CN102000089A - 一种以环索奈德与阿福特罗为活性成分的复方制剂 - Google Patents
一种以环索奈德与阿福特罗为活性成分的复方制剂 Download PDFInfo
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- CN102000089A CN102000089A CN2009103064254A CN200910306425A CN102000089A CN 102000089 A CN102000089 A CN 102000089A CN 2009103064254 A CN2009103064254 A CN 2009103064254A CN 200910306425 A CN200910306425 A CN 200910306425A CN 102000089 A CN102000089 A CN 102000089A
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Abstract
本发明涉及一种以环索奈德与阿福特罗为活性成分的复方制剂及其用途。它是以环索奈德与阿福特罗为药用活性成分，与药学上可接受的辅料混合形成的药用组合物，按照本发明所说明的技术手段制备开发成经口腔给药的气雾剂剂型，具有起效快、作用迅速、使用方便等优点。可用于治疗各种类型哮喘、COPD等疾病。
Description
技术领域
本发明为一种以环索奈德与阿福特罗为活性成分的复方制剂，属于医药技术领域。
背景技术
慢性阻塞性肺病(COPD)是一种具有气流受限特征的可以预防和治疗的疾病，气流受限不完全可逆、呈进行性发展，与肺部对香烟烟雾等有害气体或有害颗粒的异常炎症反应有关。COPD是以小气道慢性非特异性炎症和进行性呼吸道阻塞为特征的呼吸系统疾病，实质为气道、肺实质和肺血管的慢性炎症。COPD主要累及肺脏，但也可引起全身(或称肺外)的不良效应。COPD包括慢性支气管炎和肺气肿。
阿福特罗于2006年10月在美国获准上市，用于长期维持治疗慢性阻塞性肺病(COPD)引起的支气管收缩症状，包括慢性支气管炎和肺气肿。阿福特罗是福莫特罗的(R，R)对映异构体，是一种选择性的长效β2肾上腺素受体激动剂，其药效为福莫特罗消旋体的2倍，为(s，s)对映异构体的1000倍。β2受体主要分布于支气管平滑肌，阿福特罗可激活体内腺苷酸环化酶，该酶能使三磷酸腺苷(ATP)转化为3’-5一环磷腺苷(cA)。细胞内cAMP量的增加可松弛支气管平滑肌，并能减少过敏性介质从细胞特别是肥大细胞中释放。体外试验显示，阿福特罗能抑制人肺肥大细胞中组胺、白三烯等介质的释放，此外，其还能抑制麻醉豚鼠体内由组胺介导的血浆清蛋白的渗漏，并抑制气道高反应性模型犬体内由过敏原诱导的嗜酸性细胞的内流。
环索奈德是一种具有高效局部抗炎作用的糖皮质激素，能增强内皮细胞、平滑肌细胞和溶酶体膜的稳定性，抑制免疫反应，降低抗体合成，使组胺等变态反应活性介质的释放减少、活性降低，并能减轻抗原抗体结合时激发的酶促过程，抑制支气管收缩物质的合成和释放。从而减轻平滑肌的收缩反应。
经口腔给药的吸入剂有着很多有点：药物经吸入可快速沉降在肺部，能避免或减少对其他部位的毒副作用；肺部吸收表面积大，膜通透性高，血流丰富，药物吸收迅速；肺部酶活性较低，且无肝脏首过效应，这些有利于提高药物的生物利用度。而且肺部给药可用于肺部的局部疾病治疗。目前已经有很多成功的范例，如激素类、治疗哮喘类药物，开发的品种很多。目前肺部吸入给药的技术主要有3种：干粉吸入剂、气雾剂(亦成为定量吸入气雾剂)和喷雾剂。
发明内容
本发明的目的是提供了一种以环索奈德与阿福特罗为活性成分的复方吸入制剂，经肺部吸入给药。这些肺部吸入给药制剂主要以以下三种形式存在：干粉吸入剂、气雾剂、喷雾剂。
在以上三种剂型当中，优选的是干粉吸入剂及气雾剂，从给药的顺从性及制备的难易程度而言，本发明者更倾向与干粉吸入剂。
