CN101439025B - 一种水飞蓟素高效长效制剂及其制法 - Google Patents
一种水飞蓟素高效长效制剂及其制法 Download PDFInfo
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- CN101439025B CN101439025B CN2008102429887A CN200810242988A CN101439025B CN 101439025 B CN101439025 B CN 101439025B CN 2008102429887 A CN2008102429887 A CN 2008102429887A CN 200810242988 A CN200810242988 A CN 200810242988A CN 101439025 B CN101439025 B CN 101439025B
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- silymarin
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Abstract
一种水飞蓟素高效长效制剂，它由水飞蓟素的固体分散体、水飞蓟素二氧化硅纳米粒、缓释骨架材料及促释放剂组成，它们之间的质量比为：水飞蓟素固体分散体∶载水飞蓟素二氧化硅纳米粒∶缓释骨架材料∶促释放剂＝1∶0.5～1.25∶0.1～0.3∶0.1～0.3，其中载水飞蓟素二氧化硅纳米粒的载药量为51.95％～52.87％，水飞蓟素固体分散体中包含聚维酮K30、大豆磷脂、丙烯酸树脂IV号，水飞蓟素与其它辅料的质量比为水飞蓟素∶聚维酮K30∶大豆磷脂∶丙烯酸树脂iv号＝1∶1～3∶0.3～0.8∶0.2～0.5。本发明的SLM高效长效制剂体内半衰期延长2.3倍，MRT延长7.94倍，SLM在Beagle犬体内释药曲线显示其释放平稳，实现了72小时的长效缓释效果。本发明公开了其制法。
Description
技术领域
本发明涉及缓释的高效长效药物制剂及其制法，特别是一种72小时缓释的水飞蓟素高效长效制剂及其制法。
背景技术
水飞蓟素(silymarin，SLM)是从水飞蓟种子中提取的一种新型黄酮类化合物，是一种淡黄色粉末状物质，主要成分有水飞蓟宾(silybin)、异水飞蓟宾(isosilybin)、水飞蓟宁(silydianin)、水飞蓟亭(silychristin)等。其中，以水飞蓟宾含量最高，活性也最强。它具有保肝、降血脂、抗氧化、防止糖尿病、保护心肌、抗血小板聚集和抗肿瘤等生理作用。[参见：Flora K，Hahn M，Rahn H，et al.Milk thisle(silybummarianum)for the therapy of live disease.Am J Gastroenterol，1998，93(13)：139.；闫玉峰，于建东.水飞蓟化学成分及药理研究进展[J].中国药事，2000，14(5)：335.]。由于SLM难溶于水，普通口服制剂生物利用度较低，近期有关SLM新剂型与新制剂研究集中于提高其口服制剂的生物利用度，如，制成卵磷脂复合物、固体分散体、环糊精包合物等[参见：Giacomelli S，Gallo D，Apollonio P，et al.Silybin and itsbioavailable phospholipid complex(IdB1016)potentiate in vitro and in vivo theactivity of cisplatin.Life Sci，2002，70(12)：1447；李凤前，胡晋红，朱全刚.水飞蓟宾固体分散体中总黄酮的测定.中草药，2002，33(1)：31；李凤前，胡晋红，王慧，等.PEG6000固体分散体系对难溶性药物水飞蓟素的增溶作用与晶格变化的关系.药学学报，2002，37(4)：294；Lirussi F，Beccarello A，Zanette G，et al.Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitusand alcoholic liver disease.Efficacy study of a new preparation of ananti-oxidant agent.Diabets Nutr Metab，2003，15(4)：222.]
