CN101152162B - 一种含青蒿素或其衍生物的经皮给药制剂及其制药用途 - Google Patents
一种含青蒿素或其衍生物的经皮给药制剂及其制药用途 Download PDFInfo
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Abstract
本发明公开了一种含青蒿素或其衍生物的经皮给药制剂，该制剂通过经皮给药方式治疗疟疾，并有效防止疟原虫复燃。本发明经皮给药制剂是由青蒿素或其衍生物、基质、潜溶剂和透皮吸收促进剂组成。本发明的经皮给药制剂，通过皮肤体外给药，既能避免肝脏的首过效应，血药浓度平稳，使用方便。经动物实验证实，本经皮给药制剂可有效杀灭疟原虫并有抗复燃的作用，对皮肤的刺激极轻，无过敏、毒性反应。
Description
【技术领域】
本发明属于医药技术领域，涉及一种含青蒿素或其衍生物的经皮给药制剂及其制备方法和用途。
【背景技术】
青蒿素衍生物是临床上常用的强效抗疟药，在疟原虫对氯喹、法西达等药物产生严重抗药性的同时，青蒿素衍生物具有优良的抗疟效果，并对脑型疟等恶性疟有很好的治疗作用，并且没有任何毒副作用，是理想的速效、低毒的疟疾治疗药。
但是，青蒿素及其衍生物特别是青蒿素，当以片剂、胶囊剂口服给药时，存在着肝脏首过效应，为了避免首过效应，药剂工作者尝试以栓剂直肠给药和注射剂注射给药的方式。虽然直肠给药和注射给药能够避免首过效应，但由于青蒿素衍生物半衰期短，仍存在着疟原虫容易复燃的现象。
为了解决上述问题，本发明人研究开发了以青蒿素及其衍生物为有效成分，将其制备成体外经皮给药治疗系统，从而实现青蒿素及其衍生物经皮吸收，避免首过效应，长时间维持有效血药浓度，成功解决了疟原虫复燃的问题。
【发明内容】
本发明的目的是提供一种含青蒿素或其衍生物的经皮给药制剂，该制剂可将青蒿素及其衍生物通过皮肤释放到血液中，并维持其有效地血药浓度，可防止和降低疟原虫复燃率。
本发明的另外一个目的是提供该含青蒿素或其衍生物的经皮给药制剂的制备方法。
本发明的又外一个目的是提供该含青蒿素或其衍生物的经皮给药制剂在制备防止和降低疟原虫复燃率药物的用途。
本发明的含青蒿素或其衍生物的经皮给药制剂是由青蒿素或其衍生物、基质、潜溶剂和透皮吸收促进剂组成。其中各组分的用量为：
青蒿素或其衍生物 0.1～40％
基质 1～99.4％
潜溶剂 0～98.4％
透皮吸收促进剂 0.5～10％。
本发明中能够产生杀灭疟原虫的主要成分是青蒿素或其衍生物，青蒿素的衍生物是蒿甲醚、双氢青蒿素或青蒿琥酯，这些药物都是在临床上长期口服使用的强效抗疟药。在本发明的经皮给药制剂中，青蒿素或其衍生物的用量为0.1～40％，优选用量为5.6-19％。
在本发明的经皮给药制剂中，该透皮治疗系统采用水溶性、水乳性或脂溶性基质制备成软膏、贴剂、酊剂、凝胶剂等外用制剂，尤以丙烯酸酯类压敏胶制备的贴剂为最佳。丙烯酸酯聚合物、聚异丁烯、硅酮压敏胶从六十年代起就用于制备医用胶带。本身对皮肤刺激性极小，不需加入增粘剂、抗氧剂，很少引起过敏反应。本发明中所用的基质记载于《美国药用辅料手册》，具有很高的安全性。本发明中基质的用量以1～99.4％较为合适，优选用量为76-88.9％。
本发明中，青蒿素或其衍生物为产生药效的主要成分。其中青蒿素的分子式为C15H22 O5，分子量282.34，青蒿素为无色针状结晶，熔点为156～157℃。易溶于氯仿、丙酮、乙酸乙酯和苯，可溶于乙醇、乙醚，微溶于冷石油醚，几乎不溶于水。蒿甲醚为白色结晶或结晶性粉末，在丙酮或氯仿中极易溶解，在乙醇或乙酸乙酯中易溶，在水中几乎不溶，熔点为86～90℃。双氢青蒿素为白色针状结晶，分子式：C15H24O5，分子量：284.35，在三氯甲烷中易溶，在丙醇中溶解，在甲醇或乙醇中略溶，在水中几乎不溶，熔点为145-150℃。青蒿琥酯为白色结晶或结晶性粉末，在丙酮、三氯甲烷中极易溶解，在乙醇或乙酸乙酯中易溶，在水中几乎不溶。
为了保证青蒿素衍生物溶解，易于透皮吸收，本发明以水、乙醇、甘油、丙二醇、聚乙二醇300或聚乙二醇400等醇类物质为潜溶剂，这些物质与高分子丙烯酸酯聚合物、聚异丁烯、硅酮压敏胶以及青蒿素衍生物混合，在涂布干燥后，青蒿素衍生物以溶解或分散状态均有分布基质中。本发明中可并用一种或多种潜溶剂。本发明潜溶剂的用量为0～98.4％，优选用量为1.5-81.2％。
