CN110898015A - 一种伊曲康唑制剂的制备方法 - Google Patents
一种伊曲康唑制剂的制备方法 Download PDFInfo
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- CN110898015A CN110898015A CN201911406153.5A CN201911406153A CN110898015A CN 110898015 A CN110898015 A CN 110898015A CN 201911406153 A CN201911406153 A CN 201911406153A CN 110898015 A CN110898015 A CN 110898015A
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- itraconazole
- cyclodextrin
- preparing
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- granules
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Abstract
本发明涉及一种伊曲康唑制剂的制备方法，包括以下具体步骤：将伊曲康唑溶于醇性溶剂中，将环糊精与水配成溶液，然后将伊曲康唑溶液倒入环糊精水溶液中，形成环糊精包合伊曲康唑的包合物，作为粘合剂；将填充剂和崩解剂充分混匀，加入所述粘合剂经湿法制粒得到颗粒；将所得颗粒于55℃至65℃干燥至水份小于3.0%后整粒。本发明的伊曲康唑制剂的制备方法能有效提高伊曲康唑的溶解度和溶出度，工艺过程简洁，有利于环保。
Description
技术领域
本发明涉及一种伊曲康唑制剂的制备方法，属于生物医药技术领域。
背景技术
伊曲康唑（Itraconazole）为新一代三唑类高效广谱抗真菌药，可结合真菌细胞色素P450同工酶，抑制其麦角甾醇合成。本品对皮肤癣菌、念珠菌属、新生隐球菌、糠秕孢子菌属、曲霉菌属、组织胞浆菌属、巴西副球孢子菌、申克孢子丝菌、着色真菌属、枝孢霉属、皮炎芽生菌等感染有效。主要应用于深部真菌所引起的系统感染，如芽生菌病、组织胞浆菌病、类球孢子菌病、着色真菌病、孢子丝菌病、球孢子菌病等。也可用于念珠菌病和曲菌病。
伊曲康唑口服给药的生物利用度低，因其在水中的溶解度不到1ug/ml，pKa值为3.7，因此在胃液中仍保持未解离的状态。其口服生物利用度个体内和个体间有很大的差异，此外还取决于摄入的食物等因素。
为改善伊曲康唑的溶解度和溶出度，从而提高其生物利用度，已经有多种技术和公开专利。国际专利WO94/05263公开了一种包衣小丸，其将伊曲康唑和羟丙基甲基纤维素溶于二氯甲烷和温水乙醇溶液中，通过流化床将溶液喷在600～700微米的糖丸上，真空干燥后再用聚乙二醇的二氯甲烷溶液包衣后，将小丸装入硬胶囊。工艺中多次用到有毒有害的二氯甲烷，而且需要用到昂贵的流化床设备，还需要防爆。有报道称，该胶囊的绝对生物利用度约为30%，而且不稳定，个体内和个体间有很大的差异，还收饮食的影响。
中国专利文献CN1086579C（申请号：94193602.3）公开了一种用羟丙基倍他环糊精做增溶剂配制的伊曲康唑溶液。口服液中采用了40～60%的羟丙基倍他环糊精，即伊曲康唑与羟丙基倍他环糊精的比例高达1∶40～1∶60。由于成本羟丙基倍他环糊精的价格比较高，因此口服液的成本也十分昂贵；而且产品的稳定性较差，需要充氮气保存；此外，其口感也不太好，需要加入樱桃味香精掩味。
中国专利文献CN1285590C（申请号：200410016484.5）公开了一种伊曲康唑盐酸盐及其口服固体组合物，该专利技术通过在伊曲康唑溶液的有机溶剂（丙酮）中通入氯化氢气体使其成盐酸盐后与环糊精混合。该方法先通过反应将伊曲康唑制成盐酸盐，不仅用到大量的有机溶剂丙酮、乙醇和刺激性强的氯化氢气体，而且制备的时间长，需要冷却，过滤，冲洗，烘干等步骤。虽然提高溶解度和溶出度，但还要涉及到伊曲康唑的反应率和利用率，用到和有机溶剂丙酮等，过程周期长，既不利于环保，实现大生产也有难度。
