CN117510570A - 布地奈德-21-琥珀酸酯（i）或可药用盐及应用 - Google Patents
布地奈德-21-琥珀酸酯（i）或可药用盐及应用 Download PDFInfo
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- CN117510570A CN117510570A CN202211459606.2A CN202211459606A CN117510570A CN 117510570 A CN117510570 A CN 117510570A CN 202211459606 A CN202211459606 A CN 202211459606A CN 117510570 A CN117510570 A CN 117510570A
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- CN
- China
- Prior art keywords
- budesonide
- succinate
- pharmaceutically acceptable
- acceptable salt
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims abstract description 75
- 229960004436 budesonide Drugs 0.000 claims abstract description 75
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 24
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 23
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Abstract
布地奈德‑21‑琥珀酸酯(I)或其可药用的盐及应用，提供了布地奈德‑21‑琥珀酸酯(I)或其可药用盐在在制备治疗炎症性疾病的药物中的应用。布地奈德21‑琥珀酸盐或其可药用盐的每日剂量为0.05mg～5mg。还提供了一种药物组合物，含有作为活性成分的如权利要求1～4任一所述的布地奈德‑21‑琥珀酸酯(I)或其可药用的盐以及至少一种可以药用的辅料。
Description
技术领域：
本发明涉及一种甾体化合物，以及其制备方法以及治疗用途。本发明还涉及包含该化合物的吸入制剂处方、制备方法，以及该化合物在用于制备治疗肺部疾病的药物中的应用。
背景技术：
慢性阻塞性肺病(Chronic ObstructivePulmonaryDisease，COPD)是指一种不完全可逆的气流受限为特征的疾病，气流受限呈进行性发展，多与肺部对有害颗粒及气体的异常炎症反应相关。COPD是一种慢性的、长期的疾病过程，其特征为不可逆转的1秒钟用力呼气量(FEVI)降低、呼吸困难和其他呼吸道症状的表现加重、进行性的健康状况损坏。哮喘作为慢性气道炎症，其特征为可逆性气道阻塞和气道反应性增高，气道阻塞由支气管粘膜炎症引起的分泌物增加、粘膜水肿和炎症刺激平滑肌痉挛两种因素造成；而气道反应性增高也是由于气道炎症引起的支气管上皮细胞损伤的结果。人们认识到，只有控制气道粘膜的炎症，才能达到最终降低气道高反应性、缓解哮喘症状的目的。哮喘、慢性阻塞性肺炎均属于呼吸道炎症造成的气流受限疾病，目前为止，数种糖皮质激素已经被用于肺部的炎症以及过敏的治疗。其吸入制剂的处方通常受限于这几种糖皮质激素的较低的溶解度，须制备成为干粉入剂或混悬液。
