CN109453169B - 草乌甲素的用途 - Google Patents
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Abstract
本发明涉及药物领域,特别涉及草乌甲素的用途。将草乌甲素制备用于治疗皮肤瘙痒症,避免应用抗组胺类、激素类等药物引起不良反应无法长期应用,只能间断用药,导致瘙痒复发的情况。应用草乌甲素制备用于治疗皮肤瘙痒症疗效确切,无肝肾毒性副作用,可以长期服药,控制皮肤瘙痒症反复发作,避免不自觉搔抓,致使皮肤粗糙,苔藓化,可导致湿疹、神经性皮炎、结节性痒疹等继发性损害。应用草乌甲素制备用于治疗皮肤瘙痒症,解除患者常为瘙痒而苦恼,解除瘙痒夜间好发严重影响患者睡眠和休息,有效减轻患者及其家庭瘙痒带来的痛苦和精神压力。
Description
技术领域
本发明涉及药物领域,特别涉及草乌甲素的用途。
背景技术
皮肤瘙痒症又称皮痒症,是与抓痒欲望相关的普通感觉现象;引起皮肤瘙痒原因有多种多样,临床上很多疾病均会引起皮肤瘙痒,其病因也比较复杂,但临床上将仅有皮肤瘙痒而无原发性皮肤发疹者称为瘙痒症或皮肤瘙痒症。皮肤瘙痒症根据其发病部位,可分为全身性皮肤瘙痒症和局性皮肤瘙痒症。全身性皮肤症的病因多与机体代谢紊乱和内分泌异常有关。常见的原因有以下几种。老年性皮肤瘙痒症因老年人皮脂腺功能减退,末梢循环差,皮肤保水功能减弱,致使皮肤干燥,易受周围环境冷热变化的刺激而引起瘙痒。另外,老年人激素水平如性激素水平降低,也是引起瘙痒的原因之一,绝经期妇女多见。季节性皮肤瘙痒症冬季因皮肤干燥,夏季出汗汗液刺激均可引起瘙痒的发生。系统性疾病引起的皮肤瘙痒症如肿瘤、糖尿病、肾病、甲状腺功能异常、贫血、胆道疾病等均可引起瘙痒。糖尿病患者出现瘙痒,与糖代谢过程中丙酮酸及乳酸在皮肤及神经组织中堆积有关,刺激神经末梢出现瘙痒。糖尿病患者可伴全身或限局性皮肤瘙痒。甲状腺功能亢进与患者基础代谢增高、亢奋、多汗有关,而甲状腺功能低下与皮肤干燥有关。肾病患者由于代谢废物,如尿素氮、肌酐在体内堆积,部分尿素从汗腺排出,刺激皮肤而出现瘙痒。特别是肾病晚期的尿毒症患者,瘙痒更加明显。
局限性皮肤瘙痒症的病因可与全身性瘙痒症相同,如肿瘤患者既可出现全身瘙痒,亦可引起局部瘙痒。这一类瘙痒症在原发疾病得到控制后瘙痒症状亦随之消失。有些类型的瘙痒症与患者个体的精神、情绪亦有一定关系,如性病恐怖症患者出现的全身或外阴部位的瘙痒及不适就是典型例子。全身性皮肤瘙痒症可表现为疾病初发即为全身性瘙痒,也可以表现为局部,进而扩展至全身。瘙痒程度可轻可重,轻者仅为夜间瘙痒,不影响正常工作及生活;重者不论白天黑夜都瘙痒难忍、痛苦不堪,常不自觉搔抓直至皮破血流,更有甚者用利器,如刀叉、剪、钉等刺伤皮肤直至产生剧痛感而罢休。此类患者由于长期瘙痒烦恼往往伴随一定的精神紧张,脾气暴躁,稍有不顺即大发雷霆,一定程度上也加重了病情。此外,因为长期不自觉搔抓,致使皮肤粗糙,苔藓化,可导致湿疹、神经性皮炎、结节性痒疹等继发性损害。患者常常为瘙痒而苦恼。而且瘙痒在夜间好发,严重影响睡眠和休息,给患者及其家庭带来极大痛苦和精神压力。
目前,治疗皮肤瘙痒症的常用是口服扑尔敏、氯雷他定、西替利嗪、咪唑斯汀等抗组胺药物、维生素C、多塞平、谷维素、地西泮、葡萄糖酸钙等药物,重症患者口服镇静催眠类药物,皮质类固醇制剂,普鲁卡因静脉封闭,外用药如炉甘石洗剂、炉甘石薄荷脑洗剂、乳膏或霜剂等,这些药存在嗜睡作用较明显,激素类药物副作用大等问题。临床主要以抗组胺H1和H2受体拮抗剂、糖皮质激素、免疫调节及局部UV照射治疗为主,但常因出现不良反应无法长期应用,治疗间断后,瘙痒迅速复发。所以,安全有效且价格可接受的针对皮肤瘙痒症的药物研究迫在眉睫。
