CN103189108B - 用于治疗的可可碱与祛痰剂或粘液溶解剂的组合 - Google Patents

用于治疗的可可碱与祛痰剂或粘液溶解剂的组合 Download PDF

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CN103189108B
CN103189108B CN201180052248.7A CN201180052248A CN103189108B CN 103189108 B CN103189108 B CN 103189108B CN 201180052248 A CN201180052248 A CN 201180052248A CN 103189108 B CN103189108 B CN 103189108B
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CN103189108A (zh
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罗宾·马克·班尼斯特
约翰·布鲁
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Abstract

本发明涉及一种包含可可碱和祛痰剂的试剂或一种包含可可碱和粘液溶解剂的试剂。本发明的试剂可以用作在咳嗽治疗中同时使用、相继使用或分别使用的组合制剂。

Description

用于治疗的可可碱与祛痰剂或粘液溶解剂的组合
技术领域
本发明涉及一种药物组合、其组合物以及其在治疗中的用途。
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。
W098/42322公开了口服方式施用的可可碱用于治疗咳嗽的用途。
Usmeni等人在FASEB J.express article10，1096中公开了可可碱抑制感觉神经活动以及抑制咳嗽。所提供的数据示出了口服给药之后在如下情形中的作用效果：对豚鼠中柠檬酸引起的咳嗽和对人类中辣椒素咳嗽挑战，以及用单独的豚鼠的迷走神经制剂冲洗之后。
祛痰剂和粘液溶解剂能溶解粘稠的黏液，缓解呼吸困难。祛痰剂降低支气管分泌物的粘度，从而增大粘液流动，然后可以通过咳嗽除去粘液。粘液溶解剂也使粘液变稀，但是通过打破粘液分子的化学结构而实现。
祛痰剂和粘液溶解剂使粘液屏障变薄，结果能使增咳剂(如柠檬酸、灰尘，过敏原等)最大限度地渗透进入肺部，提高增咳效果。
发明概述
鉴于粘液溶解剂或祛痰剂能潜在地增咳，令人惊奇地发现，粘液剂/祛痰剂和可可碱有协同作用。基于对祛痰剂/粘液溶解剂已知的了解，过去预计祛痰剂/粘液溶解剂将减小可可碱的疗效。
本发明至少部分基于表明可可碱与愈创甘油醚(guaifenesin)的组合在柠檬酸致咳模型中的协同止咳效应的数据。当祛痰剂和/或粘液溶解剂与可可碱组合时，令人惊讶的是效果出乎意料地强，并且大于单个药物的总和；这表明该组合具有显著改善的效果。因此，显著降低的药物剂量便可以提供与各单独药物等同的效果，从而减少副反应和药物负担。
因此，本发明涉及包含可可碱和祛痰剂的试剂，或包含可可碱和粘液溶解剂的试剂。
附图说明
图1示出了暴露于柠檬酸(1M)10分钟和5分钟恢复期间，随后用赋形剂(p.o.)、可可碱(10mg.kg-1，i.p)、愈创甘油醚(30mg/kg，p.o.)或可可碱(10mg/kg，p.o.)与愈创甘油醚(30mg/kg，p.o.)的组合预治疗之后，豚鼠咳嗽的总次数。每一个柱代表均值，竖条表示均值标准差。使用ANOVA来比较在可可碱、愈创甘油醚以及可可碱与愈创甘油醚的组合的存在下和服用赋形剂的动物中总咳嗽数的变化，随后通过Dunnetts检测来比较平均值**P＜0.01，*P＜0.05。
发明内容
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。所述附加试剂(祛痰剂或粘液溶解剂)可以其已知的用量来使用，然而根据本发明的组合意味着减少的剂量可以是有效的。根据本发明的组合可以以单一配制品提供，或以单独的多种配制品形式提供，用于组合施用、同时施用或相继施用。
适用于本发明的祛痰剂是氨溴索(ambroxol)、碳酸氢铵、碳酸铵、溴己新(bromhexine)、碘化钙、羧甲司坦(carbocysteine)、愈创木酚(guaiacol)、愈创木酚苯酸酯、愈创木酚碳酸酯、愈创木酚磷酸酯、愈创甘油醚(guaifenesin)、愈甘醚茶碱(guaithylline)、氢碘酸、碘化甘油、愈创木酚磺酸钾(potassium guaiacolsulfonate)、碘化钾、柠檬酸钠、碘化钠、苏合香(storax)、芸香烯(terebene)、萜品(terpin)、三叶草(trifolium)、蜀葵根(Althea root)、五硫化二锑、木馏油(Creosote)、吐根(吐根糖浆)、左旋马鞭草烯酮(levoverbenone)、美远志(Senega)和泰洛沙泊(Tyloxapol)。优选地，祛痰剂是愈创甘油醚。
适用于本发明的粘液溶解剂为乙酰半胱氨酸(acetylcysteine)、溴己新、羧甲司坦、多米奥醇(domiodol)、厄多司坦(erdostine)、来托司汀(letostine)、溶菌酶、盐酸半胱氨酸甲酯(mecysteine hydrochloride)、美司钠(mesna)、水合蒎醇(sobrerol)、司替罗宁(stepronin)、硫普罗宁(tiopronin)、泰罗沙伯(tyloxapol)、氨溴索(ambroxol)、氯化铵、阿法链道酶(Dornase alfa)、依普拉酮(Eprazinone)、厄多司坦(Erdosteine)、来托司坦(Letosteine)、奈替克辛(Neltenexine)。
在一个优选的实施方式中，试剂包含可可碱、祛痰剂和粘液溶解剂。
在一个优选的实施方式中，本发明的试剂基本由可可碱和祛痰剂组成，或者基本由可可碱和粘液溶解剂组成，或者基本由可可碱、祛痰剂和粘液溶解剂组成。
在一个优选的实施方式中，本发明的试剂由作为活性剂的可可碱和祛痰剂组成，或者由作为活性剂的可可碱和粘液溶解剂组成，或者由作为活性剂的可可碱、祛痰剂和粘液溶解剂组成。
可以选择可可碱的任何适当形式。因为可可碱存在于可可中，所以可可碱可以以可可或巧克力的形式加入(在可可碱的量能以足够高的浓度以便在组合中提供治疗效果的条件下)。如果可可碱以可可的形式加入并且药物组合的形式是液体形式，那么有一个额外的好处，就是该药物的口感很好。
本发明的化合物优选地作为口服给药的组合，例如片剂、锭剂、糖锭、水性或口服悬浮液、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片剂或胶囊，赋形剂的实例如下所示。
