CN101112373B - 用于治疗癌症的埃博霉素类似物的给药方法 - Google Patents
用于治疗癌症的埃博霉素类似物的给药方法 Download PDFInfo
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- Medicinal Preparation (AREA)
Abstract
公开了一种制备某些用于非肠道给药的埃博霉素类似物的方法,其中将该类似物溶解于至少50%体积叔丁醇在水中的混合物中,然后将该混合物冷冻干燥,将所得的冷冻干燥产品被包装于一个小瓶中,该小瓶还带有一种位于第二个小瓶中的包含无水乙醇和适宜的非离子表面活性剂的足够数量的溶剂。所有的步骤都是在避光的条件下进行的。在使用时,将第二个或稀释小瓶的内容物加入到该冷冻干燥产品中,然后将其进行混合以形成该埃博霉素类似物,然后将所得的溶液用适宜的稀释剂进行稀释,从而制得一种包含浓度为约0.1mg/mL至约0.9mg/mL的埃博霉素类似物的用于静脉内注射的溶液。一种优选的表面活性剂是聚氧乙基化的蓖麻油,一种优选的稀释剂是乳酸盐林格氏注射液。
Description
本申请是申请日为2002年1月22日,申请号为02804090.2,发明名称为“用于治疗癌症的埃博霉素类似物的给药方法”的发明专利申请的分案申请。
相关申请的交叉参考
本申请要求了2001年1月25日申请的临时系列号为60/264,228的申请和2001年5月11日申请的临时序列号为60/290,006的申请的优先权,其在这里整体被引入作为参考。
本发明的技术领域
本发明涉及某些埃博霉素(EPOTHILONE)类似物非肠道组合物和口服组合物的给药方法,其特征在于其增强了临床功效。
本发明的背景技术
埃博霉素是在药学领域具有实用性的大环内酯化合物。例如,发现具有如下结构的埃博霉素A和B可以发挥类似于紫杉醇的微管稳定作用并因此具有对抗快速增生细胞,如肿瘤细胞或其它过度增生的细胞疾病的细胞毒素活性,见Hofle等人,Angew.Chem.Int.Ed.Eng1.,第35卷,第13/14期,1567-1569(1996);在1993年5月27日公开的WO93/10121;和在1997年5月29日公开的WO97/19086。
埃博霉素A R=H
埃博霉素B R=Me
已经合成出埃博霉素A和B的衍生物和类似物,并且该衍生物和类似物可用于治疗各种癌症和其它一些异常增生性疾病。Hofle等人,Id.;Nicolaou等人,Angew Chem.Int.Ed.Eng1.,第36卷,第19期,2097-2103(1997);和Su等人,Angew Chem.Int.Ed.Eng1.,第36卷,第19期,2093-2097(1997)中公开了该类类似物。
已经发现具有有益活性的埃博霉素类似物可以用式I表示:
其中各种符号的定义如下。虽然这些化合物具有显著的治疗学性质,但是由于某些性质方面的原因,它们对药学配制现有技术中的技术人员而言还存在一些困难,关于这方面将在下文中详细说明。根据本发明,已经发现一种制剂,其中如上所述的埃博霉素类似物可以安全的进行调剂并且可以通过注射来进行给药,没有发现效力降低。
此外,许多抗癌药具有与毒性有关的作用。实际上,由于毒性作用,许多有效的抗癌药的治疗曲线都很差。因此,还需要一些给药方法和给药剂量表以减少或避免与抗癌物质有关的毒性作用。该方法还使得可以利用某些本来不能用于临床的有效的抗癌物质。
本发明的概述
