CN110302185A - 一种不含抛射剂的异丙托溴铵气雾剂组合物及其制备方法 - Google Patents
一种不含抛射剂的异丙托溴铵气雾剂组合物及其制备方法 Download PDFInfo
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Abstract
本发明涉及治疗呼吸道疾病尤其是哮喘、慢性阻塞性肺炎、气管炎等的药物异丙托溴铵，该药物为不含抛射剂的可吸入的气雾剂，本发明还涉及该药物的制备方法。
Description
技术领域：
本发明涉及治疗呼吸道疾病尤其是哮喘、慢性阻塞性肺炎、气管炎等的药物异丙托溴铵，该药物为不含抛射剂的可吸入的气雾剂，本发明还涉及该药物的制备方法。
背景技术：
哮喘是一种慢性气道炎症，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。目前治疗哮喘等肺部疾病的药物主要有以下几种：(1)β2-受体激动剂，(2)黄嘌呤类药物，(3)抗胆碱药，(4)糖皮质激素，(5)抗过敏药。
哮喘是一种慢性气道炎症，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。目前治疗哮喘等肺部疾病的药物主要有以下几种：(1)β2-受体激动剂，(2)黄嘌呤类药物，(3)抗胆碱药，(4)糖皮质激素，(5)抗过敏药。
其中对于气道毒蕈碱乙酰胆碱能受体(M受体)有较高选择性的强效抗胆碱药近年来一直被关注，支配气道的副交感神经节后神经元的递质是乙酰胆碱，效应器上的受体即为M受体。根据与受体亚型特异性拮抗剂亲和力的高低，从药理学角度分为M1、M2、M3、M4。其中与哌仑西平、4-DAMP亲和力高的称为M1受体；与AF-DXll6亲和力高的称为M2受体；与4-DAMP亲和力高的称为M3受体；与P-F-HHSID亲和力高的称为M4受体。但至少有5种编码mAChR的不同基因，分别命名为m1、m2、m3、m4、m5，人类基因染色体位置分别是1lql2―13、7q35―36、lq43―44、11q12―11.2、15q26。m1、m2、m3、m4分别对应药理学的M1、M2、M3、M4。m5基因表达的蛋白只存在于脑的独立区域，目前尚未找到相应的功能性药理学表现，故暂无M5。气道M受体在调节气道平滑肌张力、粘液糖蛋白及粘液合成分泌、粘液纤毛清除等方面具有重要的作用。M受体各亚型在气道的分布与功能密切相关，支配粘膜下腺体的主要是M3受体，M2受体对分泌有调节作用，目前尚未发现M4受体和M5受体的直接作用。杯状细胞也可能存在胆碱能神经支配。M受体拮抗剂既可以扩张支气管，又能抑制粘液糖蛋白及粘液的高分泌，在COPD以及支气管哮喘等的治疗中有着重要的地位。抗胆碱药物已作为COPD治疗的一线药物。
异丙托溴铵是一种作用时间相对较短的药物，一般只有4到8小时。可以通过定量吸入器(MDI)或者气雾剂的方式给药。另外，它与沙丁胺醇放在同一个装置中制成的联合制剂可以作为COPD的维持用药。在哮喘治疗中其主要局限于控制急性发作时的症状。2000年早期出现了噻托溴铵，其作用时间至少为24小时，因此作为COPD维持用药时推荐每日一次给药。噻托溴铵可以通过干粉剂(DPI)的形式吸入，但最近出现了软雾吸入剂(SMI)这一种新的给药方式。
治疗哮喘等吸入性呼吸道制剂常见的有气雾剂和干粉吸入剂，其中气雾剂是指含药的乳液或混悬液与适宜的抛射剂共同装封于具有特制阀门系统的耐压容器中，使用时借助抛射剂的压力将内容物呈雾状物喷出，用于肺部吸入的制剂；干粉吸入剂是指或一种或以上的药物，经特殊的给药装置给药后以干粉形式进入呼吸道，发挥全身或局部作用的一种药物剂型；气雾剂为液体并且使用抛射剂，而干粉吸入剂则是含有载体的固体，从制剂学角度而言两种剂型之间存在明显的不同，气雾剂制剂的关键在于研究乳液或混悬液的均匀度和稳定性，干粉吸入剂的制剂关键则是研究不同固体颗粒之间的粉粒学技术。
根据哮喘、COPD患者吸入的实际情况，作为一种理想的吸入装置应当实现轻松吸入，保证药物高效沉积与气道(避免口腔沉积)和便于操作和携带。为了达到上述效果，吸入装置应当具有吸入启动流速低，起雾释放缓慢，气雾低速运行、口咽部沉积少、理想的颗粒含量、高肺部沉积率，操作简单，大小合适等特点。较快雾速和释放时间不利于颗粒穿越口咽部与气管间的曲折通路，容易造成肺部沉积率下降，口咽部沉积率提高。
近年来，德国制药巨头勃林格殷格翰公司(BI)的全新软雾吸入剂思力华(噻托溴铵)及装置(能倍乐)在全球上市。
软雾吸入剂是气雾剂的升级版。传统吸入剂与软雾吸入剂相比喷雾持续时间短，仅为0.2秒～0.3秒，很多协调能力差的患者无法充分吸入。同时，传统雾化器操作不便，且不易携带；而压力定量吸入剂需要推进剂，不环保。而软雾吸入剂经由装置实现主动喷雾，不需要患者吸气，气雾持续时间更长，延长到了1.2秒以上，气雾喷射速度慢，理想颗粒含量高达70％，保证了药物在肺部的高效沉积，达到51.6％，并且易于携带，患者的依从性大大提升。