布地奈德是较新一代的吸入用糖皮质激素，具有副作用小，安全性高的特点，其分子式如下：
现有研究表明，布地奈德药物分子进入细胞后，其21-羟基与长链脂肪酸发生可逆的酯化作用，生成更为亲酯的酯化布地奈德，延长药物在气道组织内的停留时间，吸入20分钟后，气道组织中大部分布地奈德为酯化形式。它们在酯酶的作用下缓慢释放出布地奈德，再与糖皮质激素(GCS)受体发生结合。布地奈德混悬液是目前为止在医疗应用中最常见的吸入制剂。供雾化吸入混悬液雾化吸入液体制剂，不需要患者启动雾化与吸入动作的同步协调，亦不依赖于患者较大吸气气流以启动雾化，患者在正常呼吸条件下即可实现药物的递送，因而特别适合儿童、老人及其他无法较好使用吸入气雾剂和吸入粉雾剂的患者使用。但是受限于混悬液的本身的特性令其无法脱离传统的雾化机[Mohammad Najlah,IshratParveen,Mohamed Albed Alhnan,Waqar Ahmed,Ahmed Faheem,David A.Phoenix,KevinM.G.Taylor,Abdelbary Elhissi,The effects of suspension particle size on theperformance of air-jet,ultrasonic and vibrating-mesh nebulisers,InternationalJournal of Pharmaceutics,Volume 461,Issues 1–2,2014,Pages 234-241,ISSN 0378-5173,https://doi.org/10.1016/j.ijpharm.2013.11.022.]，造成其递送效率更低，并且医疗应用受到限制。混悬液的辅料中加入了表面活性剂等多种吸入后对肺部具有不良影响的辅料，同样对其医疗应用具有不良影响[Gabrielle Pilcer,Karim Amighi,Formulationstrategy and use of excipients in pulmonary drug delivery,InternationalJournal of Pharmaceutics,Volume 392,Issues 1–2,2010,Pages 1-19,ISSN0378-5173,https://doi.org/10.1016/j.ijpharm.2010.03.017]。
(中文名“能倍乐”)作为最新一代吸入装置，具有体积小，可随身携带，使用方便，雾滴粒径小，药物递送效率高的特点，而且可以设计成适合小体积雾化吸入液体(如0.1-0.5ml)，因而雾化给药时间可大幅缩短，方便临床用药。适用于这种吸入装置的吸入剂被称为软雾剂(soft mist inhaler,SMI)，然而，由于其网孔大小为微米级3-8um，现有的布地奈德雾化吸入混悬液(如普米克令舒)中药物粒径大多为1-5μm，可能堵塞振动网孔，因而不能使用/>进行雾化给药。由于热力学特性的限制，更小粒径的混悬液存在着更严重的稳定性问题，如为了进一步稳定混悬液加入更多的表面活性剂类辅料又会对吸入后的用药安全性产生不良影响。
糖皮质激素的21-琥珀酸酯化改造，是改善糖皮质激素溶解性时经常用到的基团改性方法，现有的如琥珀酸氢化可的松或琥珀酸甲泼尼龙琥珀酸均是沿袭这种方法改造得到可溶性糖皮质激素，其21-琥珀酸酯的水解需要胆碱酯酶，作为雾化吸入剂后，由于活性成分本身作为琥珀酸盐形式存在，且水解需要的胆碱酯酶在气道组织细胞内含量较低，因此容易从细胞表面粘液中流失而难以发挥作用。
