CN110934872B - 左羟愈酚胶囊及其制备方法 - Google Patents
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Abstract
本发明涉及一种左羟愈酚胶囊及其制备方法，所述胶囊包括：按药物制剂总重量计，活性成分左羟丙哌嗪和愈创木酚甘油醚为40‑80%，填充剂为10‑60%，崩解剂为0‑10%，粘合剂为0‑10%，润滑剂为0.2‑10%，所述活性成分与填充剂的重量比为1:1.5~4:1。本发明通过大量处方筛选和原辅料相容性研究，解决了两种活性成分混合遇光和湿易变色问题，通过本发明制备的左羟愈酚胶囊崩解性好、溶出度高，稳定性好，符合药品质量标准。
Description
技术领域
本发明属于医药制剂领域，特别涉及一种左羟愈酚胶囊及其制备方法。
背景技术
镇咳祛痰治疗在临床实践中是常用的药物治疗方案，用于缓解频繁、剧烈的有痰咳嗽，提高咳嗽效率，以帮助清除呼吸道。更好地治疗呼吸道感染的同时，避免频繁、剧烈咳嗽引起的严重并发症，以及对工作、生活和患者心理带来的不良影响。
目前国内外祛痰药与镇咳药合用较为普遍，出于提高患者服药依从性、节约治疗费用和药品生产过程的产能的目的，上市了很多复方制剂。但目前国内上市的复方中镇咳药均选用中枢镇咳类药物（或平喘药物茶碱），尚无任何一个外周镇咳类药物与祛痰药组成复方制剂上市。中枢镇咳药普遍具有的成瘾、镇静、呼吸抑制、阿托品样作用等不良反应，以及对肝药酶的竞争性抑制和潜在的药物滥用风险等，限制了其在诸如儿童、从事危险职业患者、青光眼患者、服用精神类药物患者等特殊人群中的使用，也给药物监管带来很大的压力。而我司开发的镇咳祛痰复方制剂左羟愈酚胶囊，镇咳成分选择外周镇咳药左羟丙哌嗪，祛痰药选自愈创木酚甘油醚，有望弥补中枢镇咳类药物的诸多局限，给临床用药提供一个更好的选择。
本公司左羟丙哌嗪和愈创木酚甘油醚制剂原辅料相容性研究时发现，将两种活性成分互相混合，在光照和高温条件下长时间暴露于空气中存在一定程度不稳定现象，反应在产品上是样品表层颜色稍加深、或稍变红。辅料聚维酮K30的加入会增加活性成分的有关物质。
专利CN200610031775.0公开了左羟丙哌嗪愈创木酚甘油醚为活性成分的胶囊（简称左羟愈酚胶囊）的制备方法，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，起膜泛丸，制成丸芯备用。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使其黏附于丸芯表面，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，备用。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。分别将左羟丙哌嗪和愈创木酚甘油醚药丸置于包衣锅内包衣，制备含药微丸，干燥，灌装至明胶胶囊中。使用该方法解决了左羟丙哌嗪和愈创木酚甘油醚混合不稳定的问题，但该方法操作步骤复杂，使用的辅料多，不适合工业化大生产。
因此左羟丙哌嗪愈创木酚甘油醚制剂处方仍有待改进。
发明内容
本发明的目的在于提供一种崩解性、溶出度及稳定性好的左羟愈酚胶囊处方，该处方制备工艺简单，节约生产成本，适合工业化大生产，且产品质量稳定，符合药用标准。
本发明通过多项实验条件摸索，成功研发出了符合药品质量标准的左羟愈酚胶囊制剂。本发明提供一种左羟丙哌嗪愈创木酚甘油醚药物制剂，所述药物制剂包括：按药物制剂总重量计，活性成分左羟丙哌嗪和愈创木酚甘油醚为40-80%，填充剂为10-60%，崩解剂为0-10%，粘合剂为0-10%，润滑剂为0.2-10%，所述活性成分与填充剂的重量比为1:1.5~4:1。
进一步，该药物制剂包括：按药物制剂总重量计，活性成分左羟丙哌嗪和愈创木酚甘油醚为70-80%，填充剂为20-40%，崩解剂为0-10%，粘合剂为0-10%，润滑剂为4-6%，所述活性成分与填充剂的重量比为1:1.5~4:1。
