CN113134000B - 一种含松弛平滑肌的药物组合物 - Google Patents
一种含松弛平滑肌的药物组合物 Download PDFInfo
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Abstract
本发明针对慢性阻塞性肺病，提供一种治疗更加安全有效的含松弛平滑肌的药物组合物，由药用剂量的特布他林、安立生坦及适量的辅料组成。本发明的优点是：该药物组合物不仅可以平喘、解除气道痉挛和阻塞，还可以预防和治疗慢性阻塞性肺病继发的肺动脉高压。另外，本药物组合物还可以使患者服药方便，提高依从性。
Description
技术领域
本发明提供一种治疗慢性阻塞性肺病的药物组合物，由特布他林、安立生坦组成；本发明属于药学领域。
背景技术
慢性阻塞性肺病(COPD)是一种呼吸***常见病，包括慢性支气管炎、支气管哮喘和阻塞性肺气肿，可进一步发展为肺心病和呼吸衰竭。COPD病死率高，是人类第四大致死病因，全球40岁以上人群发病率高达9％～10％。
COPD的发病机制与气道对有害气体或颗粒的异常炎症反应有关，常伴有呼吸道感染，病理表现以小气道、肺实质和肺血管的慢性炎性为特征。COPD因呼气性通气受阻，易导致慢性缺氧和CO2潴留，而长期慢性缺氧导致肺血管广泛收缩，血管内膜增生、纤维化，肺血流量减少，加重缺氧，形成恶性循环。COPD急性发作期由于感染、缺氧、酸中毒等，引起毛细血管内皮损伤，释放ET-1而引起肺血管进一步收缩，加重肺通气与血流比例失调，影响肺的呼吸功能。有多种炎症介质和细胞因子参与COPD的发病过程，其中ET-1在肺循环和气道反应性中具有重要的调节作用。ET-1有很强的促血管收缩和平滑肌细胞增殖的能力。ET及其受体在呼吸***中分布广泛，对肺通气和肺循环有重要调节作用，其异常表达可能对COPD发生和发展起重要调节作用。
ET家族由3个血管活性肽(ET-1，ET-2，ET-3)成员构成，在3种ET亚型中，ET-1具有最强的缩血管作用。ET的2种主要受体为ETA和ETB，其中ETA受体主要与ET-1、ET-2结合，分布于肌肉细胞；ETB受体与3种ET均有较强的亲和力，分布于内皮细胞、上皮细胞、内分泌细胞及神经细胞等。研究显示，使用ET转化酶抑制剂、ET受体拮抗剂能有效治疗肺动脉高压、盐敏感性高血压等。
肺动脉高压(PH)是COPD发展到后期的并发症，再进一步则发展为肺源性心脏病，导致患者死亡风险迅速增加。肺动脉高压的发病机制可能包括缺氧导致的肺动脉血管收缩、肺部过度通气导致的血管变形以及肺气肿导致的肺组织结构破坏伴血管损伤。
特布他林是β2受体激动剂，有解除平滑肌痉挛、扩张支气管作用，对支气管平滑肌有高度的选择性，能够缓解COPD患者的气喘、气道受阻，而且对心脏的兴奋作用很小，无中枢性作用，可用于支气管哮喘、喘息型支气管炎、阻塞性肺气肿和其他伴有支气管痉挛的肺部疾病，尤其适用于伴有高血压、冠心病的COPD患者。
安立生坦是新一代内皮素受体拮抗剂，能选择性地与ETA结合(Ki＝0.011nM)，比与ETB结合的亲和力大4000倍以上。这种高度选择性使得安立生坦能强力抑制ETA的收缩血管作用，而不太影响ETB的扩张血管作用。
发明内容
本发明的目的是针对慢性阻塞性肺病(COPD)，提供一种治疗更加安全有效的含平滑肌舒张的药物组合物。
为实现上述目的，本发明采用以下技术方案：
一种更加安全有效的治疗COPD的药物组合物，组成成分为：
(1)药用剂量的特布他林；
(2)药用剂量的安立生坦；
(3)药剂学上可接受的载体。
在本发明中，特布他林的药用剂量选自1.25-5mg，优选1.25-2.5mg。在本发明提供的药物组合物中，特布他林可以盐类、酯类、活性代谢产物或药用前体等形式存在。本发明提供的特布他林作为药物成分，特布他林的盐类、酯类、活性代谢产物或药用前体等存在形式也在本申请保护的范围内。特布他林的盐类、酯类、活性代谢产物或药用前体等存在形式的药用剂量可以进行相应换算。