基于此，对现有的吸入糖皮质激素进行基团改造，既显著提高药物分子的溶解度使其能适用于等新一代吸入装置，又能在在气道给药时充分发挥药理活性，成为现有技术中亟待解决的问题。
发明内容：
为解决前述技术问题，本发明提供了布地奈德-21-琥珀酸酯(I)或其可药用的盐，所述化合物(I)的结构如下式：
所述的布地奈德21-琥珀酸酯的可药用盐为布地奈德琥珀酸钠、布地奈德琥珀酸钾或布地奈德琥珀酸铵；优选为布地奈德琥珀酸钠。
本发明提供了布地奈德-21-琥珀酸酯(I)的制备方法，包括以下步骤：
1)将布地奈德和琥珀酸酐加入水中，搅拌反应；
2)将步骤1)的反应液滴加入稀强酸溶液中混合产生沉淀，将沉淀经过滤提取、洗涤干燥得到白色固体，即布地奈德-21-琥珀酸酯(I)
所述布地奈德和琥珀酸酐的重量比为1:1～4，所述步骤1)反应温度为15～30℃，反应时间为2～8h。
所述布地奈德-21-琥珀酸酯(I)的可药用盐的制备方法为：将布地奈德-21-琥珀酸酯(I)与碱中和反应得到布地奈德21-琥珀酸酯的可药用盐，所述碱选自氢氧化钠、氢氧化钾、氨水，优选氢氧化钠。
本发明还提供了布地奈德-21-琥珀酸酯(I)或其可药用盐在在制备治疗炎症性疾病的药物中的应用。
所述的应用，进一步的，所述炎症性疾病为肺部炎症、哮喘、慢性阻塞性肺炎或鼻炎；更进一步的布地奈德21-琥珀酸盐或其可药用盐的每日剂量为0.05mg～5mg。
本发明还提供了一种药物组合物，所述组合物含有作为活性成分的布地奈德-21-琥珀酸酯(I)或其可药用的盐以及至少一种可以药用的辅料。
所述的药物组合物，进一步的，制备成为口服制剂、外用制剂、眼用制剂、鼻用制剂或吸入制剂，优选制备成为吸入制剂。
所述的吸入制剂，优选为吸入溶液，活性成分优选为布地奈德-21-琥珀酸酯(I)的可药用盐。
所述吸入溶液，活性成分优选为布地奈德琥珀酸钠、布地奈德琥珀酸钾或布地奈德琥珀酸铵，最优选为布地奈德琥珀酸钠。
所述的药物组合物，进一步的，还包括一种或多种附加治疗剂，所述附加治疗剂选自β2-受体激动剂、抗胆碱药物或抗菌药物。
进一步的，所述β2-受体激动剂选自短效β2-受体激动剂或长效β2-受体激动剂。
进一步的，所述短效β2-受体激动剂选自沙丁胺醇、特布他林或非诺特罗；所述长效β2-受体激动剂选自福莫特罗、阿福特罗、沙美特罗、丙卡特罗或茚达特罗。
进一步的，所述抗胆碱药物选自短效抗胆碱药物或长效抗胆碱药物。
进一步的，所述短效抗胆碱药物选自异丙托溴铵；所述长效抗胆碱药物选自噻托溴铵、噻托溴铵、氧托溴铵、乌美溴铵、阿地溴铵或雷芬那辛。
进一步的，所述抗菌药物选自妥布霉素、阿米卡星、多粘菌素E甲磺酸钠、左氧氟沙星或氨曲南赖氨酸。
在药理实验中，我们意外的发现，将布地奈德制备成21-琥珀酸酯得到的布地奈德-21-琥珀酸酯(I)，再进一步成盐得到的布地奈德琥珀酸钠后，在药理实验中表现出了更好的活性，以布地奈德琥珀酸钠为活性成分制备成的吸入溶液，与现有的布地奈德混悬液相比，在哮喘动物模型治疗、和慢阻肺的细胞药理实验和动物实验中都表现出了更好的抗炎效果。可见，除了能快速溶解外，与布地奈德相比，布地奈德琥珀酸钠表现出了更好的抗炎尤其时治疗气道炎症的效果，该效果在作为布地奈德琥珀酸钠配制成吸入溶液用于治疗慢性阻塞性肺病时尤为显著。除此之外，由于本身易溶于水，布地奈德琥珀酸钠在溶液中不存在粒径大于1um的颗粒，可顺利通过振动雾化器以及softmist雾化器进行雾化，用药体积小，雾化治疗时间短，药物利用率高，减少了药物落在患者口部，通过口腔黏膜或胃肠道系统吸收的几率，进一步了提高患者用药的顺应性。有助于拓展softmist雾化器这种新型吸入药物给药器械的应用范围，更好的发挥softmist雾化器便携、使用方便，雾滴粒径小，药物递送效率高的优点。
