CN105853367B - 地拉罗司固体分散体的制备方法及其药物制剂 - Google Patents
地拉罗司固体分散体的制备方法及其药物制剂 Download PDFInfo
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Abstract
本发明提供地拉罗司固体分散体的制备方法及其药物制剂，所述方法是将地拉罗司与药学上可接受的载体混合均匀后，加热熔融，再冷却，粉碎得到地拉罗司固体分散体，其中药学上可接受的载体选自聚维酮、羟丙甲基纤维素、共聚维酮。本发明还公开了含有所述固体分散体的地拉罗司片。本发明的制备方法无需使用有机溶剂，有助于降低安全的风险和环保的压力，并降低上产成本，利于实现产品的商业化生产。
Description
技术领域
本发明涉及地拉罗司固体分散体的制备方法及其药物制剂
背景技术
地拉罗司(deferasirox)为口服活性螯合剂，与铁(Fe3+)具有高度选择性。由诺华公司开发，于2005年在美国首次上市，商品名为Exjade。主要用于治疗2岁及以上由于输血造成的慢性铁过载疾病；10岁以上非输血依赖性地中海贫血(NTDT)患者的慢性铁过载治疗。
地拉罗司为铁质螯合剂，对于三价铁离子具有高度亲和力，2个分子可与1个Fe3+结合。它可以替代身体器官清除积聚的铁质，能减少因长期铁质积聚所致的病发症。
地拉罗司化学名为4-[3,5-双-(2-羟基苯基)-1H-[1,2,4]-三唑-1-基]苯甲酸，具有如下结构：
过去多年来国内唯一可供使用的排铁药为去铁铵(deferoxamine)，由于其无法口服吸收且半衰期短，因此必须皮下输注，每周5-7天，每次输注8-12小时，使用较为耗时且不便，且存在较多的不良反应，造成患者长期用药顺应性差，也限制了它们的广泛使用。卫生部于2007年1月批准新的口服排铁药地拉罗司，用于治疗6岁以下儿童及其他输血依赖性疾病所致的铁过载。
近年来研究显示deferasirox和deferoxamine用于慢性铁质沉淀症的效果一样。口服排铁剂因使用方便，比起传统皮下注射排铁剂有较高的接受度与满意度，且可提升患者的生活品质，对长期需要使用排铁剂的患者是较好消息，可提高患者长期用药的顺应性。
地拉罗司在US64655504中由诺华公司首次公开。
在国际专利公布WO97/49395(1997年12月31日公开，其在这里被引入作为参考)中公开了游离酸形式，其盐以及其结晶形式的混合物I。
发明内容
本发明的目的在于提供一种地拉罗司固体分散体的热熔挤出制备方法，主要特征是以亲水性高分子材料共聚维酮(PVP-VA64，Kollidon VA64)、聚维酮(PVP-K30)或羟丙甲基纤维素(HPMC-AS)作为主要的分散载体材料，必要时加入糖醇类辅料作为增塑剂，易化挤出工艺过程，有效改善药物在固体分散体中的分散状态，提高地拉罗司的溶出度。
本发明是通过以下措施实现的：
(a)将地拉罗司与药学上可接受的载体混合均匀：
(b)加热步骤(a)的混合物使其完全熔融：
(c)冷却步骤(b)的熔融物，粉碎得到地拉罗司固体分散体：
其中药学上可接受的载体选自聚维酮、共聚维酮、羟丙甲基纤维素。
根据本发明，步骤(b)的过程中应将混合物加热到足够高的温度，以使混合物完全熔融，形成均一的溶液。
根据本发明的方法制备得到的地拉罗司固体分散体为固体溶液或玻璃态固体溶体，地拉罗司在固体分散体中以分子或无定形物的形式存在，表现为XRPD图谱中地拉罗司的晶型特征峰消失。
地拉罗司在大多数溶剂中的溶解度很小，并且熔点很高(约261℃)，常规的熔融法很难使地拉罗司完全熔融或溶解于聚合物载体中，从而制备得到固体溶液或玻璃态固溶体。本发明人经过大量的实验研究，发现采用聚维酮、共聚维酮或羟丙甲基纤维素物作为载体，可以通过加热混合物得到均匀的熔融溶液，而不发生分解或碳化。
