CN1636560A - 以塔三烷衍生物为主组分的新组合物 - Google Patents

以塔三烷衍生物为主组分的新组合物 Download PDF

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CN1636560A
CN1636560A CNA021472459A CN21407245A CN1636560A CN 1636560 A CN1636560 A CN 1636560A CN A021472459 A CNA021472459 A CN A021472459A CN 21407245 A CN21407245 A CN 21407245A CN 1636560 A CN1636560 A CN 1636560A
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J·M·鲍毕
P·戴兰狄
G·古伦
M·瓦拉德
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Abstract

本发明涉及含有塔三烷类衍生物的可注射组合物，其由在作为表面活性剂吐温80中的塔三烷类衍生物的溶液和添加剂的稀释水溶液组成，并且添加剂与表面活性剂的重量比大于6％但小于或等于101.2％。本发明还涉及所述组合物的制备方法以及用于制备输注溶液的用途。

Description

以塔三烷衍生物为主组分的新组合物
本发明领域
本申请是1993年10月29日在中国提出的申请号为93119653.1的中国专利申请的分案申请。
本发明是关于一种主要含具有抗肿瘤及抗白血病活性的治疗剂的新的药物制剂。特别是关于一种含塔三烷衍生物的新的注射制剂。
背景技术
含塔三烷衍生物如塔三醇(taxol)、塔三得尔(taxotere)具有下面的通式：
Figure A0214724500051
式中(I)中R代表氢原子或乙酰基，R1代表叔丁氧羰基氨基或苯甲酰基氨基。在这些衍生物中，优选两种衍生物：R代表乙酰基及R1代表苯甲酰  基氨基；或R代表氢原子及R1代表叔丁氧羰基氨基。
上述两个化合物中第一个化合物的更为熟知的名称为塔三醇，第二个化合物以塔三得尔的名称为人们所知。
这些产品在体内对恶性肿瘤具有重要活性，在用所有其它抗肿瘤药治疗疾病发生抗药时，就可开展本项研究。
不幸的是，这些产品在水中的溶解度相当小，需要准备一种以表面活性剂和乙醇为主的注射制剂配方。乙醇是最好的药用溶剂，它使式(I)的相应分子能够溶解。
例如，按Rowinsky、Lorraine、Cazenave及Donehower在Journal of the National Cancer Institute，Vol.82，No15，1247-1259页中，1990年8月1日公开的方法，人们先制备一种溶液(所谓“母液”)，它在由下列溶剂组成的混和溶剂中含有大约6mg/ml的塔三醇：
-50％(体积)乙醇
-50％(体积)Cremophor EL
注射时将此溶液与含氯化钠或葡萄糖的输液液体混和。为了得到一种从物理和化学角度都稳定的混合液，此文献作者认为在输液溶液中活性成份的浓度应限制在0.03至0.6mg/ml左右(见上述出版物1251页，第1栏，第3段)。
当然希望能够注射足够剂量的活性成份，关于这一点临床医生希望的活性成份在输液液体中的浓度在大约0.3到1mg/ml之间，超过此剂量将出现难以处理的主要由Crémophor引起的过敏性休克(见Rowinsky的文献第1250页，第二栏，最后一段)。
为了得到这样的浓度(在0.3到1mg/ml之间)，按照此文献，注射的溶液除含有活性成份，也应同时在每100ml的输液溶液中分别含有8g的乙醇或一种Cremophor。治疗经常要求投入大剂量活性成份，然而活性成份在溶液中的浓度相对地小，大量注射溶液在治疗过程中除诱发过敏症状外面还引起乙醇中毒症状。
按照法国专利申请91.08527，人们发现实施全新的药物制剂，要么使乙醇浓度大大减低，要么彻底取消输液液体中的Cré-mophor及乙醇。
关于这一点，按照此专利申请的第一种实施方法，制备一种母液，活性成份在由乙醇(塔三烷类活性成份最好的生物相容溶剂)和一种选自下列表面活性剂的混合溶剂中：多乙氧基醚特别是商品化的Tween和Montanox，或酯醚和脂肪酸(氢化或没氢化的蓖麻油)氧化乙烯酯及甘油酯，例如商品化的Crémophor或Emulphor。
将活性成份溶解在乙醇中，然后逐渐加入表面活性剂来制备母液。这样就可以制备出在含大约50％表面活性剂的混合物中含10到100mg/ml活性成份的溶液。此溶液中所含乙醇随后通过真空蒸发或其它适当方法至少部分消除。
按照制备母液的第二种方法，直接将活性成份溶解在表面活性剂中。根据此发明优选的实施方法，制备一种表面活性剂溶液(尤其是含1-2％的乙醇)，再向此溶液中连续加入活性成份，并同时用如螺旋破碎机或撕裂涡轮搅拌。少量乙醇的存在可带来许多好处，介质的粘性较小，粉末的湿润性及溶液的最后过滤得以改善。
母液的乙醇含量是最好低于5％，如低于2％则尤为优选。这样的溶液是稳定的，并可在表面活性剂中含高达200mg/ml，优选含达80mg/ml的活性成份。
