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CN1997368B - 包含sns-595的药物组合物 - Google Patents

包含sns-595的药物组合物 Download PDF

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Publication number
CN1997368B
CN1997368B CN200580015456.4A CN200580015456A CN1997368B CN 1997368 B CN1997368 B CN 1997368B CN 200580015456 A CN200580015456 A CN 200580015456A CN 1997368 B CN1997368 B CN 1997368B
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CN
China
Prior art keywords
another embodiment
sns
naphthyridines
pyrrolidinyl
methylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN200580015456.4A
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English (en)
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CN1997368A (zh
Inventor
桧垣胜
中尾智
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sumitomo Pharma Co Ltd
Viracta Therapeutics Inc
Original Assignee
Sumitomo Dainippon Pharma Co Ltd
Sunesis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumitomo Dainippon Pharma Co Ltd, Sunesis Pharmaceuticals Inc filed Critical Sumitomo Dainippon Pharma Co Ltd
Priority to CN201210307920.9A priority Critical patent/CN103083316B/zh
Priority to CN201210307785.8A priority patent/CN103251589B/zh
Publication of CN1997368A publication Critical patent/CN1997368A/zh
Application granted granted Critical
Publication of CN1997368B publication Critical patent/CN1997368B/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Abstract

本发明涉及SNS-595和用其治疗癌症的方法。附图示出了SNS-595在各种患者实验组中随时间的血浆浓度。

Description

包含SNS-595的药物组合物
SNS-595是新的萘啶类细胞毒性试剂，之前已知为AG-7352(参见：Tsuzuki等人，Tetrahedron-Asymmetry12：1793-1799(2001)和美国专利No.5,817,669)。SNS-595的化学名称为(+)-1，4-二氢-7-[(3S，4S)-3-甲氧基-4-(甲氨基)-1吡咯烷基]-4-氧-1-(2-噻唑基)-1，8-萘啶-3-羧酸，结构如下： 
Figure DEST_PATH_GSB00001036327000011
本发明涉及用SNS-595治疗癌症的药物组合物和方法。 
附图说明
图1示出了SNS-595在不同患者群中随时间的血浆浓度。 
发明的详细描述 
在本发明的一个方面，提供了药物组合物，该药物组合物包含水性溶液的 
a)SNS-595，和 
b)酸。 
其中，该溶液的pH值为2-3.5。在本说明书中，所使用的数值范围是包含性的。 
例如，pH 2-3.5的范围既包括pH 2，也包括pH 3.5。在一实施方案中，该组合物的pH值是2-3。在另一实施方案中，该组合物的pH值是2.3-2.7。在本说明书中，所使用的水性溶液是含水的液体。 