本发明包含一种用于埃博霉素化合物的新型给药剂量表,该表可用来治疗患有实体瘤,特别是进行性实体瘤的患者。此外,本发明的方法还可以用于治疗和/或预防转移性肿瘤以及原发性肿瘤。在一个实施方案中,本发明包含以前已经单独接受了实体瘤的放疗或化疗或同时接受了实体瘤的放疗和化疗的患者的治疗。现在还发现本发明的埃博霉素化合物,特别是优选的化合物,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-二羟基-8,8,10,12,16-五甲基-3-[1-甲基-2-(2-甲基-4-噻唑基)乙烯基]-4-氧杂-17-氧杂二环[14.1.0]十七烷-5,9-二酮,可用于治疗用放疗或化疗难以治疗的肿瘤。本发明的方法可用于对抗天然对紫杉醇不敏感或后来变得对其不敏感的癌细胞,从而可以对抗肿瘤。
在一个实施方案中,本发明的给药剂量表包含将本发明的埃博霉素化合物每周给药一次,优选地在连续的基础上每周输注一(1)小时。在另一个实施方案中,每周给药一次,三周为一个周期。每周输注的剂量范围为1mg/m2至30mg/m2并且更优选地为1mg/m2至25mg/m2。在另一个实施方案中,该给药剂量表包括相同埃博霉素化合物的口服给药和静脉内给药。例如,在每周输注一次之后或之前可以进行20mg/m2或更高剂量的口服给药。在一个特定的实施方案中,给药方案包括每周静脉输注一次,每次输注约一(1)小时,三(3)周为一个周期,在一个周期的第一次静脉内给药或该周期的最后一次静脉内给药的输注之后或之前在该周内口服给药一次或多次。本发明还包括其它方案,这些方案非限制性地包括:
(a)每天给药一次,连续给药5至10天,之后至少3天不进行给药;
(b)每周给药一次,连续给药二至十周,之后至少一周不进行给药;和
(c)每三周给药一次,之后至少一周不进行给药。
本发明还考虑在埃博霉素给药前、给药后和/或给药周期之前和之后使用H1和H2抗组胺药。类似地,本发明包含与单独使用埃博霉素的给药周期或H1和H2阻滞剂和埃博霉素的给药周期一起使用的其它化疗剂,特别是使用抗肿瘤剂。
在另一个实施方案中,在紫杉醇的标准给药方案之后使用埃博霉素的给药剂量表。
正如这里所讨论的这样,本发明的方法包含了各种类型的癌症。在一个优选的实施方案中,本发明的方法被用于治疗实体瘤,所说的实体瘤非限制性的包括乳癌、头和颈部的肿瘤、肉瘤、结肠直肠瘤、UPT、黑素瘤、食管瘤、肾癌、***、甲状腺瘤、***肿瘤、卵巢肿瘤和结肠癌。
本发明的方法和组合物描述了一种用于由式I所表示的埃博霉素类似物的制剂及其制备方法:
其中各种符号具有如下所定义的含义。
在本发明制剂的一个实施方案中,首先将埃博霉素类似物用叔丁醇和水的混合物溶解,然后将其在所优化的条件下进行冷冻干燥。将冷冻干燥的药物首先用聚氧乙基化的蓖麻油表面活性剂和无水乙醇溶解,然后将其用乳酸盐林格氏注射液稀释至适宜给药的浓度。
本发明的详细描述
在一个实施方案中,本发明提供了一种用于由式I所表示的埃博霉素类似物给药的有利制剂:
正如式I以及整篇说明书中所用的这样,Q选自:
M选自氧、硫、NR8、以及CR9R10;
R1、R2、R3、R4、R5、R7、R11、R12、R13、R14和R15各自分别选自氢、烷基、被取代的烷基、芳基、被取代的芳基和杂环,并且其中R1和R2是烷基时,它们可以连接起来形成环烷基;
R6选自氢、烷基、被取代的烷基、芳基、被取代的芳基、环烷基、杂环和被取代的杂环;
R8选自氢、烷基、被取代的烷基、R11C=O、R12OC=O和R11SO2;和
R9和R10各自分别选自氢、卤素、烷基、被取代的烷基、芳基、杂环、羟基、R14C=O、以及R15OC=O。
下面是对这里描述本发明所用的各种定义进行的说明。除非在特定的例子中进行了限定,否则这里对各种定义所作的说明适用于整个说明书,该定义可是对单个个体的定义或是一个较大基团中一部分的定义。
“烷基”的定义指的是具有1至约20个碳原子的被取代或未被取代的直链或支链的饱和烃基,其优选地具有1至约7个碳原子。“低级烷基”的表述指的具有1至约4个碳原子的被取代或未被取代的烷基。
