CN101143130A - 一种卡莫司汀静脉乳剂及其制备方法 - Google Patents
一种卡莫司汀静脉乳剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及用于静脉输液的、在稳定水包油乳剂中的卡莫司汀组合物。本发明还涉及将卡莫司汀掺入油中形成稳定的水包油乳剂的方法。该组合物包括卡莫司汀，油，水和表面活性剂。
Description
发明领域
本发明涉及一种卡莫司汀的静脉乳剂及其制备方法，属医药科技领域。
背景技术
当前我国每年癌症发病人数约160万，全国每年死于癌症的人数已从70万上升到130万，治疗癌症已成为我国卫生战略重点之一。随着癌症发病率的上升，世界抗癌药市场迅速成长，1999年全球抗癌药的销售量约为238亿美元。世界上的抗癌药约有几百种，常用抗癌药约八十多种。其中用烷化剂治疗恶性肿瘤疾病已有30多年的历史，由于其药物性质非常活泼，故能于细胞中亲核基团部分发生烷化反应。烷化剂往往以核酸为主要攻击对象，使DNA结构功能破坏，细胞分裂停止活死亡。烷化剂主要包括：氮芥类、亚硝脲类、亚乙基亚胺类、烷基磺酸酯类等。自1956年美国最先对亚硝脲类化合物1-甲基-3-硝基-1-亚硝基胍研究以来，人们开发了一系列活性显著的亚硝脲类抗肿瘤药，这包括六十年代中期进入临床使用的卡莫司汀(Carmustine BCNU)、链脲霉素，七十年代上市的洛莫司汀(Lomustine CCNU)、司莫司汀(Semustine MeCCNU)，以及1980由日本三共株式会研制推向市场的尼莫司汀(Nimustine ACNU)，其中卡莫司汀(Carmustine BCNU)、洛莫司汀(Lomustine CCNU)、司莫司汀(Semustine MeCCNU)已经在国内有厂家生产。
卡莫司汀(Carmustine BCNU)别名：卡氮芥、双氯乙亚硝脲、氯乙亚硝脲；具有抗癌谱广、脂溶性高的特点，可以透过血脑屏障，所以对脑瘤或脑转移有效。卡莫司汀(Carmustine BCNU)与上述已生产的亚硝脲类抗癌药相比具有如下优点：(a)该品为盐酸盐，具有良好的水溶性，可以用注射水溶解后，静注或静滴；(b)高度脂溶性，可通过血脑屏障，浓度为血浆中原药及代谢物的30％；(c)为一广谱抗肿瘤药，可缓解脑肿瘤、胃癌、肝癌、结肠直肠癌、肺癌、慢性白血病和恶性淋巴瘤的主观或客观症状；(d)原料易得且价格便宜，工艺要求条件不苛刻，在众多成本较高的抗癌药中，卡莫司汀是一个价格较低能为大多数人所承受的化疗药品。
本品静脉注射人血后迅速分解。半衰期5分钟，生物半衰期15～30分钟。本品可通过血-脑脊液屏障。由肝脏代谢，代谢物可在血浆中停留数日，造成延迟骨髓毒性。可能有肝肠循环。96小时有60％～70％由肾排出(其中原形不到1％)，1％由粪排出，10％以二氧化碳形式由呼吸道排出。由于脂溶性好，可通过血-脑脊液屏障。脑脊液中的药物浓度为血浆中的50％或以上。
现在市场上销售的卡莫司汀是小容量注射剂，虽有四个厂家有生产批件，但只有一家生产，因该产品在常温条件下很不稳定，而且运输需要放在冰袋中才能保持稳定，因此，推广起来难度很大。
发明内容
基于卡莫司汀剂型单调的这种原因，我们通过大量研究，发明了一种卡莫司汀的静脉乳剂及其制备方法。