适合的酸的例子包括有机酸和无机酸，如乙酸、抗坏血酸、苯磺酸、乙磺酸、羟基乙酸、盐酸、氢溴酸、羟基乙磺酸、乳酸、马来酸、甲磺酸、丙酸、丁二酸、硫酸、三氟乙酸和甲苯磺酸。在一实施方案中，所述酸是盐酸、甲磺酸或乳酸。在另一实施方案中，所述酸是甲磺酸。 
在另一实施方案中，所述药物组合物还含有张度剂(tonicity agent)。合适的张度剂包括氨基酸(例如丙氨酸和甘氨酸)、电解质(例如氯化钠和氯化钾)、单糖(例如葡萄糖或半乳糖)、二糖(例如蔗糖)和六元醇(例如甘露醇和山梨醇)。另一实施方案中，该张度剂是氯化钠、葡萄糖、甘露醇或山梨醇。在另一实施方案中，该张度剂是六元醇。另一实施方案中，该张度剂是山梨醇。 
SNS-595是用于治疗癌症的细胞毒性试剂。能够使用本发明方法进行治疗的癌症类型包括但不限于：膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结肠直肠癌)、食管癌、头颈癌、白血病、肝癌、肺癌(小细胞和非小细胞的)、淋巴瘤、黑素瘤、骨髓瘤、成神经细胞瘤、卵巢癌、胰腺癌、前列腺癌、肾癌、肉瘤(包括骨肉瘤)、皮肤癌(包括磷状细胞癌)、胃癌、睾丸癌、甲状腺癌和子宫癌。 
在本发明的另一方面，提供了使用SNS-595来治疗人类癌症的方法。该方法包括基于人体表面积给患者施用剂量为10mg/m2-150mg/m2的SNS-595。人体表面积能够被计算出来，例如使用Mosteller公式计算，其中： 
人体表面积(m2)＝[身高(cm)x体重(kg)/3600]的平方根 
在另一实施方案中，所述剂量为10mg/m2-100mg/m2。在另一实施方案中，该剂量为30mg/m2-75mg/m2。在另一实施方案中，该剂量为40mg/m2-80mg/m2。在另一实施方案中，该剂量为50mg/m2-90mg/m2。 
在另一实施方案中，所述剂量为20mg/m2-30mg/m2。在另一实施方案中，该剂量为25mg/m2-35mg/m2。在另一实施方案中，该剂量为40mg/m2-50mg/m2。在另一实施方案中，该剂量为45mg/m2-55mg/m2。在另一实施方案中，该剂量为50mg/m2-60mg/m2。在另一实施方案中，该剂量为55mg/m2-65mg/m2。在另一实施方案中，该剂量为60mg/m2-70mg/m2。在另一实施方案中，该剂量为65mg/m2-75mg/m2。在另一实施方案中，该剂量为70mg/m2-80mg/m2。在另一实施方案中，该剂量为75mg/m2-85mg/m2。另一实施方案中，给药剂量为80mg/m2-90mg/m2。在另一实施方案中，该剂量为85mg/m2-95mg/m2。在另一实施方案中，该剂量为90mg/m2-100mg/m2。 
在另一实施方案中，所述剂量为95mg/m2-105mg/m2。在另一实施方案中，该剂量为100mg/m2-110mg/m2。在另一实施方案中，该剂量为105mg/m2-115mg/m2。在另一实施方案中，该剂量为110mg/m2-120mg/m2。在另一实施方案中，该剂量为115mg/m2-125mg/m2。在另一实施方案中，该剂量为120mg/m2-130mg/m2。在另一实施方案中，该剂量为125mg/m2-135mg/m2。在另一实施方案中，该剂量为130mg/m2-140mg/m2。在另一实施方案中，该剂量为135mg/m2-145mg/m2。在另一实施方案中，该剂量为140mg/m2-150mg/m2。 
SNS-595的所述给药剂量可以同时给予(例如单次弹丸注射)或者在24小时内给予(例如随时间连续灌输或随时间分次弹丸注射)，并重复该给药直到患者病情稳定或好转，或者直到患者病情恶化或产生患者不可接受的毒性。例如，对实体瘤来说，稳定的病情通常是指检测到的损伤垂直直径与上次检测到的相 比增长小于25％或更少。参见Response Evaluation Criteria in Solid Tumors(RECIST)Guidelines，Journal of the National Cancer Institute 92(3)：205-216(2000))。病情的稳定与否通过现有技术来检测，例如患者症状评价、体检、肿瘤显影(使用X射线、CAT、PET或MRI扫描成像)和其它普遍接受的评估方式。 
SNS-595的所述给药剂量可以用不是mg/m2的其它单位来表示。例如，剂量可以表示为mg/kg。如果给出患者的身高或体重或两者，本领域普通技术人员将容易的知道如何将给剂量从mg/m2转换成mg/kg(参见，例如，http:///www.fda.gov/cder/cancer/animalframe.htm)。例如，10mg/m2-150mg/m2 的药物剂量对65公斤体重的人来说约等于0.26mg/kg-3.95mg/kg。 