附图说明
图1为实施例1制得的布地奈德-21-琥珀酸酯(I)的质谱图；
图2为实施例1制得的布地奈德-21-琥珀酸酯(I)的核磁共振氢谱谱图
具体实施方式
实施例1制备布地奈德-21-琥珀酸酯(I)及其钠盐制备
将5.0g布地奈德和10.8g琥珀酸酐加入200ml纯水中，20℃搅拌4h。然后将反应液滴加入大量pH为1的盐酸溶液中，混合体系产生白色沉淀。沉淀经过滤提取，反复洗涤干燥得到白色固体，即布地奈德-21-琥珀酸酯(I)。质谱分析结果如图2所示。核磁共振氢谱(1H-NMR，DMSO)谱图如图2所示。
向瓶中加入1克BS和10ml蒸馏水，搅拌悬浮，冷却至5℃左右，滴入1.98ml 4％氢氧化钠水溶液，将溅在瓶壁上的固体迅速搅拌入水中。约1分钟后，固体完全溶解，pH6-6.5澄清溶液。5分钟后过滤，用10ml*2蒸馏水(含洗涤漏斗和反应瓶)洗涤，与滤液混合，摇匀，转移至三角瓶中，冻干至约0.87g白色蓬松结晶状固体即布地奈德琥珀酸钠。
实施例2布地奈德琥珀酸钠气雾剂制备
气雾剂的配制，按照1000喷的规格配制，HFA-134a是1,1,1,2-四氟乙烷，HFA-227为1,1,1,2,3,3,3-七氟丙烷。
活性成分
乙醇10g
HFA-134a 490g
制备工艺：将处方量活性成分1的加入处方量的乙醇，搅拌，分剂量灌装，封接剂量阀门系统，分别再加压注入HFA-134a，即得。实施例2-1～实施例2-4的活性成分用量见下表：
| 实施例号 | 活性成分1 | 剂量(μg/喷) | 总量(mg) |
| 2-1 | 布地奈德琥珀酸钠 | 100 | 100 |
| 2-2 | 布地奈德琥珀酸钠 | 500 | 500 |
| 2-3 | 布地奈德琥珀酸钠 | 1000 | 1000 |
| 2-4 | 布地奈德琥珀酸钠 | 2000 | 2000 |
实施例3布地奈德琥珀酸钠气雾剂制备
活性成分
乙醇 10g
HFA-227 490g
制备工艺：将处方量活性成分加入处方量的乙醇，搅拌，分剂量灌装，封接剂量阀门系统，分别再加压注入HFA-227，即得。实施例3-1～实施例3-4的活性成分用量见下表
| 实施例号 | 活性成分 | 剂量(μg/喷) | 总量(mg) |
| 3-1 | 布地奈德琥珀酸钠 | 100 | 100 |
| 3-2 | 布地奈德琥珀酸钠 | 500 | 500 |
| 3-3 | 布地奈德琥珀酸钠 | 1000 | 1000 |
| 3-4 | 布地奈德琥珀酸钠 | 2000 | 2000 |
实施例4布地奈德琥珀酸钠软雾剂吸入溶液制备
100ml的软雾剂吸入溶液的制剂处方(余量为水)：
制备方法：将布地奈德琥珀酸钠，抑菌剂、依地酸二钠及水混合后全溶，用0.1M盐酸调节pH值，然后分装。
实施例5布地奈德琥珀酸钠吸入溶液制备
100ml的吸入溶液的制剂处方(余量为水)：
制备方法：将布地奈德琥珀酸钠与水混合后全溶，用0.1M盐酸调节PH值。
实施例6布地奈德琥珀酸钠注射液
活性成分：布地奈德琥珀酸钠 1g
辅料：
制备方法：将氯化钠、无水亚硫酸钠、依地酸二钠溶于适量注射用水中，再加入活性成分，调整体积至1000ml，加入活性炭0.1g，搅拌均匀后放置15m1n，粗滤脱碳，过滤至澄明、灌封，121℃流通蒸气灭菌10min即可。规格为1mg/mL
实施例7布地奈德琥珀酸钠鼻喷溶液制备
活性成分：布地奈德琥珀酸钠600mg
