途。
背景技术
咳嗽是一种防御反射。持续性咳嗽可能让人很痛苦。可以使用非处方药疗法，但其有效性令人怀疑。
WO98/42322公开了可可碱在咳嗽治疗中的用途，其中可可碱是口服给药的。Usmeni等人在FASEB J 10.1096中发表的论文公开了可可碱能抑制感觉神经活动和咳嗽。所提供的数据显示，口服给药之后对柠檬酸致豚鼠咳嗽的作用，以及对人的辣椒素咳嗽激发的作用，以及分离出的豚鼠的迷走神经制剂浸泡之后。
业已开发了多种阿片类(opiate)药物用于咳嗽治疗。可待因(codeine)是这类药物的一个实例，其被广泛用作止咳剂。然而，由于可待因和其他阿片剂的致瘾性，需要一种替代的咳嗽疗法。另外，如最新的证据表明，某些患者的治疗指数非常低。
发明概述
本发明至少部分基于显示可可碱与阿片类药物(可待因)组合在柠檬酸致咳模型中的协同止咳效应的数据。数据显示，当可可碱与可待因组合时，效果出乎意料地强大，并且大于单个药物的总和；这表明该组合具有大大改善的效果。一个优点是降低了可待因的最小有效剂量，如上所述使得可待因服药过量的可能性变小。
因此，显著降低的剂量的两种药物可以给出与各单个药物等同的作用，从而减少副反应和药物负担。可待因与许多其他阿片类药物的一种副反应是镇静。业已令人惊讶地发现，可可碱抵消了阿片剂的镇静性能。
因此，根据本发明，试剂包含可可碱和阿片剂，其作为用于治疗的同时、连续或分别使用的组合制剂。
可以相信所有阿片剂都显示这种协同关系。不想束缚于任何理论，这可能归因于阿片类物质的结构相似性。
附图说明
图1显示了可可碱及可可碱与可待因的组合对柠檬酸致豚鼠咳嗽的作用。
发明内容
在本文中使用时，术语“阿片剂”描述作为鸦片罂粟植物中的天然产物被发现的任何麻醉阿片生物碱类以及所述生物碱类的多种化学衍生物。术语“阿片剂”描述了特定的一类药物，可以被本领域技术人员理解。
可以选择可可碱的任何适当形式。这些形式包括盐、前体药物和活性代谢物。可可碱还可以是可可或巧克力的形式。可可碱的适当剂量范围是本领域已知的，然而组合物的协同效应意味着有效剂量可能降低。
阿片剂可以按其已知的使用量来使用，然而根据本发明的组合意味着降低的剂量便可能有效。与可可碱一起施用的阿片剂的剂量当然要取决于常见因素(包括药性)，但优选地为至少0.1mg/kg/天、例如至少5mg/kg/天，可以为至多30mg/kg/天。
优选地，阿片剂选自可待因、吗啡、二乙酰吗啡(diamorphine)、蒂巴因(thebaine)、罂粟碱、诺斯卡品(noscapine)、奥列巴文(oripavine)、芬太尼(fentanyl)、α-甲基芬太尼、阿芬太尼(alfentanil)、舒芬太尼(sufentanil)、瑞芬太尼(remifentanyl)、卡吩坦尼(Carfentanyl)、丙氧芬(propoxyphene)、氧吗啡酮(oxymorphone)、氧可酮(oxycodone)、氢吗啡酮(hydromorphone)、哌替啶(pethidine)、双氢可待因(dihydrocodeine)、丁丙诺啡(buprenorphine)、埃托啡(etorphine)、乙基吗啡、咯哌丁胺(loperamide)、氢可酮(hydrocodone)、戊唑辛(pentazocine)、曲马多(tramadol)、替培啶(tipepidine)和诺斯卡品(noscapine)。可待因是最优选的阿片类药物，例如以3mg/kg/天的剂量使用。
本发明的化合物可以通过任何可用途径给药，例如通过口服、吸入、鼻腔、舌下、静脉注射、直肠和阴道途径。口服途径是优选的给药途径。
本发明的化合物优选地作为口服给药的组合物，例如片剂、锭剂、糖锭、水性或口服混悬剂、可分散的粉末或颗粒。本发明的优选的药物组合物是片剂和胶囊。用于口服给药的液体分散剂可以是糖浆、乳液和悬浮液。更优选地，组合的药物组合物是与常用赋形剂形成的压缩的片剂或胶囊，其实例在下面给出。
用于口服使用的组合的组合物可以根据药物组合物制备领域已知的任何方法来制备，为了提供药学上美观和口感良好的制剂，所述组合物可以包含选自由甜味剂、调味剂、着色剂和防腐剂组成的组中的一种或更多种试剂。片剂包含组合的活性成分与适用于制备片剂的无毒的药物可接受赋形剂的混合物。这些赋形剂可以例如为惰性稀释剂，例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；成粒剂或崩解剂，例如玉米淀粉或海藻酸；粘合剂，例如淀粉明胶、阿拉伯胶、微晶纤维素或聚乙烯基吡咯烷酮；以及润滑剂，例如硬脂酸镁、硬脂酸或滑石。片剂可以是无包衣的或通过已知技术被包衣的，以便在胃肠道中延迟崩解和吸收，从而在较长的时间段内提供持续作用。例如，可以使用时间延迟材料，例如单硬脂酸甘油酯或二硬脂酸甘油酯。