“被取代的烷基”的定义指的是被例如1至4个取代基所取代的烷基,其中所说的取代基如卤素、三氟甲基、三氟甲氧基、羟基、烷氧基、环烷基氧、杂环氧基、氧代、烷酰基、芳基、芳氧基、芳烷基、烷酰氧基、氨基、烷基氨基、芳基氨基、芳烷基氨基、环烷基氨基、杂环氨基、二取代的氨基,其中所说的氨基上的两个取代基选自烷基、芳基、芳烷基、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、被取代的烷酰基氨基、被取代的芳基氨基、被取代的芳烷酰基氨基、巯基、烷硫基、芳硫基、芳烷硫基、环烷硫基、杂环硫基、烷基硫羰基、芳基硫羰基、芳烷基硫羰基、烷基磺酰基、芳基磺酰基、芳烷基磺酰基、亚磺酰氨基(例如,SO2NH2)、被取代的亚磺酰氨基、硝基、氰基、羧基、氨基甲酰基(例如,CONH2)、被取代的氨基甲酰基(例如,CONH烷基、CONH芳基、CONH芳烷基或其中在氮上有两个选自烷基、芳基或芳烷基的取代基的情况)、烷氧基羰基、芳基、被取代的芳基、胍基和杂环,如,吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基等等。正如上面所提到的那样,其中取代基本身还可以进一步被取代,如进一步被选自卤素、烷基、烷氧基、芳基和芳烷基的取代基所取代。这里所给出的烷基以及被取代的烷基的定义同样也适用于烷氧基中的烷基部分。
“卤素”或“卤”的定义指的是氟、氯、溴和碘。
“环系”的定义指的是包含1至3个环并且在至少一个环中有至少一个碳坦双键的的被取代或未被取代的环系。环系的实例非限制性的包括芳基或部分不饱和或完全不饱和的杂环体系,其可以是被取代或未被取代的。
“芳基”的定义指的是在环部分具有约6至约12个碳原子的单环或双环的芳香烃基,例如苯基、萘基、联苯和二苯基,各基团都可以被取代。
“芳烷基”的定义指的是通过一个烷基基团键合到一个较大实体上的芳基,例如苄基。
“被取代的芳基”的定义指的是被例如1至4个取代基所取代的芳基,其中所说的取代基如烷基;被取代的烷基、卤、三氟甲基、三氟甲氧基、羟基、烷氧基、环烷氧基、杂环氧基、烷酰基、烷酰氧基、氨基、烷基氨基、二烷基氨基、芳烷基氨基、环烷基氨基、杂环氨基、烷酰基氨基、巯基、烷硫基、环烷硫基、杂环硫基、脲基、硝基、氰基、羧基、羧基烷基、氨基甲酰基、烷氧基羰基、烷基硫羰基、芳基硫羰基、烷基磺酰基、亚磺酰氨基、芳氧基等等。所说的取代基还可以进一步被一个或多个选自卤、羟基、烷基、烷氧基、芳基、被取代的烷基、被取代的芳基和芳烷基的基团所取代。
“环烷基”的定义指的是被取代或未被取代的饱和环烃环系,其优选地包含1至3个环,每个环包含3至7个碳原子,其可以进一步与一个不饱和的C3-C7碳环稠合。该基团的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、以及金刚烷基。取代基的实例包括一种或多种如上所述的烷基、或一种或多种上述作为烷基取代基的基团。
“杂环”、“杂环状的”和“杂环基”的定义指的是被取代或未被取代的不饱和、部分饱或完全包含的芳环或非芳族的环,例如其是一种4至7员单环、7至11员双环、或10至15员的三环体系,其在至少一个包含碳原子的环中包含至少一个杂原子。各包含杂原子的杂环可以包含1、2或3个选自氮原子、氧原子和硫原子的杂原子,其中氮和硫杂原子还可以被氧化或不被氧化,氮杂原子还可以被季铵化或不被季铵化。该杂环可以在任何杂原子或碳原子上进行挂接。