在本吸入剂中，其活性成分为环索奈德与阿福特罗，环索奈德的用量为每吸或喷为20-320mcg，优选为80-160mcg，所述的阿福特罗的用量为每吸或喷为3.75-120mcg。优选为15-30mcg。如果以酒石酸盐阿福特罗计则为5.4-172.3mcg，优选为21.6mcg-43.2mcg。
所描述的剂量及其组合中，阿福特罗是以活性成分计。使用时可以是其药用盐，如酒石酸盐、富马酸盐、盐酸盐、硫酸盐、苯磺酸盐、琥珀酸盐等成盐的形式存在。优选为酒石酸盐。此时，所述的环索奈德与阿福特罗的剂量组合优选为每吸或喷80mcg/15mcg、80mcg/30mcg、160mcg/15mcg、160mcg/30mcg。
当该吸入剂是以干粉吸入剂的形式存在时，还必须添加一些其它的辅料，这些辅料包括但不仅限于微晶纤维素、乳糖、葡萄糖、果糖、蔗糖、甘露醇、木糖醇、麦芽糖醇、甘氨酸、门冬氨酸、丙氨酸、色氨酸、苏氨酸等其中的一种或几种。如果有必要，还要添加适量的表面活性成分，如二棕榈酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、胆固醇、泊洛沙姆等。还有可能加入适当的高分子物质，如淀粉、聚乳酸、聚乳酸-羟基乙酸、聚乙二醇中的一种或几种。
当药用活性成分与这些辅料混合时，其重量比为1∶50-1∶1000。而且这些辅料与药物都需要经过微粉化处理，它们的粒径分布范围在0.02-200微米之间，优选为1-100微米之间。
如果本发明所描述的吸入剂为气雾剂的形式存在时，通常是将两种活性成分溶解或分散在一定的溶媒中，这些分散体系可以是乳剂或混悬剂。同时，还必须加入一些抛射剂，抛射剂为氟利昂、碳氢化合物以及压缩气体等。
如果本发明所述的吸入剂为喷雾剂时，所采用的分散体系可以为乳剂型和混悬型液。
不管所采用分散载体如何，药物活性成分都需要经过微粉化处理，从而达到较好的吸收和利用效果。
本发明所述的复方制剂，可用于各种原因引起的哮喘、COPD的治疗。
具体实施方式
实施例1：复方环索奈德阿福特罗吸入粉雾剂
制法：
将两味主药分别进行微粉化，使其粒径在7um左右。在无菌条件下，乳糖等量递增法，混合均匀。分别装入3号胶囊中。放入特定的吸入用装置，即可。
实施例2：复方环索奈德阿福特罗吸入喷雾剂
制法：
将阿福特罗进行微粉化，使其粒径在7um左右。将环索奈德溶于处方量的无水乙醇中，将吐温与80ml水混合均匀，加入阿福特罗搅拌使均匀，倒入环索奈德乙醇溶液，使均匀。用枸椽酸及钠盐调PH值4-6，补加纯化水至100ml，分装至瓶中，每瓶10ml，每喷100ul。
实施例3：复方环索奈德阿福特罗吸入气雾剂
制法：
将阿福特罗进行微粉化，使其粒径在7um左右。将环索奈德溶于处方量的无水乙醇中，加入吐温混合均匀，加入阿福特罗搅拌使均匀。定量分装至铝罐中，压定量阀，定量充压抛射剂134a，每瓶10ml，每喷100ul。
实施例4：复方环索奈德阿福特罗对哮喘发作的拮抗作用
实验方法：将初筛合格的40只豚鼠随机分成4组，每组10只。分别为生理盐水对照组(A组)、复方环索奈德+阿福特罗治疗组(B组)、环索奈德治疗组(C组)、阿福特罗治疗组(D组)。置豚鼠于4L容积密闭玻璃瓶内，通过中心供氧，以5L/rain流量喷射雾化吸人治疗。分别喷射雾化吸人生理盐水、环索奈德+阿福特罗、环索奈德、阿福特罗120s。连续4天按实验方案给药，于给药0.5h(第1天)、1h(第2天)、2h(第3天)、3h(第4天)后，将豚鼠置于4L容积密闭玻璃瓶内，以5L/rain流量喷射雾化吸入0.8％磷酸组织胺溶液10S诱喘，记录豚鼠出现III度哮喘(抽搐跌倒)的潜伏期，如果360s内未出现III度哮喘，则潜伏期以360S计算。
实验结果：结果显示，与对照组比较，各治疗组均明显的延长哮喘发作潜伏期，但环索奈德+阿福特罗治疗组作用更为显著，且作用持续稳定。
表1 各治疗组对豚鼠引喘潜伏期的影响(s，x±s)
实施例5：复方环索奈德阿福特罗对COPD气道炎症的影响