根据本发明，药学上可接受的载体优选为共聚维酮。
根据本发明，地拉罗司与载体的质量比为1:0.3-1:3，优选为1:0.4-1:2，更优选1:0.5-1:1。
根据本发明，地拉罗司固体分散体采用热熔挤出工艺制备，具体的，将地拉罗司与药学上可接受的载体混合均匀，置于热熔挤出机中，加热温度控制在150℃至260℃范围内，经热熔挤出机挤出后，冷却凝结成固体，将所述固体粉碎得到地拉罗司固体分散体。
根据本发明，热熔挤出机的加热温度可根据物料性质进行调节，使地拉罗司与载体的混合物完全熔融。当加热温度过低时，混合物料没有完全熔融，无法得到均一的固体分散体，部分未溶解于熔融的载体中得到均一的溶液，冷却后得到均一的固体分散体；当加热温度过高时，会加速药物的降解，使产品有关物质的含量增大，不符合药品质量要求。
根据本发明，加热温度优选为160℃至250℃。
根据本发明的一个具体实例，使用赛默飞Pharma 11双螺杆热熔挤出机完成热熔挤出操作。结合本发明的实质内容，本领域技术人员可以使用具有类似功能的单螺杆或双螺杆热熔挤出机，热熔挤出机的型号，螺杆转速等可根据批量及生产效率的要求进行选择。
本发明还提供了一种地拉罗司片，含有根据本发明制备方法得到的地拉罗司固体分散体，及药学上可接受的添加剂，其药学上可接受的添加剂包括填充剂、崩解剂和润滑剂。
根据本发明，每片地拉罗司片含有地拉罗司的量为100-1000mg，优选125-500mg，具体为125mg，250mg和500mg。
根据本发明，填充剂选自乳糖、微晶纤维素、交联聚维酮、羟丙甲基纤维素、胶态二氧化硅、硬脂酸镁，十二烷基硫酸钠。的一种或多种。根据本发明，填充剂用量占片剂总重量的20-80％。
根据本发明，崩解剂选自交联聚维酮、交联羧甲基纤维素钠或羧甲基淀粉钠中的一种或多种。根据本发明崩解剂用量占片剂总重量的2％-20％。
根据本发明，润滑剂选自滑石粉、胶态二氧化硅、硬脂酸镁或硬脂富马酸钠中的一种或多种。根据本发明，润滑剂用量占片剂总重量的0.1％-5％。
本发明还提供了一种地拉罗司片的制备方法，将根据本发明制备方法得到的地拉罗司分散体与药学上可接受的填充剂、崩解剂、润滑剂混合均匀，压制成片。
根据本发明的方法制备得到的地拉罗司固体分散体为固体溶液或玻璃态固体溶体，地拉罗司在固体分散体中以分子或无定形物的形式存在。进一步的以所述固体分散体制备得到的地拉罗司片，相对于市售产品具有更高的溶出速率。
附图说明
图1：地拉罗司原料药的X射线粉末衍射图谱
图2：实施例1的地拉罗司固体分散体X射线粉末衍射图谱
图3：实施例1的地拉罗司片与市售品地拉罗司分散片125mg的溶出曲线比较
具体实施方式
下面结合具体实施例对发明进一步说明，但本发明的范围不局限于以下实施例。
实施例1
| 物料名称 | 用量/1000片 |
| 地拉罗司 | 125g |
| 交联聚维酮 | 100 |
| 一水乳糖 | 110 |
| 微晶纤维素 | 50 |
| 共聚维酮VA64 | 280 |
| 胶态二氧化硅 | 10 |
| 硬脂酸镁 | 40 |
| 十二烷基磺酸钠 | 160 |
将地拉罗司与聚维酮混合均匀，采用赛默飞Pharma 11双螺杆热熔挤出机挤出，螺杆转速10-30rpm，控制如下表的加热温度，挤出物冷却后使用FITZ-MILL锤式粉碎机粉碎成颗粒，筛网孔径1.0mm；颗粒与交联聚维酮、乳糖、微晶纤维素、胶态二氧化硅、硬脂酸镁、十二烷基磺酸钠混合均匀，压制成片。
实施例2
| 物料名称 | 用量/1000片 |
| 地拉罗司 | 250 |
| 交联聚维酮 | 150 |
| 一水乳糖 | 150 |
| 微晶纤维素 | 80 |
| 共聚维酮VA64 | 500 |
| 微粉硅胶 | 15 |
| 硬脂酸镁 | 50 |
