CN101695474A - 用于非经肠胃给药的长春氟宁医药组合物及其制备方法和用途 - Google Patents
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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Abstract
本发明涉及一种长春氟宁医药组合物，其在pH3到4之间采用稳定的水溶性长春氟宁盐的灭菌水溶液形式。本发明还涉及制备所述组合物的方法及其作为非经肠胃给药的医药产品在治疗癌症方面的用途。
Description
本申请是申请号为200480038007.7，申请日为2004年12月17日，发明名称为“用于非经肠胃给药的长春氟宁医药组合物及其制备方法和用途”的中国发明专利申请的分案申请。
技术领域
本发明涉及用于非经肠胃给药的长春氟宁(vinflunine)医药组合物。
背景技术
对长春花(夹竹桃料)生物碱抗肿瘤活性的研究已证实吲哚结构的化合物具有这方面优异的特性，例如长春新碱(vincristine)、长春碱(vinblastine)或其衍生物，如下式(a)所示的长春氟宁：20′20′，二氟-3′4′-，二氢长春瑞宾。
在专利EP 0710240中对其进行了说明。
然而，上述活性成分的可注射制剂的发展通常会遇到在水溶液中不稳定的问题。
多年来，仅有冷冻干燥的产品上市。由于给药前需与溶剂瓶内的内容物临时配制，因此冷冻干燥剂在此处理过程中所产生的主要问题为：
-配制过程中操作错误所造成的危险，在配制过程中药物细液滴的形成可能污染操作人员，或环境；
-若将药物置于对应不同单位剂量的不同瓶内时，操作中常会造成溶剂量不足或活性成分剂量不当。
后一问题特别重要。它说明可能发生对病人给药过低的治疗剂量或使病人暴露于过量药物下。
美国专利4619935中提供一种配制可立即使用的长春花生物碱注射溶液的方法。然而，其所使用的制剂极为复杂。除活性成分之外其另外还含有：
-糖或糖基多元醇，如甘露糖醇；
-使溶液维持在pH 3.0-5.0特别是在4.4-4.8范围内的醋酸缓冲液。其摩尔浓度介于0.02到0.0005M之间以及特别是介于0.01到0.002M之间；
-抗微生物保存剂。
应当注意的是，尽管醋酸缓冲液能带来稳定效果，从而可避免因生物碱分解所造成的pH改变而导致的降解，本发明的制剂在5℃下仅能维持一年的稳定性。
已发明的配制物的复杂度有日益增加的趋势：专利FR 2653998提出一种非经肠胃给药的医药组合物，其含有双吲哚型(bis-indole)生物碱如长春新碱、长春碱或5′-去甲-脱水长春花碱。其特点为水溶液内含有双吲哚型生物碱盐的锌络合物、葡萄糖酸二价金属盐以及溶于一元醇或多元醇的保存剂。
这些组合物的稳定性为当存于冰箱内时可维持至少24个月。
欧洲专利EP 0298192述及了乙二胺四乙酸(ethylene diaminetetraacetic acid)盐，特别是其钠盐对二聚体长春碱在水溶液内稳定性的有利效果。这些水溶液用醋酸盐缓冲剂缓冲从而将pH维持在3.0到5.5之间以及优选为4.0到5.0之间。
在这些条件下，根据说明书采用的规格(生物碱的含量为理论含量的90％到110％之间)，此溶液在2至8℃的温度下可稳定保存30个月。
加拿大专利2001643提及一种长春新碱的可注射溶液，其也强调使用醋酸/醋酸钠缓冲液使溶液pH维持在3.5到5.5特别是4.0到4.5之间的必要性。该发明的制剂在5℃时可稳定保存18个月，甚至在5℃时可稳定保存24个月。
长春氟宁双酒石酸盐或20′20′-，二氟-3′，4′-二氢长春瑞宾L(+)-酒石酸盐为一种必需保存在零下的(低于-15℃)、在如氮或氢的惰性气体中的白色粉末。
已经惊奇地发现长春氟宁双酒石酸盐溶于水中时比其粉末态更为稳定。
具体地说，所述可注射水溶液可保存在+2℃到+8℃之间。由于已知其在液态媒体内较固态更易发生化学裂解反应，因此该发现非常令人意外。
发明内容
因此，本发明涉及长春氟宁医药组合物，其特点为在pH 3到4之间采用稳定的水溶性长春氟宁盐的灭菌水溶液。
本发明和先前专利所述的组合物相比为极为简单的制剂。
有利地，所述长春氟宁盐为长春氟宁双酒石酸盐。
有利地，本发明的医药组合物采用稳定的、灭菌和无热原性、即用型的可注射水溶液。
有利地，本发明的组合物不含任何的防腐剂。
在本发明的第一具体实施例中，本发明的医药组合物采用长春氟宁双酒石酸盐的简单水溶液形式，其不需另外添加缓冲溶液。因此，该组合物由长春氟宁双酒石酸盐和水的可注射制剂组成。有利地，此溶液的pH优选等于3.5。