固体分散技术由于其制备方法简单，增溶效果显著等优点，应用较为广泛[参见：邓莉等.水飞蓟素固体分散体的制备及体外溶出研究.第二军医大学学报.2000，21(10)：961.；Zhen-ping Wei，Shi-rui Mao，Dian-zhou Bi，et al.Dissolutionimprovement of cisapride by solid dispersion with HPMC.Journal of ChinesePharmaceutical Science，2004，13(4)：254.；Fude Cui，Mingshi Yang，Yanyan Jiang.Design of sustained-release nitrendipine microspheres having solid dispersionstructure by quasi-emulsion solvent diffusion method.Journal of ControlledRelease，2003，97(3)：375.]。难溶性药物制备成固体分散体后，可以增加药物的溶解度与溶出速率，改善药物的吸收，提高生物利用度，但仍存在频繁给药、峰谷浓度波动较大等缺点。缓控释制剂具有减少用药总剂量和用药次数、避免血浓峰谷现象、降低毒副作用、提高病人顺应性等优点，在临床上应用日益广泛[参见：Kathy W.Y.Lee，Tri-Hung Nguyen，Tracey Hanley，et al.Nanostructure of liquid crystallinematrix determines in vitro sustained release and in vivo oral absorption kineticsfor hydrophilic model drugs.International Journal of Pharmaceutics，2009，365(1-2)：190.；Jie-Xin Wang，Zhi-Hui Wang，Jian-Feng Chen，et al.Directencapsulation of water-soluble drug into silica microcapsules for sustainedrelease applications.Materials Research Bulletin，2008，43(12)：3374.]。将难溶性药物增溶后制备成缓释制剂，可以弥补药物增溶后产生的血药浓度波动较大、频繁给药等缺点。
近年来，具有特殊结构和特殊形貌的介孔材料研究备受关注。介孔(Mesopore)材料是孔径为2-50nm的多孔材料，根据介孔是否有序，可分为无序和有序两类。有序介孔材料结构具有以下特点：1.长程结构有序；2.孔径分布窄并可在1.5-10nm之间调节和控制；3.比表面高达1000m2/g；4.孔隙率高；5.表面富含不饱和基团等。有序介孔材料作为药物载体具有以下优点：1.本身无毒、无生理活性，生物相容；2.具有均匀可调的孔道，丰富的硅烷基可作为和有机客体分子反应的新的活性位点，有利于结合在活性位点上的药物均匀地分散在孔道内，使有序介孔材料吸附药物并具有缓释作用；3.能够保持药物结构的完整性。有序介孔材料作为疏水性药物的控释载体，能够获得理想的控释效果，不同孔道结构的有序介孔材料，控释效果不同。
本发明基于固体分散体的速释、亲水凝胶骨架材料的普通缓释、有序介孔材料的长效缓释“三重释药”机理，制备了一种兼具速释与双重缓释特征、高效与长效双重优点的72小时缓释的水飞蓟素高效长效制剂。
发明内容
将固体分散技术、有序介孔纳米粒制备技术、亲水凝胶骨架材料制备技术三者相结合，制备了一种生物利用度高、体内释药平稳、72小时缓释的水飞蓟素高效长效制剂。
本发明的技术方案如下：
