CN1306929C - 快速释放活性成分的口服氟达拉滨高纯制剂 - Google Patents
快速释放活性成分的口服氟达拉滨高纯制剂 Download PDFInfo
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Abstract
本发明涉及纯度＞99.19%的氟达拉滨(高纯氟达拉滨)作为活性成分的快速释放片剂，其仅具有限定浓度的残余污染物。
Description
技术领域
本发明涉及包含纯度＞99.19％的氟达拉滨(高纯氟达拉滨)作为活性成分且残余污染物具有限定组成的快速释放片剂。
背景技术
氟达拉滨纯度＜98％的片剂是已知的。在以下的文章中指出了各种制剂和剂型(7 Modern Pharmaceutics，Chapters 9 and 10，Banker & Rhodes，Editors，1979；Liebennan等人，Pharmaceutical Dosage Forms：Tablets，1981；Ansel，Introduction to Pharmaceutical Dosage Forms 2nd Edition，1976)。
在US 3,903,297中，通过实施例(实施例2)描述了由活性成分与乳糖、微晶纤维素、胶态二氧化硅和硬脂酸镁组成的片剂。实施例(实施例5)还描述了制剂也可包含交联羧甲基纤维素钠的事实。在WO 00/71134中描述了由乳糖、微晶纤维素、胶态二氧化硅、交联羧甲基纤维素钠和硬脂酸镁组成的普通片剂。此等组合物也可包含化学治疗物质。
从WO 97/40846中已知包含羟丙基甲基纤维素、二氧化钛和颜料如氧化铁颜料的片剂包衣。
从WO 00/50423中已知由乳糖、微晶纤维素、交联羧甲基纤维素钠等组成的片剂，而且该片剂可快速溶解。
US 6,197,785、EP 1065206、EP 819430、EP 1065204和EP 985666描述了可用于口服给药的片剂，该片剂由乳糖、微晶纤维素、胶态二氧化硅、硬脂酸镁、交联羧甲基纤维素钠、滑石等组成。作为活性成分，可包括氟达拉滨。
目前尚未知晓活性成分的纯度＞99.5％且制剂中活性成分的污染物具有限定组成的氟达拉滨制剂。
从WO 99/29710中已知纯度＞99.19％的活性成分氟达拉滨。但是在该文献中，没有提出制剂中所包含的纯氟达拉滨的限定组成。
因此，希望具有稳定的片剂，其包含高纯的氟达拉滨以及限定浓度的残余污染物，而且其快速溶解，并由此快速释放活性成分。
发明内容
现已发现，其中非微粉化但经过筛选的活性成分氟达拉滨的纯度＞99.19％并具有限定浓度的残余污染物的片剂可以克服已知片剂的缺点。
片剂中包括的活性成分的量为5-100mg，优选为8-75mg，特别优选的量为10-50mg，可在10-20mg的范围内选择。
优选的制剂物质是乳糖、胶态二氧化硅、微晶纤维素(Avicel)、交联羧甲基纤维素钠(羧甲基纤维素钠)和硬脂酸镁。
但是，也可考虑本领域技术人员已知的其他制剂物质。
片剂中制剂物质的总量为100-250mg，优选的总量为120-200mg，特别优选的总量为130-180mg。
因此，本发明涉及快速释放片剂，其包括：
1-100mg纯度＞99.19％的活性成分氟达拉滨，以及
单水合乳糖，
胶态二氧化硅，
微晶纤维素(Avicel)，
交联羧甲基纤维素钠(羧甲基纤维素钠)，
和硬脂酸镁，
其特征在于，氟达拉滨中的污染物不超过以下百分比：
0.02％2-氟-9-(β-D-阿拉伯呋喃糖基)-9H-嘌呤-6-胺，
0.12％6-氨基-9(5-O-磷酰基-β-D-阿拉伯呋喃糖基)-9H-嘌呤-2-醇，
0.02％2-氟-9H-嘌呤-6-胺，
0.02％6-氨基-9H-嘌呤-2-醇，
0.05％2-氟-9-(5-O-磷酰基-β-D-呋喃核糖基)-9H-嘌呤-6-胺，