水性悬浮液包含组合的活性成分与适用于制备水性悬浮液的赋形剂的混合物。这些赋形剂可以是悬浮剂，例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯基吡咯烷酮、黄蓍胶(gumtragacanth)和阿拉伯胶；分散剂或润湿剂，可以是天然存在的磷脂(例如卵磷脂)，或烯化氧与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯)，或氧化乙烯与长链脂肪醇的缩合产物(例如十七乙烯氧基鲸蜡醇)，或氧化乙烯与衍生自脂肪酸的偏酯的缩合产物(例如聚氧乙烯山梨醇酐单油酸酯)。水性悬浮液还可以包含一种或更多种防腐剂(例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯)、一种或更多种着色剂、一种或更多种调味剂、以及一种或更多种甜味剂(例如蔗糖或糖精)。
油悬浮液可以通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油、聚氧乙烯氢化蓖麻油、诸如油酸的脂肪酸)或在矿物油(例如液体石蜡)或在其他表面活性剂或洗涤剂中来配制。油悬浮液可以包含增稠剂，例如蜂蜡、固体石蜡或鲸蜡醇。可以加入甜味剂(如上面所列的那些)和调味剂以提供可口的口服制剂。这些组合物可以通过加入抗氧化剂(例如抗坏血酸)而保存。
适用于通过加入水来制备水性悬浮液的可分散的粉末和颗粒提供了组合的活性成分与分散剂或润湿剂、悬浮剂或一种或更多种防腐剂的混合物。也可以存在适当的甜味剂、调味剂和着色剂。
本发明的组合的药物组合物也可以是水包油乳液的形式。油相可以是植物油(例如橄榄油或花生油)、或矿物油(例如液体石蜡)、或其混合物。适当的乳化剂可以是天然存在的树胶，例如阿拉伯胶或黄蓍胶；天然存在的磷脂，例如大豆、卵磷脂；或衍生自脂肪酸和己糖醇酐的酯或偏酯，例如山梨醇酐单油酸酯；以及所述偏酯与氧化乙烯的缩合产物，例如聚氧乙烯山梨醇酐单油酸酯。乳液还可以包含甜味剂和调味剂。
糖浆和酏剂可以用甜味剂(例如甘油、丙二醇、山梨糖醇或蔗糖)配制。这种制剂也可以包含镇痛剂(demulcent)、防腐剂、调味剂和着色剂。
悬浮液和乳液可以包含载体，例如天然存在的树胶、琼脂、海藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。
在一个优选的实施方式中，与止咳药组合的可可碱通过口服途径给药。根据本发明组合的组合物可以通过使用常规配方技术来制备。特别地，喷雾干燥可用于制备包含分散或悬浮在能提供受控释放性能的材料中的活性剂的微粒。
研磨法(例如喷射研磨)也可用于配制治疗组合物。通过研磨制备细微颗粒可以使用常规技术来实现。在本文中使用时，术语“研磨”指的是施加足以使活性材料的颗粒破碎或将颗粒磨碎成细微颗粒的力的任何机械过程。多种研磨设备和条件都适用于制备本发明的组合物。选择适当的研磨条件(例如研磨强度和持续时间)以提供所需的力度在本领域技术人员的能力范围内。球磨研磨是一种优选的方法。或者，可以使用高压均质机，其中含有颗粒的流体在高压下被强迫通过阀，产生高剪切和湍流的条件。颗粒上的剪切力、颗粒与机械表面以及其他颗粒之间的冲击力以及由于流体聚集产生的空穴化均有助于颗粒的破裂。适合的均质机包括EmulsiFlex高压均质机、Niro Soavi高压均质机和MicrofluidicsMicrofluidiser。研磨法可用于提供具有上面所指定的质量平均空气动力学直径的微粒。如果活性剂是吸湿的，活性剂可以用疏水材料(如上面所指定的那些)来研磨。
如果需要，通过研磨步骤制备的微粒随后可以与附加的赋形剂配制在一起。这可以通过喷雾干燥法(例如共喷雾干燥)实现。在该实施方式中，颗粒悬浮在溶剂中，并用附加的赋形剂的溶液或悬浮液来共喷雾干燥。优选的附加的赋形剂包括多糖类。也可以使用附加的药学上有效的赋形剂。
用于吸入、局部、鼻腔、静脉注射、舌下、直肠和阴道应用的组合的组合物可以根据药物组合物制备领域已知的方法来制备。
根据本发明的治疗可以根据各种因素(例如性别、年龄或病人的病症以及是否存在一种或更多种伴随治疗)以通常已知的方式进行。
