CN107753626A - 一种降低盐酸异丙肾上腺素副作用的药物 - Google Patents
一种降低盐酸异丙肾上腺素副作用的药物 Download PDFInfo
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Abstract
本发明公开了一种降低盐酸异丙肾上腺素副作用的药物，属于药物技术领域。该药物由盐酸异丙肾上腺素、生物制剂、维生素C、七氟丙烷、油酸、乙醇、对羟基苯甲酸甲酯、苹果香精按照一定重量份制成。经临床试验证明，该药物有效的克服了单纯使用盐酸异丙肾上腺素临床治疗支气管哮喘存在的副作用问题。
Description
技术领域
本发明属于药物技术领域，尤其涉及一种临床治疗支气管哮喘中降低盐酸异丙肾上腺素副作用的药物。
背景技术
支气管哮喘是由多种细胞及细胞组分参与的慢性气道炎症，此种炎症常伴随引起气道反应性增高，导致反复发作的喘息、气促、胸闷和咳嗽等症状，多在夜间和凌晨发生。目前气雾吸入法是治疗支气管哮喘的重要方法之一，常采用盐酸异丙肾上腺素气雾剂吸入治疗，虽然效果较好，但往往也带来副作用，如口咽发干、心悸不安；少见的不良反应有头晕、目眩、面潮红、恶心、心率增速、震颤、多汗、乏力等副作用，同样给患者带来痛苦。为解决盐酸异丙肾上腺素气雾剂临床治疗支气管哮喘副作用的问题，发明人在多年的临床治疗实践中，对盐酸异丙肾上腺素气雾剂进行改进，利用中西医结合的原理，即加入可以防止产生副作用的生物制剂，经临床验证，取得了较好的效果。
发明内容
本发明的目的是提供一种降低盐酸异丙肾上腺素副作用的药物。
本发明的目的是通过以下技术方案实现的，该降低盐酸异丙肾上腺素副作用的药物由盐酸异丙肾上腺素14-18份、生物制剂9-15份、维生素C 1-3份、七氟丙烷8-12份、油酸2-6份、乙醇400-480份、对羟基苯甲酸甲酯1-1.5份、苹果香精2-4份制成。
所述生物制剂是由白背杨40份、牛西西130份粉碎混匀，加入10倍生物质重量的蒸馏水浸泡25min后加热煮沸，开始用强火，沸腾后改用文火，保持微沸30min，搅拌，趁热过滤，药渣再加蒸馏水同法煎煮20min滤过，合并滤液，六层纱布过滤，合并2次滤液浓缩干燥，高压灭菌制成。
制备方法：将生物制剂和盐酸异丙肾上腺素粉碎过200目筛，加入纯化水中搅拌溶解均匀，接着加入乙醇、维生素C和对羟基苯甲酸甲酯、油酸高剪切均质机下均质搅拌约30min，加入苹果香精，继续搅拌约20min，灌装扎阀，充抛射剂七氟丙烷，检漏称重，安装助动器即得。
本发明所述的气雾剂与市售盐酸异丙肾上腺素性状比较试验：
①每欺主药含量和含量均匀度测定：本实验采用收集第3，10，90，101，150，200喷的方法。结果表明，2种气雾剂的平均每撤主药含量均在标示量的85％-120％之间。本实验采用平均每欺主药含量的测定方法，测定2种气雾剂510瓶的平均每欺主药含量，观察其均匀度，结果表明，2种气雾剂5的含量均匀度均符合药典的要求，各批间平均每欺主药含量无显著性差异(p＞0.05)。
②空气动力学雾粒大小分布的测定：本实验采用8级Andesron多级圆盘撞击取样器测定了2种气雾剂5的空气动力学颗粒大小分布，并采用通用的USP法计算了MMAD及其GSD，实验结果表明，本发明所述的气雾剂的MMAD为约3.50-3.71μm，市售盐酸异丙肾上腺素的MMAD为3.47-3.61μm左右，均在有效粒径范围之内，而GSD数值也符合要求。