0.1％9-(3，5-O-二磷酰基-β-D-阿拉伯呋喃糖基)-2-氟-9H-嘌呤-6-胺，
0.1％9-(2，5-O-二磷酰基-β-D-阿拉伯呋喃糖基)-2-氟-9H-嘌呤-6-胺，
0.02％2-氟-9-(5-O-磷酰基-β-D-阿拉伯呋喃糖基)-9H-嘌呤-6-胺，
0.06％2-乙氧基-9-(5-O-磷酰基-β-D-阿拉伯呋喃糖基)-9H-嘌呤-6-胺，
0.02％2-(6-氨基-9H-嘌呤-2-基)-9-(5-O-磷酰基-β-D-阿拉伯呋喃糖基)-9H-嘌呤-6-胺和O，O′-二[2-(6-氨基-2-氟-9H-嘌呤-9-基)-5-脱氧-α-D-阿拉伯呋喃糖-5-基]-磷酸酯，
0.1％9-(2-氯-2-脱氧-5-磷酰基-β-D-阿拉伯呋喃糖基)-2-氟-9H-嘌呤-6-胺，和
0.1％9-(2，5-脱水-β-D-阿拉伯呋喃糖基)-2-氟-9H-嘌呤-6-胺。
优选的是包含以下成分的快速释放片剂：
1-70.00mg纯度＞99.19％的活性成分氟达拉滨，以及
50-100mg的单水合乳糖，
0.1-5mg的胶态二氧化硅，
40-100mg的微晶纤维素(Avicel)，
1-10mg的交联羧甲基纤维素钠(羧甲基纤维素钠)和
0.5-10mg的硬脂酸镁。
特别优选的快速释放片剂包括：
1-50.00mg纯度＞99.19％的活性成分氟达拉滨，以及
60-90mg的单水合乳糖，
0.5-1mg的胶态二氧化硅，
50-90mg的微晶纤维素(Avicel)，
1.5-5mg的交联羧甲基纤维素钠(羧甲基纤维素钠)和
1-3mg的硬脂酸镁。
所选的快速释放片剂包括：
10mg纯度＞99.19％的活性成分氟达拉滨，以及
74.75mg的单水合乳糖，
0.75mg的胶态二氧化硅，
60.00mg的微晶纤维素(Avicel)，
3.00mg的交联羧甲基纤维素钠(羧甲基纤维素钠)和
1.5-2.00mg的硬脂酸镁。
优选的制剂是包括纯度＞99.37％的活性成分氟达拉滨。
更优选的制剂是包括纯度＞99.57％的活性成分氟达拉滨。
特别优选的制剂是包括纯度＞99.80％的活性成分氟达拉滨。
尤其特别优选的制剂是包括纯度＞99.85％的活性成分氟达拉滨。
根据本发明的制剂可根据通常已知的方法加工成模压化合物，然后所述模压化合物被压制成片芯。这些片芯可用通常已知的方法包敷包衣。原则上，可以使用本领域技术人员已知的所有包衣。优选的包衣包括例如以下成分：
1-5mg、优选1-3mg、特别优选2.250mg的羟丙基甲基纤维素，
0.1-1mg、优选0.1-0.8mg、特别优选0.450mg的滑石，
0.1-5mg、优选0.1-2mg、特别优选1.187mg的二氧化钛，
0.01-0.1mg、优选0.01-0.05mg、特别优选0.036mg的黄色氧化铁颜料，以及
0.01-0.1mg、优选0.01-0.05mg、特别优选0.036mg的红色氧化铁颜料。
这些包衣也包括在本发明的范围内。
根据本发明的片剂可制备用于治疗癌症的药物。
因此，本发明还包括根据本发明的制剂在制备用于治疗癌症的药物中的应用。
具体实施方式
以下实施例描述了根据本发明的高纯氟达拉滨片剂的制备并对比了纯度＜98％的氟达拉滨的常规组合物和纯度＞99.19％的氟达拉滨的组合物。
实施例1
制备片剂
为制备根据本发明的片剂，活性成分氟达拉滨(磷酸氟达拉滨)首先进行筛选，然后用单水合乳糖、微晶纤维素(Avicel)和胶态二氧化硅处理至大约30％干混合物。该混合物也进行筛选。通过筛分检查质量或粒径。在额外的混合步骤中向干混合物中顺序地添加交联羧甲基纤维素钠(羧甲基纤维素钠)和硬脂酸镁。
将模压化合物压制成片芯。
如此制得的片剂例如包括以下成分：
氟达拉滨＞99.19％高纯度 10.00mg
单水合乳糖 74.75mg
胶态二氧化硅 0.75mg
微晶纤维素(Avicel) 60.00mg