发明内容
本发明要解决的技术问题是提供一种能有效提高伊曲康唑的溶解度和溶出度，工艺过程简洁，有利于环保的伊曲康唑制剂的制备方法。
本发明为解决上述技术问题提出的一种技术方案是：一种伊曲康唑制剂的制备方法，包括以下具体步骤：
A．将伊曲康唑溶于醇性溶剂中，将环糊精与水配成溶液，然后将伊曲康唑溶液倒入环糊精水溶液中，形成环糊精包合伊曲康唑的包合物，作为粘合剂；
B．将填充剂和崩解剂充分混匀，加入所述粘合剂经湿法制粒得到颗粒；
C．将所得颗粒于55℃至65℃干燥至水份小于3.0%后整粒。
上述伊曲康唑与环糊精的质量比为1∶5至5∶1。
上述伊曲康唑与环糊精的质量比为1∶2至2∶1。
上述醇性溶剂是乙醇、异丙醇、丙二醇、聚乙二醇、盐酸乙醇和苯甲醇中的一种或多种；所述环糊精是α-环糊精、β-环糊精、γ-环糊精、羟丙基-β-环糊精和甲基-β-环糊精中的一种或多种；所述填充剂是淀粉、糖粉、糊精、乳糖、可压性淀粉、微晶纤维素、磷酸氢钙、甘露醇、山梨醇和异麦芽酮糖醇中的一种或多种；所述崩解剂是交联羧甲基纤维素钠、交联聚维酮、干淀粉、羧甲基淀粉钠、羟丙基淀粉和低取代羟丙基纤维素中的一种或多种。
上述伊曲康唑制剂的制备方法是将整粒后的颗粒加入胶囊，制成胶囊剂。
上述伊曲康唑制剂的制备方法是将整粒后的颗粒按一定重量装入铝箔袋中，制成颗粒剂。
上述伊曲康唑制剂的制备方法是将整粒后的颗粒与药用辅料混合均匀后，压制成片剂。
上述药用辅料是润滑剂、润湿剂、抗氧化剂和风味剂中的一种或多种。
上述润滑剂是硬脂酸镁、山嵛酸甘油酯，二氧化硅，滑石粉，氢化植物油，聚乙二醇类与月桂醇硫酸镁中的一种或多种；所述润湿剂是纯水、乙醇和异丙醇中的一种或多种；所述抗氧化剂是二丁基羟基甲苯、丁基羟基茴香醚、特丁基对苯二酚、没食子酸丙酯、维生素E、维生素E醋酸酯、维生素C、亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠和硫代硫酸钠中的一种或多种。
上述风味剂是肉类风味香精或水果类风味香精。
本发明具有积极的效果：本发明的伊曲康唑制剂的制备方法，将伊曲康唑制成溶液与环糊精溶液混合后，形成包合物，作为粘合剂，再与辅料混合制粒。由于用到的环糊精量少，与溶液相比，既能大大降低成本，又能增加伊曲康唑的稳定性。本发明的伊曲康唑制剂的制备方法既不需要用到二氯甲烷、氯化氢等有毒有害的有机溶剂和气体，也不需要昂贵的流化床设备和特殊的熔融挤出设备，不仅能提高伊曲康唑的溶解度和溶出度，而且有利于环保。本发明的伊曲康唑制剂的制备方法工艺过程简洁，产品质量可控，非常适合大规模商业化生产。
附图说明
图1是不同伊曲康唑制剂的溶出度曲线图。
具体实施方式
实施例1
本实施例的伊曲康唑片剂的制备方法是将100g的羟丙基-β-环糊精加50g水制成水溶液。将100g的伊曲康唑溶于无水乙醇-盐酸中，加入羟丙基-β-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将200g的微晶纤维素和95g的羧甲淀粉钠混合均匀后，加入粘结剂中经湿法制粒，于20目筛湿整粒后，于60℃干燥至水分小于3.0%。 干颗粒用20目筛整理后，加入适量的二氧化硅和硬脂酸镁，混合均匀后，按照500mg/片的片重压片。
实施例2
本实施例的伊曲康唑胶囊剂的制备方法是将100g的羟丙基-β-环糊精加50g水制成水溶液。将100g的伊曲康唑溶于适量的无水乙醇-盐酸中，加入羟丙基-β-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将200g的微晶纤维素和95g的羧甲淀粉钠混合均匀后，加入粘结剂中经湿法制粒，于20目筛湿整粒后，于60℃干燥至水分小于3.0%。干颗粒粉碎成粉后过120目筛，按照伊曲康唑100mg/粒的量将粉装入0号硬胶囊。
实施例3
本实施例的伊曲康唑颗粒剂的制备方法是将20g的α-环糊精加20g水制成水溶液。将100g的伊曲康唑溶于适量无水乙醇中，加入α-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将150g的乳糖和30g的交联聚维酮混合均匀后，加入粘结剂中经湿法制粒，于60℃干燥至水份小于3.0%后整粒。
