CN104473907A - 一种他克莫司的口服缓释制剂 - Google Patents
一种他克莫司的口服缓释制剂 Download PDFInfo
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Abstract
本发明公开了一种他克莫司缓释胶囊及其制备方法。本片剂处方中含有他克莫司，还包括满足制剂需要的骨架材料、填充剂、成膜剂和润滑剂。制备方法如下：部分他克莫司与骨架材料、填充剂制颗粒，剩余他克莫司与骨架材料、成膜剂配制成喷雾液，颗粒置于包衣锅中，喷入喷雾液包衣，制备小丸。小丸干燥后与润滑剂混合均匀灌装胶囊。本发明特点是制剂释药稳定，增加了用药安全性，延长了药物作用时间。
Description
技术领域
本发明属于医药制剂领域，具体涉及一种他克莫司缓释胶囊及其制备方法。该他克莫司缓释胶囊为口服，其中部分他克莫司与特定辅料制粒；剩余他克莫司与其他辅料配成溶液后于包衣锅中喷雾包裹在颗粒上，制备成小丸；小丸与润滑剂混合后灌装胶囊。采用本工艺制备的缓释制剂释药稳定，延长了药物作用时间。
背景技术
他克莫司(tacrolimus)原名FK506，是1984年由日本滕泽制药公司从土壤真菌(链霉菌Streptomyces Tsukubaensis)中所提取到的一种大环内酷类免疫抑制剂，当时实验命名FK506后正式命名为他克莫司，商品名为普乐可复(prograf)。1989年Starzl等首次用于肝移植，取得良好效果。FK506和环孢素(Cyclosporin CsA)免疫抑制作用十分相似，但FK506的作用约是CsA的10～100倍。他克莫司的结构属于23元大环内酯类抗生素，由亲免疫性蛋白的结合区段与结合后发挥免疫抑制效应的效应区段两部分组成，具有高度脂溶性，分子量为822.05，广泛分布于各组织中，具有强大的免疫抑制作用。最早口服和静脉滴注用于骨髓移植和肝肾移植后预防排斥反应。FK506在器官移植中的应用非常广，临床主要用于各种急性排斥反应。但该药的有效血药浓度范围较窄，血药浓度稍高即可出现毒副作用，如：轻微的肾毒性、神经毒性及高血压、失眠、恶心等；稍低则出现排斥反应。由于他克莫司的这一特点，要求用药后血药浓度平稳，缓释制剂是最适宜的给药方式。
骨架型缓控释制剂是指药物与一种或多种骨架材料通过压制技术制成的制剂。药物分散在骨架材料中，通过溶出、扩散或骨架溶蚀等机制释放药物，使药物缓慢释放。骨架型缓控释制剂因其科技含量髙，处方设计合理，制备工艺简单，药物质量容易控制，且采用常规的生产设备和工艺即可生产，成本低廉等优点，在医药工业生产中已得到广泛应用。溶蚀型骨架制剂是利用骨架的阻滞作用，将药物以不同配比溶解或混悬于骨架中、制粒、压片而制得。骨架材料遇消化液后可逐渐蚀解，药物随骨架溶蚀而从溶蚀表面释放或通过骨架间隙扩散而释放。溶蚀性材料由于基本无毒、无刺激性，每日允许摄入量不受限制且可用于提高水不溶性药物体内生物利用度，其释药机制主要是溶蚀—分散—溶出过程。
可用于溶蚀型骨架的材料包括生物可降解材料和亲水凝胶骨架材料两种。生物降解骨架材料主要是指疏水性强的脂肪类或蜡类及其酯类物质，包括动物脂、蜂蜡、硬脂醇、单硬脂酸甘油醋、十八烷醇等。随着骨架材料在介质中逐渐溶蚀降解，药物渐渐从骨架中释放，释放速率取决于骨架材料的用量及其溶蚀性。还可以在制剂处方中加入一些表面活性剂如硬脂 酸钠、三乙醇胺等以加快骨架的溶蚀，可在不同程度上增加药物的释放速率。亲水凝胶骨架材料主要是指那些遇水或消化液后，能够迅速发生水化并吸水膨胀，可以通过形成凝胶层屏障而控制药物释放的物质。常用的亲水凝胶骨架材料可分为四类：包括①天然植物或动物胶如海藻酸盐、琼脂、西黄著胶等；②高分子聚合物如聚维酮、乙烯聚合物、丙稀酸树脂、聚乙稀醇等；③纤维素衍生物如甲基纤维素、羟丙甲纤维素、羟乙基纤维素、羧甲基纤维素钠等；④非纤维素多糖类如甲壳素、卡波姆、半乳糖甘露聚糖等。药物主要通过扩散作用透过凝胶层而释放，药物在凝胶层中的扩散速率取决于药物本身的性质和骨架材料形成凝胶层的黏度和用量，一般情况下，凝胶层越厚，释放速率越慢。
发明内容