| 十二烷基磺酸钠 | 180 |
将地拉罗司与聚维酮混合均匀，采用赛默飞Pharma 11双螺杆热熔挤出机挤出，螺杆转速10-30rpm，控制如下表的加热温度，挤出物冷却后使用FITZ-MILL锤式粉碎机粉碎成颗粒，筛网孔径1.0mm；颗粒与交联聚维酮、乳糖、微晶纤维素、胶态二氧化硅、硬脂酸镁、十二烷基磺酸钠混合均匀，压制成片。
实施例3
| 物料名称 | 用量/1000片 |
| 地拉罗司 | 500g |
| 交联聚维酮 | 300g |
| 一水乳糖 | 300g |
| 微晶纤维素 | 160g |
| 共聚维酮VA64 | 500g |
| 微粉硅胶 | 30g |
| 硬脂酸镁 | 100g |
| 十二烷基磺酸钠 | 300g |
将地拉罗司与聚维酮混合均匀，采用赛默飞Pharma 11双螺杆热熔挤出机挤出，螺杆转速10-30rpm，控制如下表的加热温度，挤出物冷却后使用FITZ-MILL锤式粉碎机粉碎成颗粒，筛网孔径1.0mm；颗粒与交联聚维酮、乳糖、微晶纤维素、胶态二氧化硅、硬脂酸镁、十二烷基磺酸钠混合均匀，压制成片。
实施例4
取地拉罗司原料药、实施例1的地拉罗司固体分散体样品分别进行X射线粉末衍射检测，图谱分别见图1和图2.
实施例5
按照中国药典2015年四部通则0931规定的溶出度测定法第二法(浆法)测定，以0.1mol/L盐酸1000ml为溶出介质，温度为37±0.5℃，转速为50rpm。取实施例1的地拉罗司样品、市售恩瑞格(地拉罗司分散片125mg)各6片分别检测溶出曲线，于5min、10min、15min、20min、30min、45min和60min。各取5ml，0.45μm微孔滤膜过滤，使用HPLC法测定溶出曲线，结果见图3。结果表明本发明的地拉罗司片具有比市售品明显更快的溶出速率。
Claims (2)
1.一种地拉罗司片，含有地拉罗司固体分散体，及药学上可接受的添加剂，其中药学上可接受的添加剂包括填充剂、崩解剂和润滑剂；
所述地拉罗司片的制备原料为：
所述地拉罗司固体分散体的制备方法为：
(a)将地拉罗司与共聚维酮VA64混合均匀；
(b)加热步骤(a)的混合物使其完全熔融；
(c)冷却步骤(b)的熔融物，粉碎得到地拉罗司固体分散体；
将步骤(a)的混合物置热熔挤出机中，控制加热温度130～260℃。
2.如权利要求1所述的地拉罗司片，其特征在于，所述加热温度为150-240℃。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012003987A1 (en) * | 2010-07-08 | 2012-01-12 | Ratiopharm Gmbh | Oral dosage form of deferasirox |
| CN105377256A (zh) * | 2013-05-10 | 2016-03-02 | 奇普拉股份有限公司 | 低剂量药物组合物 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012003987A1 (en) * | 2010-07-08 | 2012-01-12 | Ratiopharm Gmbh | Oral dosage form of deferasirox |
| CN105377256A (zh) * | 2013-05-10 | 2016-03-02 | 奇普拉股份有限公司 | 低剂量药物组合物 |
Non-Patent Citations (1)
| Title |
|---|
| 地拉罗司分散片的处方筛选研究;刘东等;《中国药房》;20131231;第24卷(第45期);参见全文 * |
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