单环杂环的实例包含吡咯烷基、吡咯基、吲哚基、吡唑基、氧杂环丁烷基、吡唑啉基、咪唑基、咪唑啉基、咪唑烷基、噁唑基、噁唑烷基、异噁唑啉基、异噁唑基、噻唑基、噻二唑基、噻唑烷基、异噻唑基、异噻唑烷基、呋喃基、四氢呋喃基、噻吩基、噁二唑基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧氮杂基、氮杂基、4-哌酮基、吡啶基、N-氧代-吡啶基、吡嗪基、嘧啶基、哒嗪基、四氢吡喃基、四氢硫代吡喃基、四氢硫代吡喃基砜、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜、1,3-二氧戊环和四氢-1,1-二氧代噻吩基、二噁烷基、异噻唑烷基、噻吩基、硫杂丙环基、三嗪基、以及***基等等。
双环杂环的实例包括噻唑基、苯并噁唑基、苯并噻吩基、奎宁环基、喹啉基、喹啉基-N-氧化物、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色酮基、香豆素基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基(如呋喃并[2,3-c]吡啶基、呋喃并[3,1-b]吡啶基]或呋喃并[2,3-b]吡啶基)、二氢异吲哚基、二氢喹唑啉基(如3,4-二氢-4-氧代-喹唑啉基)、苯并异噻唑基、苯并异噁唑基、苯并二嗪基、苯并呋咱基、苯并硫代吡喃基,苯并***基,苯并吡唑基,二氢苯并呋喃基,二氢苯并噻吩基,二氢苯并硫代吡喃基、二氢苯并硫代吡喃基砜、二氢苯并吡喃基、二氢吲哚基、异色酮基、异二氢吲哚基、萘啶基、酞嗪基、胡椒基、嘌呤基、吡啶并吡啶基、喹唑啉基、四氢喹啉基、噻吩并呋喃基、噻吩并吡啶基、噻吩并噻吩基等等。
用于“环系”、“杂环”、“杂环状的”和“杂环基”定义的取代基的实例包括一种或多种如上所述的用于被取代的烷基或被取代的芳基的取代基、以及较小的杂环,如,环氧化物、氮丙啶等等。
“烷酰基”的定义指的是-C(O)-烷基。
“被取代的烷酰基”指的是-C(O)-被取代的烷基。
“杂原子”的定义应当包括氧、硫和氮。
式I的化合物可与各种有机酸和无机酸形成盐。该类盐包括这些与盐酸、氢溴酸、甲磺酸、羟基乙烷磺酸、硫酸、醋酸、三氟醋酸、马来酸、苯磺酸、甲苯磺酸形成的盐以及各种药物药物配制领域技术普通技术人员所公知的其它盐。该类盐可以通过将式I的化合物在盐可以沉淀出来的介质或水性介质中与等量的酸进行反应,然后进行蒸发来形成。
此外,可以形成两性离子(“内盐”),其也包括在这里所用的盐的定义中。
在由式I所表示的这些化合物中,特别优选的埃博霉素类似物是由式II所表示的[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-二羟基-8,8,10,12,16-五甲基-3-[1-甲基-2-(2-甲基-4-噻唑基)乙烯基]-4-氮杂-7-氧杂二环[14.1.0]十七烷-5,9-二酮。
在1998年10月13日申请的美国专利申请序列号为09/170,582的专利申请和1999年3约29日申请的美国专利申请序列号为09/280,191的专利申请中对上面由式I和II所表示的在这里也被称为“本发明的埃博霉素化合物”的化合物进行了描述,该公开物在这里被引入作为参考。上面式I和II所示化合物可以以多种光学异构体、几何异构体、立体异构体的形式存在。虽然这里所表示的化合物只描述了一种光学取向,但其所有的异构体及其混合物都包括在本发明的范围内。
上述式I和II的化合物是微管稳定剂。因此,它们可用于治疗各种癌症和其它的增生性疾病,其非限制性的包括:
癌,包括膀胱癌、乳癌、结肠癌、肾癌、肝癌、肺癌、卵巢癌、胰腺癌、胃癌、***、甲状腺癌和皮肤癌,包括鳞状细胞癌;
淋巴系的造血肿瘤,包括白血病、急性淋巴细胞白血病、急性淋巴母细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非-霍奇金淋巴瘤、毛细胞淋巴瘤和Burketts淋巴瘤;