在本发明的另外一个方面，SNS-595是按照给药方案进行给药的。在一实施方案中，该方法包括： 
i)给予患者10mg/m2-150mg/m2剂量的SNS-595； 
ii)等待至少一天的时间，其间不给予患者任何SNS-595； 
iii)给予患者患者另一10mg/m2-150mg/m2剂量的SNS-595；和重复步骤ii)-iii)多次。 
例如，如果等待期是6天，那么SNS-595的初始剂量在第一天给予(步骤i)；等待期是6天(步骤ii)；接下来的SNS-595剂量在第8天给予(步骤iii)。其它举例性时间期间包括2天、3天、13天、20天和27天。在另一实施方案中，该等待期为至少2天，且步骤ii)到iii)至少重复3次。在另一实施方案中，该等待期至少为3天，且步骤ii)到iii)至少重复5次。在另一实施方案中，该等待期至少为3天，且步骤ii)到iii)至少重复3次。在另一实施方案中，该等待期至少为3天，且步骤ii)到iii)至少重复5次。在另一实施方案中，该等待期至少为6天，且步骤ii) 到iii)至少重复3次。在另一实施方案中，该等待期至少为6天，且步骤ii)到iii)至少重复5次。在另一实施方案中，该等待期至少为20天，且步骤ii)到iii)至少重复3次。在另一实施方案中，该等待期至少为20天，且步骤ii)到iii)至少重复5次。在另一实施方案中，该等待期至少为27天，且步骤ii)到iii)至少重复3次。在另一实施方案中，该等待期至少为27天，且步骤ii)到iii)至少重复5次。 
在另一实施方案中，所述给药方法包括每周给予患者一定剂量的SNS-595。在另一实施方案中，该给药方法包括每两周给予患者一定剂量的SNS-595。在另一实施方案中，该给药方法包括每三周给予患者一定剂量的SNS-595。在另一实施方案中，该给药方法包括每四周给予患者一定剂量的SNS-595。 
在另一实施方案中，所述给药方法包括循环，其中该循环包括每周给予患者一定剂量的SNS-595，持续3周，接着不给予所述患者任何SNS-595至少两周，且其中该循环重复多次。在另一实施方案中，不给予任何SNS-595的时间是2周。在另一实施方案中，不给予任何SNS-595的时间是3周。 
在本发明的另一方面，提供了治疗实体瘤的方法。该方法包括： 
i)给予患者10mg/m2-100mg/m2剂量的SNS-595； 
ii)等待至少6天，其间不给予患者任何SNS-595； 
iii)给予患者另一10mg/m2-100mg/m2剂量的SNS-595；和 
iv)重复步骤ii)-iii)多次。 
本发明的另一方面，提供了治疗血液性癌症，如白血病和淋巴瘤的方法，该方法包括： 
i)给予患者60mg/m2-150mg/m2剂量的SNS-595； 
ii)等待至少2天，其间不给予患者任何SNS-595； 
iii)给予患者另一60mg/m2-150mg/m2剂量的SNS-595；和 
iv)重复步骤ii)-iii)多次。 
在本发明的另一方面，提供了用于用SNS-595治疗过的患者的维持性护理方法，该方法包括： 
a)给予患者10mg/m2-150mg/m2剂量的SNS-595；和 
b)给予治疗有效量的维持性护理试剂。 
所述维持性护理试剂是预防或控制SNS-595治疗的不良反应的任何物质，并按照该物质的合适给药方案进行给药。例如，治疗恶心的不同维持性护理试剂具有不同的给药方案。一些在治疗前预防性给药，一些与SNS-595同时给药，还有一些在给予SNS-595后给药。维持性护理试剂的示例性例子、它们的剂量和给药方案在The Physician’s Desk Reference中可以找到。 
在一实施方案中，所述维持性护理试剂是止吐药。止吐药的示例性例子包括但不限于吩噻嗪类、丁酰苯类、苯二氮卓类、皮质激素、5-羟色胺拮抗剂、大麻素类物质、和NK1受体拮抗剂。吩噻嗪类止吐药的例子包括丙氯拉嗪和曲美苄胺。丁酰苯类止吐药的例子是氟哌啶醇。苯二氮卓类止吐药的例子是劳拉西泮。皮质激素止吐药的例子是地塞米松。5-羟色胺拮抗剂止吐药的例子包括奥坦西隆、格拉司琼和奥坦西隆。大麻类物质止吐药的例子是曲大麻酚。NK1 受体拮抗剂止吐药的例子是阿瑞吡坦(aprepitant)。 
在一实施方案中，所述止吐药是丙氯拉嗪。在另一实施方案中，该止吐药是丙氯拉嗪，且其治疗有效量为10mg。在另一实施方案中，该止吐药是丙氯 拉嗪，且其治疗有效量是在给予SNS-595之前口服10mg。在另一实施方案中，该止吐药是丙氯拉嗪，且其治疗有效量是在给予SNS-595后根据需要每4-6小时口服10mg。 