实验方法：将40只大鼠随机分为四组，每组10只。分别为模型对照组(A组)、复方环索奈德+阿福特罗治疗组(B组)、环索奈德治疗组(C组)、阿福特罗治疗组(D组)。各组均在实验第1、20天气管内注入脂多糖1mg/kg，第2～19，21～40天将大鼠放人80cm×60cm×58cm有机玻璃箱内被动吸烟，每天2次(间隔4h)，每次持续1h(10支香烟)。各治疗组均在造模第2～19，21～40天分别予相应治疗药物+生理盐水5ml，以5L/rain雾化吸入，(置于30cm×30cm x 20cm玻璃箱内)，1次/d，25min/次，连续给药40天。模型对照组仅给予生理盐水雾化吸入。另取10只健康大鼠作为空白对照(O组)，实验期间仅按时给予生理盐水雾化吸入，不做其他任何处理。40天后检测肺泡灌洗液(BALF)白细胞计数及分类。
结果：各给药组对COPD大鼠肺功能均有一定的抗炎保护作用，雾化吸人复方环索奈德+阿福特罗的抗炎作用明显好于环索奈德或者阿福特罗单方给药效果，所以适合COPD的长期治疗。
表2 BALF中白细胞总数和分类(％，x±s)
| 组别 | 总数 | 巨噬细胞 | 中性粒细胞 | 淋巴细胞 |
| O | 1.52±0.11 | 98.14±0.97 | 2.89±1.08 | 3.18±0.37 |
| A | 6.82±0.17 | 68.74±1.64 | 20.82±1.07 | 8.14±0.47 |
| B | 2.49±0.20 | 87.68±2.10 | 9.68±2.01 | 4.12±0.22 |
| C | 4.57±0.18 | 78.32±1.58 | 13.58±1.84 | 6.06±0.43 |
| D | 5.18±0.23 | 71.95±0.89 | 16.45±1.53 | 7.03±0.54 |
Claims (10)
1.本发明为一种以环索奈德与阿福特罗为活性成分的复方制剂，其特征在于，它是环索奈德与阿福特罗形成的活性成分，与药学上可接受的辅料混合形成的药用组合物。
2.如权利要求1所述的复方制剂，其特征在于，阿福特罗是以盐的形式存在，包括但不仅限于酒石酸盐、富马酸盐、盐酸盐、硫酸盐、苯磺酸盐、琥珀酸盐。优选为酒石酸盐。
3.如权利要求1所述的复方制剂，是以吸入剂型存在，包括吸入粉雾剂、吸入气雾剂、吸入喷雾剂。
4.如权利要求3所述的复方制剂，其特征在于，所述的环索奈德的用量为每吸或喷为20-320mcg，优选为80-160mcg。
5.如权利要求3所述的的复方制剂，其特征在于，所述的阿福特罗的用量以活性成分计为每揿或每喷为3.75-120mcg。优选为15-30mcg。
6.如权利要求3所述的复方制剂，其特征在于，所述的环索奈德与阿福特罗的剂量组合优选为每揿或喷80mcg/15mcg、80mcg/30mcg、160mcg/15mcg、160mcg/30mcg。
7.如权利要求3所述的复方制剂，其特征在于，其吸入粉雾剂的的药用辅料常用的是甘氨酸或乳糖，优选为乳糖。他们都需要进行微粉化处理，粒径分布范围在0.02-200微米之间，优选为1-100微米之间。
8.如权利要求3所述的复方制剂，其特征在于，其吸入气雾剂的药用辅料常用的包括分散体系和抛射剂。其中分散体系可以以乳剂、混悬液的形式存在。抛射剂为氟利昂、碳氢化合物以及压缩气体等。
9.如权利要求3所述的复方制剂，其特征在于，其吸入喷雾剂可以为乳剂型和混悬型的分散体系。
10.如权利要求1所述的复方制剂，可用于各种原因引起的哮喘、COPD的治疗。
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| CN102266344A (zh) * | 2010-06-04 | 2011-12-07 | 北京阜康仁生物制药科技有限公司 | 一种用于治疗呼吸障碍的药物组合物 |
| CN107929257A (zh) * | 2017-12-01 | 2018-04-20 | 广东力集团制药股份有限公司 | 一种酒石酸阿福特罗粉吸入剂胶囊及其制备方法 |
| CN107929257B (zh) * | 2017-12-01 | 2019-04-16 | 广东一力集团制药股份有限公司 | 一种酒石酸阿福特罗粉吸入剂胶囊及其制备方法 |
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