辅料：
依地酸二钠 0.5mg
注射用水加至 10ml
制备方法：无菌环境将无水亚硫酸钠、依地酸二钠溶于适量注射用水中，再加入活性成分，调整体积至10ml，搅拌均匀后放置15min，过滤至澄明、灌封即可。
实施例8糖皮质激素盐前体药物的溶解度评价
称取50mg制备实施例1化合物至玻璃瓶中，每次加入50ul二纯水，室温(25±3℃)超声10分钟，观察样品是否完全溶解。最终，加入0.1ml二纯水后样品完全溶解，证明其溶解等级为易溶。
试验显示，布地奈德琥珀酸钠溶解度(500mg/ml)较布地奈德(水中溶解度16ug/ml)d大大提升。
实施例9溶液型激素盐前体药物的体外递送效率评价
使用呼吸模拟器及真空抽气泵进行测定，通过真空泵产生负压，吸收通过雾化处理的实验样品。之后，用溶剂淋洗滤膜并且多次挤压洗脱滤膜，收集洗脱液，测量样品含量。
布地奈德琥珀酸钠吸入溶液采用实施例5-2和实施例5-3制备的吸入溶液，
国产布地奈德混悬液为吸入用布地奈德混悬液(天晴速畅)(正大天晴)
进口布地奈德混悬液为吸入用布地奈德混悬液(普米克令舒)(阿斯利康)
结果见下表。
实验显示，同等浓度布地奈德琥珀酸钠吸入溶液较布地奈德混悬液的递送速率和递送总量有了大幅度提高。
药理实施例1哮喘药理实验
1动物模型制备
将30只BALB/c雄性小鼠适应性喂养，一周后分成两批，第一批随机取出5只做为空白组饲养，其余25只小鼠用来造模。将剩余25只小鼠每只分别在第0、7、14天腹腔注射0.1ml用生理盐水配制的致敏液，每ml致敏液中包括100μg OVA(鸡卵白蛋白)和3mg Al(OH)3，而正常组则注射等量生理盐水。在第21-23天时，将25只小鼠随机分为5组，每组分别置于雾化箱中用生理盐水配制的2％ OVA进行雾化，每组小鼠雾化30min，连续雾化5天。正常组的小鼠用生理盐水雾化相同的时间。在雾化期间所有的小鼠禁水禁食。雾化期间观察小鼠的活动状态，若小鼠出现头面部瘙痒，呼吸加深加快，安静少动，行动迟缓，大小便失禁，腹肌抽搐等哮喘急性发作表现则表示建模成功。
2给药分组、途径与剂量
将全部建模成功的25只小鼠随机分为5组，分别为受试药物高、低剂量组，阳性布地奈德对照组和模型组，在最后一次激发1h后开始给药，连续雾化吸入给药3天(根据药物及试验情况调整)。
受试药物高、低剂量组雾化吸入给药，药物浓度分别为8mg/mL、4mg/ml(受试药物溶于含1％吐温80的生理盐水内)，吸入时间均为10min；布地奈德混悬液亦吸入给药，药物浓度4mg/ml(粒径1-5μm的布地奈德微粉分散于含1％吐温80的生理盐水内)，吸入时间均为10min。空白组和模型组雾化吸入等体积含1％吐温80的生理盐水。
3肺泡灌洗液(BALFs)的采集与处理
过量麻醉后处死小鼠，固定于解剖盘上，打开小鼠腹部及胸腔，剪去颈部皮肤及多余组织，暴露出小鼠气管，用手术线结扎小鼠左肺，用小剪刀在气管横轴上切开一个小口，插入提前处理好的1ml注射器针头，用手术线固定针头。用1ml注射器抽取0.4ml预冷的磷酸盐缓冲液(PBS)将其缓慢打入小鼠肺部，再缓慢抽吸。每只小鼠灌洗3次，共收集灌洗液约0.7-0.9ml。液体回收率约为60％-80％。
于4℃条件下将肺泡灌洗液离心，7500rpm离心5min，离心后将上清液分装，于-80℃保存；用0.5ml预冷的PBS重悬沉淀细胞，计数细胞。
4肺泡灌洗液的处理与分析
ELISA法测各组小鼠肺泡灌洗液中的白细胞介素IL-4、IL-5、IL-6、IL-13，按照说明书方法操作。实验结果见下表(n＝5)，以均数±标准差(means±s)表示，每项检测指标中2组数据的比较采用Excel进行T检验，
