CN100413491C - 一种难溶性药物的控释制剂 - Google Patents
一种难溶性药物的控释制剂 Download PDFInfo
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Abstract
一种难溶性药物的控释制剂,制剂中含有至少一种纤维素聚合物和至少一种水中易溶性辅料,其中纤维素聚合物在制粒压片过程中采用内加和外加相结合的方式加入,能使药物的释放接近零级,并使药物的溶解释放动力学对肠道pH变化不敏感。
Description
技术领域
本发明涉及一种难溶性药物的控释制剂,这种制剂能使药物的释放接近零级,并使药物的溶解释放动力学对肠道范围内pH变化不敏感。
技术背景
难溶性药物一般在胃肠系统溶解度很低,如硝苯地平(Nifedipine)、非洛地平(Felodipine)等;另有一些呈酸性或碱性,在胃肠系统的不同部位表现出受pH影响的溶解度,如格列齐特(Gliclazide)、西沙必利(Cisapride)等。
目前能够较理想地实现零级释药系统的手段仍为渗透泵制剂、经皮给药制剂等。渗透泵制剂采用半透膜材料包衣,内分两层,一层为药物层,同时含有渗透压活性物质,在该层的衣膜表面打一释药小孔;一层为膨胀层,吸水膨胀后产生推动力,将药物层的药物推出释药小孔。然而其存在技术难度、生产实现及质量控制的问题,并且释药完毕后不溶性的片体须排出体外,有可能发生片子累积在肠道的严重问题。经皮给药制剂种类较多,构造不一,如膜控释型、粘胶分散型、骨架扩散型、微贮库型等,能较好地实现零级释药,但也存在诸多问题,如适合制成该制剂的药物种类的局限性、药物透过量低、成本高、工业生产实现难度大等。
本发明的目的是提供一种工艺易行、设备成本不高的生产技术,制备难溶性药物的拟零级释药系统,使释药动力学方程可达零级。本技术无需高技术难度、高成本的工艺。
本发明的另一目的是使药物释放对模拟肠道范围内的溶解介质pH变化不敏感。
专利CN1342068中将纤维素聚合物(如羟丙基甲基纤维素)和葡萄糖浆(如麦芽糖糊精)组合应用于格列齐特缓释骨架片中,可使释药接近零级,并使得格列齐特的溶解释放动力学对pH的变动不灵敏。
本发明中采用纤维素聚合物和易溶性辅料的组合,同时用内、外加相结合的方法将纤维素聚合物加入制剂中,就可使释药接近零级,并对模拟肠道范围内的溶解介质pH变化不敏感。
附图说明
图1是实施例1药片在不同pH缓冲液中的溶出曲线
图2是实施例2药片在不同pH缓冲液中的溶出曲线
图3是实施例3药片在不同pH缓冲液中的溶出曲线
图4是实施例4药片在不同pH缓冲液中的溶出曲线
实施发明的技术措施
本发明中的生理活性成分为难溶性药物如格列齐特(Gliclazide)、西沙必利(Cisapride)、硝苯地平(Nifedipine)、非洛地平(Felodipine)等。生理活性物质的重量百分比为1%-50%,最优重量百分比为10%-30%。
本品可为干法制粒或湿法制粒后压片,其中纤维素聚合物通过内加和外加相结合的方式加入。内加:制粒时将辅料制入颗粒中;外加:压片前将辅料与颗粒混合加入。本发明中的纤维素聚合物的重量百分比为10%-60%,最优重量百分比为15%-35%。
本发明中的易溶性辅料的重量百分比为5%-50%。
为实现本发明,在纤维素聚合物、易溶性辅料与药物的混合物中可进一步加入其它常规辅料,如稀释剂微晶纤维素、磷酸氢钙二水合物、乳糖、蔗糖或淀粉;助溶剂聚维酮、聚乙二醇、泊洛沙姆、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚或它们的混合物;润滑剂硬脂酸镁、滑石粉等。
采用本发明制备得到的片剂,释药行为接近零级,并对模拟肠道范围内的溶解介质pH变化不敏感。
实施例
下面结合实施例对本发明作进一步的详细说明。
结合实施例具体说明本发明,但并不局限于下述的实施例。其中“%”是指“重量%”。
实施例1
制备工艺:
格列齐特、HPMC K4M、HPMC K100LV(内加)、磷酸氢钙二水合物、甘露醇按等量递加法混匀,以80%乙醇水溶液制软材,过20目筛,60℃烘干后加入HPMC K100LV(外加)和硬脂酸镁,压片。
实施例2
制备工艺:
格列齐特、HPMC K15M、HPMC K100LV(内加)、微晶纤维素、PEG 4000按等量递加法混匀,以12%的PVP K30乙醇溶液制软材,过20目筛,60℃烘干后加入HPMC K100LV(外加)和硬脂酸镁,压片。
实施例3
制备工艺:
西沙必利、HPMC K100M、HPMC K4M(内加)、微晶纤维素、PEG 4000按等量递加法混匀,以12%的PVP K30乙醇溶液制软材,过20目筛,60℃烘干后加入HPMC K4M(外加)和硬脂酸镁,压片。
实施例4
制备工艺:
非洛地平、HPMC K15M、HPMC K100LV(内加)、微晶纤维素、乳糖按等量递加法混匀,以12%的PVP K30乙醇溶液制软材,过20目筛,60℃烘干后加入HPMC K100LV(外加)和硬脂酸镁,压片。
释放度试验:
将制备得到的片剂按释放度测定法(中国药典2000年版二部附录XC第一法),分别以900ml的三种磷酸盐缓冲液(pH5.4,pH6.8,pH7.8)为释放介质,转速为100转/分,得到各实施例片剂的不同释放曲线,见图1~图4。
如上述说明,按照本发明可以制备得到难溶性药物的拟零级释药系统,并对模拟肠道范围内的溶解介质pH变化不敏感。同时该种技术工艺简单易行、设备成本不高,适合于工业化大生产。
Claims (1)
1. 一种非洛地平的控释制剂,其特征在于由重量百分比为2%的非洛地平、12%HPMC K15M、18%HPMC K100LV、34.2%微晶纤维素、30%乳糖、3.0%PVP K30、0.8%硬脂酸镁组成,并通过将非洛地平、HPMC K15M、10.0%HPMC K100LV、微晶纤维素、乳糖按等量递加法混匀,以12%的PVPK30乙醇溶液制软材,过20目筛,60℃烘干后加入8.0%HPMC K100LV和硬脂酸镁,压片的方法制备。
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TR200704897A1 (tr) * | 2007-07-13 | 2009-02-23 | Sanovel �La� Sanay� Ve T�Caret Anon�M ��Rket� | Uzatılmış salım sağlayan gliklazid formülasyonları@ |
CN101744786B (zh) * | 2008-12-17 | 2012-11-14 | 南京星银药业集团有限公司 | 一种非洛地平缓释片处方及制备方法 |
CN102188401B (zh) * | 2011-05-10 | 2013-07-03 | 山东威高药业有限公司 | 一种非洛地平缓释片及其制备方法 |
CN104784050A (zh) * | 2014-01-17 | 2015-07-22 | 南京瑞尔医药有限公司 | 一种格列齐特片剂组合物的制备方法 |
Citations (3)
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CN1111126A (zh) * | 1993-11-23 | 1995-11-08 | 欧罗赛铁克有限公司 | 具有难溶性药物速释片芯的缓释包衣片 |
CN1189774A (zh) * | 1995-07-03 | 1998-08-05 | 伊兰公司Plc | 难溶药物的控释制剂 |
CN1342068A (zh) * | 1999-02-01 | 2002-03-27 | 阿迪尔公司 | 在口服途径给药之后延长释放甲磺吡脲的骨架片 |
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CN1111126A (zh) * | 1993-11-23 | 1995-11-08 | 欧罗赛铁克有限公司 | 具有难溶性药物速释片芯的缓释包衣片 |
CN1189774A (zh) * | 1995-07-03 | 1998-08-05 | 伊兰公司Plc | 难溶药物的控释制剂 |
CN1342068A (zh) * | 1999-02-01 | 2002-03-27 | 阿迪尔公司 | 在口服途径给药之后延长释放甲磺吡脲的骨架片 |
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