CN1198609C - 用白蛋白稳定的紫杉醇在制备用于治疗实体瘤的药物方面的应用和由此获得的药物 - Google Patents
用白蛋白稳定的紫杉醇在制备用于治疗实体瘤的药物方面的应用和由此获得的药物 Download PDFInfo
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Abstract
用白蛋白稳定的紫杉醇的微粒在制备用于治疗对紫杉醇敏感的实体瘤的药物方面的应用，以及由此获得的药物。
Description
技术领域
本发明涉及治疗对紫杉醇(Paclitaxel)敏感的实体瘤的药物，以及掺和了紫杉醇的白蛋白微粒(通称为ABI 007)在制备该药物中的应用。
背景技术
紫杉醇是一种文献中熟知的物质，它对大量肿瘤(例如卵巢瘤，肺瘤，头和颈瘤，膀胱瘤和乳腺瘤)具有重要的临床活性。
紫杉醇不溶于水。为了使它成为可溶性和适合静脉内注射，将它与表面活性剂(例如聚乙氧基化蓖麻油，注册名称为“Cremophor EL”)混合，以及与约50％无水酒精USP(作为紫杉醇的载体)混合：该混合物由Bristol-Myers Squibb取得了专利，注册名称为“紫杉醇”(“Taxol”)，下文将提及它，为简便起见。表面活性剂和无水酒精的存在除了其它副作用之外还具有严重的缺点，例如，强过敏性。
在任何情况下，以很长时间施用(而且只能通过静脉内注射施用)紫杉醇，试图将该产品的毒性作用减到最小。
为了克服上述缺点，所述Bristol-Myers Squibb(BMS)获得了组合物的专利(欧洲专利申请EP-A-0584001、EP-A-0783885、EP-A-0783886和美国专利US 5641803和US 5670537)，所述组合物除了含紫杉醇之外还包含能阻止严重的过敏反应的其它物质或药物。
根据已知技术，如前述专利描述的那样，对接受治疗的患者静脉内施用135～175mg/m2患者体表面的紫杉醇，每次施药都是很缓慢地、在约3小时的时间中进行的：最重要的是总是应用上述药物。
US 5439686、US 5498421、US 5560933以及相应的WO 9418954描述了掺和了紫杉醇的白蛋白微粒：国际上以符号ABI 007标记这些粒子。下文提到这些微粒时为简便起见应用这个名称。
ABI 007实际上是一种通过人白蛋白USP稳定化的紫杉醇的制剂，它能分散在生理溶液中从而可以很高的紫杉醇浓度直接注射，不含毒性乳化剂。
然而，WO 94 18954没有给出关于以下内容的具体说明或实施例：为了作为药物安全而适当地施用给患者来治疗对紫杉醇敏感的肿瘤，溶液中ABI 007的浓度应该为多大。
后来提交的WO 98 14174改进了WO 94 18954的教导并且给出了关于如下内容的说明(仅一个实施例，实施例20)：为了制备可直接给患者注射来治疗肿瘤的药物，其溶液中ABI 007的浓度应该为多大—该药物应当由ABI 007(在该文中称为“CAPXOL”)在生理溶液中的分散体组成，其中ABI 007应当以20mg/ml溶液的很高浓度存在，从而对于200-500mg的总剂量而言输注体积非常小(10-25ml)，它是通过快速静脉内药团在数分钟的短时间内施用的。
发明内容
意外地发现了，ABI 007可被用于制备药物，其中，ABI 007作为生理溶液中的分散体以2～8mg/ml这些溶液的浓度存在，而且可将该药物直接注入对与紫杉醇敏感性肿瘤相关的区供血的那些动脉，施药在很多分钟的短时间内完成，而且只重复数次。
与上述以前已知的BMS专利的教导相比，可以注意到，按本发明，应用ABI 007获得这样的药物：它们的应用能使患者比已知的BMS教导施用剂量高得多的紫杉醇而且输注时间短得多，获得良好的结果(响应百分数极高且令人意外)，在所有情况下观察到很低的毒性。
与WO 98 14174的教导相比，可以注意到，按照本发明，将ABI 007用于制备一种药物，该药物中，ABI 007以一定的浓度分散于一种生理溶液中(2-8mg/ml溶液)，于是，药物的毒性比WO 98 14174中达到的毒性低得多，因此，可以在很多分钟的时间内将该药物直接注射入对肿瘤相关的区供血的动脉，而且注射可以重复数次。
更具体地说，动脉内施用本发明的药物可以间隔3～4周，获得治疗上很好的结果，即，高于71％的治疗响应百分数(与用紫杉醇常规治疗达到的40％相比，例如在头和颈癌的治疗中)。
更具体地说，可应用本发明的药物治疗患有对紫杉醇敏感的肿瘤的患者获得意外的结果，将该药物直接注射入对肿瘤相关的区供血的动脉，注意使用包含190～500mg ABI 007/m2患者体表面的一定量的药物，并且在约25～60分钟内完成注射。然后重复2～5次类似的动脉内注射，彼此间隔3～5周。
已证实对所述治疗有响应的肿瘤是鳞状细胞癌，包括肺、头和颈、子宫和肛门道的某些肿瘤。
从进行的试验可见，优选地，用于动脉内治疗肿瘤的药物量包含200～300mg ABI 007/m2患者体表面(每次施药)，而且分散体的每次单一剂量的施药大约进行30分钟。
具体实施方式
描述了一些涉及不同类别和位置的肿瘤治疗的实施例，是为了阐释对本发明的理解和本发明的特征。
实施例1
用ABI 007在生理溶液中的分散体(呈白蛋白的微粒形式的紫杉醇)分别以220、230、250和275mg/m2体表面的剂量分独立的四次接连动脉内注射(彼此间隔4周)入髂内动脉来治疗一名57岁的女患者(PR)，该患者患有肛门道癌的骨盆复发，以前接受过化学疗法、放射疗法和手术治疗，经判断不宜手术。
注射的分散体浓度为6mg ABI 007/ml它们的溶液。
计算机体层摄影术跟踪肿瘤的减小。观察到显著的肿瘤减小并且认为肿瘤块实际上完全消退了，进行了外科手术，表明不存在组织瘤。
实施例2
对一名64岁的女患者(ZN)施用ABI 007：接连4个周期分别以210、230、200和200mg/m2的剂量，以4mg/ml的浓度施药入左舌动脉，所述患者的左半边舌患有很大的瘤形成，以前从未接受过任何治疗。
通过临床检查和磁共振跟踪对治疗的响应，因为存在固定的假牙。
观察到显著的肿瘤消退，治疗结束后一个月估计消退90％，提议做了外科手术，表明组织不存在肿瘤。
实施例3
