CN110876724A - 依地酸盐恰当改变噻托溴铵奥达特罗喷雾剂表面张力的应用 - Google Patents
依地酸盐恰当改变噻托溴铵奥达特罗喷雾剂表面张力的应用 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、气管炎等的药物噻托溴铵奥达特罗喷雾剂,其中依地酸盐作为改变不含有抛射剂的由噻托溴铵或其水合物、奥达特罗药用盐、水组成的物药物组合物的表面张力的应用。
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、气管炎等的药物噻托溴铵奥达特罗喷雾剂,其中依地酸盐作为改变不含有抛射剂的由噻托溴铵或其水合物、奥达特罗药用盐、水组成的物药物组合物的表面张力的应用。
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1lq l2―13、7q35―36、lq 43―44、11q 12―11.2、15q 26。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。而喷雾剂指不含抛射剂,借助于手动泵的压力将液喷射成雾状的制剂。不难看出喷雾剂、气雾剂二者最大的区别在与前者靠借助外力喷射,后者借助内压及抛射剂喷出。另外后者相对前者的缺点有:1成本较高(因内压容器、阀门系统和特殊的生产设备)。2抛射剂有致冷效应,多次使用于受伤皮肤创面可引起不适于刺激。3抛射剂有一定的毒性,不适宜心脏病患者作为吸入气雾剂使用。4易发生爆炸。
噻托溴铵(Tiotropiumbromide)是一个既定的每日一次的LAMA,提高COPD患者一系列的功能和改善患者的结局,降低中度和重度的急性加重发作,减少急性发作次数和降低死亡率。奥达特罗(Olodatero)是一种新型的每日一次的LABA,这是德国勃林格殷格翰公司专门为与噻托溴铵组合而设计的,作用可持续24小时,能够改善患者肺功能、改善患者症状和提高运动能力。噻托溴铵和奥达特罗具有互补性的药代动力学和药效学特征,每日一次的固定剂量组合能够治疗COPD患者维持支气管扩张。
中国专利CN200580012621.0、CN200680037725.1公开了噻托溴铵奥达特罗喷雾剂的技术方案。
依地酸盐能与多种二价、三价金属螯合,既可以作为药物。具有螯合重金属的作用,也可以作为辅料,避免活性成分在金属离子的作用下进行转化。
发明内容:
我们惊奇的发现,依地酸盐作为改变不含有抛射剂的由噻托溴铵或其水合物、水组成的物药物组合物的表面张力的应用。
依地酸盐作为改变不含有抛射剂的由噻托溴铵的其水合物、奥达特罗的药用盐、水组成的物药物组合物的表面张力的应用。
上述的应用,其特征在于在依地酸盐调节由噻托溴铵或其水合物、奥达特罗的药用盐、水组成组合物的表面张力为52±2mN/m。
上述的应用,其特征在于依地酸盐为依地酸二钠、依地酸钙钠中的一种或几种。
上述的应用,其特征在于噻托溴铵或其水合物含量为以噻托铵计0.2-0.5毫克/毫升。
上述的应用,其特征在于奥达特罗的其药用盐含量为以奥达特罗计0.2-0.55毫克/毫升。
上述的应用,其特征在于还可以加入酸性PH值调节剂。上述的应用,其特征在于酸性PH值调节剂将组合物调节PH值为3.0±0.2。上述的应用,其特征在于酸性PH值调节剂为盐酸、甲磺酸、苯甲酸、醋酸中的一种或几种。
上述的应用,其特征在于在奥达特罗的药用盐为盐酸盐、磷酸盐、醋酸盐中的一种。
上述的应用,其特征在于在奥达特罗的药用盐为盐酸盐。
一种不含有抛射剂的噻托溴铵气雾剂药物组合物,其特征在于组合物由噻托溴铵或其水合物、奥达特罗或其药用盐、依地酸盐、无机酸性PH值调节剂和水组成,在PH为3.0±0.2的条件下,用依地酸盐调节表面张力为52±2mN/m。
一种不含有抛射剂的噻托溴铵气雾剂药物组合物,其特征在于组合物含有噻托溴铵或其水合物、奥达特罗或其药用盐、依地酸盐、无机酸性PH值调节剂和水,在PH为3.0±0.2的条件下,用依地酸盐调节表面张力为52±2mN/m。
鉴于噻托溴铵一水合物、噻托溴铵在技术方案范围内均全溶于水中,噻托溴铵一水合物、噻托溴铵对制剂无影响。
本发明中的表面张力使用悬滴法测定。
具体实施方式
本发明实施例中的表面张力使用德国Kruss(克吕士)DSA25S在20℃用悬滴法测定得出。
实施例1
