CN101084898B - 一种镇咳祛痰的复方化学药及其制备工艺 - Google Patents
一种镇咳祛痰的复方化学药及其制备工艺 Download PDFInfo
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Abstract
本发明提供一种镇咳祛痰的复方化学药物及其制备工艺，尤其涉及由以左羟丙哌嗪和愈创木酚甘油醚为有效成份与药物可接受的辅料组成的药物及其生产工艺。本发明所采用的左羟丙哌嗪为外周性镇咳药，与目前市场上常用的中枢性镇咳药相比而言，镇咳效果更明显，不良反应更少。
Description
发明领域
本发明属化学药品领域，涉及一种镇咳祛痰的复方化学药物及其制备工艺，尤其涉及以左羟丙哌嗪和愈创木酚甘油醚为有效成分的复方化学药物。
背景技术
咳嗽、咯痰是临床上呼吸系统疾病常见的症状，轻度而不频繁的咳嗽，只要能将痰液或异物排出，就可以自然缓解，无须用药。然而过于频繁的剧咳，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。
目前常用的镇咳祛痰药有复方右美沙芬制剂，多是以中枢性镇咳药氢溴酸右美沙芬和祛痰药愈创木酚甘油醚为有效成份的复方化学药物。其中氢溴酸右美沙芬为麻醉性镇痛剂左啡诺的同类药，是通过抑制脊髓咳嗽中枢或有关的更高的中枢来抑制咳嗽反射，即该药直接作用于中枢神经，目前虽无成瘾性或耐药性的相关报道，但其副作用较多。临床试验证明，较理想的镇咳药应降低肺内感觉神经的敏感性，阻断有髓鞘或无髓鞘神经内的感觉神经传导(如局麻药物)，但局麻药物有抑制肺防御反射和诱发支气管收缩等副作用。
而左羟丙哌嗪是一种手性外周性镇咳药物，最早由意大利的Dompe公司(商品名levotuss)和Mediolanum公司(商品名Danka)开发，1988年10月在意大利上市。研究证实，左羟丙哌嗪能明显减少传入迷走C-fibres对化学刺激的反应，具有外周作用机制，部分抑制组胺作用和促神经肽释放的作用。由于左羟丙哌嗪具有选择性好、镇咳作用强，对中枢系统几乎没有影响，无嗜睡、呼吸抑制、依赖性等副作用，对心血管和呼吸系统不产生任何明显作用等优点，故我们在本发明中选用左羟丙哌嗪为复方制剂中的镇咳药。愈创木酚甘油醚是痰液稀释药，口服后使气管、支气管内腺体分泌增加，痰液变稀，从而使痰液易于咳出。同时由于愈创木酚甘油醚有一定的消毒防腐作用，在抑杀痰液中细菌、病毒等病原微生 物的同时还可保护呼吸道粘膜，防止了痰液腐败。故将左羟丙哌嗪与愈创木酚甘油醚作为复方制剂的有效成分组合在一起，对呼吸系统感染的患者来说，既起到镇咳祛痰的效果，还具有减轻炎症感染和扩散的作用，同时不良反应更少，安全性更高，故本发明将给患者带来一定的福音，具有一定的社会意义。
发明内容
本发明的目的旨在提供一种镇咳祛痰的复方化学药物，
本发明的目的是通过下述方式实现的：
本发明组合物有效药用成份为镇咳药左羟丙哌嗪和祛痰药愈创木酚甘油醚。两者按以下重量比配制而成：左羟丙哌嗪15～85％和愈创木酚甘油醚85～15％。
所述的有效成份左羟丙哌嗪和愈创木酚甘油醚还可按以下重量比配制而成：左羟丙哌嗪25～75％和愈创木酚甘油醚75～25％。
所述的有效成份左羟丙哌嗪和愈创木酚甘油醚还可按以下重量比配制而成：左羟丙哌嗪30～70％和愈创木酚甘油醚70～30％。
所述的有效成份左羟丙哌嗪和愈创木酚甘油醚按以下重量比配制最佳：所述的有效成份左羟丙哌嗪和愈创木酚甘油醚按以下重量比配制而成：左羟丙哌嗪37.5％和愈创木酚甘油醚62.5％。
本发明的另一目的旨在提供一种镇咳祛痰药物的制备方法。将所述的有效成份通过适宜的药物制剂的制备手段与药物可接受的任何辅料制成的速释、缓释或普通的药物制剂。
本发明所述的有效成份与药物可接受的任何辅料制成的药物制剂可以是任何一种药剂学上所述的口服制剂。
所述的口服制剂可以是片剂、胶囊剂或口服液等。
本发明所述的镇咳祛痰复方药物，口服日剂量为左羟丙哌嗪60～200mg和愈创木酚甘油醚40～800mg，一日1～3次。
具体实施方式
实施例1：
称取左羟丙哌嗪60g，愈创木酚甘油醚100g，按以下方法制备成片剂：
称取适量的辅料乳糖、羟丙甲基纤维素(15cp)、硬脂酸镁，另称取适量的钛白粉、聚乙二醇400、羟丙甲基纤维素(7cp)作包衣用的辅料，将原辅料分别粉碎，过100目筛，备用。先将各辅料混匀(硬脂酸镁除外)，再加入左羟丙哌嗪 和愈创木酚甘油醚混匀。再用70％乙醇制软材，24目筛制粒，60～65℃烘烤2小时，至水分约1～3％，24目筛整粒，加入硬脂酸镁，混匀。压片，准备包衣。将已称取的羟丙甲基纤维素溶于70％的乙醇中，放置过夜。并将称、量取钛白粉和聚乙二醇400置于研钵中，加入少量的羟丙甲基纤维素乙醇溶液研磨成胶浆。再将剩余的羟丙甲基纤维素醇溶液与上述胶浆混匀，然后将素片置于包衣锅中，开启包衣机，用50～60℃的热风预热5分钟，开始喷包衣液雾，边喷边用50～60℃的热风干燥，包至衣重为片蕊重的2％后，继续干燥10分钟，即制成包衣片1000片。