一种水飞蓟素高效长效制剂，它由水飞蓟素的固体分散体、水飞蓟素二氧化硅纳米粒、缓释骨架材料及促释放剂组成，它们之间的质量比为：水飞蓟素固体分散体∶载水飞蓟素二氧化硅纳米粒∶缓释骨架材料∶促释放剂＝1∶0.5～1.25∶0.1～0.3∶0.1～0.3，其中载水飞蓟素二氧化硅纳米粒的载药量为51.95％～52.87％，水飞蓟素固体分散体中包含聚维酮K30、大豆磷脂、丙烯酸树脂IV号，水飞蓟素与其它辅料的质量比为水飞蓟素∶聚维酮K30∶大豆磷脂∶丙烯酸树脂iv号＝1∶1～3∶0.3～0.8∶0.2～0.5。
上述的水飞蓟素高效长效制剂为片剂或胶囊。
一种制备上述水飞蓟素高效长效制剂的方法，它基本上由下列步骤组成：
步骤1.称取水飞蓟素1g，PVP-K30 1-3g，大豆磷脂0.3-0.8g，丙烯酸树脂IV号0.2-0.5g，加入20-40ml无水乙醇溶解(必要时可置于70℃水浴中加速溶解)后，于60℃水浴，90rpm旋转蒸发至近干，于70℃水浴完全挥去溶剂，置-20℃冰箱中2h后，放置60℃烘箱12h，粉碎，过80目筛，得水飞蓟素固体分散体，备用；
步骤2.取20-80ml环己烷，加入NP-10 4-8ml，混匀；加入1-3ml正己醇，25.6％氨水1-3ml，室温搅拌1h；缓慢滴加正硅酸四乙酯3-5ml，室温搅拌24h；加入无水乙醇40-80ml，超声1h；在15000rpm，离心15min，沉淀用蒸馏水洗三次；加入适量水冷冻干燥，得到二氧化硅纳米粒粉末8g-32g；
取1g上述二氧化硅纳米粒加入0.6mol/L Na2CO3溶液1000ml，60-70℃，200W分别超声4-5min，15000rpm，离心15min，蒸馏水洗涤三次；加入10ml蒸馏水，冷冻干燥，得到介孔二氧化硅纳米粒；
取2g水飞蓟素，溶于10-20ml无水乙醇，加入1g介孔二氧化硅纳米粒浸润24小时，15000rpm离心15min，沉淀用无水乙醇洗三次，加入10ml蒸馏水冷冻干燥得载水飞蓟素纳米粒2g，载药量为51.95％～52.87％；
步骤3.取步骤1制得的水飞蓟素固体分散体1g，与羟丙甲纤维素K4M 0.2-0.3g、低取代羟丙基纤维素0.1-0.2g，混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒1；
步骤4.取步骤1制得的水飞蓟素固体分散体1g，与羟丙甲纤维素K4M0.1-0.2g、低取代羟丙基纤维素0.2-0.3g，步骤2制得的载水飞蓟素二氧化硅纳米粒1.25-2.5g混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒2；
步骤5.取步骤3制得的缓释颗粒1和步骤4制得的缓释颗粒2，按照缓释颗粒1∶缓释颗粒2＝1∶2.75～1∶4的比例混合后，压片，压力控制在40-60N，制得本发明的水飞蓟素高效长效片剂。
上述的水飞蓟素高效长效制剂的制备方法，它可以将步骤3制得的缓释颗粒1和步骤4制得的缓释颗粒2按照缓释颗粒1∶缓释颗粒2＝1∶2.75～1∶4的比例混合后灌装胶囊，制得本发明的水飞蓟素高效长效胶囊。
有益效果
1.本发明基于固体分散体的速释、亲水凝胶骨架材料的普通缓释、有序介孔材料的长效缓释“三重释药”机理，以速释与普通缓释相结合的“双释药”缓释制剂制备技术为基础，又充分利用有序介孔材料具有高的比表面和大的孔体积，有利于吸附药物，能够长时间缓慢释放药物的优点，选择有序介孔二氧化硅纳米粒为载体材料，将固体分散技术、有序介孔纳米粒制备技术、亲水凝胶骨架材料制备技术三者相结合，制备先速释、后缓释、再长效缓释的SLM长效缓释制剂，使其具有速释与双重缓释特征。所制备的SLM高效长效制剂及对照制剂经Beagle犬体内药动学研究，结果表明：SLM高效长效制剂体内半衰期延长2.3倍，MRT延长7.94倍，SLM在Beagle犬体内释药曲线显示其释放平稳，实现了72小时的长效缓释效果，结果见图3。
2.本发明采用固体分散技术与纳米技术的结合，一方面在制备SLM速释固体分散体时加入了大豆磷脂，可促进SLM的体内吸收；另一方面，由于纳米粒的运用，SLM纳米化后显著增加了SLM在机体内吸收的速度和程度，同样有利于提高SLM长效缓释制剂的生物利用度。因此，本发明制备的SLM缓释制剂既是一种长效缓释制剂，也是一种高效制剂，是兼具“高效与长效”双重优点的新型缓释制剂。所制备的SLM长效缓释制剂及对照制剂经Beagle犬体内药动学研究，结果表明：SLM长效缓释制剂相对生物利用度为3017％。可用于3天给药1次的现代高效长效缓释制剂的开发。