意欲用于口服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，并且为了提供药学上精致和可口的制剂，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和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，例如甘油单硬脂酸酯或甘油二硬脂酸酯。
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(gum tragacanth)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)，或氧化烯烃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)。
油性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)或矿物油(例如液体石蜡)或其他表面活性剂或洗涤剂中来配制。油性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)来保存。
通过向适于制备水性悬浮液的可分散粉末和颗粒中添加水来获得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还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，例如大豆磷脂、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。
可以用甜味剂(例如甘油、丙二醇、山梨糖醇或蔗糖)配制糖浆和酏剂。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，与祛痰剂和/或粘液溶解剂组合的可可碱通过口服途径给药。根据本发明的组合的组合物可以通过使用常规配制技术来制备。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。这特别适用于想通过吸入给药的颗粒。通过研磨制备精细颗粒可以使用常规技术来实现。在本文中使用时，术语“研磨”指的是任何施加足以使活性材料的颗粒破碎或将颗粒磨碎成精细颗粒的力的机械过程。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)以提供所需的力度处于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碰撞、以及由于流体的加速导致的空化现象都可能造成颗粒的破碎。适合的均质机包括EmulsiFlex高压均质机、Niro Soavi高压均质机和Microfluidics Microfluidiser。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来研磨(如上所述)。
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，并与附加的赋形剂的溶液或悬浮液一起共喷雾干燥。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。
意欲用于吸入应用、局部应用、鼻内应用、舌下应用、静脉应用、直肠应用和阴道应用的本发明的组合的组合物可以根据药物组合物制备领域已知的任意方法来制备。
用于治疗呼吸疾病的任何合适的药学上有效的药物也可与本发明的组合物共同施用。例如，2-受体激动剂(例如沙丁胺醇(salbutamol)、沙美特罗(salmeterol)和福莫特罗(formoterol))可以配制用于共同施用。额外抗毒蕈碱类化合物也可以共同施用。例如，可以施用异丙托铵(例如，异丙托溴铵)或噻托溴铵。
其他治疗剂(包括类固醇)也可以共同施用。合适的类固醇的实例包括二丙酸倍氯米松(beclomethasone dipropionate)和氟替卡松(fluticasone)。适用于共同施用的其他合适的治疗剂包括粘液溶解剂、基质金属蛋白酶抑制剂、白三烯(leukotriene)、抗生素、抗感染剂、抗肿瘤药、肽、镇咳药、尼古丁、PDE4抑制剂、弹性蛋白酶抑制剂、色甘酸钠。
根据本发明的治疗可以以通常已知的方式进行，这取决于各种因素，例如性别、年龄或患者的病况以及是否存在一种或更多种伴随治疗。患者人群(patient population)可能是重要的，例如在患有肝病的患者的治疗中。
每单位剂量的组合中可可碱的量可以为1mg到3000mg。优选地，其单位剂量为50mg到1500mg。更优选地，其单位剂量为400mg到1000mg，每天给药1到4次。
在一个优选的实施方式中，可可碱以1-1000mg/kg、优选5-50mg/kg的量给药。
在一个优选的实施方式中，祛痰剂和/或粘液溶解剂以1-1000mg/kg、优选1-100mg/kg的量给药。
本发明至少部分地基于如下的研究。
研究
测试剂量
组1-赋形剂对照组
组2-可可碱(10mg/kg，p.o.)
组3-愈创甘油醚(30mg/kg，p.o.)
组4-可可碱(10mg/kg，p.o.)+愈创甘油醚(30mg/kg，p.o.)
方法
动物
在整项研究中使用雄性Dunkin Hartley豚鼠(400-510g，由Harlan UKLtd提供)。
实验方案
根据盲法编码(blinding code)将24只豚鼠随机分配至3个治疗组中的每一个(参见表1)。直到记录测量了所有动物的咳嗽之后才向调查者揭示盲法编码。
豚鼠在柠檬酸暴露之前0.5小时经由口服强饲方式服用可可碱(剂量体积2mL/kg)。愈创甘油醚和赋形剂在柠檬酸暴露前60分钟服用。
将各个豚鼠在柠檬酸暴露之前t-10min时置于具有2L/min气流的暴露室中以使其适应新环境。在t＝0min时，通过暴露于由超声气雾器以0.6mL/min的喷雾速度产生的柠檬酸气雾剂(1M)中10分钟来引起咳嗽响应。
记录整个10分钟柠檬酸暴露过程中的咳嗽数以及暴露后5分钟的咳嗽数。
表1：用于研究的治疗组(n＝每组6只豚鼠)
结果
在赋形剂治疗的豚鼠中记录的柠檬酸诱导的咳嗽的平均次数为30±4次。采用可可碱(10mg/kg，p.o.)的预治疗造成柠檬酸诱导的咳嗽的数量显著(P＜0.05)降低(15±3)。然而与之相比，愈创甘油醚(30mg/kg，p.o.)对柠檬酸暴露引起的咳嗽总数量没有显著作用(28±3)。与愈创甘油醚(30mg/kg，p.o.)组合之后，可可碱对柠檬酸诱导的咳嗽行为的抑制响应就观察到的咳嗽总数(13±3c.f.15±3)方面而言显示出药效增强的趋势。该协同作用如图1所示。