在本发明的第二具体实施例中，本发明的医药组合物含有一种pH缓冲系统以将pH维持在3到4之间。更优选地，本发明的医药组合物由长春氟宁双酒石酸盐、用于可注射制剂的水以及将pH维持在约3到4之间的pH缓冲液组成。有利地，pH缓冲系统的摩尔浓度优选介于0.002M到0.2M之间。
有利地，此缓冲系统由醋酸/醋酸钠缓冲液或柠檬酸/柠檬酸钠缓冲液组成。
有利地，所述pH是从摩尔浓度介于0.05M到0.2M之间的醋酸/醋酸钠缓冲液或柠檬酸/柠檬酸钠缓冲液获得的。
更有利地，所述pH缓冲物由醋酸/醋酸钠缓冲液组成，则所述组合物的pH为3.5，或者pH缓冲物由柠檬酸/柠檬酸钠缓冲液组成，则所述组合物的pH为4。
有利地，本发明组合物含有长春氟宁双酒石酸盐，该长春氟宁双酒石酸盐碱基长春氟宁(base vinflunine)的浓度为介于1到50mg/ml之间，优选为介于25到30mg/ml之间，特别优选为25mg/ml或30mg/ml。因而此浓度表示为碱基长春氟宁。给药量视病人身体表面积而定。
在一优选具体实施例中，本发明的组合物相当于下列制剂之一：68.35mg长春氟宁双酒石酸盐于2ml标准量(qs)的水中，或136.70mg长春氟宁双酒石酸盐于4ml标准量的水中，或341.75mg长春氟宁双酒石酸盐于10ml标准量的水中；长春氟宁双酒石酸盐的量在各制剂中分别相当于50mg碱基长春氟宁，100mg碱基长春氟宁以及250mg碱基长春氟宁。这些数据整理于下列表1中。
表1：水溶液的单位组合物的实施例
上述表1显示可通过将浓度为25mg/ml的表达为碱基长春氟气宁的同一长春氟宁双酒石酸盐水溶液分散于不同体积的瓶内来配制3种单位剂量的长春氟宁。
在本发明的另一具体实施例中，本发明的组合物可稳定保存在5℃±3℃下至少36个月。
在本发明一个特定具体实施例中，本发明的医药组合物为在溶解于如0.9％氯化钠或5％葡萄糖溶液的灌注溶液之后以静脉灌注的方式给药。
因此，由于本发明的组合物作为药物产品使用，所以本发明还涉及医药组合物，特别指用于治疗癌症，优选为非经肠胃给药，优选为经由静脉灌注，以及更优选为在化学治疗中作为一种抗癌和抗肿瘤剂。
本发明也涉及利用本发明的组合物制造非经肠胃给药的药物，所述药物优选为经由静脉灌注，且该药物优选用于治疗癌症。
本发明所述的非经肠胃给药，特别是可经由静脉给药长春氟宁医药组合物使对长春氟宁作用敏感的癌症进行治疗成为可能。
本发明也涉及制备本发明组合物的方法，其包括下列连续的步骤：
-(a)将长春氟宁盐溶解于水中作为注射制剂；
-(b)视需要添加pH缓冲剂；
-(c)通过过滤该散装溶液来进行灭菌。
在本发明一特定具体实施例中，本发明的方法还另外包括在氮气下将步骤(c)得到的灭菌组合物无菌分装到容器内的步骤(d)。所述容器优选自玻璃小药瓶(phial)，其优选为琥珀或无色类型I、玻璃瓶，优选为带有弹性塞和卷边铝制盖或任何适用于即用系统的琥珀或无色类型I，例如预充填注射筒。
因此本发明也涉及一种含有本发明的组合物的包装容器。
所述包装容器可选自优选为玻珀或无色类型I的玻璃小药瓶或玻璃瓶，该玻璃瓶优选为带有弹性塞和卷边铝制盖或任何适用于即用系统的琥珀或无色类型I容器，例如预充填注射筒。
附图说明
图1显示表3中的各制剂利用HPLC在严格条件下(在60℃下45天)测定的以时间为函数的长春氟宁总相对不纯度的量的变化。
具体实施方式
下列实施例为本发明的非限制性说明。
实施例1：粉状长春氟宁双酒石酸盐和水溶液中的长春氟宁双酒石酸盐(本发明的组合物)的稳定性比较
下表2显示了在25℃保存3个和6个月之后某批次粉状冷冻干燥长春氟宁双酒石酸盐(批次503)和一批由相同匹次长春氟宁双酒石酸盐制备的含25mg/ml碱基长春氟宁的水溶液(批次SB0222)的稳定性比较结果。通过观察呈现的长春氟宁相对不纯度的总量的变化来检测其稳定性。
表2：长春氟宁双酒石酸盐/水溶液的稳定性比较结果
| 长春氟宁双酒石酸盐(批次503)(相对于100％活性成分的％不纯度) | 含有25mg/ml的水溶液(批次SB0222)(相对100％活性成分的％不纯度) | |
| to | 1.17 | 1.23 |
| t3月 | 2.75 | 1.45 |
| t6月 | 3.48 | 2.00 |
在25℃下保存6个月之后，长春氟宁相对不纯度的总量增加为：
-水溶性长春氟宁双酒石酸盐溶液为62％；
-粉状长春氟宁双酒石酸盐为197％。
实施例2：以pH为函数的本发明组合物的稳定性研究
在pH 2.5到5.0之间，特别是在3.0到4.0之间进行水溶性长春氟宁双酒石酸盐水溶液的稳定性研究。所述pH是利用0.2摩尔醋酸/醋酸钠或柠檬酸/柠檬酸钠缓冲液获得的。