本发明片剂药效学试验：
1、病例标准：具有急性上呼吸道感染、急性气管支气管炎、社区获得性肺炎以及慢性支气管炎急性发作引起的咳嗽症状的门诊或住院患者120对。
2、用药方法：对患者进行多中心、随机、双盲双模拟、阳性药平行对照的临床试验研究。将240位患者随机分为治疗组和安慰组，每组120位。按双盲双模拟阳性药平行对照的方法用药，一组服用本发明药物，另一组服用对照药物愈美片。各组均为每天口服3次，每次2片(包括模拟片)，疗程均为5天。
3、合并用药：视病情可合并使用抗菌素及退热药，但不应加用其他止咳、镇静、抗过敏药物。
4、观察指标：一般项目如血压、脉率、体温、呼吸等；咳嗽症状；胸透；血尿常规；肝肾功能；不良反应记录；心电图。
注：对治疗中出现异常的各项指标，应在疗程结束后7天内，再进行复查。如果持续异常，随访至正常为止。
5、疗效评价：
A、咳嗽程度评分标准：0分：无咳嗽1分(轻度)：间断咳嗽，不影响正常生活和工作。2分(中度)：介于轻度及重度咳嗽之间。3分(重度)：昼夜咳嗽频繁，影响工作和睡眠。
B、疗效判断标准：临床控制：症状完全消失；显效：咳嗽症状由3分转变为1分；好转：咳嗽症状由3分转变为2分或由2分转变为1分；无效：咳嗽症状无好转或加重。
6、试验结果：
疗效对比表：
以上结果表明两组药物治疗咳嗽均是有效的，且本发明药物疗效较对照药更好些。另两药对血尿常规、肝肾功能、甲状腺功能、血压、心率及心电图均无明显影响，不良反应发生率较低，其中有虚汗、头晕、嗜睡、厌食、口干等，本发明组发生不良反应17例，发生率14.78％，氢溴酸右美沙芬组发生不良反应26例，发生率22.41％。由此可见本发明药物安全性相对较高。
实施例2：
称取左羟丙哌嗪50g，愈创木酚甘油醚150g，按以下方法制备成口服液：
称取或量取适量的辅料对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、阿司帕坦、甲基纤维素、柠檬等，将原辅料分别粉碎、过筛备用。将已备好的原辅料加乙醇搅拌、溶解，并加水至1000ml，即得。
实施例3：
称取左羟丙哌嗪、愈创木酚甘油醚适量，按以下方法制备成胶囊：
称取适量的聚维酮、乳糖、微晶纤维素、滑石粉、淀粉和硬脂酸镁。将淀粉用稀乙醇作湿润剂，起模泛丸，取20～35目大小的丸芯备用。用3％聚维酮的乙醇液喷湿丸芯表面，加入已混匀的左羟丙哌嗪、微晶纤维素和滑石粉含药粉使其粘附于丸芯表面，用热风吹至表面干燥，放入烘箱干燥备用。愈创木酚甘油醚含药丸如法制作。两者均选用20～35目大小的含药丸并测定含量备用。再称取适量醋酸纤维素、聚丙烯酸树脂、十二烷基硫酸钠、滑石粉用90％的乙醇溶解制成包衣液。将一定量的左羟丙哌嗪含药微丸置于包衣锅内，用包衣液进行喷雾包衣，使在翻滚旋转的状态下进行增长、干燥，形成含药微丸，干燥。再将40mg愈创木酚甘油醚含药微丸与经包衣的95mg左羟丙哌嗪含药微丸混匀，灌装至明胶胶囊中，即得。
Claims (8)
1.一种镇咳祛痰的复方化学药，其特征在于：由以左羟丙哌嗪和愈创木酚甘油醚为有效成份与药物可接受的辅料组成。
2.根据权利要求1所述的一种镇咳祛痰的复方化学药，其特征在于：所述的有效成份左羟丙哌嗪和愈创木酚甘油醚按以下重量比配制而成：左羟丙哌嗪15～85％和愈创木酚甘油醚85～15％。
3.根据权利要求1所述的一种镇咳祛痰的复方化学药，其特征在于：所述的有效成份左羟丙哌嗪和愈创木酚甘油醚按以下重量比配制而成：左羟丙哌嗪25～75％和愈创木酚甘油醚75～25％。
4.根据权利要求1所述的一种镇咳祛痰的复方化学药，其特征在于：所述的有效成份左羟丙哌嗪和愈创木酚甘油醚按以下重量比配制而成：左羟丙哌嗪30～70％和愈创木酚甘油醚70～30％。
5.根据权利要求1所述的一种镇咳祛痰的复方化学药，其特征在于：所述的有效成份左羟丙哌嗪和愈创木酚甘油醚按以下重量比配制而成：左羟丙哌嗪37.5％和愈创木酚甘油醚62.5％。
6.根据权利要求1-5任一项所述的一种镇咳祛痰的复方化学药，是由所述的有效成份与药物可接受的任何辅料制成的速释、缓释或普通药物制剂。
7.根据权利要求6所述的一种镇咳祛痰的复方化学药，所述的药物制剂是口服制剂。
8.根据权利要求7所述的一种镇咳祛痰的复方化学药，所述的口服制剂是片剂、胶囊剂、口服液。
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