交联羧甲基纤维素钠 3.00mg
(羧甲基纤维素钠)
硬脂酸镁 1.5-2.00mg
这些片芯接着用含水包衣混悬液进行包衣。此等薄膜包衣例如包括以下成分：
羟丙基甲基纤维素 2.250mg
滑石 0.450mg
二氧化钛 1.187mg
氧化铁颜料，黄色 0.036mg
氧化铁颜料，红色 0.036mg
片剂的总重为 154mg。
如此制得的薄膜片剂接着进一步处理。薄膜片可包装在例如铝泡罩袋中，由此可确保该制剂的稳定性。
实施例2
纯度＜98％(97.67％)的氟达拉滨的常规组合物与纯度＞99.19％或＞99.57％的氟达拉滨的组合物以及通过离子交换剂纯制的99.19％氟达拉滨组合物的对比。
结果示于以下表中。
*高纯氟达拉滨
*高纯氟达拉滨
*高纯氟达拉滨
*高纯氟达拉滨
*高纯氟达拉滨
*高纯氟达拉滨
这些结果显示，由市售氟达拉滨(最高97.67％氟达拉滨)组成的制剂或者包含通过离子交换剂纯制的氟达拉滨(最高99.19％氟达拉滨)的制剂比根据本发明的制剂中所包含的高纯氟达拉滨(＞99.37％至＞99.57％氟达拉滨)具有更多的污染性副产物。
用常规的纯制方法如非常强的离子交换色谱，仅能得到非常中等的纯度。
根据本发明的氟达拉滨制剂包含已在WO 99/29710中描述的通过钠盐释放的高纯氟达拉滨。用钾盐(99.8％)或锂盐(99.85％)可制得更高纯度的氟达拉滨。
Claims (11)
1、快速释放片剂，其包含1-100mg纯度＞99.19％的活性成分氟达拉滨，以及
单水合乳糖，
胶态二氧化硅，
微晶纤维素，
交联羧甲基纤维素钠或羧甲基纤维素钠，
和硬脂酸镁，其特征在于，氟达拉滨中的污染物不超过以下百分比：
0.02％2-氟-9-(β-D-阿拉伯呋喃糖基)-9H-嘌呤-6-胺
0.12％6-氨基-9(5-O-磷酰基-β-D-阿拉伯呋喃糖基)-9H-嘌呤-2-醇
0.02％2-氟-9H-嘌呤-6-胺
0.02％6-氨基-9H-嘌呤-2-醇
0.05％2-氟-9-(5-O-磷酰基-β-D-呋喃核糖基)-9H-嘌呤-6-胺
0.1％9-(3，5-O-二磷酰基-β-D-阿拉伯呋喃糖基)-2-氟-9H-嘌呤-6-胺
0.1％9-(2，5-O-二磷酰基-β-D-阿拉伯呋喃糖基)-2-氟-9H-嘌呤-6-胺
0.02％2-氟-9-(5-O-磷酰基-β-D-阿拉伯呋喃糖基)-9H-嘌呤-6-胺
0.06％2-乙氧基-9-(5-O-磷酰基-β-D-阿拉伯呋喃糖基)-9H-嘌呤-6-
胺
0.02％2-(6-氨基-9H-嘌呤-2-基)-9-(5-O-磷酰基-β-D-阿拉伯呋喃糖基)-9H-嘌呤-6-胺以及O，O′-二[2-(6-氨基-2-氟-9H-嘌呤-9-基)-5-脱氧-α-D-阿拉伯呋喃糖-5-基]-磷酸酯
0.1％9-(2-氯-2-脱氧-5-磷酰基-β-D-阿拉伯呋喃糖基)-2-氟-9H-嘌呤-6-胺
0.1％9-(2，5-脱水-β-D-阿拉伯呋喃糖基)-2-氟-9H-嘌呤-6-胺。
2、如权利要求1所述的快速释放片剂，其包括：
1-70mg纯度＞99.19％的活性成分氟达拉滨，以及
50-100mg的单水合乳糖，
0.1-5mg的胶态二氧化硅，
40-100mg的微晶纤维素，
1-10mg的交联羧甲基纤维素钠或羧甲基纤维素钠，和
0.5-10mg的硬脂酸镁。
3、如权利要求1所述的快速释放片剂，其包括：
1-50mg纯度＞99.19％的活性成分氟达拉滨，以及
60-90mg的单水合乳糖，
0.5-1mg的胶态二氧化硅，
50-90mg的微晶纤维素，
1.5-5mg的交联羧甲基纤维素钠或羧甲基纤维素钠，和
1-3mg的硬脂酸镁。
4、如权利要求1所述的快速释放片剂，其包括：
10mg纯度＞99.19％的活性成分氟达拉滨，以及
74.75mg的单水合乳糖，
0.75mg的胶态二氧化硅，
60.00mg的微晶纤维素，
