CN100496486C - 一种难溶性药物的控释制剂 - Google Patents
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Abstract
一种难溶性药物的控释制剂，制剂中含有聚乙二醇水溶性树脂，这种树脂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
难溶性药物中有一些如硝苯地平(Nifedipine)、非洛地平(Felodipine)，是非解离型的，在胃肠系统有较低的溶解度；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。例如格列齐特(Gliclazide)的溶解度在酸性pH值时非常小，pH升高时略有提高；西沙必利(Cisapride)自身呈碱性，在胃肠系统上段的酸性条件下有较低的溶解度，进一步下移则表现出更弱的溶解度。
目前实现零级释药系统较为可靠的手段仍为渗透泵制剂，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。
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。本技术无需打孔及半透膜包衣等高技术难度、高成本的技术。
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。
专利US6090411中将骨架材料羟丙基甲基纤维素K4M或聚乙二醇4M与占骨架材料重量50％-100％的无机盐(如氯化钠、氯化钙、碳酸氢钠、碳酸氢钾、
硫酸氢钠、硫酸钠、硫酸镁等)组合用于药物系统，这里无机盐并非用作pH调节剂，当遇到水性介质时，无机盐在骨架外围形成一个硬化的边界，控制水由外向内的扩散速率，从而使释药接近零级，并且对于pH介于1.5-7.5的溶出介质，药物释放行为与pH变化无关。
本发明中采用纤维素聚合物或多种辅料的组合，仅将高分子量的聚氧乙烯应用于难溶性药物的控释制剂中，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。
本发明者进一步发现，通过对上述技术制备的片剂包衣，可避免药物在胃中释放，实现在肠道范围内的拟零级释药。
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)、格列本脲(Glyburide)等。生理活性物质的重量百分比为0.1％-50％，最优重量百分比为10％-30％。
聚氧乙烯为白色、自由流动的亲水性粉末，特指高分子量的非离子型聚乙二醇聚合物，分子量范围为100,000-7,000,000。表1显示了Dow公司不同型号的聚氧乙烯POLYOX(NF级)相应的分子量。
表1 POLYOX(NF级)不同型号及对应分子量
在水中高分子量的聚氧乙烯能非常迅速地形成水凝胶，控制药物的释放，从而使得含有聚氧乙烯的释药系统比其它系统更易于达到零级释放行为。本发明中将聚氧乙烯与难溶性药物、其它辅料等共混后制软材或直接压片，其中聚氧乙烯的重量百分比为10％-60％，对于分子量为4,000,000的聚氧乙烯，优选重量百分比为15％-35％。
为实现本发明，在聚氧乙烯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。
在制备软材的过程中，可以根据不同型号的聚氧乙烯选择不同浓度的乙醇水溶液作为润湿剂。
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。
本发明中用来进行片剂包衣的聚合物材料为单独的或混合在一起的可溶或不溶性纤维素衍生物，如羟丙甲纤维素酞酸酯、醋酸羟丙甲纤维素琥珀酸酯、乙基纤维素或其与纤维素类衍生物的混合物，或丙烯酸树脂，如
或相互间的混合物等。可使药物在胃中不释放，仅在肠中释放。
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、POLYOX 301、磷酸氢钙二水合物、微晶纤维素pH101按等量递加法混匀，以70％乙醇水溶液制软材，过24目筛，45℃烘干后加入硬脂酸镁，压片。
实施例2
制备工艺：
格列齐特、POLYOX 301、磷酸氢钙二水合物、微晶纤维素pH101按等量递加法混匀，以90％乙醇水溶液制软材，过24目筛，45℃烘干后加入硬脂酸镁，压片。
实施例3
制备工艺：
西沙必利、POLYOX 1105、微晶纤维素pH101按等量递加法混匀，以95％乙醇溶液制软材，过24目筛，45℃烘干后加入硬脂酸镁，压片。
实施例4
制备工艺：
将非洛地平和聚维酮K30溶于适量95％乙醇，使之完全溶解，得溶液A；POLYOX 301、乳糖、微晶纤维素pH101、聚乙二醇4000按等量递加法混匀，以溶液A制软材，过24目筛，45℃烘干后加入硬脂酸镁，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(pH6.0，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。
实施例1
实施例2
实施例3
实施例4
实施例5
将实施例2制备的片剂置于包衣锅内，先包隔离层，再以含有Eudragit L的乙醇溶液包衣，包衣增重为4％。试验表明在0.1mol/l的盐酸溶液中2h药物无释放，片表面衣层无破裂现象；在释放介质为pH6.0、pH6.8和pH7.8的三种磷酸盐缓冲液中释放曲线基本同实施例2。
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 (3)
1.一种含有格列齐特的控释制剂，其特征在于含有占重量百分比15％的格列齐特、15％的POLYOX301、40％的磷酸氢钙二水合物、29.40％的微晶纤维素PH101和0.60％的硬脂酸镁。
2.一种含有格列齐特的控释制剂，其特征在于含有占重量百分比15％的格列齐特、25％的POLYOX301、37.30％的磷酸氢钙二水合物、22.10％的微晶纤维素PH101和0.60％的硬脂酸镁。
3.如权利要求1所述的制剂，其特征在于采用直接压片或湿法制粒后压片制备。
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Non-Patent Citations (4)
| Title |
|---|
| Development and characterizationof buccal adhesivenifedipine tablets. J. Varshosaz, Z. Dehghan.European Journal of FPharmaeutics and Biopharmaceutics,Vol.54 . 2002 |
| Development and characterizationof buccal adhesivenifedipine tablets. J. Varshosaz, Z. Dehghan.European Journal of FPharmaeutics and Biopharmaceutics,Vol.54. 2002 * |
| Effects of drug solubility, drug loading, andpolymermolecularweight on drug release from polyox?tablets. Kim C.-J.Drug Development and Industrial Pharmacy,Vol.24 No.7. 1998 |
| Effects of drug solubility, drug loading, andpolymermolecularweight on drug release from polyox?tablets. Kim C.-J.Drug Development and Industrial Pharmacy,Vol.24 No.7. 1998 * |
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