制备方法:将噻托溴铵或噻托溴铵一水合物与用盐酸调节PH值的水混合均匀,用依地酸二钠调节溶液的表面张力。
100ml的药物制剂:
实施例2
制备方法:将噻托溴铵或噻托溴铵一水合物与用盐酸调节PH值的水混合均匀,用依地酸钙钠调节水溶液的表面张力。
100ml的药物制剂:
制备方法同实施例1。
对照实施例1
制备方法:将噻托溴铵或噻托溴铵一水合物与用盐酸调节PH值的水混合均匀,用吐温或司盘调节水溶液的表面张力。
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,弃去药物组合物前2揿喷雾,测定药物组合物后揿喷雾平均喷雾液滴粒径,放置4天后,再次进行10揿喷雾,测定平均喷雾液滴粒径。
喷雾时间试验
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,测定喷雾开始后至结束时的时间,测定10次,取平均值。
序号 | 平均喷雾时间(秒) |
实施例 | |
1-1 | 1.41 |
1-2 | 1.51 |
1-3 | 1.44 |
1-4 | 1.43 |
1-5 | 1.50 |
1-6 | 1.45 |
2-7 | 1.45 |
2-8 | 1.51 |
2-9 | 1.48 |
2-10 | 1.49 |
2-11 | 1.52 |
2-12 | 1.48 |
对照实施例 | |
1-1 | 1.17 |
1-2 | 1.27 |
1-3 | 1.29 |
1-4 | 1.34 |
1-5 | 1.22 |
1-6 | 1.17 |
1-7 | 1.07 |
1-8 | 1.16 |
1-9 | 1.28 |
1-10 | 1.38 |
1-11 | 1.23 |
1-12 | 1.16 |
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。
序号 | 轴向速度(米/秒) |
实施例 | |
1-1 | 0.85 |
1-2 | 0.82 |
1-3 | 0.83 |
1-4 | 0.84 |
1-5 | 0.81 |
1-6 | 0.86 |
2-7 | 0.4 |
2-8 | 0.80 |
2-9 | 0.86 |
2-10 | 0.85 |
2-11 | 0.80 |
2-12 | 0.87 |
对照实施例 | |
1-1 | 1.06 |
1-2 | 1.02 |
1-3 | 0.97 |
1-4 | 0.91 |
1-5 | 0.99 |
1-6 | 1.03 |
1-7 | 1.14 |
1-8 | 1.04 |
1-9 | 1.00 |
1-10 | 0.98 |
1-11 | 0.94 |
1-12 | 1.02 |
通过上述实施例证明依地酸盐可以恰当的改变不含有抛射剂的由噻托溴铵或其水合物、水组成的物气雾剂药物组合物的表面张力的应用,同时这种药物组合物的表面张力通过喷雾粒径试验、喷雾时间试验、喷雾速度试验证明了其具有更好的效果。
Claims (10)
1.依地酸盐作为改变不含有抛射剂的由噻托溴铵的其水合物、奥达特罗的药用盐、水组成的物药物组合物的表面张力的应用。
2.如权利要求1所述的应用,其特征在于在依地酸盐调节由噻托溴铵或其水合物、奥达特罗的药用盐、水组成组合物的表面张力为52±2mN/m。
3.如权利要求1所述的应用,其特征在于依地酸盐为依地酸二钠、依地酸钙钠中的一种或几种。
4.如权利要求1所述的应用,其特征在于噻托溴铵或其水合物含量为以噻托铵计0.2-0.5毫克/毫升。
5.如权利要求1所述的应用,其特征在于奥达特罗的其药用盐含量为以奥达特罗计0.2-0.55毫克/毫升。
6.如权利要求1所述的应用,其特征在于还可以加入酸性PH值调节剂。
7.如权利要求6所述的应用,其特征在于酸性PH值调节剂将组合物调节PH值为3.0±0.2。
8.如权利要求1所述的应用,其特征在于在奥达特罗的药用盐为盐酸盐。
9.一种不含有抛射剂的噻托溴铵气雾剂药物组合物,其特征在于组合物由噻托溴铵或其水合物、奥达特罗或其药用盐、依地酸盐、无机酸性PH值调节剂和水组成,在PH为3.0±0.2的条件下,用依地酸盐调节表面张力为52±2mN/m。
