CN106038506A - 一种富马酸喹硫平片及其制备方法 - Google Patents
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Abstract
本发明公开了一种富马酸喹硫平片，为缓释片，所述的富马酸喹硫平缓释片由含药颗粒与药学上可接受的辅料混匀后直接压片而成，所述的含药颗粒是将富马酸喹硫平加入到低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的乙醇溶液中形成混悬液，加热蒸干后过筛而得，本发明制剂减少了缓释材料的用量，将颗粒包衣和制粒一步完成，药物释放平稳，适于工业化生产。
Description
技术领域
本发明属于医药制剂技术领域，具体而言，涉及一种富马酸喹硫平片及其制备方法。
背景技术
喹硫平是一种非经典抗精神病药物，化学名为2-[2-(4-二苯并[b,f][1,4]硫氮杂卓-11-基-1-哌嗪基)乙氧基]-乙醇富马酸盐。喹硫平是二苯氧氮杂卓类药物，结构与氯氮平和奥氮平相似，同属多受体作用药。其抗精神病作用机理可能主要是通过阻断中枢多巴胺D2受体和5-HT2受体。药理实验显示喹硫平在脑中对五羟色胺(5-HT2)受体具有高度亲和力，且大于对脑中多巴胺D1和多巴胺D2受体的亲和力。喹硫平对组织胺受体和肾上腺素能α1受体同样有高亲和力，对肾上腺素能α1受体亲和力低，但对胆碱能毒受体或苯二氮卓受体基本没有亲和力。喹硫平对抗精神病药物活性测定如条件回避反射呈阳性结果。临床试验显示，喹硫平片对治疗精神分裂症的阳性和阴性症状均有效。一项与氯丙嗪，两项与氟哌啶醇对照的试验显示，喹硫平片的短期疗效与对照药物相当。
目前喹硫平普遍的剂型是25mg、100mg、200mg和300mg普通片剂，国内常规口服剂量为：初始剂量为每次25mg，每日2次。每隔1～3日增加25mg，逐渐增至治疗总剂量每日300～600mg，通过2～3次服药。喹硫平口服吸收快速，约1.0～1.8小时血药浓度达峰值，消除半衰期较短。总体说来，患者每日用药较为频繁，又由于精神分裂症患者需要长期用药，给患者及家属带来极大的不便及痛苦。
发明内容
现有技术中，采用凝胶骨架材料作为缓释材料，存在的问题是前期释药快，后期释放不完全；采用不溶性骨架材料，难以很好的控制药物释放，药物或者难以释放，或者释放迅速；用不溶性材料包衣，通过包衣控制释放，产业化困难，批间差异大。
针对现有技术的不足，发明人的目的在于对处方和工艺进行研究，提供一种片重小、释放平稳、缓释材料用量少的富马酸喹硫平片，为缓释片。
具体而言，本发明是通过如下技术方案实现的：
一种富马酸喹硫平缓释片，所述的富马酸喹硫平缓释片由含药颗粒与药学上可接受的辅料混匀后直接压片而成，所述的含药颗粒是将富马酸喹硫平加入到低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的乙醇溶液中形成混悬液，加热蒸干后过筛而得。
所述的富马酸喹硫平缓释片，富马酸喹硫平与低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的重量用量比为1-5:0.5-0.8：0.8-1.2,低粘度羟丙甲纤维素的粘度为2000-5000mPa·s。
所述的富马酸喹硫平缓释片，富马酸喹硫平与低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的重量用量比为2:0.6:1,低粘度羟丙甲纤维素的粘度为4000mPa·s。
所述的富马酸喹硫平缓释片，所述的药学上可接受的辅料包括填充剂和润滑剂。
所述的富马酸喹硫平缓释片，所述的填充剂选自微晶纤维素、乳糖和预胶化淀粉中的一种或多种。
所述的富马酸喹硫平缓释片，所述的润滑剂选自硬脂酸镁、微粉硅胶和滑石粉中的一种或多种。
所述的富马酸喹硫平缓释片的制备方法，其特征在于包括如下步骤：
(1)将富马酸喹硫平粉碎过200目筛，备用；
(2)将低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30溶解在乙醇中，备用；
(3)搅拌条件下，将富马酸喹硫平细粉加入到低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的乙醇溶液中，将此混悬液加热，蒸干后，过筛，将过筛后的颗粒与药学上可接受的辅料混合均匀，压片。
本发明中，发明人创造性的将颗粒包衣技术与制备颗粒技术结合，利用药物在不同溶剂中溶解度的差异，制备药物微细颗粒，同时将制备的颗粒包衣，很好的控制了药物的释放。
与现有技术相比，本发明减少了缓释材料的用量，将颗粒包衣和制粒一步完成，药物释放平稳，适于工业化生产。
附图说明
图1为实施例1制备的缓释片中富马酸喹硫平累计释放曲线图。
图2为实施例2制备的缓释片中富马酸喹硫平累计释放曲线图。
图3为实施例3制备的缓释片中富马酸喹硫平累计释放曲线图。
图4为对比实施例1制备的缓释片中富马酸喹硫平累计释放曲线图。
具体实施方式
以下实施例进一步描述本发明的制备过程和有益效果，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
实施例1富马酸喹硫平缓释片及其制备方法