骨髓系的造血肿瘤,包括急性和慢性骨髓性白血病和早幼粒细胞白血病;
间质起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;
其它肿瘤,包括黑素瘤、***瘤、畸胎瘤、成神经细胞瘤和神经胶质瘤;
中枢和外周神经***肿瘤,包括星形细胞瘤、成神经细胞瘤、神经胶质瘤、以及神经鞘瘤;
间质起源的肿瘤,包括纤维肉瘤、横纹肌肉瘤、以及骨肉瘤;和
其它肿瘤,包括黑素瘤、着色性干燥病、角化棘皮瘤、***瘤、甲状腺滤泡癌和畸胎瘤。
由式I和II所示的化合物可用于治疗之前已经进行过癌症的治疗的患者已经这些之前没有接受过癌症治疗的患者。实际上,本发明的方法和组合物可用第一代和第二代癌症的治疗。此外,由式I和II所示的化合物可用于治疗难以治疗的癌症。
上面式I和II所示的化合物还可以抑制血管生成,从而影响了肿瘤的生长并且提供了对肿瘤和与肿瘤有关的疾病的治疗作用。式I和II所示化合物的该类抗-血管生成的作用还可用于治疗对抗血管生成剂有响应的其它状况,非限制性的包括某些形式的涉及视网膜血管形成的失明、关节炎、尤其是炎性关节炎、多发性硬化、restinosis和牛皮癣。
式I和II所示的化合物将诱发或诱导细胞凋亡,所说的细胞凋亡是一种对于正常发展和内环境稳定都很关键的生理学细胞死亡过程。在各种人类疾病的发病机理中都涉及细胞凋亡途径的改变。作为细胞凋亡的调控剂,由式I和II所表示的化合物将能用于治疗各种带有细胞凋亡畸变的人类疾病,所说疾病非限制性的包括癌症和癌症前期的损害、与免疫反应有关的疾病、病毒感染、肌与骨骼***的变性疾病以及肾病。
由式I和II所表示的各个化合物还可以与其它治疗物质一起进行制备或一起给药,所说的其它治疗物质由于其在与上述情况有关的给药治疗中特别有用而被选择。例如,式I和II的各种化合物可以与预防恶心、过敏、和胃部刺激的物质如止吐剂以及H1和H2抗组胺药一起进行制备。当与式I或II的化合物联合应用时,上述治疗物质可以以Physicians′Desk Reference(PDR)的指导剂量来进行应用,或者可以由现有技术中的普通技术人员来决定其使用数量。
此外,式I或II的化合物可以与其它的抗癌药和细胞毒素物质以及治疗癌症或其它增生性疾病所用的治疗物质联合给药。尤其有用的是抗癌药和细胞毒素药物组合物,其中所选择的第二种药物以与本发明在G2-M相发挥作用的式I和II的化合物起作用的方式不同的方式起作用或在细胞循环的不同阶段例如S相起作用。抗癌药和细胞毒素物质的实例非限制性地包括烷化剂,如氮芥、烷基磺酸盐、亚硝基脲、氮丙啶、以及三氮烯;抗代谢物,如叶酸盐拮抗剂、嘌呤类似物、以及嘧啶类似物;抗生素,如anthracyclines、博莱霉素、丝裂霉素、更生霉素、以及普卡霉素;酶,如L-天门冬酰胺酶;法呢基-蛋白转移酶抑制剂;激素物质,如糖皮质激素、***/抗***、雄激素/抗雄激素、孕激素、以及促黄体激素释放激素拮抗剂、醋酸奥曲肽;微管破坏剂,如ecteinascidins或其类似物及衍生物;微管稳定剂如紫杉醇(紫杉酚)docetaxel得自植物的产品,如长春花属生物碱、表鬼臼毒素、taxanes;和拓扑异构酶抑制剂;异戊二烯基-蛋白转移酶抑制剂;和杂项的物质,如羟基脲、甲基苄肼、邻氯苯对氯苯二氯乙烷、六甲密胺、铂协同复合物如顺铂和卡铂;以及用作抗癌药和细胞毒素物质的其它物质,如生物响应改性剂、生长因子;免疫调节剂、以及单克隆抗体。式I和II所示的化合物还可以与放疗联用。