本发明至少部分地基于下列研究。
研究
通过使用柠檬酸导致豚鼠咳嗽。一组豚鼠被施用7mg/kg的可可碱，两组豚鼠被施用与8或16mg/kg的可待因组合的可可碱。第四组作为对照组被施用可待因，第五组仅得到赋形剂。通过口服途径给药。
结果显示在图1中。数据表明，与可可碱单一疗法和可待因单一疗法相比，可可碱与可待因的组合对咳嗽治疗具有明显改善的效果。
Claims (11)
1.一种用于咳嗽治疗的可可碱和可待因的组合试剂，其中，所述可待因的剂量为至多3mg/kg/天。
2.如权利要求1所述的组合试剂，其中，所述可待因的剂量为至少0.1mg/kg/天。
3.如权利要求1-2中任意一项所述的组合试剂，其特征在于，所述试剂被制备用于口服施用。
4.如权利要求1-2中任意一项所述的组合试剂，其特征在于，所述试剂被制成片剂、胶囊、锭剂、粉末、颗粒、悬浮液、糖浆或乳液。
5.一种药物组合物，其特征在于，其包含权利要求1-2中任意一项所述的试剂。
6.如权利要求5所述的药物组合物，其特征在于，进一步包含一种或更多种赋形剂，以及任选地一种或更多种甜味剂、调味剂、着色剂和/或防腐剂。
7.如权利要求5或权利要求6所述的药物组合物，其特征在于，所述药物组合物被制备用于口服施用。
8.如权利要求5或权利要求6所述的药物组合物，其特征在于，所述组合物被制成片剂、胶囊、锭剂、粉末、颗粒、悬浮液、糖浆或乳液。
9.权利要求1-2中任意一项所定义的组合试剂或权利要求5-6中任意一项所定义的药物组合物在制备用于治疗咳嗽的药物中的用途。
10.如权利要求9所述的用途，其中所述药物被制备用于口服施用。
11.如权利要求9所述的用途，其中所述药物被制成片剂、胶囊、锭剂、粉末、颗粒、悬浮液、糖浆或乳液。
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| GB0919893.8 | 2009-11-13 | ||
| PCT/GB2010/051896 WO2011058374A1 (en) | 2009-11-13 | 2010-11-12 | Drug combination with theobromine and its use in therapy |
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| GB0910375D0 (en) | 2009-06-16 | 2009-07-29 | Biocopea Ltd | Drug composition and its use in therapy |
| GB201111485D0 (en) * | 2011-07-05 | 2011-08-17 | Biocopea Ltd | Drug composition and its use in therapy |
| US9308211B2 (en) | 2009-06-16 | 2016-04-12 | Infirst Healthcare Limited | Drug combinations and uses in treating a coughing condition |
| US9314465B2 (en) | 2009-06-16 | 2016-04-19 | Infirst Healthcare Limited | Drug combinations and uses in treating a coughing condition |
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| ES2528384T3 (es) * | 2001-12-12 | 2015-02-09 | The Government Of The United States Of America, As Represented By The Secretary Department Of Healt | Métodos de utilización de inhibidores del receptor de adenosina para potenciar la respuesta inmunitaria y la inflamación |
| DE602004020597D1 (de) * | 2003-02-28 | 2009-05-28 | Ym Biosciences Inc | Opioidabgabesystem |