实施例4
本实施例的伊曲康唑颗粒剂的制备方法是将100g的羟丙基-β-环糊精加50g水制成水溶液。将100g的伊曲康唑溶于适量无水乙醇中，加入羟丙基-β-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将80g的异麦芽酮糖醇和20g的交联聚维酮混合均匀后，加入粘结剂中经湿法制粒，于60℃干燥至水份小于3.0%后整粒。
实施例5
本实施例的伊曲康唑颗粒剂的制备方法是将100g的β-环糊精加50g水制成水溶液。将20g的伊曲康唑溶于适量无水乙醇中，加入β-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将150g的微晶纤维素和30g的交联羧甲基纤维素钠混合均匀后，加入粘结剂中经湿法制粒，于60℃干燥至水份小于3.0%后整粒。
实施例6
本实施例的伊曲康唑颗粒剂的制备方法是将50g的β-环糊精加50g水制成水溶液。将100g的伊曲康唑溶于适量无水乙醇中，加入β-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将200g的磷酸氢钙和50g的交联羧甲基纤维素钠混合均匀后，加入粘结剂中经湿法制粒，于60℃干燥至水份小于3.0%后整粒。
实施例7
本实施例的伊曲康唑颗粒剂的制备方法是将100g的γ-环糊精加50g水制成水溶液。将100g的伊曲康唑溶于适量无水乙醇中，加入γ-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将130g的微晶纤维素和70g的干淀粉混合均匀后，加入粘结剂中经湿法制粒，于60℃干燥至水份小于3.0%后整粒。
实施例8
本实施例的伊曲康唑颗粒剂的制备方法是将100g的γ-环糊精加50g水制成水溶液。将50g的伊曲康唑溶于适量无水乙醇中，加入γ-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将210g的微晶纤维素和40g的干淀粉混合均匀后，加入粘结剂中经湿法制粒，于60℃干燥至水份小于3.0%后整粒。
实施例9
本实施例的伊曲康唑颗粒剂的制备方法是将20g的羟丙基-β-环糊精加20g水制成水溶液。将100g的伊曲康唑溶于适量无水乙醇中，加入羟丙基-β-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将280g的甘露醇和100g的低取代羟丙基纤维素钠混合均匀后，加入粘结剂中经湿法制粒，于60℃干燥至水份小于3.0%后整粒。
实施例10
本实施例的伊曲康唑颗粒剂的制备方法是将100g的羟丙基-β-环糊精加50g水制成水溶液。将20g的伊曲康唑溶于适量无水乙醇中，加入羟丙基-β-环糊精的水溶液中，搅拌10min，作为粘结剂备用。将300g的淀粉和80g的低取代羟丙基纤维素钠混合均匀后，加入粘结剂中经湿法制粒，于60℃干燥至水份小于3.0%后整粒。
对比例
本对比例的伊曲康唑片剂的制备方法是将100g的伊曲康唑过60目筛后与100g的羟丙基-β-环糊精、200g的微晶纤维素、95g的羧甲基淀粉钠混合均匀后，用水做粘合剂制粒，于20目筛湿整粒后于60度干燥至水分小于3.0%。干颗粒用20目筛整理后，加入2.5g的二氧化硅和2.5g的硬脂酸镁，混合均匀后，按照500mg/片的片重压片。
实验数据
1、溶出曲线对比结果。
按照中国药典2015年版二部溶出度试验方法和伊曲康唑胶囊的质量标准，依法测定实施例1、实施例2、对比例和原研药（斯皮仁诺Sporanox胶囊，西安杨森制药有限公司分装，批号015456328）的溶出曲线。溶出曲线对比结果如图1所示。
从图1可以看出，对比例的片剂溶出效果最差，其按照片剂一半的制备过程进行制粒压片所得，120min后的溶出率仅仅60%左右。实施例2胶囊的溶出效果最好，在15min即可达到80%以上的溶出率，30min左右即可完全溶出。实施例1片剂的溶出较胶囊略缓慢。但在30min溶出度可达60%以上，45min溶出率达到80%，60min时基本完全溶出。因为片剂的颗粒大，而且经过压力后辅料与辅料间的缝隙更小，减缓溶出介质的渗入从而溶出度变慢。即便如此，仍然比原研药的溶出效果好。通过对比可知，通过本发明的技术方案制得的产品，确实能有效提高伊曲康唑的溶出度。