在本发明中，安立生坦的药用剂量选自2.5-10mg，优选2.5-5mg。在本发明提供的药物组合物中，安立生坦可以盐类、酯类、活性代谢产物或药用前体等形式存在。本发明提供的安立生坦作为药物成分，安立生坦的盐类、酯类、活性代谢产物或药用前体等存在形式也在本申请保护的范围内。安立生坦的盐类、酯类、活性代谢产物或药用前体等存在形式的药用剂量可以进行相应换算。
作为一种优选,本发明提供的药物组合物的组成是1.25mg特布他林、2.5mg安立生坦。
在本发明中，组合物有效成分的药用剂量是指该药药效成分在该组合物中与其他药效成分组合后使组合物发挥药效的剂量范围。优选剂量是组合物有效成分的药用剂量的优选，优选剂量的药效比药用剂量的药效效果好。通常组合物有效成分的药用剂量包括使组合物产生最大药效的最佳剂量或最佳剂量范围，此最佳剂量或最佳剂量范围将使患者更多获益。
该药物组合物中还含有药剂学可接受的载体，可制成普通口服制剂，包括普通片剂、普通胶囊、颗粒剂等，制成片剂时所述可药用载体包括有助于将活性化合物配制成药用制剂的赋形剂和辅药，如微晶纤维素、无机盐类、乳糖、氯化钠、柠檬酸和亚硫酸钠等的一种或几种物质的组合物，属于本领域常识。
本发明所述药物组合物还可以变通的以"组合药盒"形式使用。这种"组合药盒"是一种盒状容器，内置多种剂量形式的药物组合，及其服用说明书。"组合药盒"更适用于个体化用药。
本发明提供的药物组合物，其有益效果在于两个活性成份具有协同增效的药理作用：特布他林可松弛支气管平滑肌、扩张支气管、缓解气流受限；安立生坦可以降低肺动脉压力。特布他林与安立生坦合用，则可以在解痉、平喘基础上阻止COPD向肺动脉高压演变，其临床获益远大于单用特布他林，因此是更好的组合药物产品。特布他林与安立生坦合用，还可以减少特布他林的用量，从而减少后者的副作用。所以本发明中的组合物与现有的β2受体激动剂特布他林相比是更好的治疗COPD药物，尤其适用于治疗COPD合并肺动脉高压，或者预防COPD向肺动脉高压的转化。
下面结合具体实施方式对本发明做进一步说明，并非对本发明的限定，凡依照本发明内容进行的任何本领域的等同替换，均属于本发明的保护范围。
具体实施方式
实施例1-2：特布他林/安立生坦片的制备(1000片)
制备工艺：
将特布他林、安立生坦混合，加入羧甲淀粉钠、十二烷基硫酸钠混合，再加入微晶纤维素、预胶化淀粉混合均匀，用适量的10％聚维酮乙醇溶液制成软材，制粒、干燥、整粒，将含水量为3％左右的颗粒与适量的硬脂酸镁混合均匀，压片制成1000片即得。
实施例3-4：特布他林/安立生坦胶囊的制备(1000粒)
| 配方组成 | 实施例3 | 实施例4 |
| 特布他林 | 1.25g | 5g |
| 安立生坦 | 2.5g | 10g |
| 乳糖 | 60g | 66g |
| 微晶纤维素 | 85g | 90g |
| 十二烷基硫酸钠 | 8g | 8g |
| 交联羧甲基纤维素钠 | 4.5g | 3.6g |
| 5％羟丙甲纤维素溶液 | 适量 | 适量 |
| 硬脂酸镁 | 2g | 2g |
制备工艺：
将羧甲淀粉钠过100目筛，乳糖、微晶纤维素过80目筛备用；将原料药与交联羧甲基纤维素钠、十二烷基硫酸钠混合，再加入微晶纤维素、乳糖混合，用5％羟丙甲纤维素溶液制粒，50-60℃干燥2h，将制得的可以与硬脂酸镁混合，用1号胶囊灌装。制成1000粒即得。
实施例5-6：特布他林/安立生坦颗粒剂的制备(1000袋量)
制备工艺：
(1)称取处方量的特布他林/安立生坦，过100目筛后按等量递增法混合均匀备用；
(2)其他辅料分别过100目筛后备用；
(3)称取处方量的乳糖、预胶化淀粉、羧甲淀粉钠和阿司帕坦混匀后再与混好的原料药等量递增法混合均匀；
(4)加入适量粘合剂制软材，24目筛制粒，40～45℃干燥；
(5)20目筛整粒，然后用80目筛筛去细粉；
(6)干颗粒加入适量硬脂酸镁混匀，含量测定后装袋。
实施例7：特布他林+安立生坦治疗对COPD大鼠的影响
将健康SPF级SD大鼠52只，体重180±20g，雌雄各半。10只大鼠作为正常组对照组，其余的进行COPD模型的制造。