| 实验分组 | IL-4(pg/mL) | IL-5(pg/mL) | IL-6(pg/mL) | IL-13(pg/mL) |
| 阴性对照组 | 230.9±21.7 | 360.2±89.3 | 18.7±4.1 | 910.2±47.5 |
| 低剂量组 | 469.3±50.5 | 814.9±58.3 | 39.7±5.4 | 1218.5±121.7 |
| 高剂量组 | 320.2±41.1 | 462.5±133.6 | 21.3±3.2 | 1015.4±98.8 |
| 布地奈德对照组 | 620.6±23.6 | 948.7±15.2 | 60.9±6.7 | 1645.9±173.6 |
| 阳性对照组 | 1150.8±372.9 | 1703.0±486.8 | 82.3±12.9 | 2418.4±322.7 |
实验结果表明高、低剂量组实验动物的的炎症因子浓度与阳性对照组相比均产生了显著差异(P＜0.01)，说明药物在哮喘动物模型中具有显著的抗炎能力。其中低剂量组实验动物的相关炎症因子浓度与也显著低于布地奈德对照组，说明采用布地奈德琥珀酸钠为活性成分雾化吸入给药，效果明显优于布地奈德混悬液，并具有浓度依赖性。
药理实施例2慢性阻塞性肺疾病细胞药理实验
以RLE-6TN/RAW264.7细胞为原料建立慢性阻塞性肺疾病体外细胞模型，将造模完成的阳性细胞的单细胞悬液，用培养液调整细胞浓度至105个细胞/mL。悬液接种于96孔板，终体积为200μL/孔。细胞在37.5％ CO2的细胞培养箱中培养12h，使细胞贴壁。然后弃上清液，用PBS(pH 7.4)溶液洗涤两次，用无血清DMEM洗涤一次。弃上清液后，按分5组(4组给药，1组阳性对照)每组6个重复在孔中加入不同活性成分浓度的新鲜无血清DMEM培养液200μL，进一步培养12h。同时采用未造模的阴性细胞作为阴性对照组(6个重复)。在培养24h后，对实验组以及阳性对照组进行脂多糖(LPS)刺激，LPS终浓度为1μg/mL，取上清液，采用ELISA试剂盒检测细胞培养上清中IL-6、IL-8、IL-10和TNF-α的含量，并按试剂盒说明进行检测。实验结果如下表所示(n＝5)，以均数±标准差(means±s)表示，2组数据的比较采用Excel进行T检验
上述实验数据证明慢性阻塞性肺疾病模型细胞的炎症因子浓度在给药前后有差异，其中抑制效果最明显的IL-6在50μg/mL的给药浓度下即可发生显著的抑制(P＜0.01)，说明布地奈德琥珀酸钠对于慢性阻塞性肺疾病模型细胞具有显著的抗炎能力，并具有浓度依赖性。
药理实施例3慢性阻塞性肺疾病动物药理实验
将20只C57BL/6N雄性小鼠适应性喂养，一周后分成两批，第一批随机取出5只做为空白组饲养，其余15只小鼠用来造模。将剩余15只小鼠于第1、14天使用静脉套管针气道注射100μg/kg的脂多糖(LPS)。于2-13天、15-28天每天置于有机玻璃密封箱中60分钟，并暴露于8支香烟形成的香烟烟雾中。正常组的小鼠用生理盐水雾化相同的时间。在此期间所有的小鼠禁水禁食。观察小鼠的活动状态，毛发、呼吸。每周给事前1h称重。
2给药分组、途径与剂量
将建模成功的小鼠随机分为3组，分别为受试药物剂量组，布地奈德混悬液对照组和模型组，连续雾化吸入给药7天。
受试药物组雾化吸入给药，药物浓度为4mg/ml(受试药物溶于含1％吐温80的生理盐水内)，吸入时间为10min；布地奈德混悬液亦吸入给药，药物浓度4mg/ml(受试药物分散于含1％吐温80的生理盐水内)，吸入时间均为10min。空白组和模型组雾化吸入等体积含1％吐温80的生理盐水。