草乌甲素(BLA)是从滇西特有药用植物滇西嘟啦中分离出来的乌头属植物生物碱,具有良好的抗炎镇痛及免疫调节作用。草乌甲素作为新型第三类镇痛药物,不属于NSAID,可对钠离子通道进行调节,很少有心理依赖性和器质性器官毒性作用,可避免NSAID和阿片类镇痛药物可能导致的胃肠道和心血管及肾脏不良反应、药物依赖等潜在危险。目前,临床上广泛用于治疗类风湿关节炎(RA)、骨关节炎、肌纤维炎、颈肩痛、腰腿痛、癌性疼痛以及各种原因导致的慢性疼痛。但是,对于草乌甲素在治疗皮肤瘙痒症的作用与功效迄今为止尚未见相关报道;同时,该草乌甲素药物单体是从中药中提取出来的活性药物,具有安全性好,副作用较少,无成瘾性的特点。因此,对于中草药提取物草乌甲素药物进一步深入研究具有一定市场前景。
发明内容
有鉴于此,本发明提供了草乌甲素的用途。应用草乌甲素制备用于治疗皮肤瘙痒症疗效确切,无肝肾毒性副作用,可以长期服药,控制皮肤瘙痒症反复发作,避免不自觉搔抓,致使皮肤粗糙,苔藓化,可导致湿疹、神经性皮炎、结节性痒疹等继发性损害。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了草乌甲素在制备治疗和/或预防皮肤瘙痒症或其继发性损害的药物中的应用。
在本发明的一些具体实施方案中,所述草乌甲素的剂量为0.125mg/kg小鼠体重/d~0.5mg/kg小鼠体重/d。
在本发明的一些具体实施方案中,所述草乌甲素的剂量为0.01375mg/kg人体体重/d~0.055mg/kg人体体重/d。
在本发明的一些具体实施方案中,所述皮肤瘙痒症为神经病理性瘙痒。
在本发明的一些具体实施方案中,所述皮肤瘙痒症为组胺和/或氯喹引起的瘙痒。
在本发明的一些具体实施方案中,所述药物包括草乌甲素及药学上可接受的载体;所述草乌甲素在所述药物中的质量百分含量为24.74%~88%。
在本发明的一些具体实施方案中,所述药物的剂型为口服制剂、注射制剂或外用制剂。
在本发明的一些具体实施方案中,所述口服制剂为硬胶囊、滴丸、颗粒、片剂、合剂、软胶囊、浓缩丸、口服液或散剂。
在本发明的一些具体实施方案中,所述注射制剂为注射液或冻干粉针剂。
在本发明的一些具体实施方案中,所述外用制剂为酊剂、软膏剂、乳膏剂、糊剂、气雾剂、喷雾剂、散剂、耳用制剂、洗剂、冲洗剂、搓剂、涂剂、涂膜剂、凝胶剂或贴剂。
本发明提供了草乌甲素的新用途,其作用机理可能是通过对钠离子通道调节,从而对外周和中枢神经专门负责瘙痒感传导的特异性神经元起到抑制作用;同时也可能是通过对钠离子通道调节,抑制瘙痒介质激活和传导以及致痒物质的选择性受体的调节,从而抑制瘙痒。
1、将草乌甲素制备用于治疗皮肤瘙痒症,避免应用抗组胺类、激素类等药物引起不良反应无法长期应用,只能间断用药,导致瘙痒复发的情况。
2、应用草乌甲素制备用于治疗皮肤瘙痒症疗效确切,无肝肾毒性副作用,可以长期服药,控制皮肤瘙痒症反复发作,避免不自觉搔抓,致使皮肤粗糙,苔藓化,可导致湿疹、神经性皮炎、结节性痒疹等继发性损害。
3、应用草乌甲素制备用于治疗皮肤瘙痒症,及可能解除患者常为瘙痒而苦恼,解除瘙痒夜间好发严重影响患者睡眠和休息,有效减轻患者及其家庭瘙痒带来的痛苦和精神压力。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示实验流程;BLA:草乌甲素;D:天;h:小时;
图2示组胺组的30min内的搔抓次数,*:与溶剂组相比P<0.05;***:与溶剂组相比P<0.001;
图3示氯喹组的30min内的搔抓次数,**:与溶剂组相比P<0.005;***:与溶剂组相比P<0.001;
图4示动物剂量之间的换算关系。
具体实施方式
本发明公开了草乌甲素的用途,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