在另一实施方案中，所述止吐药是地塞米松。在另一实施方案中，该止吐药是地塞米松，且其治疗有效量是至少4mg。在另一实施方案中，该止吐药是地塞米松，且其治疗有效量是在给予SNS-595之前口服4mg。在另一实施方案中，该止吐药是地塞米松，且其治疗有效量是在给予SNS-595之前口服8mg。在另一实施方案中，该止吐药是地塞米松，且其治疗有效量是在给予SNS-595之前静脉注射约10-20mg。在另一实施方案中，该止吐药是地塞米松，且其治疗有效量是在给予SNS-595之后根据需要每6-12小时口服4mg。 
在另一实施方案中，所述止吐药是劳拉西泮。在另一实施方案中，该止吐药是劳拉西泮，且其治疗有效量是1mg。在另一实施方案中，该止吐药是劳拉西泮，且其治疗有效量是在给予SNS-595之前口服1mg。在另一实施方案中，该止吐药是劳拉西泮，且其治疗有效量是在给予SNS-595之前静脉注射1mg。在另一实施方案中，该止吐药是劳拉西泮，且其治疗有效量是在给予SNS-595之后根据需要每4-6小时口服1mg。 
在另一实施方案中，所述止吐药是多拉司琼。在另一实施方案中，该止吐药是多拉司琼，且其治疗有效量是100mg。在另一实施方案中，该止吐药是多拉司琼，且其治疗有效量是在给予SNS-595之前口服100mg。在另一实施方案中，该止吐药是多拉司琼，且其治疗有效量是在给予SNS-595之前静脉注射100mg。 
在另一实施方案中，所述止吐药是奥坦西隆。在另一实施方案中，该止吐 药是奥坦西隆，且其治疗有效量是至少10mg。在另一实施方案中，该止吐药是奥坦西隆，且其治疗有效量是在给予SNS-595之前静脉注射10mg。在另一实施方案中，该止吐药是奥坦西隆，且其治疗有效量是在给予SNS-595之前静脉注射32mg。 
在另一实施方案中，所述止吐药是格拉司琼。在另一实施方案中，该止吐药是格拉司琼，且其治疗有效量是10μg/kg。在另一实施方案中，该止吐药是格拉司琼，且其治疗有效量是在给予SNS-595之前静脉注射10μg/kg。在另一实施方案中，该止吐药是格拉司琼，且其治疗有效量是至少1mg。在另一实施方案中，该止吐药是格拉司琼，且其治疗有效量是在给予SNS-595之前口服1mg。在另一实施方案中，该止吐药是格拉司琼，且其治疗有效量是在给予SNS-595之前口服2mg。 
在另一实施方案中，所述止吐药是阿瑞吡坦。在另一实施方案中，该止吐药是阿瑞吡坦，且其治疗有效量是至少80mg。在另一实施方案中，该止吐药是阿瑞吡坦，且其治疗有效量是在给予SNS-595之前口服125mg。在另一实施方案中，该止吐药是阿瑞吡坦，且其治疗有效量是在给予SNS-595之后每日口服80mg，至少持续2天。 
在另一实施方案中，所述维持性护理试剂是生血性试剂。生血性试剂是刺激造血作用的分子。生血性试剂的示例性例子包括但不限于：粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、促红细胞生成素和红细胞生成刺激蛋白、以及它们的衍生物。G-CSF的例子包括但不限于：非格司亭及其衍生物，包括乙二醇化非格司亭(pegfilgrastim)。GM-CSF的例子是沙莫司亭。促红细胞生成素的例子是阿法依泊汀(epoetin alfa)。红细胞生成刺激 蛋白的例子是阿法达贝泊汀(darbepoetinα)。 
在另一实施方案中，所述生血性试剂是G-CSF。在另一实施方案中，该生血性试剂是非格司亭。在另一实施方案中，该生血性试剂是非格司亭，且其治疗有效量是至少4μg/kg。在另一实施方案中，该生血性试剂是非格司亭，且其治疗有效量是在给予SNS-595之后每天至少4μg/kg，持续至少7天。在另一实施方案中，该生血性试剂是非格司亭，且其治疗有效量是在给予SNS-595之后第三天开始每天皮下注射约4μg/kg-8μg/kg，持续至少7天。在另一实施方案中，该生血性试剂是非格司亭，且其治疗有效量是在给予SNS-595之后第三天开始每天皮下注射约4μg/kg-10μg/kg，持续至少14天。 
在另一实施方案中，所述生血性试剂是乙二醇化非格司亭。在另一实施方案中，该生血性试剂是乙二醇化非格司亭，且其治疗有效量是6mg。在另一实施方案中，该生血性试剂是乙二醇化非格司亭，且其治疗有效量是在给予SNS-595之后每天皮下注射6mg。在另一实施方案中，该生血性试剂是乙二醇化非格司亭，且其治疗有效量是100μg/kg。在另一实施方案中，该生血性试剂是乙二醇化非格司亭，且其治疗有效量是在给予SNS-595之后每天100μg/kg。 
在另一实施方案中，该生血性试剂是GM-CSF。在另一实施方案中，该生血性试剂是沙莫司亭。在另一实施方案中，该生血性试剂是沙莫司亭，且其治疗有效量是250μg/m2。在另一实施方案中，该生血性试剂是沙莫司亭，且其治疗有效量是每天静脉或皮下注射250μg/m2。在另一实施方案中，该生血性试剂是沙莫司亭，且其治疗有效量是在给予SNS-595之后从第3天开始根据需要每天静脉或皮下注射250μg/m2。在另一实施方案中，该生血性试剂是沙莫司亭，且其治疗有效量是在给予SNS-595之后从第10天开始每天静脉或皮下注 射250μg/m2。 