3.二氧化硅生物相容，安全无毒，来源广泛；用本发明的方法制备二氧化硅纳米粒，具有制备方法简单、不需要特殊设备、制备过程中影响因素少、重现性好等优点。
附图说明
图1为本发明制备的介孔二氧化硅纳米粒的透射电镜图；
图2为本发明制备的介孔二氧化硅纳米粒的粒径分布图；
图3为本发明制备的水飞蓟素高效长效缓释制剂Beagle犬体内药时曲线。
具体实施方式
以下实施例所用材料和仪器
实验材料：聚维酮K30(上海胜浦新型材料有限公司)；大豆磷脂(上海太伟药业有限公司)；IV号丙烯酸树脂(淮南山河药用辅料有限公司)；正硅酸四乙酯(国药集团化学试剂有限公司)；羟丙甲纤维素K4M(上海卡乐康包衣技术有限公司)；低取代羟丙基纤维素(上海卡乐康包衣技术有限公司)；NP-10(上海嘉芳贸易有限公司)。
实验仪器：旋转蒸发仪(Heidolph公司，德国)；H66025超声清洗机(无锡超声电子设备厂)；ADP单冲压片机(上海天祥健台制药机械有限公司)。
实施例一
称取SLM 1g，PVP-K30 1g，大豆磷脂0.2g，IV号丙烯酸树脂0.1g，加入20ml无水乙醇溶解(必要时可置于70℃水浴中加速溶解)后，于60℃水浴，90rpm旋转蒸发至近干，于70℃水浴完全挥去溶剂，置-20℃冰箱中2h后，放置60℃烘箱12h，粉碎，过80目筛，得固体分散体，备用。
取30ml环己烷，加入NP-104ml，混匀；加入1ml正己醇，25.6％氨水1ml，室温搅拌1h；缓慢滴加正硅酸四乙酯3ml，室温搅拌24h；加入无水乙醇40ml，超声1h；在15000rpm，离心15min，沉淀用蒸馏水洗三次；加入适量水冷冻干燥，得到二氧化硅纳米粒粉末。
取2g二氧化硅纳米粒加入0.6M Na2CO3 2000ml，60℃，200W分别超声4min，15000rpm，离心15min，蒸馏水洗涤三次；加入10ml蒸馏水，冷冻干燥，得到介孔二氧化硅纳米粒(见图1和图2)。
取3gSLM，溶于20ml无水乙醇，加入1.5g介孔二氧化硅纳米粒浸润24小时，15000rpm离心15min，沉淀用无水乙醇洗三次，加入10ml蒸馏水冷冻干燥得载药二氧化硅纳米粒。
取SLM固体分散体1g，与羟丙甲纤维素K4M 0.2g、低取代羟丙基纤维素0.2g，混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒1。
取取SLM固体分散体1.8g，与羟丙甲纤维素K4M 0.36g、低取代羟丙基纤维素0.4g，载药二氧化硅纳米粒2g混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒2。
缓释颗粒1和缓释颗粒2按照1∶2的比例混合后，压片，压力控制在40-60N，制得水飞蓟素高效长效片剂。
实施例二
称取SLM 1g，PVP-K30 3g，大豆磷脂0.8g，丙烯酸树脂IV号0.5g，加入40ml无水乙醇溶解(必要时可置于70℃水浴中加速溶解)后，于60℃水浴，90rpm旋转蒸发至近干，于70℃水浴完全挥去溶剂，置-20℃冰箱中2h后，放置60℃烘箱12h，粉碎，过80目筛，得固体分散体，备用。
取80ml环己烷，加入NP-10 8ml，混匀；加入3ml正己醇，25.6％氨水3ml，室温搅拌1h；缓慢滴加正硅酸四乙酯5ml，室温搅拌24h；加入无水乙醇80ml，超声1h；在15000rpm，离心15min，沉淀用蒸馏水洗三次；加入适量水冷冻干燥，得到二氧化硅纳米粒粉末。
取3g二氧化硅纳米粒加入0.6M Na2CO3 3000ml，60℃，200W分别超声4min，15000rpm，离心15min，蒸馏水洗涤三次；加入10ml蒸馏水，冷冻干燥，得到介孔二氧化硅纳米粒。
