CN1293570A - 紫杉烷的药物制剂 - Google Patents

紫杉烷的药物制剂 Download PDF

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CN1293570A
CN1293570A CN00800018A CN00800018A CN1293570A CN 1293570 A CN1293570 A CN 1293570A CN 00800018 A CN00800018 A CN 00800018A CN 00800018 A CN00800018 A CN 00800018A CN 1293570 A CN1293570 A CN 1293570A
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F·H·豪歇尔
D·穆拉里
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Abstract

一种紫杉烷抗肿瘤剂、特别是紫杉醇或多西泰索(docetaxel)或其可药用盐和N－甲基吡咯烷－2－酮(NMP)、和/或二甲基乙酰胺(DMA)、和/或二甲基异脱二水山梨醇(DMI)的药物制剂。该制剂可包含其他赋形剂和/或稀释剂,并适于对癌症患者给药。

Description

紫杉烷的药物制剂
发明领域
本发明涉及紫杉烷、特别是抗肿瘤药紫杉醇(Taxol)和Docetaxel(泰索帝(Taxotere))或其衍生物、和N-甲基吡咯烷-2-酮(NMP)、二甲基乙酰胺(DMA)和／或二甲基异脱二水山梨醇(dimethylisosorbide)(DMI)的组合物的药物制剂。
发明背景
1、紫杉醇和多西泰索(Docetaxel)的背景
紫杉烷类，特别是目前可获得的两种药物-紫杉醇和Docetaxel，是有效的抗肿瘤剂。紫杉烷是从某些种紫杉树的树皮或针状叶中天然产生或半合成的。紫杉醇发现于七十年代后期，并已发现它是一种作用机理不同于现有化学治疗剂的有效的抗肿瘤剂。
特别是，据报道，紫杉醇、Docetaxel和其他紫杉烷通过增强微管蛋白的聚合作用而发挥细胞毒性作用，微管蛋白是梭形微管形成时的必需蛋白质。该细胞毒性作用的结果是形成非常稳定的、非功能性小管，据信这抑制了细胞的复制并导致肿瘤细胞死亡。紫杉烷被认为是对其他抗肿瘤剂不响应的许多固体肿瘤的有效治疗剂。
紫杉醇的结构复杂，如下式Ⅰ所示：
紫杉醇极难溶于水(小于10μg／mL)，因此几乎不能用水配制后用于静脉给药。目前，紫杉醇是用聚氧乙基化蓖麻油(聚烃氧基酯(Polyoxyl)35或克列莫佛(Cremaphor))作为基本溶剂配制成溶液后对癌症患者静脉给药。用高浓度的乙醇作为共溶剂。紫杉醇给药时的主要困难之一是会发生过敏反应。这些反应，包括严重的皮疹、荨麻疹、面红、呼吸困难、心动过速等等，至少部分归因于制剂中用作溶剂的高浓度的Polyoxyl 35。而且，现有紫杉醇制剂中高浓度的乙醇也容易使许多患者发生急性醇中毒。
Docetaxel是一种紫杉醇类似物，最近已被美国食品和药物管理局批准对癌症患者给药。Docetaxel具有以下结构：
与紫杉醇一样，Docetaxel极难溶于水。目前用于溶解Docetaxel的最优选的溶剂是聚山梨醇酯80(吐温80)。象Polyoxyl 35一样，聚山梨醇酯经常引起患者的过敏反应。另外，聚山梨醇酯不能与PVC释放装置一起使用，因为它容易吸附具有高度毒性的邻苯二甲酸二乙基己基酯。
由于Cremaphor的粘度相当高，因此必须使用共溶剂才能将该制剂对患者静脉输注。一些常用的共溶剂包括各种低级醇，植物油和其他油类，以及其他有机和无机溶剂的组合物。其他药物赋形剂也可用于制备这些药物的制剂。目前，只有紫杉醇或Docetaxel的静脉制剂可供对患者给药。
2、N-甲基吡咯烷酮
N-甲基吡咯烷-2-酮，也叫做N-甲基吡咯烷酮、1-甲基-2-吡咯烷酮、NMP以及其他类似名称，是一种常用的工业溶剂。NMP也在药物制剂中作为赋形剂用于增强局部用制剂的皮肤渗透性。NMP是一种缓慢蒸发的、高极性的、质子惰性的通用溶剂，它可以与水和大多数有机溶剂完全混溶。
NMP已用于药物化合物的制剂中作为各种药物的溶剂，即作为依托泊苷、四环素、多西环素、替尼泊苷、金霉素、喜树碱和其他难溶于水的药物化合物的溶剂。有关NMP药物应用的在先专利包括美国专利5，900，419；5，880，133；5，859，023；5，859，022；5，726，181；以及其他。
3、二甲基乙酰胺和二甲基异脱二水山梨醇
二甲基乙酰胺(DMA)和二甲基异脱二水山梨醇(DMI)是有机溶剂，先前已教导它们有可能作为高亲脂性喜树碱类似物的溶剂。美国专利5，447，936；5，468，754；5，597，829；5，604，233；5，633，260；5，674，873；以及其他文献中指出，使用DMA和DMI作为配制各种难溶于水的喜树碱类似物的有用溶剂。DMI还被用作其他药剂诸如肌肉松弛药、阿司匹林和各种类固醇的溶剂。
DMA和DMI都具有良好的安全性能，并且可与许多有机溶剂，诸如乙醇、丙二醇、肉豆蔻酸异丙酯、二乙醚、植物油等混溶，也可以与水混溶。
美国专利5，877，205公开了使用DMA／EG作为共溶剂的紫杉醇制剂，将该储备制剂稀释成含水脂质乳剂后对患者给药。
该5，877，205号专利公开了用于将紫杉醇／DMA／PEG储备溶液最终稀释成含水脂质乳剂所需要的溶剂，即大豆油。
发明概述
本发明的药物制剂包括作为主要成分的有效量的紫杉烷(活性成分)，适量的NMP，和一种足以溶解整个活性成分的包含适量DMA和／或DMI的共溶剂。该制剂还可包含适于静脉给药的制剂中常用的其他药物赋形剂。
因此，本发明的一个目的是提供一种新型药物制剂，它包括作为活性成分之一的有效量的紫杉烷。
本发明的另一个目的是提供一种易于对患者给药且安全的紫杉烷药物制剂，该制剂比目前可供给药用的制剂具有更小的毒性。