在另一实施方案中，所述生血性试剂是促红细胞生成素。在另一实施方案中，该生血性试剂是阿法依泊汀。在另一实施方案中，该生血性试剂是阿法依泊汀，且其治疗有效量是至少150单位/kg。在另一实施方案中，该生血性试剂是阿法依泊汀，且其治疗有效量是在给予SNS-595之后每周三次静脉或皮下注射150单位/kg。在另一实施方案中，该生血性试剂是阿法依泊汀，且其治疗有效量是在给予SNS-595之后每周三次静脉或皮下注射300单位/kg。在另一实施方案中，该生血性试剂是阿法依泊汀，且其治疗有效量是40,000单位/kg。在另一实施方案中，该生血性试剂是阿法依泊汀，且其治疗有效量是在给予SNS-595之后每周40,000单位/kg。 
在另一实施方案中，所述生血性试剂是红细胞生成刺激蛋白。在另一实施方案中，该生血性试剂是阿法达贝泊汀。在另一实施方案中，该生血性试剂是阿法达贝泊汀，且其治疗有效量是约1.5-4.5μg/m2。在另一实施方案中，该生血性试剂是阿法达贝泊汀，且其治疗有效量是每周约1.5-4.5μg/m2。 
所有引用的参考资料在此均引为参考。 
实施例1.适合于注射或静脉内灌输的药物组合物
酸性组合物(pH＜4)使提高的SNS-595溶解性和希望的药物学属性之间得到适当平衡(例如，通过减少给药部位的刺激而增加了患者的舒适感)。适合组合物的示例性例子包括10mg/mL的SNS-595水溶液，其中含有4.5％的山梨醇，用甲磺酸调节pH至2.5。制备规格为100mg/10mL的上述溶液的方案包括：将100mg的SNS-595和450mg的D-山梨醇加入到适量的蒸馏水中；将体积调整到 10mL；用甲磺酸将所得溶液pH调节至2.5。所得的组合物还适于冻干。该冻干形式在使用前再与无菌水重新配成合适的浓度。 
实施例2.SNS-595在癌症患者体内的药代动力学
向招募的患者给予SNS-595多至6个循环。一个循环为3周的时间，在每个循环的第一天(0天)给予SNS-595，接着观察至少21天。SNS-595被给予至少有3例患者的实验组，按比例增加连续实验组的给药剂量。SNS-595的给药剂量与AUC∞成线性关系，其药代动力学性质在同一实验组的患者中显著一致。图1描述了SNS-595在不同患者实验组中随时间的血浆浓度。表1显示了从中衍生出的药代动力学参数。 
表1 
  剂量  (mg/m2)   HI.(hr)   C0(ng/mL)   Cmax   (ng/mL)   最终AUC  (hr×ng/mL)   AUCINF-观察  (hr×ng/mL)   CI-观察  (mL/min/kg)   Vz-观察  (L/kg)   Vss-观察  (L/kg)   MRTINF-观察  (hr)
                   
  3   16.27   152.25   138.80   750.08   1139.55   1.14   1.55   1.44   21.96
  50   4.574   32.282   80.566   87.622   263   0.318   0.207   0.277   6.836
  6   20.50   376.69   347.00   2400.00   2990.28   0.71   1.28   1.24   29.05
  50   0.327   243.598   214.98   170.555   245.64   0.153   0.295   0.216   1.15
  12   17.81   2889.68   2245.57   5395.53   6329.15   0.76   1.17   1.07   23.67
  50   3.550   1302.71   1055.145   292.291   101.004   0.126   0.250   0.184   5.021
  24   16.14   2924.40   2703.33   11133.03   12655.32   0.33   1.15   1.06   21.65
  50   2.601   2084.702   2573.02   468.453   851.450   0.108   0.124   0.165   5.261
  48   21.32   1994.52   2868.00   21008.53   27347.36   0.99   1.57   1.46   28.90
  50   6.32   159.677   2379.899   8405.346   14382.787   0.815   0.567   0.47   8.01