本发明涉及一种缓释胶囊剂，该制剂包括：药物活性成分大环内酯类免疫抑制剂他克莫司，溶蚀骨架材料如羟丙甲纤维素、卡波姆、羟乙基纤维素、羟甲基纤维素钠和聚乙烯醇等，填充剂如蔗糖、淀粉、微晶纤维素、乳糖、甘露醇和山梨醇等，成膜剂如不同分子量聚乙二醇、甘油，润滑剂如硬脂酸镁、滑石粉和二氧化硅等。
本发明涉及的他克莫司缓释胶囊制备方法如下：
将部分他克莫司与骨架材料、填充剂分别过80目筛后混匀，以水作为粘合剂，于一步制粒机中制粒，整粒和干燥后，筛去细粉，保留30目以下颗粒。将溶蚀型骨架材料溶解于水中，加入成膜材料溶解，将剩余的他克莫司溶解于乙醇后两部分液体混合，作为喷雾液。将制备好的颗粒置于包衣锅中滚转，不断喷入上述喷雾液，并吹干。反复操作，直至喷雾液全部用完，继续滚至圆形小丸为止，干燥。小丸与润滑剂混匀后灌装胶囊。制备的胶囊溶出平稳。
附图说明
图1是实施例1、实施例3和实施例4的溶出释放曲线。
具体实施方式
以下实施例用于对本发明进行举例说明，并无意于限定本发明的范围。
实施例1
他克莫司 100克
微晶纤维素 250克
羟丙甲纤维素 80克
将他克莫司、微晶纤维素和羟丙甲基纤维素过80目筛，以水作为粘合剂，于一步制粒机中制粒，整粒和干燥后，筛去细粉，保留30目以下颗粒。
将羟丙甲基纤维素和聚乙二醇溶解在水中，他克莫司溶解于乙醇中，两部分液体混合。制备好的颗粒置于包衣锅中滚转，不断喷入上述液体，并吹干。反复操作，直至液体全部用完，继续滚至圆形小丸为止，干燥。小丸与润滑剂混匀后灌装胶囊。
实施例2
将他克莫司、乳糖和羟丙甲基纤维素过80目筛，以水作为粘合剂，于一步制粒机中制粒，整粒和干燥后，筛去细粉，保留30目以下颗粒。
将羟丙甲纤维素和聚乙二醇溶解在水中，他克莫司溶解于乙醇中，两部分液体混合。制备好的颗粒置于包衣锅中滚转，不断喷入上述液体，并吹干。反复操作，直至液体全部用完，继续滚至圆形小丸为止，干燥。小丸于润滑剂混匀后灌装胶囊。
实施例3
他克莫司 100克
微晶纤维素 150克
羟丙甲纤维素 150克
将他克莫司、微晶纤维素和羟丙甲纤维素过80目筛，以水作为粘合剂，于一步制粒机中制粒，整粒和干燥后，筛去细粉，保留30目以下颗粒。
将羟丙甲纤维素和聚乙二醇溶解在水中，他克莫司溶解于乙醇中，两部分液体混合。制备好的颗粒置于包衣锅中滚转，不断喷入上述液体，并吹干。反复操作，直至液体全部用完，继续滚至圆形小丸为止，干燥。小丸与润滑剂混匀后灌装胶囊。
实施例4
他克莫司 100克
微晶纤维素 150克
卡波姆 150克
将他克莫司、微晶纤维素和羟丙甲纤维素过80目筛，以水作为粘合剂，于一步制粒机中制粒，整粒和干燥后，筛去细粉，保留30目以下颗粒。
将羟丙甲纤维素和聚乙二醇溶解在水中，他克莫司溶解于乙醇中，两部分液体混合。制备好的颗粒置于包衣锅中滚转，不断喷入上述液体，并吹干。反复操作，直至液体全部用完，继续滚至圆形小丸为止，干燥。小丸与润滑剂混匀后灌装胶囊。
释放度试验：
测定样品为实施例1、实施例3和实施例4制备的缓释胶囊。根据中国药典2010年版第二部附录XC测定第二法，在溶出仪中加入测定样品10ml，转速为每分钟75转，使用900ml含0.1％十二烷基硫酸钠的水溶液。在第4h、8h、16h和24h取样，利用高效液相色谱法测定释放度，溶出结果见图1。
图1的释放曲线可以看出，本发明的他克莫司缓释胶囊在24小时内可持续稳定的释放药物，保证血药浓度的稳定，达到了本发明的目的。
Claims (4)
1.一种他克莫司缓释胶囊，其特征在于：他克莫司分别存在于颗粒和包衣层上；颗粒除他克莫司外还包括填充剂和骨架材料，包衣层除他克莫司外还包括骨架材料和成膜剂；颗粒经包衣后形成小丸，与润滑剂混匀后填充胶囊。
2.权利要求1中所述骨架材料为羟丙甲基纤维素、卡波姆、羟乙基纤维素、羟甲基纤维素钠和聚乙烯醇中的一种或几种。
3.权利要求1中所述填充剂为蔗糖、淀粉、微晶纤维素、乳糖、甘露醇和山梨醇中的一种或几种。
4.权利要求1中所述成膜材料为柠檬酸三乙酯、PEG4000、PEG6000、甘油和丙二醇中的一种或几种。
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