取3gSLM，溶于20ml无水乙醇，加入1.5g介孔二氧化硅纳米粒浸润24小时，15000rpm离心15min，沉淀用无水乙醇洗三次，加入10ml蒸馏水冷冻干燥得载药纳米粒。
取SLM固体分散体1.8g，与羟丙甲纤维素K4M 0.4g、低取代羟丙基纤维素0.4g，混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒1。
取SLM固体分散体1.8g，与羟丙甲纤维素K4M 0.36g、低取代羟丙基纤维素0.4g，载药二氧化硅纳米粒3g混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒2。
缓释颗粒1和缓释颗粒2按照2∶3的比例混合后，灌装胶囊，制得水飞蓟素高效长效胶囊。
实施例三
称取SLM 1g，PVP-K30 1.2g，大豆磷脂0.4g，丙烯酸树脂IV号0.3g，加入25ml无水乙醇溶解(必要时可置于70℃水浴中加速溶解)后，于60℃水浴，90rpm旋转蒸发至近干，于70℃水浴完全挥去溶剂，置-20℃冰箱中2h后，放置60℃烘箱12h，粉碎，过80目筛，得固体分散体，备用。
取30ml环己烷，加入NP-10 5ml，混匀；加入1.2ml正己醇，25.6％氨水1.5ml，室温搅拌1h；缓慢滴加正硅酸四乙酯3.5ml，室温搅拌24h；加入无水乙醇50ml，超声1h；在15000rpm，离心15min，沉淀用蒸馏水洗三次；加入适量水冷冻干燥，得到二氧化硅纳米粒粉末。
取1g二氧化硅纳米粒加入0.6M Na2CO3 1000ml，65℃，200W分别超声4.5min，15000rpm，离心15min，蒸馏水洗涤三次；加入10ml蒸馏水，冷冻干燥，得到介孔二氧化硅空心纳米粒。
取2gSLM，溶于20ml无水乙醇，加入1g介孔二氧化硅空心纳米粒浸润24小时，15000rpm离心15min，沉淀用无水乙醇洗三次，加入10ml蒸馏水冷冻干燥得载药纳米粒。
取SLM固体分散体1g，与羟丙甲纤维素K4M 0.2g、低取代羟丙基纤维素0.2g，混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒1。
取SLM固体分散体1g，与羟丙甲纤维素K4M 0.1g、低取代羟丙基纤维素0.3g，载药二氧化硅纳米粒2g混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒2。
缓释颗粒1和缓释颗粒2按照2∶3的比例混合后，压片，压力控制在40-60N，制得水飞蓟宾高效长效片剂。
实施例四
称取SLM1g，PVP-K30 1.5g，大豆磷脂0.5g，丙烯酸树脂IV号0.4g，加入30ml无水乙醇溶解(必要时可置于70℃水浴中加速溶解)后，于60℃水浴，90rpm旋转蒸发至近干，于70℃水浴完全挥去溶剂，置-20℃冰箱中2h后，放置60℃烘箱12h，粉碎，过80目筛，得固体分散体，备用。
取50ml环己烷，加入NP-10 6ml，混匀；加入2.2ml正己醇，25.6％氨水1.8ml，室温搅拌1h；缓慢滴加正硅酸四乙酯4.2ml，室温搅拌24h；加入无水乙醇60ml，超声1h；在15000rpm，离心15min，沉淀用蒸馏水洗三次；加入适量水冷冻干燥，得到二氧化硅纳米粒粉末。
取1g二氧化硅纳米粒加入0.6M Na2CO3 1000ml，65℃，200W分别超声4.5min，15000rpm，离心15min，蒸馏水洗涤三次；加入10ml蒸馏水，冷冻干燥，得到介孔二氧化硅空心纳米粒。
取2gSLM，溶于20ml无水乙醇，加入1g介孔二氧化硅纳米粒浸润24小时，15000rpm离心15min，沉淀用无水乙醇洗三次，加入10ml蒸馏水冷冻干燥得载药纳米粒。
取SLM固体分散体1g，与羟丙甲纤维素K4M 0.22g、低取代羟丙基纤维素0.22g，混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒1。
