CN1330551A - Didemnin化合物的药物制剂 - Google Patents
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Abstract
一种didemnin化合物的稳定药用组合物,包括首先是含水溶性原料的冻干didemnin制剂,其次是混合溶剂的重新配制的溶液。
Description
本发明涉及药物制剂，更具体地说，涉及didemnin化合物的药物制剂。
背景
Rinehart在美国专利5,294,603中，对含有与药学上可接受的载体、赋形剂或稀释剂混合的didemnin的药用组合物提出权利要求。在那个专利中，提供了大量的研究以测试生物活性，特别提供了对细胞毒性和抗病毒的检验结果。
问题
实际上，在适于向患者供药的didemnin化合物的药用组合物的制备中，存在某些困难，特别需要稳定的母体药物剂型。更具体地说，对药物剂型的最佳稳定的制剂，尤其是冷冻干燥制剂而言，需要使didemnin化合物如脱氢didemnin B，也称作海鞘素(aplidine)，与膨胀剂，如甘露醇混合。
用于此目的的某些膨胀剂，如甘露醇，当药物如海鞘素难溶于水时，需用水增溶。然而，在使用前，给予患者的药物需要将冻干的原料再悬浮。
本发明
本发明通过提供didemnin化合物的药用组合物解决了此问题。它包括，首先是含水溶性原料的冻干didemnin制剂，其次是混合溶剂的重新配制的溶液。由于水有助于溶解水溶性原料而其它溶剂有助于溶解didemnin化合物，混合溶剂包括一含水溶剂。
优选实施方案
本发明的药物制剂特别为稳定的母体药物剂型，它宜于重新配制以向患者供药作抗癌治疗。本发明解决了药物如海鞘素的问题，即海鞘素必须以两种或多种可溶于互不相容的(incompatible)溶剂中的物质的冻干混合物出现。它优选提供单独瓶装的或其它容器装纳的预混合三组分：表面活性剂/链烷醇/水的溶剂混合物。在给药治疗疾病前，为便于该药物剂型进行适当再悬浮，提供单独包装的溶剂混合物，以加入含药物和水溶性物质如甘露醇的冻干制剂中。
本发明的药用组合物中的优选didemnin化合物，包括didemnin和didemnin衍生物，如去氢didemnin、nordidemnins、didemnin同族元素(congeners)和didemnin类似物。本发明特指有限水溶性的didemnin，包括如去氢didemnin B(也称作海鞘素)。
抗癌剂海鞘素(去氢didemnin B)是一种从地中海runicate海鞘(Aplidium albicans)分离出的天然存在的环状depsipeptide。通过采用一些色谱和光谱测定的技术鉴定海鞘素的特征。溶解性测试表明，海鞘素水溶性差。而且，目前尚未知海鞘素在溶液中的长期稳定性。
优选通过冷冻干燥didemnin/链烷醇/水混合物制备冻干didemnin制剂，特别采用叔丁醇作为链烷醇。所述链烷醇/水混合物宜含25-60％(体积)的链烷醇。已知在该冻干剂形的制剂中也可包括膨胀剂如甘露醇是有用的，尽管也可包括其它常规的水溶性添加剂。
优选由表面活性剂/链烷醇/水混合物组成的可重新配制的溶液，特别采用非离子表面活性剂和链烷醇如乙醇。表面活性剂宜为混合物的10-25％(v/v)；链烷醇宜为混合物的10-25％(v/v)；水宜为混合物的50-80％(v/v)。
实施例
对注射用水(”WFI)(含25mg/ml的甘露醇作为膨胀剂)中的40％(v/v)叔丁醇水溶液中的1.0mg/ml海鞘素溶液进行冷冻干燥。进行示差扫描量热法研究以确定冷冻干燥周期参数。发现就溶解性、冷冻持续周期的长度和剂量需求而言，每管形瓶含1.0mg海鞘素和25mg甘露醇的原型(prototype)是最佳制剂。
发现由Cremophor El/无水乙醇/WFI为15/15/70％(体积)组成的溶液为最佳重新配制的溶液，Cremophor El是从德国BASF公司得到的甘油-聚乙烯乙二醇蓖麻醇酸盐。
重新配制的产物的稀释剂一般含盐量达到1∶200，表明它在配制后至少24小时是稳定的。冷冻干燥制剂的质量控制表明，制备工艺没有改变海鞘素的完整性。迄今得到的储存期限数据表明，制剂贮存在+4℃阴暗处至少在6个月中是稳定的。
因此，本发明优选的海鞘素制品是双包装的，包括：
每管形瓶冻干制品含1mg海鞘素的注射管形瓶，和含2mlCremophor El/乙醇/水为15/15/70％(v/v)的重新配制的溶液的注射管形瓶。
采用Cremophor El/乙醇/水为15/15/70％(v/v)的作为冻干制品的重新配制的溶液是无先例的。Cremophor El/乙醇的结合在工业产品中仅仅被用作溶液的赋形剂(如：紫杉醇或环孢菌素)。
Cremophor El/乙醇/水溶媒的研究提供了有效的助溶剂表面活性剂体系，它在未来的药物制剂中可用作重新配制的溶液，并允许加入水溶性膨胀剂如甘露醇。而且，通过减少Cremophor El的相对量，得到更少毒性的溶媒。
该冻干产品的制备方法也有特点。一般地，药物的冷冻干燥从药的水溶液开始。就海鞘素来说，40％(v/v)的叔丁醇/水混合物优选用作冷冻干燥介质。尽管前述(如rhizoxin)的从40％叔丁醇/水混合物开始冷冻干燥不是通常的做法。
总之，叔丁醇/水混合物中的药物的冻干和后继的、含remophor El/乙醇/水为15/15/70％(v/v/v)的冻干产物的重新配制的的结合是独特的。
Claims (11)
1.一种didemnin化合物的药用组合物，它包括首先是含水溶性原料的冻干didemnin制剂，其次是混合溶剂的重新配制的溶液。
2.根据权利要求1的didemnin组合物，用于给予患者作为抗肿瘤治疗药物的重新配制。