| CN1593451A (zh) * | 2003-09-12 | 2005-03-16 | 杨喜鸿 | 促进男性勃起的外用药物 |
| JPWO2006064780A1 (ja) * | 2004-12-14 | 2008-06-12 | 塩野義製薬株式会社 | 便秘治療剤 |
| KR20080009994A (ko) * | 2006-07-25 | 2008-01-30 | 안국약품 주식회사 | 기침 치료용 조성물 |
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| WO1989003213A1 (en) * | 1987-10-08 | 1989-04-20 | Andor Bilas | Mixture of substances for stabilyzing metabolism |
| CN1130354A (zh) * | 1993-09-07 | 1996-09-04 | 普罗克特和廿保尔公司 | 含有丙酸类非甾体消炎药氨基酸盐和减充血药、祛痰药、抗组胺药和镇咳药中至少一种的组合物 |
| CN1251039A (zh) * | 1997-03-26 | 2000-04-19 | 代热·科尔博尼兹 | 镇咳组合物 |
| WO2000030715A1 (en) * | 1998-11-25 | 2000-06-02 | Chinoin Gyógyszer És Vegyészeti | Composition containing an analgesic and a xanthine or a xanthine derivative |
| WO2008002514A2 (en) * | 2006-06-26 | 2008-01-03 | Levine Brian M | Combination cough treatment compounds and method of treating common coughs |
Also Published As
| Publication number | Publication date |
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| CA2780704C (en) | 2018-07-17 |
| CN102740853A (zh) | 2012-10-17 |
| RU2587329C2 (ru) | 2016-06-20 |
| SG10201407496SA (en) | 2015-02-27 |
| CA2780704A1 (en) | 2011-05-19 |
| GB0919893D0 (en) | 2009-12-30 |
| EP2498776A1 (en) | 2012-09-19 |
| JP2016041748A (ja) | 2016-03-31 |
| ZA201204247B (en) | 2013-02-27 |
| ECSP12011892A (es) | 2012-09-28 |
| RU2012124063A (ru) | 2013-12-20 |
| JP2013510842A (ja) | 2013-03-28 |
| IL219769A0 (en) | 2012-07-31 |
| MX2012005538A (es) | 2012-09-28 |
| ECSP12011893A (es) | 2012-10-30 |
| AU2010317668A1 (en) | 2012-06-07 |
| WO2011058374A1 (en) | 2011-05-19 |
| AU2010317668B2 (en) | 2015-01-22 |
| NZ599957A (en) | 2014-05-30 |
| BR112012011224A2 (pt) | 2017-03-01 |
| PE20121472A1 (es) | 2012-11-30 |
| AU2010317668C1 (en) | 2016-02-11 |
| UA105940C2 (uk) | 2014-07-10 |
| CO6551745A2 (es) | 2012-10-31 |
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