进一步，该药物制剂包括：按药物制剂总重量计，活性成分左羟丙哌嗪和愈创木酚甘油醚为70-80%，淀粉和预胶化淀粉为20-30%，润滑剂为4-6%。
进一步，上述填充剂为乳糖、甘露醇、淀粉、预胶化淀粉、微晶纤维素中的一种或几种，优选淀粉和预胶化淀粉。
进一步，上述崩解剂为低取代羟丙甲纤维素、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠中的一种或几种。
进一步，上述粘合剂为羟丙甲纤维素、羟丙纤维素和羧甲基纤维素钠中的一种或几种，优选羟丙甲纤维素。
进一步，上述润滑剂为硬脂酸镁、滑石粉、二氧化硅、胶态二氧化硅、硬脂富马酸钠、山嵛酸甘油酯和聚乙二醇中的一种或几种，优选硬脂酸镁、滑石粉、二氧化硅和胶态二氧化硅。
本发明还提供一种左羟愈酚胶囊的制备方法，该方法包括但不局限于：
1）将活性成分过筛，与填充剂、粘合剂、崩解剂混合均匀；
2）边搅拌边将乙醇溶液加至步骤1）混合物中制软材，制粒，整粒；
3）将步骤2）制得的颗粒和润滑剂混合均匀，即得。
进一步，在左羟愈酚胶囊的制备制备过程中，步骤2）制粒后干燥方式为将湿颗粒在35～55℃条件下干燥至水分控制在3%以内。
进一步，步骤2）中的乙醇溶液为70%乙醇溶液。
根据本发明的的一个具体实施例，左羟丙哌嗪过40目筛、愈创木酚甘油醚过80目筛，备用。称取玉米淀粉30mg、左羟丙哌嗪60mg、愈创木酚甘油醚200mg、预胶化淀粉40mg，按顺序加入混合均匀。上述混匀物料边搅拌边加入适量70%乙醇溶液制软材，24目筛制粒。湿颗粒于40±5℃干燥至水分控制1%～3%。24目整粒。干燥颗粒中加入处方量滑石粉、二氧化硅混合均匀。进行中间体的检测后即填充得胶囊。
采用本发明制备的左羟愈酚胶囊有如下优势：
1、本发明方法有效的解决了活性成分混合物在光照和高温条件长时间暴露于空气中不稳定问题；
2、本发明处方制备工艺简单，节约生产成本，适合工业化大生产；
3、本发明制备的左羟愈酚胶囊有良好的溶出度、崩解性及稳定性，符合药用标准。
具体实施方式
下面通过具体实施例对本申请作进一步详细说明。以下实施例仅对本申请进行进一步说明，不应理解为对本申请的限制。
本发明所用的试剂和原料均市售可得。
实施例1：原辅料相容性实验研究
参照《化学药物制剂研究基本技术指导原则》要求，分别取单独原料药、辅料、原辅料混合粉末，按《化学药物原料药和制剂稳定性研究技术指导原则》的要求进行影响因素（光照、高温试验。
光照试验：将原料药、辅料、各配比的原辅料混合粉末分别敞口置光照4500±500Lx条件下10天，取样，检测外观性状和有关物质。
高温试验：将原料药、辅料、各配比的原辅料混合粉末分别以称量瓶敞口（不加盖）、加盖两种形式放样、置高温60℃条件下10天，取样，检测外观性状和有关物质。
活性成分与辅料配比：
实验结果：
分析上述数据可知，原辅料相容性试验不同条件下10天两个单独原料药各项指标均无明显变化；表明单独原料均稳定性好。混合原料高温60℃（不加盖）10天样品表层粉末稍有变红；光照10天样品表层粉末颜色稍加深，其它各项指标均无明显变化。上述结果表明，混合原料需避免高温60℃、或光照（4500±500Lx）条件在空气中长时间暴露，防止样品变色。
原辅料相容性样品外观性状分析，高温60℃（不加盖）10天，硬脂酸镁、滑石粉相容性样品均表层粉末稍有变红，聚维酮K30相容性样品颜色稍加深、泥状。而润滑剂硬脂酸镁、滑石粉均多为外加总混方式，样品制备过程温度因素对润滑剂基本无影响。
原辅料相容性样品有关物质分析，除聚维酮K30相容性样品高温60℃（不加盖）10天、高温60℃（不加盖）10天、光照10天条件下左羟丙哌嗪有关物质明显增加，其它条件样品及其它样品在各条件下左羟丙哌嗪有关物质均无明显变化；各条件下样品愈创木酚甘油醚有关物质及右羟丙哌嗪均无明显变化。