2、稳定性实验数据。
将实施例1的伊曲康唑片剂样品进行加速试验（40℃）和长期稳定性试验（25℃），检测样品的外观、含量及杂质，并与0天的数据相比较，结果如表1所示。
表1 稳定性实验数据表
加速6个月（40±2℃，相对湿度65%±5%）和长期稳定性12个月（25±2℃，相对湿度60%±5%）后，产品外观无明显变化，伊曲康唑的含量基本没有变化，有关物质略有增加。结果表明样品在加速条件下和长期条件下的稳定性良好。
显然，上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而这些属于本发明的精神所引伸出的显而易见的变化或变动仍处于本发明的保护范围之中。
Claims (10)
1.一种伊曲康唑制剂的制备方法，其特征在于，包括以下具体步骤：
将伊曲康唑溶于醇性溶剂中，将环糊精与水配成溶液，然后将伊曲康唑溶液倒入环糊精水溶液中，形成环糊精包合伊曲康唑的包合物，作为粘合剂；
将填充剂和崩解剂充分混匀，加入所述粘合剂经湿法制粒得到颗粒；
将所得颗粒于55℃至65℃干燥至水份小于3.0%后整粒。
2.根据权利要求1所述的一种伊曲康唑制剂的制备方法，其特征在于：所述伊曲康唑与环糊精的质量比为1∶5至5∶1。
3.根据权利要求2所述的一种伊曲康唑制剂的制备方法，其特征在于：所述伊曲康唑与环糊精的质量比为1∶2至2∶1。
4.根据权利要求1所述的一种伊曲康唑制剂的制备方法，其特征在于：所述醇性溶剂是乙醇、异丙醇、丙二醇、聚乙二醇、盐酸乙醇和苯甲醇中的一种或多种；所述环糊精是α-环糊精、β-环糊精、γ-环糊精、羟丙基-β-环糊精和甲基-β-环糊精中的一种或多种；所述填充剂是淀粉、糖粉、糊精、乳糖、可压性淀粉、微晶纤维素、磷酸氢钙、甘露醇、山梨醇和异麦芽酮糖醇中的一种或多种；所述崩解剂是交联羧甲基纤维素钠、交联聚维酮、干淀粉、羧甲基淀粉钠、羟丙基淀粉和低取代羟丙基纤维素中的一种或多种。
5.根据权利要求1至4中任一项所述的一种伊曲康唑制剂的制备方法，其特征在于：将整粒后的颗粒加入胶囊，制成胶囊剂。
6.根据权利要求1至4中任一项所述的一种伊曲康唑制剂的制备方法，其特征在于：将整粒后的颗粒按一定重量装入铝箔袋中，制成颗粒剂。
7.根据权利要求1至4中任一项所述的一种伊曲康唑制剂的制备方法，其特征在于：将整粒后的颗粒与药用辅料混合均匀后，压制成片剂。
8.根据权利要求7所述的一种伊曲康唑制剂的制备方法，其特征在于：所述药用辅料是润滑剂、润湿剂、抗氧化剂和风味剂中的一种或多种。
9.根据权利要求8所述的一种伊曲康唑制剂的制备方法，其特征在于：所述润滑剂是硬脂酸镁、山嵛酸甘油酯，二氧化硅，滑石粉，氢化植物油，聚乙二醇类与月桂醇硫酸镁中的一种或多种；所述润湿剂是纯水、乙醇和异丙醇中的一种或多种；所述抗氧化剂是二丁基羟基甲苯、丁基羟基茴香醚、特丁基对苯二酚、没食子酸丙酯、维生素E、维生素E醋酸酯、维生素C、亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠和硫代硫酸钠中的一种或多种。
10.根据权利要求8所述的一种伊曲康唑制剂的制备方法，其特征在于：所述风味剂是肉类风味香精或水果类风味香精。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113768885A (zh) * | 2021-09-16 | 2021-12-10 | 海南海神同洲制药有限公司 | 一种伏立康唑干混悬剂的制备工艺 |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1258220A (zh) * | 1997-06-05 | 2000-06-28 | 詹森药业有限公司 | 含环糊精的药物组合物 |
| WO2001097853A1 (en) * | 2000-06-21 | 2001-12-27 | Biochemie Gesellschaft Mbh | Improvement of itraconazole bioavailability |