按照此发明塔三醇母液的活性成份在表面活性剂中的浓度在6-20mg/ml之间。塔三得尔母液的活性成份在表面活性剂中的浓度优选在20-80mg/ml之间。
这些在表面活性剂中的可能含有少量乙醇的溶液可被溶解在输液液体中，但要借助于如Vorten型装置的非常剧烈的搅拌。所有医院都没有这种设备，但这些设备在帮助上述组合物形成溶液时是必要的，这就是本发明的目的。
另一种使母液溶解于输液溶液中的方法是加热，使整体温度约达40℃。但在这种情况下，式(I)的化合物部分分解。
发明内容
本发明在于在塔三烷类衍生物在表面活性剂中的溶液和含有添加剂的水溶液之间形成一种中间溶液，其中添加剂此后可以帮助上述中间溶液溶解于输液溶液中。
所用的添加剂选自那些能够破坏或避免在含有塔三烷类衍生物的乳化剂与水之间形成胶化层的添加剂。
在这些可以破坏或避免这种胶化层形成的添加剂中，可以例举出那些分子量等于或小于200的衍生物。在这些化合物中更优选那些至少带有一个羟基或一个胺基功能团的化合物，例如氨基酸。
作为这样的化合物的例子列举如下：
             -乙醇
             -葡萄糖
             -甘油
             -丙二醇
             -甘氨酸
             -山梨醇
             -甘露糖醇
             -苯甲醇
             -聚乙二醇。
也可以用无机盐，如氯化钠。
添加剂的用量随着它的性质而变化，优选大于6％(重量，按表面活性剂的重量计)。对于多元醇如甘油、葡萄糖或山梨醇更优选重量大于15％。
塔三塔衍生物在表面活性剂中的溶液与稀释添加剂水溶液最好放在烧瓶、卵形瓶或有两个室的装置中，使在注入输液袋时两种溶液能当即混和。
然后，按想要注射的活性成份的量将预先计算好的塔三得尔或塔三醇的输液注入人体。用这种溶液时观察不到在用以前工艺制备的溶液时看到的过敏性休克现象。
这样新的输液使注入人体的表面活性剂的量如与原工艺比较减少80％左右。
具体实施方案
下列实施例将补充说明本发明，但不得视为对本发明的限制。
实施例1
按照专利申请91.08527制备塔三烷衍生物的溶液
将32g的塔三得尔溶解在340ml的绝对乙醇中，然后加入830g的多乙氧基醚80。在30℃、15mm汞柱(2000Pa)压力下用旋转蒸发器蒸发乙醇2小时。
所得溶液稳定性好，含40mg/ml的塔三得尔。
将1ml的这种溶液与3ml含重量为70％水及30％甘油的水溶液混合。手工搅拌后彻底溶解。这种情况下，如果将水/甘油混合物用水单独代替，搅拌后观察到非均匀胶的形成。仅加入2ml这种甘油水溶液时得到了同样的结果，即一种流体溶液。
实施例2
用含35％(重量)的葡萄糖水溶液代替甘油溶液重复实施例1。用手工搅拌后，溶液为流体状。
实施例3-4
用不同的表面活性剂代替多乙氧基醚重复实施例1，结果列于下表：
    试验  表面活性剂     稀释混和液     观察
    34C1C2  Crémophor ELCrémophor RH 40Crémophor ELCrémophor RH 40     水-甘油(64/36)水-甘油(64/36)水水     流体状″呈块状″
实施例5-12
在与实施例1相同的条件下操作，但要将1g多乙氧基醚80与1g列于下表中的稀释混和液混和；观察到液体相的性质
试验     稀释混和液(％质量)  比例添加剂-Tween 80(％质量) 混和液外貌
    5     水     ：62甘油   ：38  甘油    ：27,5Tween 80：72,5     流体状
    6     水     ：62山梨醇 ：38  山梨醇  ：27,5Tween 80：72,5     ″
    7 水     ：62PEG 200：38 PEG 200 ：27,5Tween 80：72,5     ″
    8     水     ：62葡萄糖 ：38  葡萄糖  ：27,5Tween 80：72,5     ″
    9     水     ：62丙二醇：38 丙二醇  ：27,5Tween 80：72,5     ″
10     水     ：78NaCl   ：22  NaCl    ：15,4Tween 80：84,6     ″
    11     水     ：62甘油   ：19葡萄糖   19  甘油    ：13,8葡萄糖  ：13,8Tween 80：72,4     ″
    12     水       62甘油     15,2葡萄糖   15,2NaCl     7,6  甘油    ：11,0葡萄糖  ：11,0NaCl    ：5,5Tween 80：72,5     ″
实施例13-14
向6g多乙氧基醚80的溶液中加入xg的添加剂及4ml水，观察溶液的流体性。
结果列于下表：
    试验     添加剂     结果
    13     苯甲醇0,5g     流体状
    14     甘氨酸0,4g     ″
    15     乙二醇1,90g     ″
    16     乙醇0,60g     ″
    17     甘油0,53g乙醇0,53g     ″