术语解释:
皮肤瘙痒症:是指以皮肤瘙痒为主要特征的一组皮肤病,其中既包括仅有皮肤瘙痒而缺乏原发性皮肤发疹的瘙痒症,也有皮肤瘙痒与原发性皮肤发疹同时并存的神经性皮炎、痒疹、结节性痒疹等。
皮肤瘙痒症或其继发性损害:“继发性损害”是指因皮肤瘙痒症反复发作,搔抓导致的皮肤粗糙,苔藓化,湿疹,神经性皮炎,结节性痒疹等病症。
本发明提供的草乌甲素的用途中所用原料及试剂均可由市场购得。
下面结合实施例,进一步阐述本发明:
实施例1
实验目的:
多年来的研究表明,瘙痒主要是由两类C纤维传导的,一类对组胺敏感,另一类对氯喹敏感。因此,皮下注射组胺或氯喹引起的动物搔抓反应是国际公认的急性瘙痒模型。本发明旨在探究草乌甲素(BLA)灌胃能否抑制组胺和氯喹引起的急性瘙痒。
实验材料与方法:
实验采用6-8周C57小鼠(体重17-20克,动物来源于中山大学实验动物中心)。把小鼠随机分为四组:溶剂+组胺对照组、BLA+组胺组、溶剂+氯喹对照组和BLA+氯喹组。在实验开始前三天,在用异氟烷短暂麻醉时刮掉了颈背部的毛(至少3×5cm),便于皮下注射和观察搔抓。对照组:皮下注射组胺(2mg/ml)或氯喹(4mg/ml)50μl,在注射前2小时溶剂(羧甲基纤维素)灌胃。实验组:在注射组胺或氯喹前2小时,灌胃不同剂量的BLA(0.12、0.25和0.5mg/kg)。提前2小时使用BLA是因为从灌胃到起效需要1.5-2小时。以往的研究中表明,组胺和氯喹诱导的急性搔抓反应在注射余额30分钟后消退,于是我们计数各组在此期间的总的搔抓次数并进行对比。实验流程见图1。
实验记录时小鼠被放置在单独的、透明的亚克力盒子中,每个盒子规格为15×15×20厘米。每个盒子上方有两个小开口允许空气流通。由于老鼠搔抓颈背部的行为基本都是正对老鼠背部上方视角,所以将摄像机放置在老鼠上方,以录像记录他们的搔抓行为。
抓挠行为容易因分散注意力而被抑制。为了增大限度地减少意力转移,消除紧张感,每个透明盒子中都放置少量的垫料,以吸收任何由老鼠排出的尿液,环境温度保持在23-27℃。为了保障实验环境安静,记录时所有人员离场。实验在9:00-14:00h之间进行。为了让动物适应试验环境,在正式实验前两天每天9:00和13:00让老鼠在透明盒子中适应一个小时。由于小鼠的搔抓进行过程往往很快,将小鼠后爪开始搔抓颈背部至其后爪落地或者放入嘴中进行清洁皮屑视为一次搔抓行为。
统计学方法:搔抓次数用均值±标准差表示,用Turkeytest比较不同组间的差异。
相关溶液的配制及应用方法:称取0.05g的BLA溶于1000ml的0.5%的羧甲基纤维素纳溶液中。组胺与氯喹均是用0.9%无菌生理盐水配制,组胺的剂量为100μg,氯喹为200μg。为了尽量使得注射部位的皮肤损伤最小化,在微量注射器针口接上了一段更细的0.3ml的胰岛素针头来降低对小鼠造成的损伤。
实验结果:
在皮下注射组胺或氯喹前30分钟内,小鼠的搔抓次数为3.4±2.4,而在注射组胺或氯喹后的30分钟内搔抓次数分别上升到29.4±16.6(n=12)或73.8±34.1(n=12),表明模型制作成功。试验结果表明,BLA灌胃剂量依赖性地抑制组胺或氯喹引起的瘙痒。剂量为0.5mg/kg时,BLA可完全抑制(P<0.001)组胺或氯喹引起的急性瘙痒,BLA灌胃小鼠的搔抓次数为0,但小鼠有嗜睡现象;剂量为0.25mg/kg时,BLA显著抑制组胺(P<0.05)或氯喹(P<0.005)引起的搔抓反应(如表1、表2及图2、图3所示);而剂量为0.125mg/kg时,BLA对组胺或氯喹引起的急性瘙痒仅有轻度抑制作用,但未达到统计学显著水平(P>0.05,如表1、表2及图2、图3所示)。在后两个剂量小鼠未见嗜睡现象和其他副作用。