| CN1198655C (zh) * | 1995-11-23 | 2005-04-27 | 詹森药业有限公司 | 通过熔体挤出法制备的环糊精固体混合物 |
| CN1660841A (zh) * | 2004-02-23 | 2005-08-31 | 上海医药工业研究院 | 伊曲康唑盐酸盐及其口服固体组合物和制备方法 |
| JP2008308417A (ja) * | 2007-06-13 | 2008-12-25 | Ohkura Pharmaceutical Co Ltd | 抗真菌剤の医薬組成物 |
| CN101686949A (zh) * | 2007-04-20 | 2010-03-31 | 纳瓦拉公司科学与技术研究所 | 包含环糊精和生物活性分子的纳米颗粒及其用途 |
| CN102499909A (zh) * | 2011-12-27 | 2012-06-20 | 哈尔滨三联药业有限公司 | 伊曲康唑分散片及其制备方法 |
| CN106606786A (zh) * | 2015-10-22 | 2017-05-03 | 天津市汉康医药生物技术有限公司 | 一种含艾沙康唑的药物组合物 |
-
2019
- 2019-12-31 CN CN201911406153.5A patent/CN110898015A/zh active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1198655C (zh) * | 1995-11-23 | 2005-04-27 | 詹森药业有限公司 | 通过熔体挤出法制备的环糊精固体混合物 |
| CN1258220A (zh) * | 1997-06-05 | 2000-06-28 | 詹森药业有限公司 | 含环糊精的药物组合物 |
| WO2001097853A1 (en) * | 2000-06-21 | 2001-12-27 | Biochemie Gesellschaft Mbh | Improvement of itraconazole bioavailability |
| CN1660841A (zh) * | 2004-02-23 | 2005-08-31 | 上海医药工业研究院 | 伊曲康唑盐酸盐及其口服固体组合物和制备方法 |
| CN101686949A (zh) * | 2007-04-20 | 2010-03-31 | 纳瓦拉公司科学与技术研究所 | 包含环糊精和生物活性分子的纳米颗粒及其用途 |
| JP2008308417A (ja) * | 2007-06-13 | 2008-12-25 | Ohkura Pharmaceutical Co Ltd | 抗真菌剤の医薬組成物 |
| CN102499909A (zh) * | 2011-12-27 | 2012-06-20 | 哈尔滨三联药业有限公司 | 伊曲康唑分散片及其制备方法 |
| CN106606786A (zh) * | 2015-10-22 | 2017-05-03 | 天津市汉康医药生物技术有限公司 | 一种含艾沙康唑的药物组合物 |
Non-Patent Citations (4)
| Title |
|---|
| 刘想虎等: "伊曲康唑-羟丙基-β-环糊精包合物颗粒的制备与质量控制", 《医药导报》 * |
| 吴清: "《物理药剂学》", 30 November 2018 * |
| 朱洪法: "《精细化工常用原材料手册》", 31 December 2003, 金盾出版社 * |
| 程侣柏等: "《精细化工产品的合成及应用 第2版》", 30 April 1999, 大连理工大学出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113768885A (zh) * | 2021-09-16 | 2021-12-10 | 海南海神同洲制药有限公司 | 一种伏立康唑干混悬剂的制备工艺 |
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