通过阅读下述说明书，本发明的其他目的将变得显而易见。
对优选实施方案的说明
本文中描述的优选实施方案并不是穷举的，也不打算将本发明限于所公开的精确方式。选择并描述它们是为了解释本发明的原理和其应用与具体实施，以使本领域的其他技术人员遵循其教导。
本发明的药物制剂包括两个基本成分：1)紫杉烷(活性成分)；和2)适量的足以溶解整个活性成分的基本溶剂。该溶剂优选为NMP，或DMA或DMI。该制剂被包装成已批准使用活性成分，用于对需要治疗的癌症患者静脉给药的形式。
根据需要该制剂还可包含一定量的各种其他赋形剂。赋形剂可在配制药物时用于多种目的，即作为表面活性剂、增稠剂／稀释剂、pH调节剂、稳定剂等。下面描述了一些典型赋形剂的实例以及它们的常规用法和功能。
表1聚乙二醇(PEG 200，PEG 300，    增稠剂／溶剂PEG 400等)有机酸和无机酸                 降低pH的试剂有机碱和无机碱                 升高pH的试剂环氧化蓖麻油(Cremaphor)        表面活性剂醇(优选乙醇或苯甲醇)           共溶剂／抗菌剂泊咯沙姆(Poloxamer)和／或聚山  表面活性剂梨醇酯(407，PF-127，吐温80等)甘油                           共溶剂NMP，和DMA和／或DMI            共溶剂水                             稀释剂盐水                           稀释剂
该制剂中使用的所有稀释剂、载体和赋形剂都是可药用化合物。
该制剂优选用下述方式制备。首先，将活性成分完全溶于基本溶剂中。其次，加入其他添加剂和赋形剂完成该制剂，这些添加剂和赋形剂或者单个加入或者结合在一起加入。然后特有地包装该制剂并将它们运送到医院或诊所。
最后，该制备好的制剂用水稀释，或者用常规的胃肠外释放载体稀释，诸如盐水溶液(0．1％-0．9％NaCl)、乳酸盐林格氏溶液、5％葡萄糖(美国药典)或类似溶液。最终的稀释步骤通常在医院或治疗中心，刚好在对患者给药之前进行。
优选的紫杉烷药物制剂包括药物有效量的紫杉烷，它们溶解在足以溶解所有紫杉烷的适量的基本溶剂中，形成溶液。
当前推荐的紫杉醇的剂量范围是100-250mg／m2，Docetaxel的剂量范围是50-150mg／m2。由于成年患者的体表面积一般为1．5-2．0m2，所以紫杉醇的优选总剂量范围是150-500mg，Docetaxel是75-300mg。当患者的体表面积在这些范围之外时，根据该变化对剂量进行调节。
已确定紫杉醇和Docetaxel在NMP中的最大溶解度是大约40mg／mL。既然优选NMP的量足以溶解所有紫杉烷，那么，优选的紫杉醇制剂将包括至少4-13mLNMP，Docetaxel制剂包括至少2-8mLNMP。这些体积经常会更高，以确保紫杉烷完全溶于基本溶剂。
至于DMA，已观测到紫杉醇和Docetaxel在其中的最大溶解度大于l00mg／mL。考虑到优选DMA的量足以溶解所有紫杉烷，因此优选的紫杉醇和Docetaxel制剂将包括约1-5mL DMA。这些体积经常会更高，以确保紫杉烷完全溶于基本溶剂。
对于DMI，紫杉醇和Docetaxel的最大溶解度是约40mg／mL。既然优选DMI的量足以溶解所有紫杉烷，那么，优选的紫杉醇制剂将包括至少4-15mL DMI，Docetaxel制剂将包括至少2-10mL DMI。这些体积经常会更高，以确保紫杉烷完全溶于基本溶剂。
优选的制剂是通过将有效量的紫杉烷加入到预定体积的、足以溶解所有紫杉烷的NMP中制备的。向该净制剂中加入所需赋形剂。然后包装并分发该浓缩制剂。同上所述，就在对患者给药之前，用常规的胃肠外释放载体稀释该浓缩制剂。
下表2中显示了优选的紫杉烷／NMP制剂。
表2
成分         具体化合物    用量
活性成分     紫杉醇        200mg
溶剂         NMP           10mL
共溶剂       DMA           0-10mL
稀释剂       乙醇          10-100mL
表面活性剂   Cremaphor     0-500mL
pH调节剂     柠檬酸        1-5mL
赋形剂       PEG200        10-500mL
表面活性剂   吐温80        0-500mL
下表3中显示了优选的紫杉烷／DMA制剂。
表3
成分        具体化合物    用量
活性成分    紫杉醇        200mg
溶剂        DMA           5-10mL
稀释剂      乙醇          10-100mL
表面活性剂  Cremaphor     0-500mL
pH调节剂    柠檬酸        1-5mL
赋形剂      PEG200        0-500mL
表面活性剂  吐温80        0-500mL
下表4中显示了优选的紫杉烷／DMI制剂。
表4
成分        具体化合物    用量
活性成分    紫杉醇        200mg
溶剂        NMP           0-10mL
溶剂        DMI           5-10mL
稀释剂      乙醇          10-100mL
表面活性剂  Cremaphor     10-500mL
pH调节剂    柠檬酸        1-5mL
赋形剂      PEG200        0-500mL
表面活性剂  吐温80        0-500mL
制剂包装好后，考虑推荐剂量和主治医师规定的给药时间表后，按照患者的治疗方案将其对患者给药。
应当理解，上述说明的目的仅仅是为了阐明本发明，而决不应解释为将本发明局限于上面所给出的精确细节。