  60   17.63   4797.47   4537.50   28112.17   33515.16   0.83   1.20   1.08   23.71
  50   4.15   2215.20   1947.80   9127.12   13051.44   0.352   0.37   0.218   6.83

Claims (21)

1.一种水溶性药物组合物，其含有(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1-吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸和甲磺酸，其中，当所述组合物溶于蒸馏水形成水溶液，且(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1-吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸在该水溶液中的浓度为10mg/mL时，该水溶液的pH为2.3-2.7。
2.如权利要求1所述的药物组合物，该组合物还含有水。
3.如权利要求1所述的药物组合物，该组合物还含有张度剂。
4.如权利要求3所述的药物组合物，其中所述的张度剂选自氨基酸、电解质、单糖、二糖、六元醇和其混合物。
5.如权利要求3所述的药物组合物，其中所述的张度剂包含山梨醇。
6.如权利要求2所述的药物组合物，其中(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1-吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸以10mg/mL的量存在。
7.如权利要求2所述的药物组合物，其还包含山梨醇，每10mL该组合物含有450mg该山梨醇。
8.如权利要求2所述的药物组合物，其中所述组合物的pH为2.5。
9.如权利要求7所述的药物组合物，其中每10mL该组合物包含100mg(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1-吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸和450mg山梨醇。
10.如权利要求1所述的药物组合物，其中所述水溶液的pH为2.5。
11.如权利要求1所述的药物组合物，其中所述组合物包含100mg(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸和450mg山梨醇。
12.如权利要求2所述的药物组合物，其中每10mL该组合物包含100mg(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1-吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸和450mg山梨醇。
13.权利要求1所述的药物组合物，所述组合物经配制用于静脉内施用。
14.权利要求13所述的药物组合物在制备用于治疗癌症的药物中的应用。
15.权利要求13所述的药物组合物在制备用于治疗白血病的药物中的应用。
16.一种粉末，该粉末含有如权利要求1所述的组合物。
17.一种水溶液，其包含100mg(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸，450mg山梨醇和甲磺酸，其中该水溶液的pH为2.3至2.7。
18.一种冻干粉末，该冻干粉末含有如权利要求1所述的组合物。
19.一种冻干粉末，该冻干粉末含有(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1-吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸和甲磺酸，其中该冻干粉末适于在无菌水中重建而获得pH在2.3至2.7之间的水溶液。
20.一种水溶液，其包含10mg/mL(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1-吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸、45mg/mL山梨醇，和足以使该水溶液的pH为2.3至2.7的甲磺酸。
21.一种水溶液，其包含10mg/mL(+)-1,4-二氢-7-[(3S,4S)-3-甲氧基-4-(甲氨基)-1-吡咯烷基]-4-氧-1-(2-噻唑基)-1,8-萘啶-3-羧酸、45mg/mL山梨醇，和足以使该水溶液的pH为2.5的甲磺酸。
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