对一名61岁的男患者(BP)施用ABI 007：3个周期(间隔4周)以240mg/m2的剂量和3mg/ml的浓度施药入外部的颈动脉，所述患者患有在右颈侧淋巴结处转移的右喉咽癌，以前从未接受过任何治疗。通过计算机体层摄影术和临床检查观察到了治疗响应，在喉咽部以前的肿瘤部位进行了多次深度活组织检查，表明组织不存在瘤形成。
淋巴结转移瘤尺寸也减少了80％以上，并且通过外科手术除去了在该水平存在的肿瘤。
实施例4
对一名37岁的女患者(EP)施用ABI 007：4个周期(间隔4周)，每个周期以250mg/m2的剂量、7mg/ml的浓度施药入髂内动脉，所述患者患有肛门道的复发癌，以前接受过放射化学疗法。
通过妇科检查和计算机体层摄影术观察到了治疗响应，提议做了新的外科手术，表明组织不存在肿瘤。
实施例5
对一名59岁的男患者(GC)施用ABI 007：分别以200、240和260mg/m2的剂量、7.5mg/ml的浓度施药入髂内动脉，所述患者患有肛门道的复发癌，以前接受过放射化学疗法。
通过临床检查和经直肠的echoendosonography观察到了响应，提议做了外科手术，表明组织不存在肿瘤。
Claims (5)
1.用白蛋白稳定的紫杉醇的微粒在制备用于治疗对紫杉醇敏感的实体瘤的药物方面的应用，其特征在于，将所述微粒分散在生理溶液中，其中，所述微粒以2～8mg/ml该溶液的浓度存在。
2.权利要求1的应用，其特征在于，所述实体瘤是鳞状细胞癌。
3.权利要求1或2的应用，其特征在于，所述微粒在生理溶液中的浓度为3～7.5mg/ml生理溶液。
4.一种用于治疗对紫杉醇敏感的实体瘤的药物，它包含用白蛋白稳定的紫杉醇的微粒在生理溶液中的分散体，其特征在于，所述微粒的浓度为2～8mg/ml生理溶液。
5.权利要求4的药物，其特征在于，所述微粒在所述生理溶液中的浓度为3～7.5mg/ml生理溶液。
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| Application Number | Priority Date | Filing Date | Title |
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| ITMI2000A001107 | 2000-05-18 | ||
| IT2000MI001107A ITMI20001107A1 (it) | 2000-05-18 | 2000-05-18 | Metodo per il trattamento di tumori solici mediante microparticelle di albumina incorporanti paclitaxel |
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| CN104940929A (zh) * | 2006-11-06 | 2015-09-30 | 阿布拉科斯生物科学有限公司 | 紫杉醇和白蛋白纳米颗粒联合贝伐单抗对抗癌症 |
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| US8137684B2 (en) | 1996-10-01 | 2012-03-20 | Abraxis Bioscience, Llc | Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
| US20030199425A1 (en) * | 1997-06-27 | 2003-10-23 | Desai Neil P. | Compositions and methods for treatment of hyperplasia |
| US8853260B2 (en) | 1997-06-27 | 2014-10-07 | Abraxis Bioscience, Llc | Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
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| DE69433723T3 (de) | 1993-02-22 | 2008-10-30 | Abraxis Bioscience, Inc., Los Angeles | Verfahren für die in-vivo-verabreichung von biologischen substanzen und hierfür verwendbare zusammensetzungen |
| US5916596A (en) * | 1993-02-22 | 1999-06-29 | Vivorx Pharmaceuticals, Inc. | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof |
| US6096331A (en) * | 1993-02-22 | 2000-08-01 | Vivorx Pharmaceuticals, Inc. | Methods and compositions useful for administration of chemotherapeutic agents |
| KR100789008B1 (ko) * | 1997-06-27 | 2007-12-26 | 아브락시스 바이오사이언스 인크. | 신규 약물 제제 |
| EP1100494A1 (en) | 1998-07-30 | 2001-05-23 | Novopharm Biotech, Inc. | Pharmaceutically composition comprising an aqueous solution of paclitaxel and albumin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104940929A (zh) * | 2006-11-06 | 2015-09-30 | 阿布拉科斯生物科学有限公司 | 紫杉醇和白蛋白纳米颗粒联合贝伐单抗对抗癌症 |
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