3肺泡灌洗液(BALFs)的采集与处理
过量麻醉后处死小鼠，固定于解剖盘上，打开小鼠腹部及胸腔，剪去颈部皮肤及多余组织，暴露出小鼠气管，用手术线结扎小鼠左肺，用小剪刀在气管横轴上切开一个小口，插入提前处理好的1ml注射器针头，用手术线固定针头。用1ml注射器抽取0.4ml预冷的磷酸盐缓冲液(PBS)将其缓慢打入小鼠肺部，再缓慢抽吸。每只小鼠灌洗3次，共收集灌洗液约0.7-0.9ml。液体回收率约为60％-80％。
于4℃条件下将肺泡灌洗液离心，7500rpm离心5min，离心后将上清液分装，于-80℃保存；用0.5ml预冷的PBS重悬沉淀细胞，计数细胞。
4肺泡灌洗液的处理与分析
ELISA法测各组小鼠肺泡灌洗液中的白细胞介素IL-6、IL-8、TNF-α，按照说明书方法操作。实验结果如下表所示(n＝5)，以均数±标准差(means±s)表示，2组数据的比较采用Excel进行T检验
| 实验分组 | IL-6(pg/mL) | IL-8(pg/mL) | TNF-α |
| 阴性对照组 | 57.7±7.9 | 17.3±2.5 | 30.2±15.4 |
| 受试药物组 | 89.2±17.2 | 14.7±3.8 | 56.1±4.0 |
| 布地奈德对照组 | 142.8±26.7 | 22.4±5.5 | 73.7±6.2 |
| 阳性对照组 | 392.5±294.8 | 53.9±14.2 | 158.8±24.9 |
上述实验数据基本验证了细胞模型的结论，证明慢性阻塞性肺疾病动物模型的炎症因子浓度在给药前后有差异，可以说明药物在哮喘动物模型中具有显著的疗效，受试药物组的相关炎症因子浓度与也均显著低于布地奈德对照组(P＜0.01)，说明在给药剂量相同的情况下以布地奈德琥珀酸钠为活性成分的吸入溶液的抗炎效果药效优于相同剂量的布地奈德混悬液。
Claims (10)
1.布地奈德-21-琥珀酸酯(I)或其可药用的盐，所述化合物(I)的结构如下式：
2.如权利要求1所述布地奈德-21-琥珀酸酯(I)或其可药用的盐，其特征是所述的布地奈德21-琥珀酸酯的可药用盐为布地奈德琥珀酸钠、布地奈德琥珀酸钾或布地奈德琥珀酸铵。
3.如权利要求1所述布地奈德-21-琥珀酸酯(I)或其可药用的盐，其特征是所述的布地奈德21-琥珀酸酯的可药用盐为布地奈德琥珀酸钠。
4.如权利要求1～3任一所述布地奈德-21-琥珀酸酯(I)或其可药用盐在在制备治疗炎症性疾病的药物中的应用。
5.如权利要求4所述的应用，其特征是，所述炎症性疾病为肺部炎症、哮喘、慢性阻塞性肺炎或鼻炎。
6.如权利要求5所述的应用，其特征是布地奈德21-琥珀酸盐或其可药用盐的每日剂量为0.05mg～5mg。
7.一种药物组合物，其特征是所述组合物含有作为活性成分的如权利要求1～4任一所述的布地奈德-21-琥珀酸酯(I)或其可药用的盐以及至少一种可以药用的辅料。
8.如权利要求7所述的药物组合物，其特征是所述组合物制备成为口服制剂、外用制剂、眼用制剂、鼻用制剂或吸入制剂。
9.如权利要求8所述的药物组合物，其特征是所述组合物制备成为吸入制剂，所述吸入制剂为吸入溶液，活性成分为布地奈德-21-琥珀酸酯(I)的可药用盐。
10.如权利要求7～9任一所述的药物组合物，其特征是，所述组合物还包括一种或多种附加治疗剂，所述附加治疗剂选自β2-受体激动剂、抗胆碱药物或抗菌药物。
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