下表3为所使用成分的百分比。它们相当于30mg/ml的碱基长春氟宁浓度。
表3：缓冲水溶液的制剂
此结果和保存相同条件下的未添加缓冲剂的简单长春氟宁双酒石酸盐水溶液相比较。该溶液的pH为3.5。
组合物和测试溶液的参考见下表4。
表4：组合物和测试溶液的参考
| 组合物 | 制剂参考 |
| PH＝2.5的溶液(柠檬酸盐缓冲剂) | BS 1325 |
| PH＝3的溶液(柠檬酸盐缓冲剂) | BS 1326 |
| PH＝3.5的溶液(柠檬酸盐缓冲剂) | BS 1330 |
| PH＝4的溶液(柠檬酸盐缓冲剂) | BS 1327 |
| PH＝5的溶液(柠檬酸盐缓冲剂) | BS 1328 |
| PH＝3.5的溶液(柠檬酸盐缓冲剂) | BS 1332 |
| 未缓冲的水溶液 | BS 1331 |
图1显示表3中的各制剂利用HPLC在严格条件下(在60℃下45天)测定的以时间为函数的长春氟宁总相对不纯度的量的变化。
它们通过下表4的结果来补足，说明了所述溶液在60℃下经7天后的颜色变化。
这些溶液在410nm紫外线下监测的吸光度显示了无法以HPLC层析出的长春氟宁氧化衍生物的存在。
表5：吸光度的变化
仅pH＝3.5的无缓冲溶液在60℃下7天后具有低于0.200的吸光度。
此结果显示长春氟宁的稳定性在pH值介于3.0到4.0之间时较优选，但需视缓冲剂所含离子的性质而定。在pH 3.5时，醋酸/醋酸钠缓冲液可提供比柠檬酸/柠檬酸钠缓冲液更好的稳定性。对于后者，其在pH 4时具有较好的结果。
已惊奇地发现，pH本身就为3.5的水溶性长春氟宁双酒石酸盐溶液的稳定性比缓冲至pH 3.5的长春氟宁双酒石酸盐的水溶性溶液好。
这些好的结果经下表6所列的长期观察结果证实，这些结果说明本发明的可注射水溶性长春氟宁医药组合物可在5℃±3℃下至少保存36个月而不产生任何实质上的降解。
表6：本发明的水溶性医药组合物的稳定性结果
| to | t3个月 | t6个月 | t12个月 | t24个月 | t36个月 | |
| 匹次CLP004以mg/ml表示的长春氟宁含量(理论＝30.0) | 30.8 | 30.4 | 30.4 | 30.4 | 30.3 | 30.2 |
Claims (12)
1.一种长春氟宁医药组合物，其特征在于其在pH3到4之间采用稳定的水溶性长春氟宁双酒石酸盐的灭菌水溶液形式，且其不需另外添加缓冲溶液。
2.根据权利要求1所述组合物，其特征在于该组合物含有长春氟宁双酒石酸盐，该长春氟宁双酒石酸盐的碱基长春氟宁浓度介于1到50mg/ml之间。
3.根据权利要求2所述组合物，其特征在于所述碱基长春氟宁浓度介于25到30mg/ml之间。
4.根据权利要求3所述组合物，其特征在于所述碱基长春氟宁浓度为25mg/ml。
5.根据权利要求4所述的组合物，其特征在于其对应于下列制剂之一：68.35mg长春氟宁双酒石酸盐于2毫升标准量的水中，或136.70mg长春氟宁双酒石酸盐于4ml标准量的水中，或341.75mg长春氟宁双酒石酸盐于10ml标准量的水中；所述长春氟宁双酒石酸盐各自分别对应于50mg碱基长春氟宁，100mg碱基长春氟宁以及250mg碱基长春氟宁。
6.根据前述权利要求中任一项所述的组合物，其特征在于其在5℃士3℃下至少保持36个月稳定。
7.一种根据权利要求1至6项中任一项所述的组合物在制备非经肠胃给药的医药产品中的用途。
8.根据权利要求7所述的用途，其中所述给药是经由静脉灌注。
9.根据权利要求7或8所述的用途，其特征在于所述医药产品用于治疗癌症。
10.一种制备根据权利要求1至6项中任一项所述的组合物的方法，其包括下列连续的步骤：
-(a)将长春氟宁盐溶解于水中作为注射制剂；
-(b)通过过滤散装溶液进行灭菌
-(c)在氮气下将步骤(b)得到的灭菌组合物无菌分装于容器内。
11.根据权利要求10所述的方法，其中所述步骤(c)的容器选自玻璃小药瓶、玻璃瓶或预充填注射筒。
12.一种包装容器，其含有根据权利要求1至6项任一项所述的组合物。
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| US20110015221A1 (en) * | 2003-12-23 | 2011-01-20 | Pierre Fabre Medicament | Pharmaceutical composition of vinflunine which is intended for parenteral administration preparation method thereof and use of same |