③温度下降效应测定及年泄漏率等的测定：本实验采用直接测定的方式进行了2种抛射剂气雾剂的温度下降效应测定，实验发现本发明所述的气雾剂其温度下降值与市售盐酸异丙肾上腺素气雾剂基本一致。本实验采用中国药典2005年二部的方法测定了6批气雾剂的年泄漏率；同时分别测定了其每瓶总欺次和微生物限度，结果微生物限度均符合规定。
毒性试验
1、实验动物 清洁级健康SD雌性大鼠32只，体质量(190±6)g，用作慢性毒理实验；清洁级健康昆明雌性小白鼠20只，体质量(24±3)g，用作急性毒理实验。喂以普通饲料，普通饮水。室温控制在(23±4)℃，湿度(54±6)％，自然光照。
2、急性毒理实验根据(中药、天然药物研究注册工作手册)，选用清洁级健康昆明雌性小白鼠20只，随机分为2组，治疗组和空白对照组各10只。治疗组按正常成人吸入量折算成小白鼠的剂量，每日灌服本发明的气雾剂1次。空白对照组予1mL/20g体质量0.9％氯化钠注射液灌服。
3、慢性毒性实验 清洁级健康SD雌性大鼠32只，随机分为4组，正常对照组及治疗组的小、中、大剂量组，每组各8只。对照组予1ml/20g体质量0.9％氯化钠注射液，治疗组的小、中、大剂量组是成人正常用量折算成大鼠剂量的15、30、50倍，均为灌胃给药，每日1次，实验周期为3个月。
4、急性毒性实验结果 小白鼠在给药10d内无死亡，给药后观察小鼠外观、毛色、光泽正常，社会行为、反应均正常，摄食、排泄正常。10d后人工处死解剖，观察其心脏、肝脏、脾脏、肺脏、肾脏、脑、卵巢、子宫均未见异常。病理学检查：苏木精一伊红(HE)染色，治疗组脏器表面光滑，组织结构排列有序，细胞大小、形态正常，胞浆、胞核染色清晰，与空白对照组比较差异无统计学意义(P＞0.05)。
5、慢性毒理实验结果 治疗组的小、中、大剂量组和正常对照组大鼠的外观、毛色，社会行为、刺激性等和对周围环境、食物、水的兴趣等比较差异均无统计学意义(P＞0.05)。4组大鼠实验后体质量均较本组实验前增加(P＜0.05)，但4组实验后体质量比较差异均无统计学意义(P＞0.05)，4组大鼠实验后血液细胞学指标、血液生化学指标、重要脏器系数比较差异均无统计学意义(P＞0.05)。4组大鼠处死后重要脏器行病理切片染色检查，HE染色。治疗组大鼠脏器组织结构排列有序，细胞大小、形态正常，胞浆、胞核染色清晰，与正常对照组比较差异无统计学意义(P＞0.05)。
毒性试验表明，本发明所述的药物给药大、小白鼠后未见毒性反应。
临床资料
1、一般资料 选择2011年3月至2014年12月在本院住院的180例支气管炎哮喘患者，其中男100例，女80例；哮喘诊断和严重度分级均参照2003年中华医学会呼吸病分会制定的支气管哮喘防治指南。将180例患者随机分为治疗组、对照组，每组均为90例患者。使用盐酸异丙肾上腺素气雾剂为对照组、使用本发明所述的气雾剂为治疗组。各组在年龄、性别等一般资料比较无统计学意义，具有可比性。
2、排除标准 排除急性支气管炎、肺气肿、肺结核及慢性喘息性支气管炎、哮喘持续状态及合并心力衰竭、呼吸衰竭患者。
3、治疗方法 治疗组采用本发明所述的气雾剂吸入治疗，对照组采用盐酸异丙肾上腺素气雾剂吸入治疗；两组均每次2喷，每目3-6次；两组均用药4周后观察疗效。
4、疗效判定标准 显效：咳嗽、喘息等症状消失，肺部喘鸣音、中细湿音消失；有效：咳嗽、喘息等症状明显改善，肺部喘鸣音、中细湿音明显减少；无效：咳嗽、喘息等症状无改善，肺部喘鸣音、中细湿音无减少。
5、治疗结果如下表所示
| 组别 | 例数 | 日吸量(ml) | 显效 | 有效 | 无效 | 副作用 | 总有效率 |
| 治疗组 | 90 | 10 | 50 | 34 | 6 | 0 | 93.3％ |
