CN1170586C - 膜海鞘素化合物的药物制剂 - Google Patents

膜海鞘素化合物的药物制剂 Download PDF

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CN1170586C
CN1170586C CNB998050393A CN99805039A CN1170586C CN 1170586 C CN1170586 C CN 1170586C CN B998050393 A CNB998050393 A CN B998050393A CN 99805039 A CN99805039 A CN 99805039A CN 1170586 C CN1170586 C CN 1170586C
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J��H���ڶ�
J·H·贝内恩
B·努延
C
R·E·C·亨拉尔
A·戈麦斯
��˹��ŵ��
J·希门诺
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

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

膜海鞘素化合物的药物制剂
技术领域
本发明涉及药物制剂，更具体地说，涉及膜海鞘素(didemnin)化合物的药物制剂。
背景技术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膜海鞘素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。
实际上，在适于向患者供药的膜海鞘素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，需要使膜海鞘素化合物如脱氢膜海鞘素B(dehydrodidemnin 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。
发明内容本发明通过提供膜海鞘素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膜海鞘素制剂，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膜海鞘素化合物，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优选包括一管形瓶的含水溶性增量剂的冻干膜海鞘素制剂，和另一管形瓶的非离子表面活性剂/乙醇/水的预混合物。
本发明的药用组合物中的优选膜海鞘素化合物，包括膜海鞘素和膜海鞘素衍生物，如去氢膜海鞘素、降膜海鞘素(nordidemnins)、膜海鞘素同源物(didemnin congeners)和膜海鞘素类似物。本发明特指有限水溶性的膜海鞘素，包括如去氢膜海鞘素B(也称作海鞘素)。
抗癌剂海鞘素(去氢膜海鞘素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。
优选通过冷冻干燥膜海鞘素/链烷醇/水混合物制备冻干膜海鞘素制剂，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)。
具体实施方式
                         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 (7)

1.一种膜海鞘素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膜海鞘素制剂，其次是混合溶剂的重新配制的溶液，其中重新配制的溶液包含链烷醇/水混合物，所述链烷醇为乙醇，该混合物包含非离子表面活性剂，其中的非离子表面活性剂为溶液的10-25％v/v；乙醇为该溶液的10-25％v/v；水为溶液的50-80％v/v。
2.根据权利要求1的膜海鞘素组合物，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的膜海鞘素组合物，其中的膜海鞘素从膜海鞘素、去氢膜海鞘素dehydrodidemnin、降膜海鞘素nordidemnins、膜海鞘素同源物和膜海鞘素类似物中选择。
4.根据权利要求3的膜海鞘素组合物，其中的膜海鞘素化合物为海鞘素。
5.根据权利要求1或2的膜海鞘素组合物，它包括一管形瓶的含水溶性增量剂的冻干膜海鞘素制剂，和另一管形瓶的非离子表面活性剂/乙醇/水的预混合物。
6.一种制备膜海鞘素化合物的药用组合物的方法，它包括冷冻干燥膜海鞘素/水溶性添加剂/叔丁醇/水混合物，以提供冻干的初级组分，并另提供链烷醇/水混合物作为重新配制的溶液，所述链烷醇为乙醇，该混合物包含非离子表面活性剂，其中的非离子表面活性剂为溶液的10-25％v/v；乙醇为该溶液的10-25％v/v；水为溶液的50-80％v/v。
7.根据权利要求6的方法，其中所述叔丁醇/水混合物中的叔丁醇量为25-60％v/v。
CNB998050393A 1998-02-18 1999-02-18 膜海鞘素化合物的药物制剂 Expired - Lifetime CN1170586C (zh)

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BRPI9908088B8 (pt) 2017-03-07
WO1999042125A1 (en) 1999-08-26
JP4536255B2 (ja) 2010-09-01
DK1054686T3 (da) 2002-06-17
EP1054686B1 (en) 2002-05-15
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CA2321116A1 (en) 1999-08-26
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IL137911A0 (en) 2001-10-31
US8420130B1 (en) 2013-04-16
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BR9908088A (pt) 2000-10-31
HK1032538A1 (en) 2001-07-27
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BRPI9908088C1 (pt) 2021-05-25
ATE217532T1 (de) 2002-06-15
GB9803448D0 (en) 1998-04-15

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