CN114796168A - 一种羧甲司坦雾化吸入用溶液制剂及其制备方法 - Google Patents
一种羧甲司坦雾化吸入用溶液制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种含有羧甲司坦的雾化吸入用溶液制剂及其制备方法，单剂量的羧甲司坦雾化吸入用溶液制剂包括以下组分：20‑120mg羧甲司坦或其盐和/或其水合物(以游离羧甲司坦计)、0.1‑5mg金属络合剂、适量的pH调节剂及注射用水。本发明制备的含有羧甲司坦的雾化吸入用溶液制剂，具有高效、低毒、稳定性好、安全度高的特点，特别是极大地降低了患者用药的肝肾毒性。
Description
本申请作为发明专利，申请号201711089083.6、发明名称为“一种羧甲司坦雾化吸入用溶液制剂及其制备方法”的分案申请提出。
技术领域
本发明属于药物制剂领域，具体涉及一种羧甲司坦雾化吸入用溶液制剂及其制备方法。
背景技术
由于人口密集、吸烟人群较多及环境污染等因素，近年来呼吸系统疾病的发病率及病死率均居高不下，据美国统计学年鉴的数据，在所有的死因归类中，与呼吸道相关疾病(不包括肿瘤)的死因排位从1970年的第10位上升到1991年的第4位(慢性阻塞性肺病)及第8位(肺炎、流感及其上呼吸道感染)，而我国呼吸系统疾病的发病率在任何年龄组均占多种疾病之首。这一问题日益引起人们的重视，因此治疗呼吸系统疾病的药物(简称呼吸药)的开发也成为药物研究的重要研发领域。
咳嗽、咯痰是临床上呼吸系统疾病常见的症状，过于频繁的剧咳，不仅增加患者的痛苦，影响休息和睡眠，增加体力消耗，甚至促进病症的发展，产生其他并发症，如肺炎、慢性咽炎、慢性支气管炎、支气管扩张、肺脓肿与空洞型肺结核等。此时除针对呼吸系统疾病对症下药治疗外，还需适当应用镇咳祛痰药，以缓解咳嗽。应用镇咳药只是缓解症状，根本的是要针对咳嗽的病因治疗。大多数的咳嗽是由炎症介质如气管炎、哮喘、肺炎和肺肿瘤等病症时过量释放的介质所引起；故还需针对病情使用祛痰药。
目前常用的祛痰药多是以中枢性镇咳药可待因或氢溴酸右美沙芬与祛痰药愈创木酚甘油醚为有效成份的复方化学药物。右美沙芬作用与可待因相似或较强，2005年6 月，美国FDA发布公告指出，右美沙芬不当使用可能造成死亡或者其他负面作用，比如大脑损伤、失去意识和心律不齐等。
羧甲司坦用于慢性支气管炎、支气管哮喘等疾病引起的痰液粘稠、咳痰困难和痰阻塞气管等病的治疗，主要作用于支气管腺体的分泌，使低粘度的唾液粘蛋白分泌增加，高粘度的岩藻粘蛋白产生减少，因而使痰液的粘稠性降低而易于咳出。专利 CN104511025A公开了一种羧甲司坦口服溶液及其制备方法，用于治疗慢性支气管炎、支气管哮喘等疾病引起的痰液粘稠或咳痰困难。该口服溶液包含2％-10％的羧甲司坦、氢氧化钠、抗氧化剂、溶液稳定剂组合和矫味剂，其pH值为6.0-7.5。该羧甲司坦用氢氧化钠溶液成盐后溶于水中，然后加入抗氧化剂、溶液稳定剂组合和矫味剂，经搅拌、定容、过滤、罐装和灭菌后制得，但口服液服用量大，肝肾代谢较多，容易造成器官损伤，到达靶器官的药量较少，且起效较慢。
发明内容
为解决上述问题，本发明提供了一种羧甲司坦雾化吸入用溶液制剂，用于慢性支气管炎、支气管哮喘等疾病引起的痰液粘稠、咳痰困难和痰阻塞气管等病的治疗。该制剂由口鼻直接吸入，避免了肝脏的首过效应及胃肠道的破坏与降解，并且大大减少了由肝肾对药物的代谢过程，极大降低了对患者的器官损伤。本发明吸入用溶液制剂弥补了目前国内市场上的空白，提供了一种羧甲司坦新型安全有效的给药制剂及给药方式。
本发明的第一目的在于提供一种羧甲司坦雾化吸入用溶液制剂，采用以下技术方案：
一种羧甲司坦的雾化吸入用溶液制剂，主要包括以下成分：羧甲司坦、其盐和/或其水合物、金属络合剂、pH调节剂及注射用水。
所述制剂还包括一种或多种适用于肺部给药的药用辅料，所述药用辅料可以包括抗氧化剂、表面活性剂等。
所述制剂单剂量为：20-120mg羧甲司坦或其盐和/或其水合物(以游离羧甲司坦计)、 0.1-5mg金属络合剂、适量的pH调节剂及注射用水。