3.根据权利要求1或2的didemnin组合物，其中的didemnin从didemnins、去氢didemnin、nordidemnins、didemnin同族元素(congeners)和didemnin类似物中选择。
4.根据权利要求3的didemnin组合物，其中的didemnin化合物为海鞘素。
5.根据前述权利要求任一项的didemnin组合物，其中的重新配制的溶液包含链烷醇/水混合物。
6.根据权利要求5的didemnin组合物，其中的重新配制的溶液包含非离子表面活性剂。
7.根据权利要求6的didemnin组合物，其中的非离子表面活性剂为溶液的10-25％(v/v)；链烷醇为乙醇且为该溶液的10-25％(v/v)；水为溶液的50-80％(v/v)。
8.根据前述任一项权利要求的didemnin组合物，它包括一管形瓶的含水溶性膨胀剂的冻干didemnin制剂，和另一管形瓶的非离子表面活性剂/乙醇/水的预混合物。
9.一种制备didemnin化合物的药用组合物的方法，它包括冷冻干燥didemnin/水溶性添加剂/链烷醇/水混合物，以提供冻干的初级(first)组分，并另提供链烷醇/水混合物作为重新配制的溶液。
10.根据权利要求9的方法，其中混合物中的链烷醇为叔丁醇。
11.根据权利要求9或10的方法，其中所述链烷醇/水混合物中的链烷醇量为25-60％(v/v)。
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| GBGB9803448.1A GB9803448D0 (en) | 1998-02-18 | 1998-02-18 | Pharmaceutical formulation |
| GB9803448.1 | 1998-02-18 |
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| CN1170586C CN1170586C (zh) | 2004-10-13 |
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| EP (1) | EP1054686B1 (zh) |
| JP (2) | JP4536255B2 (zh) |
| KR (1) | KR100595597B1 (zh) |
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| GB (1) | GB9803448D0 (zh) |
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| CN100335495C (zh) * | 2006-01-23 | 2007-09-05 | 南方医科大学 | 一种海鞘多肽及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100335495C (zh) * | 2006-01-23 | 2007-09-05 | 南方医科大学 | 一种海鞘多肽及其制备方法 |
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| HK1032538A1 (en) | 2001-07-27 |
| BR9908088B1 (pt) | 2013-05-21 |
| CN1170586C (zh) | 2004-10-13 |
| GB9803448D0 (en) | 1998-04-15 |
| AU754073B2 (en) | 2002-11-07 |
| DE69901487T2 (de) | 2002-12-19 |
| PT1054686E (pt) | 2002-09-30 |
| CA2321116A1 (en) | 1999-08-26 |
| AU2538999A (en) | 1999-09-06 |
| ATE217532T1 (de) | 2002-06-15 |
| DE69901487D1 (de) | 2002-06-20 |
| BRPI9908088C1 (pt) | 2021-05-25 |
| BR9908088A (pt) | 2000-10-31 |
| ES2175940T3 (es) | 2002-11-16 |
| WO1999042125A1 (en) | 1999-08-26 |
| CA2321116C (en) | 2009-10-06 |
| IL137911A (en) | 2006-04-10 |
| JP2002503704A (ja) | 2002-02-05 |
| IL137911A0 (en) | 2001-10-31 |
| DK1054686T3 (da) | 2002-06-17 |
| JP2010163443A (ja) | 2010-07-29 |
| EP1054686B1 (en) | 2002-05-15 |
| EP1054686A1 (en) | 2000-11-29 |
| KR20010040993A (ko) | 2001-05-15 |
| US8420130B1 (en) | 2013-04-16 |
| BRPI9908088B8 (pt) | 2017-03-07 |
| JP4536255B2 (ja) | 2010-09-01 |
| KR100595597B1 (ko) | 2006-07-03 |
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