综上所述，混合原料需避免高温60℃、或光照（4500±500Lx）条件在空气中长时间暴露，防止样品颜色变化；优选相容性较好的辅料玉米淀粉、预胶化淀粉、低取代羟丙纤维素、滑石粉、硬脂酸镁进行处方筛选。
实施例2-21左羟愈酚胶囊处方及制备方法
表1实施例2 -6左羟愈酚胶囊处方
表2实施例7-11左羟愈酚胶囊处方
表3实施例12 -16左羟愈酚胶囊处方
表4实施例17 -21左羟愈酚胶囊处方
以上处方制备方法：
混合：活性成分过筛，将处方量填充剂、崩解剂（处方无则不加）、粘合剂（处方无则不加）与活性成分混合均匀；
制粒：在混合物中加入润湿剂70%乙醇制软材，并选择24目筛制粒；
干燥：将湿颗粒置45-55℃条件烘干，水分控制在水分控制1%～3%范围内；
整粒、总混；
填充：将干燥颗粒整粒，加入处方量润滑剂，混合均匀后进行胶囊填充。
实施例22实施例1处方左羟愈酚胶囊进行稳定性研究
对实施例1进行中试放大样品的制备（一批14万粒）
取中试放大样品于温度40±2℃、相对湿度为75±5%的条件下放置6个月，于0、1、2、3、6末分别取样检测，对性状、溶出度、有关物质和含量等项目进行考察（检测方法按照《中国药典》2015年版四部通则项下方法检测），结果见下表：
表5：加速稳定性考察结果表
根据稳定性研究结果显示，本发明制备的左羟愈酚胶囊0-6个月实验稳定性好，溶出度、有关物质含量和含量均符合质量标准要求。
以上内容是结合具体的实施方式对本申请所作的进一步详细说明，不能认定本申请的具体实施只局限于这些说明。对于本申请所属技术领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本申请的保护范围。
Claims (8)
1.一种左羟丙哌嗪、愈创木酚甘油醚药物制剂，其特征在于，所述药物制剂包括：按药物制剂总重量计，活性成分左羟丙哌嗪和愈创木酚甘油醚为40-80％，填充剂为10-60％，崩解剂为0-10％，粘合剂为0-10％，润滑剂为0.2-10％，所述活性成分与填充剂的重量比为1:1.5～4:1；所述的填充剂为乳糖、甘露醇、淀粉、预胶化淀粉、微晶纤维素中的一种或几种；所述的崩解剂为低取代羟丙甲纤维素、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠中的一种或几种；所述粘合剂为羟丙甲纤维素、羟丙纤维素和羧甲基纤维素钠中的一种或几种；所述润滑剂为硬脂酸镁、滑石粉、二氧化硅、胶态二氧化硅、硬质富马酸钠、山嵛酸甘油酯和聚乙二醇中的一种或几种。
2.根据权利要求1所述的药物制剂，其特征在于，所述药物制剂包括：按药物制剂总重量计，活性成分左羟丙哌嗪和愈创木酚甘油醚为70-80％，填充剂为20-40％，崩解剂为0-10％，粘合剂为0-10％，润滑剂为4-6％。
3.根据权利要求1或2所述的药物制剂，其特征在于，所述填充剂为淀粉和预胶化淀粉中的一种或几种。
4.根据权利要求3所述的药物制剂，其特征在于，所述淀粉与预胶化淀粉的重量比为1:3～1:1。
5.根据权利要求1所述的药物制剂，其特征在于，所述粘合剂为羟丙甲纤维素；所述润滑剂为硬脂酸镁、滑石粉、二氧化硅、胶态二氧化硅中的一种或几种。
6.根据权利要求1所述的药物制剂，其特征在于，所述药物制剂包括：按药物制剂总重量计，活性成分左羟丙哌嗪和愈创木酚甘油醚为70-80％，淀粉和预胶化淀粉为20-30％，润滑剂为4-6％。
7.权利要求1所述药物制剂制备方法，步骤如下：
1)将活性成分过筛，与填充剂、粘合剂、崩解剂混合均匀；
2)边搅拌边将乙醇溶液加至步骤1)混合物中制软材，制粒，整粒；
3)将步骤2)制得的颗粒和润滑剂混合均匀，即得。
8.权利要求1所述药物制剂制备方法，步骤如下：
1)将活性成分过筛，与淀粉、预胶化淀粉混合均匀；
2)边搅拌边将乙醇溶液加至步骤1)混合物中制软材，24目筛制粒，整粒；
3)将步骤2)制得的颗粒和滑石粉、二氧化硅混合均匀，即得。
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