所述制剂单剂量优选为：50-100mg羧甲司坦或其盐和/或其水合物(以游离羧甲司坦计)、0.5-2mg金属络合剂、适量的pH调节剂及注射用水。
本发明提供的单剂量羧甲司坦吸入溶液采用单剂量药物包装，所述的单剂量是指单次吸入所使用的药用活性成分的剂量。
所述pH调节剂为碳酸氢钠、氢氧化钠、磷酸氢二钠、枸橼酸钠、磷酸氢二钾等碱性溶液。所述pH值调节为5-8，优选pH为7-8。优选溶液偏碱性，可以增加羧甲司坦的溶解度。
所述金属络合剂为依地酸、依地酸二钠、依地酸钙钠等依地酸盐类中的一种或其以任何比例混合的混合物。这几种络合剂对金属离子都有较强的络合能力，且络合的离子种类众多，其中优选依地酸盐(例如钙盐、钠盐)，尤其优选依地酸二钠(EDTA-2Na)，以避免由配液过程引入的金属离子对药液质量产生影响。
本发明提供的羧甲司坦雾化吸入用溶液制剂与现有技术中的其它制剂相比，不仅疗效和雾化效果大幅提高，并且解决了羧甲司坦现有制剂中稳定性差的问题，并且通过加入碱性试剂调节pH使其成盐，解决了其溶解性差的问题。
本发明的另一目的在于提供一种所述羧甲司坦雾化吸入用溶液制剂的制备方法，该方法包括以下步骤：
1)向配液器中加入50-80％用水总量的注射用水，水温控制在25±10℃，并向注射用水内充氮气保护，持续至配液结束，并保持配液罐中氮气正压，测定残氧＜2mg/L后进行下一步操作；
2)准确称取处方量的金属络合剂，缓缓加入至注射用水中，搅拌至金属络合剂全部溶解；
3)后缓慢加入处方量的羧甲司坦，搅拌至其全部溶解；
4)加入pH调节剂调节pH至5-8，同时测定残氧至＜2mg/L进行下一步操作；
5)补加注射用水至全量，搅拌使其混合均匀；
6)用0.45微米滤膜进行初滤，0.22微米滤膜进行精滤，均为无菌过滤，并充氮气，灌封于安瓿中，装量为5ml。
本发明提供的雾化吸入用溶液制剂为单剂量，使用过程便捷，无需稀释、配制；可大大降低使用过程中的微生物污染和浪费，采用单次用药的剂量而避免了多剂量大包装溶液所导致的反复量取、反复稀释配制易滋生微生物的弊端。本发明提供了一种现有技术所缺乏的药用剂量准确，药品质量优质、稳定，临床应用安全、简捷的新制剂及其制备方法。
与现有技术相比，本发明的有益效果是：
(1)与其他剂型相比，药物直接到达靶器官，避免了肝脏的首过效应及胃肠道的破坏与降解，降低了全身器官尤其是肝肾损伤，用药更安全。
(2)本发明由于是吸入式的，针对呼吸系统疾病相比较口服剂型见效快，避免了药物需先经胃肠道吸收，然后再随血液循环发挥全身作用，起效慢的缺陷。
(3)提高了羧甲司坦的稳定性，长期放置各项检测指标没有明显变化，保证有效期内产品质量合格；
(4)加入的辅料种类少，用药安全性高；生产工艺简单，成本低，可以工业化规模生产。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。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。
实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例1：单剂量羧甲司坦雾化吸入用溶液制剂
处方：
羧甲司坦 20mg
依地酸二钠 0.1mg
氢氧化钠 适量，pH调至5
实施例2：单剂量羧甲司坦雾化吸入用溶液制剂
处方：
羧甲司坦 40mg
依地酸二钠 0.5mg
氢氧化钠 适量，pH调至6
实施例3：单剂量羧甲司坦雾化吸入用溶液制剂
处方：
羧甲司坦 50mg
依地酸二钠 2mg
氢氧化钠 适量，pH调至6
实施例4：单剂量羧甲司坦雾化吸入用溶液制剂
处方：
羧甲司坦 80mg
依地酸二钠 5mg
氢氧化钠 适量，pH调至7
实施例5：单剂量羧甲司坦雾化吸入用溶液制剂
处方：
羧甲司坦 100mg
依地酸二钠 1.25mg
氢氧化钠 适量，pH调至8
实施例6：单剂量羧甲司坦雾化吸入用溶液制剂
处方：
羧甲司坦 120mg
依地酸二钠 4mg