| 对照组 | 90 | 12 | 45 | 35 | 10 | 15 | 88.9％ |
通过以上临床资料可知，治疗组虽然吸入的药量较少，但是取得了理想的治疗效果，总有效率高于对照组，而且毒性降低，没有出现毒副作用。而对照组使用盐酸异丙肾上腺素气雾剂吸入治疗，有5例伴发头晕，有6例出现恶心、4例出现心率增速症状。由此可知，治疗组中各成份配伍后发生了协同增效作用，有效的克服了盐酸异丙肾上腺素气雾剂临床治疗支气管哮喘副作用的问题。
在对以上治疗组患者进行随访时，其中有3例自述“服用本发明的制剂后，不但支气管哮喘得到了有效治疗，而且咽炎症状也好了”。为进一步验证这一发现，我们随即对20例患有不同程度咽炎患者，采用本发明的气雾剂治疗。疗效标准痊愈：咽痛、干燥及异物感症状完全消失，咽部粘膜恢复正常；显效：咽痛、干燥及异物感症状基本消失，咽部粘膜急性充血消退；无效：上述症状无改变，咽部仍充血。结果20例患者中，痊愈11例(55％)，显效8例(40％)，无效1例(5％)，总有效率按痊愈和显效计为95％。由此可知，本发明的气雾剂，不但治疗支气管哮喘疗效显著，而且对咽炎具有很好的治疗效果，值得临床推广应用。
具体实施方式
实施方式一：该降低盐酸异丙肾上腺素副作用的药物由盐酸异丙肾上腺素14g、生物制剂9g、维生素C 1g、七氟丙烷8g、油酸2g、乙醇400g、对羟基苯甲酸甲酯1g、苹果香精2g制成。将生物制剂和盐酸异丙肾上腺素粉碎过200目筛，加入纯化水中搅拌溶解均匀，接着加入乙醇、维生素C和对羟基苯甲酸甲酯、油酸高剪切均质机下均质搅拌约30min，加入苹果香精，继续搅拌约20min，灌装扎阀，充抛射剂七氟丙烷，检漏称重，安装助动器即得。所述生物制剂是由白背杨40g、牛西西130g粉碎混匀，加入10倍生物质重量的蒸馏水浸泡25min后加热煮沸，开始用强火，沸腾后改用文火，保持微沸30min，搅拌，趁热过滤，药渣再加蒸馏水同法煎煮20min滤过，合并滤液，六层纱布过滤，合并2次滤液浓缩干燥，高压灭菌制成。
实施方式二：该降低盐酸异丙肾上腺素副作用的药物由盐酸异丙肾上腺素16g、生物制剂12g、维生素C 2g、七氟丙烷10g、油酸4g、乙醇440g、对羟基苯甲酸甲酯1.2g、苹果香精3g制成，制备方法同实施方式一。
实施方式三：该降低盐酸异丙肾上腺素副作用的药物由盐酸异丙肾上腺素18g、生物制剂15g、维生素C 3g、七氟丙烷12g、油酸6g、乙醇480g、对羟基苯甲酸甲酯1.5g、苹果香精4g制成，制备方法同实施方式一。
Claims (3)
1.一种降低盐酸异丙肾上腺素副作用的药物，其特征在于该药物由盐酸异丙肾上腺素、生物制剂、维生素C、七氟丙烷、油酸、乙醇、对羟基苯甲酸甲酯、苹果香精制成。
2.如权利要求1所述的一种降低盐酸异丙肾上腺素副作用的药物，其特征在于所述生物制剂是由白背杨、牛西西粉碎混匀，加入10倍生物质重量的蒸馏水浸泡25min后加热煮沸，开始用强火，沸腾后改用文火，保持微沸30min，搅拌，趁热过滤，药渣再加蒸馏水同法煎煮20min滤过，合并滤液，六层纱布过滤，合并2次滤液浓缩干燥，高压灭菌制成。
3.如权利要求1所述的一种降低盐酸异丙肾上腺素副作用的药物，其特征在于将生物制剂和盐酸异丙肾上腺素粉碎过200目筛，加入纯化水中搅拌溶解均匀，接着加入乙醇、维生素C和对羟基苯甲酸甲酯、油酸高剪切均质机下均质搅拌约30min，加入苹果香精，继续搅拌约20min，灌装扎阀，充抛射剂七氟丙烷，检漏称重，安装助动器制成。
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