Claims (18)

1.含有塔三烷类衍生物的可注射组合物，其由在作为表面活性剂的吐温80中的塔三烷类衍生物的溶液和选自下列成分的添加剂的稀释水溶液组成：葡萄糖，甘油，山梨醇，甘露(糖)醇，甘氨酸，聚乙二醇，丙二醇，苄醇，乙醇或其混合物；并且添加剂与表面活性剂的重量比大于6％但小于或等于101.2％。
2.权利要求1的组合物，其特征在于该组合物具有双室或两个室，所述的双室或两个室组成如下：
-其中一个室为带有乙醇的含有在作为表面活性剂的吐温80中的塔三烷类衍生物的溶液，并且
-另一个室中为选自葡萄糖，甘油，山梨醇，甘露(糖)醇，甘氨酸，聚乙二醇，丙二醇，苄醇，乙醇或其混合物的添加剂的稀释水溶液。
3.权利要求2的组合物，其中含有塔三烷的溶液中的乙醇用量小于5％。
4.权利要求1-3任一项所述的组合物，其特征在于塔三烷类衍生物是选自具有式(I)的塔三烷类衍生物的化合物
Figure A021472450002C1
其中R代表氢原子或乙酰基并且R1代表叔丁基氧羰基氨基或苯甲酰基氨基。
5.权利要求1-3任一项所述的组合物，其特征在于在式1化合物中，R代表乙酰基，R1代表苯甲酰基氨基。
6.权利要求1-3任一项所述的组合物，其特征在于在式1化合物中，R代表氢并且R1代表叔丁基氧羰基氨基。
7.制备含有塔三烷类衍生物的可注射组合物的方法，其包括将在作为表面活性剂的吐温80中的塔三烷类衍生物的溶液与选自葡萄糖，甘油，山梨醇，甘露(糖)醇，甘氨酸，聚乙二醇，丙二醇，苄醇，乙醇或其混合物的添加剂的稀释水溶液进行混合；并且添加剂与表面活性剂的重量比大于6％但小于或等于101.2％。
8.权利要求7中的制备方法，其中的可注射组合物具有双室或两个室，所述的双室或两个室组成如下：
-其中一个室为带有乙醇的含有在作为表面活性剂的吐温80中的塔三烷类衍生物的溶液，并且
-另一个室中为选自葡萄糖，甘油，山梨醇，甘露(糖)醇，甘氨酸，聚乙二醇，丙二醇，苄醇，乙醇或其混合物的添加剂的稀释水溶液。
9.权利要求8的方法，其中含有塔三烷的溶液中的乙醇用量小于5％。
10.权利要求7-9任一项所述的方法，其特征在于塔三烷类衍生物是选自具有式(I)的塔三烷类衍生物的化合物：
Figure A021472450003C1
其中R代表氢原子或乙酰基，R1代表叔丁基氧羰基氨基或苯甲酰基氨基。
11.权利要求7-9任一项所述的方法，其特征在于在式1化合物中，R代表乙酰基，R1代表苯甲酰基氨基。
12.权利要求7-9任一项所述的方法，其特征在于在式1化合物中，R代表氢并且R1代表叔丁基氧羰基氨基。
13.含有塔三烷类衍生物的可注射组合物制备输注溶液的用途，其中所述的可注射组合物由在作为表面活性剂的吐温80中的塔三烷类衍生物的溶液和选自葡萄糖，甘油，山梨醇，甘露(糖)醇，甘氨酸，聚乙二醇，丙二醇，苄醇，乙醇或其混合物的添加剂的稀释水溶液组成；并且添加剂与表面活性剂的重量比大于6％但小于或等于101.2％。
14.权利要求13的用途，其中的可注射组合物具有双室或两个室，所述的双室或两个室组成如下：
-其中一个室为带有乙醇的含有在作为表面活性剂的吐温80中的塔三烷类衍生物的溶液，并且
-另一个室中为选自葡萄糖，甘油，山梨醇，甘露(糖)醇，甘氨酸，聚乙二醇，丙二醇，苄醇，乙醇或其混合物的添加剂的稀释水溶液。
15.权利要求14的用途，其中含有塔三烷的溶液中的乙醇用量小于5％。
16.权利要求13-15任一项所述的用途，其中的塔三烷类衍生物是选自具有式(I)的塔三烷类衍生物的化合物：
其中R代表氢原子或乙酰基，R1代表叔丁基氧羰基氨基或苯甲酰基氨基。
17.权利要求13-15任一项所述的用途，其中在式1化合物中，R代表乙酰基并且R1代表苯甲酰基氨基。
18.权利要求13-15任一项所述的用途，其中在式1化合物中，R代表氢并且R1代表叔丁基氧羰基氨基。
CNB021472459A 1992-12-02 1993-10-29 以塔三烷衍生物为主组分的新组合物 Ceased CN1291713C (zh)

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