表1组胺组灌胃BLA两个小时到两个半小时小鼠的搔抓次数
表2氯喹组灌胃BLA两个小时到两个半小时小鼠的搔抓次数
上述试验结果表明:口服草乌甲素可剂量依赖性地抑制组胺或氯喹引起的瘙痒。因此,口服草乌甲素可用于治疗多种疾病和药物引起的神经病理性瘙痒。
我们测试的小鼠浓度大致相当于成年人的0.11*0.125mg/kg=0.01375mg/kg,0.11*0.25mg/kg=0.0275mg/kg,0.11*0.5mg/kg=0.055mg/kg,即在测试相当于人的0.01375mg/kg到0.055mg/kg的浓度中,草乌甲素都具有一定的抑制急性瘙痒的作用。
实施例2
本发明的草乌甲素在神经病理性瘙痒方面的应用,可以将草乌甲素制成不同剂型的药物使用。具体来说,可以将草乌甲素制成包括胶囊、片剂或颗粒剂等剂型。具体的药物可包括草乌甲素和其它药学上可接受的载体,对于药物中各成分的用量可以按照药物制剂中对于成分的配比要求进行调整即可,对于草乌甲素的有效含量也可以按照不同剂型等常规的剂型要求计算,实施例1中描述的0.01375mg/kg到0.055mg/kg人体体重/d,本实施例在此只提供一个参考值范围,并不是具体的限定。更进一步说明,其中药学上可接受的载体可以采用矮味剂、填充剂、崩解剂、着色剂和增粘剂等。矮味剂如葡萄糖、山梨醇、甘露醇等,但并不限定于这些矮味剂,增粘剂等;填充剂如微晶纤维素等;崩解剂如羟甲基淀粉钾等。
实施例3
一种含草乌甲素的片剂,每片含0.275mg草乌甲素与辅料130mg的薄膜衣片。将草乌甲素用食用级或药用级乙醇溶解;将辅料乳糖20mg、糖粉25mg、微晶纤维素40mg和羟丙基纤维素10mg混合,然后加入草乌甲素乙醇液混合,再加适量纯化水混合制成软材,再制成颗粒后干燥,在干燥的颗粒中加入硬酯酸镁和羧甲基淀粉钠数分钟分钟压片,然后包薄膜衣制得。
实施例4
一种草乌甲素每粒胶囊含0.4mg草乌甲素与辅料150mg,辅料为糖粉80mg、淀粉25mg、微晶纤维素20mg、低取代羟丙基纤维素15mg、硬酯酸镁5mg和邻苯二甲酸酯5mg,然后加入润湿剂制乙醇成软材,再制成微丸后干燥,然后包肠溶衣丙烯酸树脂15mg制得。干燥微丸放至室温后,用丙烯酸树脂包衣,包衣后的微丸用硬胶囊进行装填后进行内包、外包后即得微丸剂胶囊成品。
实施例5
一种草乌甲素控释片,每片好0.98mg草乌甲素、缓冲释骨架材料、辅料投入湿法制粒机中混合均匀,然后加入润湿剂制成适宜的软材;通过制粒器将软材制成湿颗粒;将湿颗粒进行干燥;再将干燥的颗粒用整粒机进行整粒;然后整好粒的颗粒及辅料由混合机混合均匀,并用压片机进行压片,压制好的片子用包衣材料用薄膜包衣机进行包衣制得。
Claims (7)
1.草乌甲素在制备治疗和/或预防皮肤瘙痒症的药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述皮肤瘙痒症为神经病理性瘙痒;
所述神经病理性瘙痒为组胺和/或氯喹引起的瘙痒。
3.如权利要求2所述的应用,其特征在于,所述药物包括草乌甲素及药学上可接受的载体;所述草乌甲素在所述药物中的质量百分含量为24.75%~88%。
4.如权利要求3所述的应用,其特征在于,所述药物的剂型为口服制剂、注射制剂或外用制剂。
5.如权利要求4所述的应用,其特征在于,所述口服制剂为硬胶囊、滴丸、颗粒、片剂、合剂、软胶囊或浓缩丸。
6.如权利要求4所述的应用,其特征在于,所述注射制剂为注射液或冻干粉针剂。
7.如权利要求4所述的应用,其特征在于,所述外用制剂为酊剂、软膏剂、乳膏剂、糊剂、气雾剂、喷雾剂、散剂、洗剂、冲洗剂、搓剂、涂剂、凝胶剂或贴剂。
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