| FR2910812B1 (fr) * | 2006-12-29 | 2009-03-20 | Pierre Fabre Medicament Sa | Compositions pharmaceutiques injectables lyophilisees de derives hemi-synthetiques d'alcaloide de vinca stables a temperature ambiante |
| FR2912406B1 (fr) * | 2007-02-13 | 2009-05-08 | Pierre Fabre Medicament Sa | Sels cristalins anhydres de vinflunine, procede de preparation et utilisation en tant que medicament et moyen de purification de la vinflunine. |
| EP1997534A1 (en) * | 2007-05-31 | 2008-12-03 | Pierre Fabre Medicament | Cancer treatment combination therapy comprising vinflunine and trastuzumab |
| CN101129374B (zh) * | 2007-06-26 | 2010-09-08 | 齐鲁制药有限公司 | 长春氟宁药物组合物及其制备方法与应用 |
| FR2918567B1 (fr) * | 2007-07-11 | 2012-08-03 | Pf Medicament | Composition pharmaceutique stable d'un sel hydrosoluble de vinorelbine. |
| FR2918566B1 (fr) * | 2007-07-11 | 2009-10-09 | Pierre Fabre Medicament Sa | Composition pharmaceutique stable d'un sel hydrosoluble de vinflunine. |
| CN101607968A (zh) * | 2008-06-17 | 2009-12-23 | 江苏豪森药业股份有限公司 | 长春氟宁盐、其制备方法及其药物组合物 |
| UY33975A (es) * | 2011-03-29 | 2012-10-31 | Sanofi Sa | Formulaciones de otamixaban con estabilidad mejorada |
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| JPH06100452A (ja) * | 1993-04-06 | 1994-04-12 | Asta Medica Ag | イホスファミド用の製薬学的容器 |
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| DE19706255C2 (de) * | 1997-02-18 | 2000-11-30 | Schott Glas | Sterilisierbarer Glasbehälter für medizinische Zwecke, insbesondere zur Aufbewahrung pharmazeutischer oder diagnostischer Produkte |
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| JP3642492B1 (ja) * | 2003-10-31 | 2005-04-27 | 小野薬品工業株式会社 | オザグレルナトリウム含有水溶液を充填してなる注射用容器 |
| FR2863891B1 (fr) * | 2003-12-23 | 2006-03-24 | Pf Medicament | Composition pharmaceutique de vinflunine destinee a une administration parentale, procede de preparation et utilisation |
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Application publication date: 20100421 |