将准备造模的大鼠放置在一个透明箱子里面(体积300L)，留有小孔通气，每天点燃8支烟，通过外接导管把烟雾导入箱内，维持12周。正常对照组放置于无烟的环境下中饲养，实验结束后，任取2只做病理切片，光镜观察，提示COPD模型造模成功。
造模结束后3d，将造模成功的大鼠分成模型组与特布他林组、安立生坦组和特布他林/安立生坦组。特布他林组、安立生坦组和特布他林/安立生坦组在造模成功后开始治疗，剂量浓度分别为0.125mg/kg、0.25mg/kg、0.125/0.25mg/kg，按照每100g体重1ml体积灌胃给药，给药8周。
实验结束后用3％戊巴比妥钠腹腔注射麻醉大鼠，暴露颈部及胸腹腔，分离结扎右主支气管，经左主支气管行左肺支气管肺泡灌洗。用4ml生理盐水反复3次灌洗，收集支气管肺泡灌洗液(BALF)，计数细胞总数，测定PLA2，IL-8和TNF-α因子。
统计方法：
1.试验数据结果均以表示。组间比较采用t检验，P<0.05有显著性统计学差异，P<0.01有非常显著性统计学差异。
2.为证实本发明提供的药物组合物的科学性，说明药物组合物的两种组分配伍合理，相互结合可以发挥协同增效作用，而不是简单的两药药理作用的叠加，对实验结果采用金正均Q值法分析。金正均Q值法又称概率相加法，根据在量效曲线区内，两种药物联用的药理作用及两种药物单用的药理作用，用如下计算公式计算：Q＝EA+B/(EA+EB-EA*EB)，式中分子代表“实测合并效应”，分母代表“期望合并效应”，(为满足组分及组合物药理作用关系的分析，将它们的药理作用转化为可以直观体现药理作用强弱的效应，计算公式：Ei＝1-Pi/P模型组，Pi为各组分的药理指标，P模型组为模型组的药理指标)，Q为两者之比：Q小于0.85时认为两种药物联用为拮抗作用，小于1.15大于0.85时，认为是相加作用，大于1.15时认为是协同作用。
表1：支气管肺泡灌洗液细胞总数结果
注：t检验，与正常组比，△△P＜0.01；与模型组比较，**P＜0.01，*P＜0.05；组合物与安立生坦组比较，##P＜0.01，与特布他林组比较，□P＜0.05。
表2：支气管肺泡灌洗液细胞总数结果的效应分析
与正常组相比，模型组大鼠白细胞、中性粒细胞、淋巴细胞都有所升高，单核-巨噬细胞下降，而且有明显差异，说明造模成功。0.125mg/kg特布他林组降低COPD大鼠白细胞数量，与模型组相比，差异具有显著性；0.125mg/kg特布他林组对COPD大鼠单核-巨噬细胞、中性粒细胞、淋巴细胞作用无显著性变化；0.25mg/kg安立生坦组对COPD大鼠白细胞、单核-巨噬细胞、中性粒细胞、淋巴细胞作用无显著性变化。特布他林/安立生坦组显著降低COPD大鼠白细胞、中性粒细胞、淋巴细胞，与模型组相比，具有显著统计学差异，P＜0.01或P＜0.05。使用金正均Q值法，对特布他林/安立生坦组大鼠白细胞、中性粒细胞、淋巴细胞进行分析，Q值分别为1.22、1.77、2.83，均大于1.15，说明特布他林和安立生坦组合后产生意料不到的协同作用。
表3：各组大鼠支气管肺泡灌洗液细胞总数结果
注：t检验，与正常组比，△P＜0.05；与模型组比较，*P＜0.05；组合物与安立生坦组比较，#P＜0.05，与特布他林组比较，□□P＜0.01。
表4：各组大鼠支气管肺泡灌洗液细胞总数结果的效应分析
与正常组相比，模型组大鼠PLA2、IL-8都有所升高，而且有具有显著性差异，说明造模成功。0.125mg/kg特布他林组和0.25mg/kg安立生坦组对COPD大鼠PLA2作用无显著性变化。特布他林/安立生坦组能够显著降低COPD大鼠PLA2、IL-8，与模型组相比，差异具有显著性。上述实验结果表明特布他林+安立生坦能够明显改善COPD模型大鼠的肺部炎症特征，并且组合的效果显著优于单药应用(P<0.05或P<0.01)。使用金正均Q值法，对特布他林/安立生坦组大鼠PLA2、IL-8分析，Q值分别为1.22、1.46，均大于1.15，说明特布他林和安立生坦组合后产生意料不到的协同作用。
上述研究结果表明本发明提供的药物组合物在治疗慢性阻塞性肺病方面具有协同增效的作用，本发明为慢性阻塞性肺病的治疗提供了一种疗效显著优于β2受体激动剂的药物组合物。