取富马酸喹硫平500g、粘度为5000mPa·s的低粘度羟丙甲纤维素150g、聚乙烯吡咯烷酮K30 250g、乙醇600g、微晶纤维素100g、硬脂酸镁7g，称取处方量的富马酸喹硫平粉碎过200目筛，称取处方量的低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30溶解在乙醇中；搅拌条件下，将富马酸喹硫平粉末加入到低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的乙醇溶液中，将此混悬液加热至80℃，缓慢蒸干后，过20目筛，将过筛后的颗粒与处方量的微晶纤维素、硬脂酸镁混合均匀，压片。
实施例2富马酸喹硫平缓释片及其制备方法
取富马酸喹硫平500g、粘度为5000mPa·s的低粘度羟丙甲纤维素250g、聚乙烯吡咯烷酮K30 400g、乙醇600g、微晶纤维素150g、硬脂酸镁10g，称取处方量的富马酸喹硫平粉碎过200目筛，称取处方量的低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30溶解在乙醇中；搅拌条件下，将富马酸喹硫平粉末加入到低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的乙醇溶液中，将此混悬液加热至80℃，缓慢蒸干后，过20目筛，将过筛后的颗粒与处方量的微晶纤维素、硬脂酸镁混合均匀，压片。
实施例3富马酸喹硫平缓释片及其制备方法
取富马酸喹硫平500g、粘度为5000mPa·s的低粘度羟丙甲纤维素80g、聚乙烯吡咯烷酮K30 120g、乙醇600g、微晶纤维素150g、硬脂酸镁10g，称取处方量的富马酸喹硫平粉碎过200目筛，称取处方量的低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30溶解在乙醇中；搅拌条件下，将富马酸喹硫平粉末加入到低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的乙醇溶液中，将此混悬液加热至80℃，缓慢蒸干后，过20目筛，将过筛后的颗粒与处方量的微晶纤维素、硬脂酸镁混合均匀，压片。
对比实施例1富马酸喹硫平缓释片及其制备方法
取富马酸喹硫平(以喹硫平计)200g粉碎，过80目筛，与60g改性预胶化淀粉(AsahiKASEI公司提供，商品名为SWELSTRARTM MX-1),混匀，以9g 10％聚乙烯吡咯烷酮K-30为粘合剂制软材；过18目筛制粒，干燥，用18目筛整粒，加入3g硬脂酸镁，混匀，压片。(参考专利申请号201210123709.1一种含有富马酸喹硫平的缓释片剂)
实施例4富马酸喹硫平缓释片的释放度考察
释放度测定方法：参照中国药典2010年版二部附录XD释放度测定第一法，采用2010年版二部附录XC溶出度测定第二法的装置，900mL水为释放介质，转速为50r·min-1，温度为37℃，依法操作。于2h，4h，6h，8h，12h与24h分别取样2mL，同时补加等量释放液，并立即离心，取上清液，进行HPLC分析，计算药物的累计释放量。实施例1-3制备的缓释片释放度测定结果见附图1-3，对比实施例1制备的缓释片释放度测定结果见附图4.
根据附图1-4的试验结果可知，本发明实施例1-3制备的富马酸喹硫平缓释片释放平稳(参见图1-3)；对比实施例1将富马酸喹硫平与预胶化淀粉等混合后制粒，由于制备的颗粒中富马酸喹硫平未被充分包裹，故释放过快(参见图4)。
Claims (7)
1.一种富马酸喹硫平片，其特征在于：所述的富马酸喹硫平片由含药颗粒与药学上可接受的辅料混匀后直接压片而成，所述的含药颗粒是将富马酸喹硫平加入到低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的乙醇溶液中形成混悬液，加热蒸干后过筛而得。
2.根据权利要求1所述的富马酸喹硫平片，其特征在于：富马酸喹硫平与低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的重量用量比为1-5:0.5-0.8：0.8-1.2,低粘度羟丙甲纤维素的粘度为2000-5000mPa·s。
3.根据权利要求2所述的富马酸喹硫平片，其特征在于：富马酸喹硫平与低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的重量用量比为2:0.6:1,低粘度羟丙甲纤维素的粘度为4000mPa·s。
4.根据权利要求1-3任一项所述的富马酸喹硫平片，其特征在于：所述的药学上可接受的辅料包括填充剂和润滑剂。
5.根据权利要求4所述的富马酸喹硫平片，其特征在于：所述的填充剂选自微晶纤维素、乳糖和预胶化淀粉中的一种或多种。
6.根据权利要求4所述的富马酸喹硫平片，其特征在于：所述的润滑剂选自硬脂酸镁、微粉硅胶和滑石粉中的一种或多种。
7.一种根据权利要求1-3任一项所述的富马酸喹硫平片的制备方法，其特征在于包括如下步骤：
(1)将富马酸喹硫平粉碎过200目筛，备用；
(2)将低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30溶解在乙醇中，备用；
(3)搅拌条件下，将富马酸喹硫平细粉加入到低粘度羟丙甲纤维素、聚乙烯吡咯烷酮K30的乙醇溶液中，将此混悬液加热，蒸干后，过筛，将过筛后的颗粒与药学上可接受的辅料混合均匀，压片。
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