Claims (18)

1.一种试剂，其由可可碱和愈创甘油醚组成，其作为在咳嗽治疗中使用的组合制剂。
2.如权利要求1所述的试剂，其中，所述可可碱的量为1-3000mg。
3.如权利要求2所述的试剂，其中所述可可碱的量为50-1500mg。
4.如权利要求2所述的试剂，其中所述可可碱的量为400-1000mg。
5.如权利要求1-4中任意一项所述的试剂，其被制备用于口服给药。
6.如权利要求1-5中任意一项所述的试剂，其被制备为片剂、胶囊、锭剂、糖锭、可分散的粉末或颗粒、悬浮液、糖浆或乳液。
7.在咳嗽治疗中使用的口服药物组合物，其由如下物质组成：如权利要求1-6中任意一项中所限定的试剂，赋形剂，以及任选地甜味剂、调味剂、着色剂和/或防腐剂中的一种或多种。
8.如权利要求7所述的口服药物组合物，其被制备用于口服给药。
9.如权利要求8所述的口服药物组合物，其被制备为片剂、胶囊、锭剂、糖锭、可分散的粉末或颗粒、悬浮液、糖浆或乳液。
10.如权利要求1-6中任意一项中所限定的试剂在制备用于治疗咳嗽的药物中的用途。
11.如权利要求7-9中任意一项中所限定的口服药物组合物在制备用于治疗咳嗽的药物中的用途。
12.如权利要求10或11所述的用途，其中所述可可碱的量为1-3000mg。
13.如权利要求12所述的用途，其中所述可可碱的量为50-1500mg。
14.如权利要求13所述的用途，其中所述可可碱的量为400-1000mg。
15.如权利要求10或11所述的用途，其中所述可可碱的量为1-1000mg/kg。
16.如权利要求15所述的用途，其中所述可可碱的量为5-50mg/kg。
17.如权利要求10或11所述的用途，其中所述愈创甘油醚的量为1-1000mg/kg。
18.如权利要求17所述的用途，其中所述愈创甘油醚的量为1-100mg/kg。
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JP2016196504A (ja) 2016-11-24
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GB201014391D0 (en) 2010-10-13
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