Claims (14)

1、一种包含紫杉烷和NMP的药物制剂。
2、如权利要求1所述的药物制剂，其中所述紫杉烷是紫杉醇。
3、如权利要求1所述的药物制剂，其中所述紫杉烷是多西泰索。
4、如权利要求1所述的药物制剂，其中所述制剂还包括低级醇。
5、如权利要求1所述的药物制剂，其中所述制剂进一步包括非离子表面活性剂。
6、一种药物制剂，它包含紫杉醇或多西泰索或其可药用盐，NMP和二甲基乙酰胺。
7、如权利要求6所述的药物制剂，其中所述制剂进一步包括低级醇。
8、如权利要求6所述的药物制剂，其中所述制剂进一步包括非离子表面活性剂。
9、一种包含紫杉烷和二甲基异脱二水山梨醇的药物制剂。
10、如权利要求9所述的药物制剂，其中所述紫杉烷是紫杉醇。
11、如权利要求9所述的药物制剂，其中所述紫杉烷是多西泰索。
12、如权利要求9所述的药物制剂，其中所述制剂还包括作为共溶剂的NMP。
13、如权利要求9所述的药物制剂，其中所述制剂进一步包括非离子表面活性剂。
14、如权利要求11所述的药物制剂，其中所述制剂进一步包括非离子表面活性剂。
CNB008000182A 1999-01-08 2000-01-07 紫杉烷的药物制剂 Expired - Fee Related CN1169525C (zh)

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CN1169525C (zh) 2004-10-06
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ATE514424T1 (de) 2011-07-15
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AU2496300A (en) 2000-07-24
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