10.一种不含有抛射剂的噻托溴铵气雾剂药物组合物,其特征在于组合物含有噻托溴铵或其水合物、奥达特罗或其药用盐、依地酸盐、无机酸性PH值调节剂和水,在PH为3.0±0.2的条件下,用依地酸盐调节表面张力为52±2mN/m。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114259481A (zh) * | 2021-11-26 | 2022-04-01 | 南京华盖制药有限公司 | 一种奥达特罗复方吸入溶液 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014016548A2 (en) * | 2012-07-27 | 2014-01-30 | Cipla Limited | Pharmaceutical composition |
US20140235627A1 (en) * | 2012-12-21 | 2014-08-21 | Boehringer Ingelheim International Gmbh | ß2-ADRENOCEPTOR AGONIST FOR IMPROVEMENT OF EXERCISE TOLERANCE |
CN104306361A (zh) * | 2014-09-24 | 2015-01-28 | 万特制药(海南)有限公司 | 一种含噻托溴铵的吸入性溶液 |
CN104606205A (zh) * | 2015-01-13 | 2015-05-13 | 段希福 | 一种奥达特罗和布地奈德的药物组合物及其用途 |
CN105435227A (zh) * | 2014-08-08 | 2016-03-30 | 深圳君圣泰生物技术有限公司 | 一种液体制剂组合物及其制备方法、用途和固体制剂 |
CN106214631A (zh) * | 2016-08-22 | 2016-12-14 | 李刚 | 一种治疗偏头痛的口服糖浆及其制备方法 |
-
2018
- 2018-09-06 CN CN201811039943.XA patent/CN110876724A/zh active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014016548A2 (en) * | 2012-07-27 | 2014-01-30 | Cipla Limited | Pharmaceutical composition |
US20140235627A1 (en) * | 2012-12-21 | 2014-08-21 | Boehringer Ingelheim International Gmbh | ß2-ADRENOCEPTOR AGONIST FOR IMPROVEMENT OF EXERCISE TOLERANCE |
CN105435227A (zh) * | 2014-08-08 | 2016-03-30 | 深圳君圣泰生物技术有限公司 | 一种液体制剂组合物及其制备方法、用途和固体制剂 |
CN104306361A (zh) * | 2014-09-24 | 2015-01-28 | 万特制药(海南)有限公司 | 一种含噻托溴铵的吸入性溶液 |
CN104606205A (zh) * | 2015-01-13 | 2015-05-13 | 段希福 | 一种奥达特罗和布地奈德的药物组合物及其用途 |
CN106214631A (zh) * | 2016-08-22 | 2016-12-14 | 李刚 | 一种治疗偏头痛的口服糖浆及其制备方法 |
Non-Patent Citations (4)
Title |
---|
何雄奎: "《高效施药技术与机具》", 29 February 2012 * |
崔一民等: "《特殊释药系统的临床药代动力学试验设计》", 31 July 2018 * |
辛喆: "《汽车拖拉机发动机原理》", 31 January 2015 * |
邹力行: "《陶瓷生产技术问答》", 31 August 1993 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114259481A (zh) * | 2021-11-26 | 2022-04-01 | 南京华盖制药有限公司 | 一种奥达特罗复方吸入溶液 |
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