氢氧化钠 适量，pH调至7
实施例7：单剂量羧甲司坦雾化吸入用溶液制剂
处方：
羧甲司坦 120mg
依地酸 3mg
碳酸氢钠 适量，pH调至7.5
实施例8：制备羧甲司坦雾化吸入用溶液制剂1000ml(实施例5的处方比例)
1)向配液器中加入用水总量70％注射用水700ml，水温控制在30℃，并向注射用水内充氮气保护，持续至配液结束，并保持配液罐中氮气正压，测定残氧量为1.6mg/L后进行下一步操作；
2)准确称取金属络合剂依地酸二钠2g，缓缓加入至注射用水中，搅拌至金属络合剂全部溶解；
3)后缓慢加入羧甲司坦20g，搅拌至其全部溶解；
4)加入pH调节剂调节pH至8，同时测定残氧量为1.5mg/L进行下一步操作；
5)补加注射用水至全量1000ml，搅拌5分钟使其混合均匀；
6)用0.45微米滤膜进行初滤，0.22微米滤膜进行精滤，均为无菌过滤，并充氮气，灌封于安瓿中，装量为5ml。
为了进一步说明本发明的技术效果，提供了以下具体实验例。
实验例1
金属络合剂(稳定剂)对吸入用羧甲司坦溶液的影响
按实施例8的制备方法，分别加入等量的三种不同的金属络合剂依地酸、依地酸二钠、依地酸钠钙配制吸入用羧甲司坦溶液，相应得到三种羧甲司坦吸入溶液。考察一年后该三种溶液中羧甲司坦含量及溶液澄清度的变化。结果如表1。
表1.保存一年后吸入用羧甲司坦溶液含量变化和澄清度的影响
实验例2
不同含量的依地酸二钠对吸入用羧甲司坦溶液的影响
按实施例8的制备方法，分别加入不同量的依地酸二钠配制了吸入用羧甲司坦溶液，得依地酸二钠含量分别为0mg、0.5mg、1mg、2mg、4mg吸入溶液各5ml。考察一年后该三种溶液中羧甲司坦含量及溶液澄清度的变化。结果如表2。
表2.保存一年后吸入用羧甲司坦溶液含量变化和澄清度的影响
实验例3
本发明的雾化吸入制剂(由实施例8制备)与羧甲司坦口服(市售)在小鼠给药时的肝细胞各监测数据的比较
选小鼠60只(20±2g)，雌雄各半，随机分为正常对照组、口服给药组和雾化给药组，共3组，每组20只。羧甲司坦雾化吸入溶液由实施例8的方法制备，口服给药组灌胃由实施例8制备的等量的羧甲司坦，正常对照组腹腔注射等量的生理盐水，持续给药2周14d，每天上午10.00、下午4.00各1次，每次0.1mL。给药两周后，对各给药组小鼠模型肝细胞上清液中的AST、ALP、LDH的数值进行检测，统计分析研究羧甲司坦对致肝损伤的影响。实验发现口服给药组小鼠ALP、ALT、AST数值显著升高(P<0.01)，雾化吸入各组ALP、ALT、AST活性与之相比明显较低(P<0.01)，结果如表3。
表3.各给药组小鼠模型肝细胞上清液中的ALP、ALT、AST数值检测结果。
Claims (7)
1.一种羧甲司坦雾化吸入用溶液制剂，其特征在于所述制剂包括：20-120mg羧甲司坦、其盐和/或其水合物，以游离羧甲司坦计、0.1-5mg金属络合剂、适量的pH调节剂及注射用水；所述的制剂的制备方法包括如下步骤：
1)向配液器中加入50-80％用水总量的注射用水，水温控制在25±10℃，并向注射用水内充氮气保护，持续至配液结束，并保持配液罐中氮气正压，测定残氧＜2mg/L后进行下一步操作；
2)准确称取处方量的金属络合剂，缓缓加入至注射用水中，搅拌至金属络合剂全部溶解；
3)后缓慢加入处方量的羧甲司坦，搅拌至其全部溶解；
4)加入pH调节剂调节pH，同时测定残氧至＜2mg/L进行下一步操作；
5)补加注射用水至全量，搅拌使其混合均匀；
6)用0.45微米滤膜进行初滤，0.22微米滤膜进行精滤，均为无菌过滤，灌封于安瓿中，并充氮气，装量为5ml。
2.根据权利要求1所述的制剂，其特征在于所述制剂还包括一种或多种适用于肺部给药的药用辅料，所述药用辅料包括抗氧化剂、表面活性剂。
3.根据权利要求1-2任意一项所述的制剂，其特征在于所述制剂单剂量为：50-100mg羧甲司坦、其盐和/或其水合物，以游离羧甲司坦计、0.5-2mg金属络合剂、适量的pH调节剂及注射用水。