一种供静脉输液用的含卡莫司汀的稳定乳剂的组合物，其特征在于它包含：
卡莫司汀0.01％～5％、油1％～40％、表面活性剂0.01％～10％、助乳化剂0％～10％、抗氧剂0.01％～10％、共溶剂0.01％～1％、水。
所述的油可以为：大豆油、玉米油、花生油、芝麻油、橄榄油、亚麻籽油、棉籽油、藏红花有、桐油、蓖麻油、椰子油和棕榈油。
油还可以为上述油中一种以上的混合油。
所述的表面活性剂可以为：蛋黄卵磷脂、大豆磷脂、胆固醇、乙氧基化胆固醇、二乙酰甘油、二烷基醚甘油。
优选的表面活性剂为蛋黄卵磷脂。
所述的助乳化剂为：油酸。
所述的抗氧剂为：亚硫酸盐、维生素C衍生物、硫代化合物、氨基酸类、有机酸类、酚类、胺类、油溶性抗氧剂或其中两种及两种以上抗氧剂的混合物。
优化的抗氧剂为维生素E。
另外，本发明还提供了一种卡莫司汀的静脉乳剂的制备方法，即将卡莫司汀的油溶液分散到水中构成稳定的水包油乳剂的方法：将卡莫司汀溶于共溶剂中，加至已加入抗氧剂的油中混匀得到油相；表面活性剂可以分散到油相或水相中；其中水相可选择性包含甘油以调节所需渗透压，在高速搅拌水相的情况下，将油相均匀倒入水相以形成初乳剂，将初乳剂转入均质机均质，然后经过滤，灌封和密封即得乳剂。
我们所研制的卡莫司汀静脉乳剂与现有剂型相比，它具有一定的缓释性，降低了药品的毒副作用和其对血管的刺激性；药物也因包裹于油滴中而提高了稳定性。
具体实施例
以下通过非限定的实施例对本发明的一些相关目的作进一步的了解。
实施例1
将卡莫司汀1.2g溶于8g苯甲醇中，在于12g蛋黄卵磷脂分别溶于100g经加热至80℃ 的大豆油(已加入维生素E 0.6g)制得油相，在高速搅拌条件下，将上述油相缓缓注入加有22.5g甘油的注射用水(约800ml)，7000rpm条件下搅拌30min制得初乳，定容至1000ml，转入均质机均质，然后经过滤、灌封和灭菌即得。
实施例2、
将卡莫司汀1.2g溶于8g苯甲醇中，溶于100g经加热至80℃ 的大豆油(已加入维生素E 0.6g)制得油相，在高速搅拌条件下，将上述油相缓缓注入加有22.5g甘油和12g蛋黄卵磷脂的注射用水(约800ml)，7000rpm条件下搅拌30min制得初乳，定容至1000ml，转入均质机均质，然后经过滤、灌封和灭菌即得。
实施例二
将卡莫司汀1.2g溶于8g苯甲醇中，在于12g蛋黄卵磷脂分别溶于100g经加热至80℃ 的大豆油(已加入维生素E 0.6g和油酸0.3g)制得油相，在高速搅拌条件下，将上述油相缓缓注入加有22.5g甘油的注射用水(约800ml)，7000rpm条件下搅拌30min制得初乳，定容至1000ml，转入均质机均质，然后经过滤、灌封和灭菌即得。
实施例3
卡莫司汀静脉乳剂的刺激性试验
1、家兔耳缘皮下注射法
试验方法：选择健康无耳疾家兔6只，体重2.0_3.0kg，随即分两组。给药组耳缘皮下注射卡莫司汀乳剂0.05ml，对照组家兔耳缘皮下注射0.9％生理盐水注射液，观察一小时.
观察指标：注射时，家兔安静，无因刺激所致摇头动作，注射后，兔耳无红肿，充血等受刺激现象，一小时后，可以看到，给药兔耳与对照组兔耳相比，兔耳给药局部药物吸收良好，无结硬块或坏死现象.
结论：卡莫司汀乳剂给家兔耳缘皮下注射后，对兔耳组织无刺激或损伤作用.
