CN108451917A - 高稳定性米安色林制剂的制备方法 - Google Patents
高稳定性米安色林制剂的制备方法 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
- A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
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- General Health & Medical Sciences (AREA)
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Abstract
本发明属于药物制备技术领域，公开了高稳定性米安色林制剂的制备方法，其包括如下步骤：分别称取米安色林、淀粉、微晶纤维素、糊精、羧甲淀粉钠，过80目筛，混匀，然后加入10%聚维酮K30乙醇液，20目筛制粒，55℃烘干至水分含量为2.0%，20目筛整粒，加硬脂酸镁，压片制成1000片，包薄膜衣即得。本发明制剂含量、含量均匀度和溶出度均符合要求，具有高的稳定性，生产方法简单，宜于工业化生产。
Description
技术领域
本发明属于药物制备技术领域，具体涉及高稳定性米安色林制剂的制备方法。
背景技术
米安色林在化学结构上是一个非三环类抗抑郁药，它的活性成分属于哌嗪-氮卓化合物。米安色林为四环类抗抑郁药。米安色林没有明显的抗毒蕈碱作用，却有明显的镇静作用。不能阻止周围去甲肾上腺的再摄取，却可阻断中枢突触前α-受体，加快脑内去甲肾上腺上腺上腺素转换。米安色林还能阻断脑内某些部位的5-HT受体。米安色林易于吸收，口服后约2h可达血药峰值。在肝内经首过代谢，生物利用度约为70%。吸收后迅速分布全身，可透过血-脑脊液屏障和胎盘，并进入乳汁。蛋白结合率约为90%。终末t1/2为6～40h。在肝内的代谢途径包括N-氧化、N-去甲基、羟基化和与葡糖醛酸结合。几乎完全以代谢物随尿排出，小部分由粪便排出。米安色林用于治疗各种类型的抑郁症，对重性抑郁症和神经性抑郁均有良效。尤适合用于门诊治疗和患有心血管疾病及老年患者。
抑郁症或抑郁障碍是全球性主要精神卫生问题，其病因很复杂，至今尚未完全阐明，随着现代社会竟争日趋加剧，人们的心理压力不断增加，情志性疾病成为当代的主要疾病，世界卫生组织指出二十一世纪人们面临的最大疾病是精神疾病。抑郁症作为一种发病率较高的精神障碍，药物治疗是主要的治疗方法。米安色林是常用的药物。如何提供米安色林制剂的稳定性是医药企业需要关注的问题。
发明内容
为了克服现有技术的缺陷，本发明提供了高稳定性米安色林制剂的制备方法。
本发明是通过如下技术方案来实现的：
高稳定性米安色林制剂的制备方法，其包括如下步骤：
分别称取米安色林、淀粉、微晶纤维素、糊精、羧甲淀粉钠，过80目筛，混匀，然后加入10%聚维酮K30乙醇液，20目筛制粒，55℃烘干至水分含量为2.0%，20目筛整粒，加硬脂酸镁，压片制成1000片，包薄膜衣即得。
进一步地，
所述制备方法包括如下步骤：分别称取米安色林30g、淀粉48g、微晶纤维素15g、糊精3g、羧甲淀粉钠3g，过80目筛，混匀，然后加入10%聚维酮K30乙醇液 28g，20目筛制粒，55℃烘干至水分含量为2.0%，20目筛整粒，加硬脂酸镁2g，压片制成1000片，包薄膜衣即得。
进一步地，
所述包薄膜衣的流程如下：
取片芯40kg，均匀地加入70%单糖浆1kg，调节锅速为10-15转/分钟，待糖浆分布均匀后启动热风和排风干燥，热风温度为50℃-60℃，锅速调至8-10转/分钟，10-15分钟，关闭热风把片芯降至35℃-40℃，如此重复包衣，直至把糖浆加完；然后均匀地撒入0.5kg色糖浆，调锅转速为10-15r/min，启动热风和排风干燥，锅速调至8-10转/分，10分钟，关闭热风把片芯降至常温；完全干燥后，关闭热风和排风，将锅温降至35℃以下，转速为8-10 r/min，撒入80g的虫白蜡细粉,待片面开始发亮时再加入30g的虫白蜡，打光时间30分钟。
与现有技术相比，本发明取得的有益效果主要包括：
本发明经过严格、科学的筛选得到上述配方和比例；本发明制备的片剂可压性和流动性均较好；本发明制得的片剂的大小合适，外观平整光滑，成本低，崩解时间适宜，片剂含量、含量均匀度和溶出度均符合要求，具有高的稳定性，生产方法简单，宜于工业化生产。
具体实施方式
为了使本技术领域的人员更好地理解本申请中的技术方案，下面将结合本申请具体实施例，对本发明进行更加清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都应当属于本发明保护的范围。
实施例1
高稳定性米安色林制剂的制备方法，其包括如下步骤：
分别称取米安色林30g、淀粉48g、微晶纤维素15g、糊精3g、羧甲淀粉钠3g，过80目筛，混匀，然后加入10%聚维酮K30乙醇液 28g，20目筛制粒，55℃烘干至水分含量为2.0%，20目筛整粒，加硬脂酸镁2g，压片制成1000片，包薄膜衣即得。
所述米安色林的精制工艺包括如下步骤：