实施例8：特布他林联合安立生坦治疗COPD的临床观察
纳入符合COPD诊断标准的患者46例，男女各半，年龄在50-75岁。所有患者在给药前清晨空腹抽血，测定血浆hs-CRP，ET-1含量，桡动脉取血进行血气分析，测定PO2和PCO2等指标。肺功能仪检测受试者肺功能，详细记录患者VC和FEV/FVC等指标。然后将患者随机分为研究组和对照组，每组23例，研究组给予特布他林+安立生坦(1.25mg+2.5mg)治疗，对照组仅给予特布他林(1.25mg)，治疗期均为4周，每天服用一次，一次一片。治疗后用同样的方法测定上述指标。
表5：本发明组合物治疗对COPD患者的hs-CRP，ET-1影响
与特布他林组比较，*P<0.05,**P<0.01。
经过两组治疗后，患者hs-CRP都有所下降，但是相对于单用特布他林，特布他林+安立生坦降低hs-CRP效果更为明显，且有显著性差异(P<0.01)，证明本发明组合物能够更有效的减少因hs-CRP而导致的炎症反应。血浆ET-1(内皮素)具有缩血管的作用，COPD患者剂型发作期和缓解期由于感染、缺氧等因素引起毛细血管内皮损伤，可以释放出ET-1而引起肺血管进一步收缩，从而影响呼吸功能。经过两组治疗后，患者ET-1都有所下降，但是相对于单用特布他林，特布他林+安立生坦降低ET-1效果更为明显，且有显著性差异(P<0.01)，证明本发明组合物能够更有效的减少因ET-1而导致的集气管收缩反应，有效舒张气道。
表6：本发明组合物治疗对患者肺功能参数与血气分析对比
与分组前比较，#P<0.05,##P<0.01，与特布他林组比较，*P<0.05,**P<0.01。
肺活量(VC)：最大吸气后做最大呼气，所能呼出的最大气量(VC＝TV+IRV+ERV)。一秒钟用力呼气容积(FEV1)及FEV1％(FEV1/FVC)：深吸气后用力快速呼气过程中，第一秒时间内呼出的气量称为FEV1，临床上常用一秒钟用力呼气容积占用力肺活量的比值(FEV1％)来评价。PaO2:血氧分压指血液中的氧分子所产生的张力(或压力)。PaCO2：动脉血二氧化碳分压
本发明联合用药组与单用特布他林相比，肺活量VC经过特布他林+安立生坦联合治疗后有明显的提高(P<0.01)，FEV/FVC、PO2明显升高(P<0.01)，PCO2明显降低(P<0.01)，这些都表明加用安立生坦有协同改善气道阻塞的效果,对于COPD的治疗能够显著改善肺功能，大大提高治疗效果。
Claims (4)
1.一种治疗慢性阻塞性肺病的药物组合物，组成成分为：
（1）1.25mg特布他林；
（2）2.5mg安立生坦；
（3）药剂学上可接受的载体。
2.根据权利要求1所述的药物组合物，其特征在于所述的药物组合物制成口服制剂，包括片剂、胶囊剂、颗粒剂。
3.权利要求1或2所述的药物组合物在制备治疗慢性阻塞性肺病的药物中的用途。
4.权利要求1或2所述的药物组合物在制备用于治疗慢性阻塞性肺病合并肺动脉高压的药物中的用途。
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| CN101530618A (zh) * | 2009-04-13 | 2009-09-16 | 莫始平 | 一种治疗慢性阻塞性肺病、支气管哮喘的药物组合物 |
| CN108567787A (zh) * | 2017-03-10 | 2018-09-25 | 辛衍雪 | 一种治疗慢性阻塞性肺病的药物组合物 |
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| CN101530618A (zh) * | 2009-04-13 | 2009-09-16 | 莫始平 | 一种治疗慢性阻塞性肺病、支气管哮喘的药物组合物 |
| CN108567787A (zh) * | 2017-03-10 | 2018-09-25 | 辛衍雪 | 一种治疗慢性阻塞性肺病的药物组合物 |
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