取SLM固体分散体1g，与羟丙甲纤维素K4M 0.15g、低取代羟丙基纤维素0.25g，载药二氧化硅纳米粒2g混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒2。
缓释颗粒1和缓释颗粒2按照2∶3的比例混合后，压片，压力控制在40-60N，制得水飞蓟宾高效长效片剂。
实施例五
称取SLM 1g，PVP-K30 2.5g，大豆磷脂0.7g，丙烯酸树脂IV号0.4g，加入40ml无水乙醇溶解(必要时可置于70℃水浴中加速溶解)后，于60℃水浴，90rpm旋转蒸发至近干，于70℃水浴完全挥去溶剂，置-20℃冰箱中2h后，放置60℃烘箱12h，粉碎，过80目筛，得固体分散体，备用。
取70ml环己烷，加入NP-10 6ml，混匀；加入1ml正己醇，25.6％氨水1.5ml，室温搅拌1h；缓慢滴加正硅酸四乙酯6ml，室温搅拌24h；加入无水乙醇60ml，超声1h；在15000rpm，离心15min，沉淀用蒸馏水洗三次；加入适量水冷冻干燥，得到二氧化硅纳米粒粉末。
取2g二氧化硅纳米粒加入0.6M Na2CO3 2000ml，70℃，200W分别超声5min，15000rpm，离心15min，蒸馏水洗涤三次；加入10ml蒸馏水，冷冻干燥，得到介孔二氧化硅空心纳米粒。
取2gSLM，溶于15ml无水乙醇，加入1g介孔二氧化硅空心纳米粒浸润24小时，15000rpm离心15min，沉淀用无水乙醇洗三次，加入10ml蒸馏水冷冻干燥得载药纳米粒。
取SLM固体分散体1.2g，与羟丙甲纤维素K4M 0.3g、低取代羟丙基纤维素0.3g，混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒1。
取SLM固体分散体1.8g，与羟丙甲纤维素K4M 0.36g、低取代羟丙基纤维素0.32g，载药二氧化硅纳米粒2g混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒2。
缓释颗粒1和缓释颗粒2按照1∶1的比例混合后，压片，压力控制在40-60N，制得水飞蓟宾高效长效片剂。
实施例六
称取SLM 1g，PVP-K30 2g，大豆磷脂0.8g，丙烯酸树脂IV号0.2g，加入40ml无水乙醇溶解(必要时可置于70℃水浴中加速溶解)后，于60℃水浴，90rpm旋转蒸发至近干，于70℃水浴完全挥去溶剂，置-20℃冰箱中2h后，放置60℃烘箱12h，粉碎，过80目筛，得固体分散体，备用。
取60ml环己烷，加入NP-10 5ml，混匀；加入1ml正己醇，25.6％氨水1.5ml，室温搅拌1h；缓慢滴加正硅酸四乙酯5.5ml，室温搅拌24h；加入无水乙醇70ml，超声1h；在15000rpm，离心15min，沉淀用蒸馏水洗三次；加入适量水冷冻干燥，得到二氧化硅纳米粒粉末。
取2g二氧化硅纳米粒加入0.6M Na2CO3 2000ml，70℃，200W分别超声5min，15000rpm，离心15min，蒸馏水洗涤三次；加入10ml蒸馏水，冷冻干燥，得到介孔二氧化硅空心纳米粒。
取2gSLM，溶于15ml无水乙醇，加入1g介孔二氧化硅空心纳米粒浸润24小时，15000rpm离心15min，沉淀用无水乙醇洗三次，加入10ml蒸馏水冷冻干燥得载药纳米粒。
取SLM固体分散体1.4g，与羟丙甲纤维素K4M 0.3g、低取代羟丙基纤维素0.3g，混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒1。
取SLM固体分散体2.1g，与羟丙甲纤维素K4M 0.42g、低取代羟丙基纤维素0.48g，载药二氧化硅纳米粒2g混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒2。
缓释颗粒1和缓释颗粒2按照1∶1的比例混合后，压片，压力控制在40-60N，制得水飞蓟宾高效长效片剂。
Claims (4)