(1)、在反应釜中投入苯甲醛，并滴加乙醇胺，两者物质的摩尔配比为1∶1，反应温度为：30-40℃，反应时间为：3～5小时，反应完全后，再加入甲醇和硼氢化钾，反应3～5小时，过滤、收集滤液，加水搅拌静置分层，减压蒸馏油层，要求真空度为0.096～0.1MPa，接收160～170℃的馏份，得中间体I；
(2)、在反应釜中投入中间体I，升温至90～100℃时滴加氧化苯乙烯，两者物质的摩尔配比为1∶1，滴毕在120～140℃反应2小时，得中间体II；
(3)、在步骤2)中投入吡啶、氯苯，在50～60℃滴加氯化亚砜，氯化亚砜与步骤2)中的氧化苯乙烯的摩尔配比为2.2∶1，反应温度为：60～70℃，反应时间为：2～3小时，再加氢氧化钠调PH5～6，得中间体III；
(4)、在步骤3)中投入碳酸钾、水、氯苯、邻氨基苄醇，邻氨基苄醇与步骤2)中的氧化苯乙烯的摩尔配比为0.8∶1，回流反应4～6小时，静置分去水层减压蒸除溶剂，再将富马酸、丙酮投入反应釜中回流0.5～1小时，冷却过滤、干燥得中间体IV；
(5)、在反应釜中投入浓硫酸，浓硫酸与步骤2)中的氧化苯乙烯的摩尔配比为12.3∶1，控温30℃～40℃，加入中间体IV，保温反应30～50分钟，然后升温70～80℃反应1小时，将冰水投入反应釜中降温，在34～36℃搅拌1小时，降温过滤得固体，再将甲苯、乙醇、碳酸钠投入反应釜中，碳酸钠与浓硫酸的摩尔配比为12.3∶4，在75℃反应40～60分钟，分层，水洗至中性，减压蒸除溶剂，得中间体V；
(6)、在反应釜中投入中投入甲苯，再加入中间体V，滴加氯甲酸乙酯，氯甲酸乙酯与步骤2)中的氧化苯乙烯的摩尔配比为1.42∶1，回流3～4小时，减压蒸除溶剂，再将正丁醇、氢氧化钾投入反应釜中，氢氧化钾与步骤2)中的氧化苯乙烯的摩尔配比为3.1∶1，回流3～4小时，加水搅拌分层，饱和食盐水洗至中性，去食盐水层，得中间体VI；
(7)、在反应釜中投入甲醛，加入中间体VI，回流1小时，滴加甲酸，甲醛和甲酸与步骤2)中的氧化苯乙烯的摩尔配比为4.5∶12∶1，滴毕继续回流6小 时，减压蒸溶剂，降温30～40℃，加入氢氧化钠、甲苯、水，搅拌分层，减压蒸除溶剂得中间体VII；
(8)、在反应釜中投入丙酮，加入中间体VII，加热溶解，用盐酸-乙酸乙酯调PH2～3，冷却，过滤，干燥，精制即得。实施例2
高稳定性米安色林制剂的制备方法，其包括如下步骤：
分别称取米安色林30g、淀粉48g、微晶纤维素15g、糊精3g、羧甲淀粉钠3g，过80目筛，混匀，然后加入10%聚维酮K30乙醇液 28g，20目筛制粒，55℃烘干至水分含量为2.0%，20目筛整粒，加硬脂酸镁2g，压片制成1000片，包薄膜衣即得。
所述包薄膜衣的流程如下：
取片芯40kg，均匀地加入70%单糖浆1kg左右，调节锅速为10-15转/分钟，待糖浆分布均匀后启动热风和排风干燥，热风温度为50℃-60℃，这时锅速可调至8-10转/分钟，约10-15分钟，关闭热风把片芯降至35℃-40℃，如此重复包衣，直至把糖浆加完；然后均匀地撒入0.5kg色糖浆，调锅转速为10-15r/min，启动热风和排风干燥，这时锅速可调至8-10转/分，约10分钟，关闭热风把片芯降至常温；完全干燥后，关闭热风和排风，将锅温降至35℃以下，转速为8-10 r/min，撒入80g的虫白蜡细粉,待片面开始发亮时再加入30g的虫白蜡，打光时间30分钟。
经检测：溶出度30min为97.3%；光照10天，有效成分下降0.51%；高温10天，有效成分下降1.37%；高湿10天，有效成分下降0.59%。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (3)
1.高稳定性米安色林制剂的制备方法，其包括如下步骤：
分别称取米安色林、淀粉、微晶纤维素、糊精、羧甲淀粉钠，过80目筛，混匀，然后加入10%聚维酮K30乙醇液，20目筛制粒，55℃烘干至水分含量为2.0%，20目筛整粒，加硬脂酸镁，压片制成1000片，包薄膜衣即得。
2.根据权利要求1所述的制备方法，其特征在于，所述制备方法包括如下步骤：分别称取米安色林30g、淀粉48g、微晶纤维素15g、糊精3g、羧甲淀粉钠3g，过80目筛，混匀，然后加入10%聚维酮K30乙醇液 28g，20目筛制粒，55℃烘干至水分含量为2.0%，20目筛整粒，加硬脂酸镁2g，压片制成1000片，包薄膜衣即得。
3.根据权利要求1-2所述的制备方法，其特征在于，所述包薄膜衣的流程如下：取片芯40kg，均匀地加入70%单糖浆1kg，调节锅速为10-15转/分钟，待糖浆分布均匀后启动热风和排风干燥，热风温度为50℃-60℃，锅速调至8-10转/分钟，10-15分钟，关闭热风把片芯降至35℃-40℃，如此重复包衣，直至把糖浆加完；然后均匀地撒入0.5kg色糖浆，调锅转速为10-15r/min，启动热风和排风干燥，锅速调至8-10转/分，10分钟，关闭热风把片芯降至常温；完全干燥后，关闭热风和排风，将锅温降至35℃以下，转速为8-10 r/min，撒入80g的虫白蜡细粉,待片面开始发亮时再加入30g的虫白蜡，打光时间30分钟。
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