在本发明的透皮治疗系统中，优选加入透皮吸收促进剂。本发明中主要成分青蒿素衍生物须经皮吸收，进入血液循环，人体皮肤角质层是药物透过皮肤进入体内的天然屏障，一般情况下，药物难以透过皮肤。透皮吸收促进剂能够大大提高药物的经皮吸收量，产生良好的治疗效果。本发明中透皮吸收促进剂可选自氮酮、油酸、尿素、DMSO、高级脂肪酸、二甲基吡咯烷酮、肉豆蔻酸异丙脂或DMF中。本发明中透皮促进剂的用量为0.5～10.0％，优选用量为4-5.5％。
本发明青蒿素或其衍生物的透皮治疗系统的制备方法是将主要成分青蒿素或其衍生物、潜溶剂如甘油、乙醇、聚乙二醇300或聚乙二醇400、基质如水溶性、水乳性或脂溶性基质以及透皮促进剂如氮酮、油酸、尿素、DMSO、高级脂肪酸、二甲基吡咯烷酮或DMF充分混合均匀，制备成软膏、贴剂、酊剂、凝胶剂等青蒿素或其衍生物经皮给药制剂系统。
本发明制备的青蒿素或其衍生物经皮给药制剂，经药效学试验，结果证明本经皮给药制剂具有优良的抗疟效果，且无不良反应，基本解决疟原虫复燃问题。其药效学试验结果如下。
实验方法：
ICR小鼠，体重21-23g，雄性。按体重随机分组9组，模型对照组，口服青蒿素组、青蒿素经皮给药组、口服蒿甲醚组、蒿甲醚经皮给药组、口服双氢青蒿素组、双氢青蒿素经皮给药组、口服青蒿琥酯组、青蒿琥酯经皮给药组，每组10只，提前一天用脱毛剂在小鼠背部皮肤脱毛，次日腹腔内定量接种含有1000万个感染鼠疟原虫的红细胞，接种量0.2ml/只，各组青蒿素及其衍生物经皮给药制剂，接种当日在小鼠背部皮肤给药。口服青蒿素衍生物各组，每天灌胃给药，每日一次，连续4天，第5天除去药物。自第5天开始，尾部取血染片，吉姆萨染色。显微镜观察计数每组动物的疟原虫平均感染率。与对照组平均感染率比较，求出每个剂量组小鼠红细胞感染抑制率或者观察杀灭及其复燃时间。
表1青蒿素衍生物经皮给药制剂对感染疟原虫小鼠的影响
表2青蒿素经皮给药制剂对疟原虫的抑制和杀灭作用
结果表明青蒿素及其衍生物经皮给药均能有效杀灭疟原虫，与口服组比较，各经皮给药组较各口服组降低给药剂量后，仍均能有效抑制疟原虫复燃，而口服组停药9天后均100％复燃，说明将青蒿素及其衍生物经皮给药后，能大大提高药物效价，解决疟原虫复燃问题。
【具体实施方式】
下面以本发明的实施例为基础详细说明本发明，但本发明并不局限于此。
[实施例1]
取青蒿素80g，PEG400100g混合，研磨均匀，再加入丙烯酸酯压敏胶800g，氮酮45g混合均匀，用涂布机涂于背衬上，干燥，用保护膜复合，冲切即得。
[实施例2]
将蒿甲醚200g溶于800g丙烯酸酯压敏胶中，加入N-甲基-2-吡咯烷酮56g，混合均匀，用涂布机涂于背衬上，干燥，用保护膜复合，冲切即得。
[实施例3]
将双氢青蒿素50g溶于800g聚异丁烯压敏胶中，加入油酸50g，混合均匀，用涂布机涂于背衬上，干燥，用保护膜复合，冲切即得。
[实施例4]
将青蒿琥酯150g溶于800g丙烯酸酯压敏胶中，加入氮酮45g，丙二醇15g，混合均匀，用涂布机涂于背衬上，干燥，用保护膜复合，冲切即得。
[实施例5]
取青蒿素100g，脂溶性软膏基质800g混合，氮酮45g，研磨均匀，即得。
[实施例6]
取卡波姆40g，加水800g搅拌均匀，NaOH调节pH至7，加入双氢青蒿素100g，油酸45g，研磨均匀，即得。
Claims (7)
1.一种治疗疟疾的青蒿素经皮给药制剂，其特征在于组分为：青蒿素8％、丙烯酸酯压敏胶78％、PEG40010％和氮酮4％。
2.一种治疗疟疾的青蒿素衍生物经皮给药制剂，其特征在于组分为：蒿甲醚19％、丙烯酸酯压敏胶76％和N-甲基-2-吡咯烷酮5％。
3.一种治疗疟疾的青蒿素衍生物经皮给药制剂，其特征在于组分为：双氢青蒿素5.6％、聚异丁烯压敏胶88.9％和油酸5.5％。
4.一种治疗疟疾的青蒿素衍生物经皮给药制剂，其特征在于组分为：青蒿琥酯14.8％、丙烯酸酯压敏胶79.2％、丙二醇1.5％和氮酮4.5％。
5.一种治疗疟疾的青蒿素经皮给药制剂，其特征在于组分为：青蒿素10.6％、脂溶性软膏基质84.6％和氮酮4.8％。
6.一种治疗疟疾的青蒿素衍生物经皮给药制剂，其特征在于组分为：双氢青蒿素10％、水81.2％、卡波姆4.2％和油酸4.6％。
7.如权利要求1-6中任何一项所述的制剂在制备抗疟原虫复燃药物中的用途。
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| CN1650854A (zh) * | 2004-12-08 | 2005-08-10 | 广州中生生物技术有限公司 | 一种含有蒿甲醚（或蒿乙醚或蒿琥酯）微乳剂的制备工艺 |
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