3.00mg的交联羧甲基纤维素钠或羧甲基纤维素钠，和
1.5-2.00mg的硬脂酸镁。
5、如权利要求1所述的快速释放片剂，其包括纯度＞99.37％的活性成分氟达拉滨。
6、如权利要求1所述的快速释放片剂，其包括纯度＞99.57％的活性成分氟达拉滨。
7、如权利要求1所述的快速释放片剂，其包括纯度＞99.80的活性成分氟达拉滨。
8、如权利要求1所述的快速释放片剂，其包括纯度＞99.85％的活性成分氟达拉滨。
9、如权利要求1-8之一所述的快速释放片剂，其中片芯用包含以下成分的包衣进行包封：
1-5mg的羟丙基甲基纤维素，
0.1-1mg的滑石，
0.1-5mg的二氧化钛，
0.01-0.1mg的黄色氧化铁颜料以及
0.02-0.1mg的红色氧化铁颜料。
10、如权利要求9所述的快速释放片剂，其中片芯用包含以下成分的包衣进行包封：
1-3mg的羟丙基甲基纤维素，
0.1-0.8mg的滑石，
0.1-2mg的二氧化钛，
0.01-0.05mg的黄色氧化铁颜料和
0.01-0.05mg的红色氧化铁颜料。
11、如权利要求9所述的快速释放片剂，其中片芯用包含以下成分的包衣进行包封：
2.250mg的羟丙基甲基纤维素，
0.450mg的滑石，
1.187mg的二氧化钛，
0.036mg的黄色氧化铁颜料和
0.036mg的红色氧化铁颜料。
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| DE10164510.4 | 2001-12-20 | ||
| DE10164510A DE10164510A1 (de) | 2001-12-20 | 2001-12-20 | Orale Fludara reinst Formulierung mit schneller Freisetzung des Wirkstoffes |
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| EP2432457A1 (en) * | 2009-05-19 | 2012-03-28 | Grindeks, A Joint Stock Company | Stable pharmaceutical composition of fludarabine phosphate |
| US20120010216A1 (en) * | 2010-07-06 | 2012-01-12 | Brown Arthur M | Pharmaceutical compositions containing vanoxerine |
| EP2428201A1 (en) | 2010-09-08 | 2012-03-14 | Merck Serono S.A. | Oral administration of nucleoside monophosphates |
| CN101947208B (zh) * | 2010-10-09 | 2012-05-23 | 江苏奥赛康药业股份有限公司 | 一种供注射用的磷酸氟达拉滨组合物及其制备方法 |
| CN102091046B (zh) * | 2011-02-12 | 2012-07-18 | 海南锦瑞制药股份有限公司 | 一种磷酸氟达拉滨冻干粉针剂及其制备方法 |
| WO2017036356A1 (zh) * | 2015-08-28 | 2017-03-09 | 浙江海正药业股份有限公司 | 磷酸氟达拉滨的晶型及其制备方法和用途 |
| CN111423458A (zh) * | 2020-04-29 | 2020-07-17 | 东南大学 | 磷酸氟达拉滨杂质h对照品的制备方法 |
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