4.根据权利要求1-2任一项所述的制剂，其特征在于所述pH调节剂为碳酸氢钠、氢氧化钠、磷酸氢二钠、枸橼酸钠、磷酸氢二钾。
5.根据权利要求1-2任一项所述的制剂，其特征在于所述pH值调节为5-8。
6.根据权利要求5所述的制剂，其特征在于所述pH值调节为6-7。
7.根据权利要求1-2任一项所述的制剂，其特征在于所述金属离子络合剂为依地酸、依地酸二钠、依地酸钙钠中的一种或其以任何比例混合的混合物。
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| JPH0558888A (ja) * | 1991-09-06 | 1993-03-09 | Kyorin Pharmaceut Co Ltd | 吸入剤 |
| WO2013104892A1 (en) * | 2012-01-13 | 2013-07-18 | Hovione Inter Limited | Application of high dose compounds via inhalation |
| US20160166505A1 (en) * | 2014-12-10 | 2016-06-16 | Cmpd Licensing, Llc | Methods And Compositions For Treatment Of Respiratory Tract Infections |
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| FR226M (fr) * | 1960-08-19 | 1961-02-27 | Rech S Et Propagande Scient | Médicament soufré, utilisable en particulier en oto-rhino-laryngologie et en pneumologie. |
| JPH0813737B2 (ja) * | 1986-12-19 | 1996-02-14 | 杏林製薬株式会社 | シロツプ剤 |
| JPH0558887A (ja) * | 1991-09-06 | 1993-03-09 | Kyorin Pharmaceut Co Ltd | 吸入剤 |
| US20070202051A1 (en) * | 2006-02-10 | 2007-08-30 | Pari Gmbh | Aerosols for sinunasal drug delivery |
| CN104511025B (zh) * | 2013-09-27 | 2017-09-12 | 北京诚济制药股份有限公司 | 羧甲司坦口服溶液及其制备方法 |
| CN106680386A (zh) * | 2016-12-07 | 2017-05-17 | 万全万特制药（厦门）有限公司 | 液相色谱法分离测定羧甲司坦原料药和制剂的有关物质 |
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| JPH0558888A (ja) * | 1991-09-06 | 1993-03-09 | Kyorin Pharmaceut Co Ltd | 吸入剤 |
| WO2013104892A1 (en) * | 2012-01-13 | 2013-07-18 | Hovione Inter Limited | Application of high dose compounds via inhalation |
| US20160166505A1 (en) * | 2014-12-10 | 2016-06-16 | Cmpd Licensing, Llc | Methods And Compositions For Treatment Of Respiratory Tract Infections |
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