1.一种水飞蓟素高效长效制剂，其特征是：它包含了水飞蓟素的固体分散体、水飞蓟素二氧化硅纳米粒、缓释骨架材料及促释放剂组成，它们之间的质量比为：水飞蓟素固体分散体∶载水飞蓟素二氧化硅纳米粒∶缓释骨架材料∶促释放剂＝1∶0.5～1.25∶0.1～0.3∶0.1～0.3，其中载水飞蓟素二氧化硅纳米粒的载药量为51.95％～52.87％，水飞蓟素固体分散体中包含聚维酮K30、大豆磷脂、丙烯酸树脂IV号，水飞蓟素与其它辅料的质量比为：水飞蓟素∶聚维酮K30∶大豆磷脂∶丙烯酸树脂iv号＝1∶1～3∶0.3～0.8∶0.2～0.5，所述的促释放剂为低取代羟丙基纤维素，所述的缓释骨架材料为羟丙甲纤维素K4M。
2.根据权利要求1所述的水飞蓟素高效长效制剂，其特征是：片剂或胶囊。
3.一种制备权利要求1所述水飞蓟素高效长效制剂的方法，其特征是它基本上由下列步骤组成：
步骤1.称取水飞蓟素1g，PVP-K301-3g，大豆磷脂0.3-0.8g，丙烯酸树脂IV号0.2-0.5g，加入20-40ml无水乙醇溶解后，于60℃水浴，90rpm旋转蒸发至近干，于70℃水浴完全挥去溶剂，置-20℃冰箱中2h后，放置60℃烘箱12h，粉碎，过80目筛，得水飞蓟素固体分散体，备用；
步骤2.取20-80ml环己烷，加入NP-104-8ml，混匀；加入1-3ml正己醇，25.6％氨水1-3mL，室温搅拌1h；缓慢滴加正硅酸四乙酯3-5ml，室温搅拌24h；加入无水乙醇40-80ml，超声1h；在15000rpm，离心15min，沉淀用蒸馏水洗三次；加入适量水冷冻干燥，得到二氧化硅纳米粒粉末8g-32g；
取1g上述的二氧化硅纳米粒加入0.6mol/L Na2CO31000ml，60-70℃，200W分别超声4-5min，15000rpm，离心15min，蒸馏水洗涤三次；加入10ml蒸馏水，冷冻干燥，得到介孔二氧化硅纳米粒；
取2g水飞蓟素，溶于10-20ml无水乙醇，加入1g介孔二氧化硅纳米粒浸润24小时，15000rpm离心15min，沉淀用无水乙醇洗三次，加入10ml蒸馏水冷冻干燥得载水飞蓟素二氧化硅纳米粒2g，载药量为51.95％～52.87％；
步骤3.取步骤1制得的水飞蓟素固体分散体1g，与羟丙甲纤维素K4M 0.2-0.3g、低取代羟丙基纤维素0.1-0.2g，混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒1；
步骤4.取步骤1制得的水飞蓟素固体分散体1g，与羟丙甲纤维素K4M0.1-0.2g、低取代羟丙基纤维素0.2-0.3g，步骤2制得的载水飞蓟素二氧化硅纳米粒1.25-2.5g混匀后，加入适量70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘30分钟后取出，过16目筛整粒，得缓释颗粒2；
步骤5.将步骤3制得的缓释颗粒1和步骤4制得的缓释颗粒2，按照缓释颗粒1∶缓释颗粒2＝1∶2.75～1∶4的比例混合后，压片，压力控制在40-60N，即制得水飞蓟素高效长效片剂。
4.根据权利要求3所述的水飞蓟素高效长效制剂的制备方法，其特征是：将步骤3制得的缓释颗粒1和步骤4制得的缓释颗粒2按照缓释颗粒1∶缓释颗粒2＝1∶2.75～1∶4的比例混合后灌装胶囊，制得水飞蓟素高效长效胶囊。
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| CN1543943A (zh) * | 2003-11-26 | 2004-11-10 | 沈阳药科大学 | 口服水飞蓟素缓释制剂及其制备方法 |
| CN1561201A (zh) * | 2001-09-28 | 2005-01-05 | 诺瓦提斯公司 | 包含胶态二氧化硅的药物组合物 |
| US20070166255A1 (en) * | 2004-11-22 | 2007-07-19 | Gupta Shyam K | Treatment of Topical Discomforts Including Acne, Sunburn, Diaper Rash, Wound, Wrinkles and Dandruff/Hair Loss by Natural Lignans via Fatty Acid Desaturase Inhibition |