2、小白鼠静脉注射法
试验方法：选择健康小白鼠10只，体重20.0_25.0g.随机分两组.一组5只小鼠，尾静脉注射0.2ml卡莫司汀乳剂注射液，对照组5只小鼠，尾静脉注射同剂量0.9％生理盐水。
观察指标：给药后一小时内.观察给药小鼠无异常行为，无刺激性反映，小鼠活动和饮食不受影响，所注射的卡莫司汀乳剂对血管无刺激性。
结论：卡莫司汀乳剂给小鼠尾静脉注射后，对小鼠血管静脉组织无刺激损伤作用。
实施例6、卡莫司汀乳剂的溶血和红细胞凝集试验
试验方法：取家兔一只，心脏取血10ml，玻璃棒搅除纤维蛋白原，使成脱纤血液，加入100ml生理盐水摇匀，离心，除去上清液，沉淀的红细胞再用生理盐水洗涤4次至上清液不显红色，将所得红细胞3ml，加生理盐水150ml，制备成2％红细胞混悬液待用。
取试管7支，标明1_7号，按下表排比，依次加入2％红细胞混悬液和生理盐水，置37 ℃恒温箱内30分钟，然后加入不同量的卡莫司汀乳剂，第六管为阴性对照管，第七管为阳性溶血样本.摇匀后，置37 ℃恒温箱中约隔20分钟观察一次，观察至6小时，1_5管与6管相比，上清液的澄清度相同，均未出现透明红色和红棕色絮状沉淀物，7管学红细胞完全溶血，1-5管与7管相比，现象完全相反，试验结果见表1：
表1卡莫司汀乳剂溶血凝集试验(ml)
| 编号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 受试药液 | 0.1 | 0.2 | 0.3 | 0.4 | 0.5 | 0 | 0 |
| 生理盐水 | 2.4 | 2.3 | 2.2 | 2.1 | 2.0 | 2.5 | 0 |
| 去离子水 | 0 | 0 | 0 | 0 | 0 | 0 | 2.5 |
| 2％红细胞混悬液 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
结果判断：1-5管在2-6小时内，其上清液与6管相比基本相同，均未出现透明红色和棕色絮状沉淀物。1-5管在2-6小时内，与7管相比，则现象完全相反，7管出现了全部红色溶血现象。
结论：卡莫司汀乳剂无凝血、无红细胞凝集作用。
Claims (3)
1.一种供静脉输液用的含卡莫司汀的稳定水包油乳剂的组合物，其特征在于它包含：卡莫司汀0.01％～5％、油1％～40％、表面活性剂0.01％～10％、助乳化剂0％～10％、抗氧剂0.01％～10％、共溶剂0.01％～1％、水。
2.如权利要求1所述的组合物，其特征在于所述的油可以为大豆油、玉米油、花生油、芝麻油、橄榄油、亚麻籽油、棉籽油、藏红花油、桐油、蓖麻油、椰子油和棕榈油中之少一种。
3.如权利要求1所述的组合物，其特征在于所述的表面活性剂可以为：蛋黄卵磷脂、大豆磷脂、胆固醇、乙氧基化胆固醇、二乙酰甘油、二烷基醚甘油。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018096466A1 (en) | 2016-11-25 | 2018-05-31 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| WO2019193477A1 (en) | 2018-04-05 | 2019-10-10 | Emcure Pharmaceuticals Limited | Carmustine formulation |
| CN110339174A (zh) * | 2019-07-09 | 2019-10-18 | 江苏康缘药业股份有限公司 | 一种银杏内酯滴丸及其制备方法 |
| US11865206B2 (en) | 2018-09-05 | 2024-01-09 | Emcure Pharmaceuticals Ltd | Stable ready-to-use carmustine pharmaceutical composition |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018096466A1 (en) | 2016-11-25 | 2018-05-31 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| US10583101B2 (en) | 2016-11-25 | 2020-03-10 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| WO2019193477A1 (en) | 2018-04-05 | 2019-10-10 | Emcure Pharmaceuticals Limited | Carmustine formulation |
| US20210361599A1 (en) * | 2018-04-05 | 2021-11-25 | Emcure Pharmaceuticals Limited | Carmustine formulation |
| EP3773484A4 (en) * | 2018-04-05 | 2021-12-29 | Emcure Pharmaceuticals Limited | Carmustine formulation |
| US12427127B2 (en) | 2018-04-05 | 2025-09-30 | Emcure Pharmaceuticals Limited | Carmustine formulation |
| US11865206B2 (en) | 2018-09-05 | 2024-01-09 | Emcure Pharmaceuticals Ltd | Stable ready-to-use carmustine pharmaceutical composition |
| CN110339174A (zh) * | 2019-07-09 | 2019-10-18 | 江苏康缘药业股份有限公司 | 一种银杏内酯滴丸及其制备方法 |
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