软雾剂与常规气雾剂装置相比，采用机械势能进行驱动(不使用抛射剂)，触发主动喷雾，持续时间长而运行速度较慢的气雾，可以给患者提供较长的吸入时间，而对口眼协调的同步性要求不高。
软雾剂作为一种具有治疗呼吸道疾病优势的新剂型，在吸入装置上具有较高的技术门槛，对于药物仿制具有较高的技术难度，可以较好的避免产能过剩造成的恶性竞争。
赖氨酸是一种常见的药物，尤其是氨基酸可以作为干粉吸入剂(粉雾剂)中的载体使用，气雾剂中未见报道。
能倍乐(噻托溴铵/沙丁胺醇)的说明书中提出药物中除了噻托溴铵外还有苯扎氯铵、依地酸二钠和注射用水。
CN201610353067.2专利中介绍了异丙托溴铵气雾剂处方含有无水枸橼酸、无水乙醇、1,1,1,2-四氟乙烷。
发明内容：
我们惊奇的发现，当异丙托溴铵、赖氨酸制成气雾剂药物组合物后，使用能倍乐装置时，可以降低气雾剂的喷雾速度，从而提高患者的肺部沉积率和患者口咽部药物沉积率降低！
鉴于异丙托溴铵一水合物、异丙托溴铵在技术方案范围内均全溶于水中，异丙托溴铵一水合物、异丙托溴铵对制剂无影响。
一种不含有抛射剂的异丙托溴铵气雾剂药物组合物，其特征在于含有异丙托溴铵或其水合物、抑菌剂、螯合剂和水。
上述的药物组合物，其特征在于抑菌剂为苯扎氯铵、苯扎溴铵中的一种。
上述的药物组合物，其特征在于抑菌剂为苯扎氯铵。
上述的药物组合物，其特征在于抑菌剂含量为8-12mg/100ml。
上述的药物组合物，其特征在于苯扎氯铵或苯扎溴铵含量为8-12mg/100ml。
上述的药物组合物，其特征在于异丙托溴铵或其水合物含量为以异丙托铵计0.1-0.5毫克/毫升。
上述的药物组合物，其特征在于螯合剂为乙二胺四乙酸及其药学上可接受的盐。
上述的药物组合物，其特征在于螯合剂含量为8-12mg/100ml。
上述的药物组合物，其特征在于螯合剂为乙二胺四乙酸二钠。
上述的药物组合物，其特征在于PH为3.0±0.2。
具体实施方式
实施例1
100ml的药物制剂处方：
制备方法：将异丙托溴铵一水合物或异丙托溴铵，抑菌剂、依地酸二钠及水混合后全溶，用盐酸调节PH值。
实施例2
100ml的药物制剂处方：
制备方法同实施例1。
对照实施例1
100ml的药物制剂处方：
制备方法同实施例1。
喷雾粒径试验
将实施例、对照实施例得到药物组合物，采用BI公司的喷雾装置-能倍乐进行喷雾，采用德国SYMPATEC激光粒度仪(HELOS-SPRAYER)检测喷雾液滴粒径。检测方式是，对于药物组合物进行10揿喷雾，测定平均喷雾液滴粒径，放置4天后，再次进行10揿喷雾，测定平均喷雾液滴粒径。
喷雾速度试验
实验仪器：采用相位多普勒技术的丹麦Dantec Dynamics A/S公司的粒子动态分析(PDA)(Particle Dynamic Analyzer,PDA)
试验方法：将实施例、对照实施例得到药物组合物，采用BI公司的喷雾装置-能倍乐进行喷雾，测定喷雾开始后0.8秒时喷雾的轴向速度。
Claims (10)
1.一种不含有抛射剂的异丙托溴铵气雾剂药物组合物，其特征在于含有异丙托溴铵或其水合物、抑菌剂、螯合剂和水。
2.如权利要求1所述的药物组合物，其特征在于抑菌剂为苯扎氯铵、苯扎溴铵中的一种。
3.如权利要求1所述的药物组合物，其特征在于抑菌剂为苯扎氯铵。
4.如权利要求1所述的药物组合物，其特征在于抑菌剂含量为8-12mg/100ml。
5.如权利要求1所述的药物组合物，其特征在于苯扎氯铵或苯扎溴铵含量为8-12mg/100ml。
6.如权利要求1所述的药物组合物，其特征在于异丙托溴铵或其水合物含量为以异丙托铵计0.1-0.5毫克/毫升。
7.如权利要求1所述的药物组合物，其特征在于螯合剂为乙二胺四乙酸及其药学上可接受的盐。
8.如权利要求1所述的药物组合物，其特征在于螯合剂含量为8-12mg/100ml。
9.如权利要求1所述的药物组合物，其特征在于螯合剂为乙二胺四乙酸二钠。
10.如权利要求1所述的药物组合物，其特征在于PH为3.0±0.2。
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| CN106667975A (zh) * | 2017-02-15 | 2017-05-17 | 杭州百诚医药科技股份有限公司 | 一种吸入用异丙托溴铵溶液的制备方法 |
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| CN106667975A (zh) * | 2017-02-15 | 2017-05-17 | 杭州百诚医药科技股份有限公司 | 一种吸入用异丙托溴铵溶液的制备方法 |
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