| CN101164537A (zh) * | 2006-10-16 | 2008-04-23 | 江苏大学 | 高效口服水飞蓟宾缓释制剂及其制备方法 |
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| US6699900B2 (en) * | 2001-04-07 | 2004-03-02 | Jan E. Zielinski | Hydrophilic and lipophilic silibinin pro-forms |
| EP1499895B1 (en) * | 2002-04-22 | 2008-05-07 | University Of Florida | Functionalized nanoparticles and methods of use |
| AU2004249211A1 (en) * | 2003-06-16 | 2004-12-29 | Andrx Pharmaceuticals, Llc | Oral extended-release composition |
| WO2006023286A2 (en) * | 2004-08-19 | 2006-03-02 | Alza Corporation | Controlled release nanoparticle active agent formulation dosage forms and methods |
| US20060068022A1 (en) * | 2004-09-29 | 2006-03-30 | Playford Raymond J | Bioactive agent compositions for repair of cell injuries |
| ITMI20051942A1 (it) * | 2005-10-14 | 2007-04-15 | S I I T S R L Servizio Interna | Composizioni galattogeniche a base di silimarina |
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| CN1561201A (zh) * | 2001-09-28 | 2005-01-05 | 诺瓦提斯公司 | 包含胶态二氧化硅的药物组合物 |
| CN1543943A (zh) * | 2003-11-26 | 2004-11-10 | 沈阳药科大学 | 口服水飞蓟素缓释制剂及其制备方法 |
| US20070166255A1 (en) * | 2004-11-22 | 2007-07-19 | Gupta Shyam K | Treatment of Topical Discomforts Including Acne, Sunburn, Diaper Rash, Wound, Wrinkles and Dandruff/Hair Loss by Natural Lignans via Fatty Acid Desaturase Inhibition |
| CN101164537A (zh) * | 2006-10-16 | 2008-04-23 | 江苏大学 | 高效口服水飞蓟宾缓释制剂及其制备方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2010075663A1 (zh) | 2010-07-08 |
| US8962017B2 (en) | 2015-02-24 |
| US20110201680A1 (en) | 2011-08-18 |
| CN101439025A (zh) | 2009-05-27 |
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