这些类别的抗癌药和细胞毒素物质的代表性实例非限制性的包括盐酸氮芥、环磷酰胺、苯丁酸氮芥、异环磷酰胺、白消安、卡氮芥、罗氮芥、甲环亚硝脲、链脲霉素、噻替派、达卡巴嗪、甲氨蝶呤、硫鸟嘌呤、巯基嘌呤、氟达拉滨、pentastatin、克拉立平、阿糖孢苷、氟尿嘧啶、盐酸阿霉素、柔红霉素、依达比星、硫酸博莱霉素、丝裂霉素C、放线菌素D、safracins、saframycins、quinocarcins、discodermolides、长春新碱、长春碱、维诺利宾酒石酸盐、依托泊苷、替尼泊苷、紫杉醇、他莫昔芬、***氮芥、磷酸***氮芥钠、氟他胺、布舍瑞林、亮丙瑞林、蝶啶、diyneses、左旋咪唑、aflacon、干扰素、白介素、阿地白介素、非格司亭、沙格司亭、rituximab、BCG、视黄酸、盐酸依立替康、倍他米松(betamethosone)、gemcitabinehydrochloride、六甲蜜胺、以及topoteca和它们任何一种类似物或衍生物。
在这些类的物质中非限制性地优选地包括紫杉醇、顺铂、卡铂、阿霉素、洋红霉素、柔红霉素、氨基蝶呤、甲氨蝶呤、甲喋呤、丝裂霉素C、ecteinascidin743、泊非霉素、5-氟尿嘧啶、6-巯基嘌呤、吉西他滨、阿糖胞苷、鬼臼毒素或鬼臼毒素衍生物如依托泊苷、磷酸依托泊苷或替尼泊苷、美法仑、长春碱、长春新碱、异长春碱、长春地辛、以及环氧长春碱。
抗癌药和其它细胞毒素物质的实例包括:如可在WO99/24416中找到的依赖细胞周期蛋白的激酶的抑制剂;和可在WO97/30992和WO98/54966中找到的异戊二烯基-蛋白转移酶抑制剂。
不受任何有关机理和形态学理论的限制,由式I和II所示的化合物还可以用于治疗除癌症或其它增生性疾病外的情况。该类情况非限制性的包括病毒感染如疱疹病毒、痘病毒、埃-巴二氏病毒、辛德比斯病毒和腺病毒感染;自身免疫性疾病如全身性红斑狼疮、免疫介导的肾小球性肾炎、类风湿性关节炎、牛皮癣、炎症性肠病和自身免疫性糖尿病;神经变性性疾病如阿耳茨海默氏疾病、与AIDS有关的痴呆、帕金森氏病、肌萎缩性脊髓侧索硬化、色素性视网膜炎、杜-阿二氏肌萎缩和小脑退化;AIDS;脊髓发育不良综合征;再生障碍性贫血;与心肌梗死有关的局部缺血性损伤;中风和多次灌注性损伤;再狭窄;心律失常;动脉粥样硬化;毒素诱导的或醇诱导的肝病;血液病如慢性贫血和再生障碍性贫血;肌与骨骼***的变性疾病如骨质疏松症和关节炎;阿司匹林过敏的鼻窦炎;囊性纤维化;多发性硬化;肾病;以及癌症疼痛。
因为它们在水性介质中具有非常低的溶解度、在与水性介质接触时会迅速降解、当在溶液中时对低pH敏感、对光敏感、是“D类”细胞毒素、并且具有异常差的润湿性,所以由式I和II所示的化合物,特别是后者难于进行制备。这些特性中的任何一种或两种在配制静脉内给药的药物制剂时是可以克服的,但是所有这些性质同时存在时对药物配制的药剂师而言就是一个巨大的挑战。如果存在配制静脉制剂约制因素的物质必需用来静脉给药,则意想不到的发现本发明所提供的制剂可用于克服如上所述的主题物质埃博霉素类似物不利于其进行制备的不利性质。因为主题物质——埃博霉素类似物在水性介质中的溶解性很差的事实,实际上其一旦与水性介质接触就会迅速降解,所以一开始认为其应被制成冷冻干燥的形式。
已经发现一种适宜形成一种冷冻干燥用主题化合物的溶液的介质是一种叔丁醇和注射用水的混合物。这种混合物必需有至少约50%v/v,优选约50%至约80%v/v的叔丁醇以防止主题物质——埃博霉素类似物的降解。此外,由于主题物质——埃博霉素类似物的润湿性特别差,所以最初的溶液必需通过使用一种至少约60%v/v,优选约60%至约95%v/v叔丁醇和水的混合物来形成。一旦制备出该溶液,可以加入必需数量的水或叔丁醇-水混合物以获得如上所述冷冻干燥所需的最终浓度。
已经意外地发现可以通过在低于室温的温度下,优选约5℃至约15℃,更优选约5℃的温度下完成该溶液的制备来增强主题物质——埃博霉素类似物的稳定性。此外,制备该溶液的方法以及随后的冷冻干燥法都可以在容器中进行以保护该埃博霉素类似物不与光进行接触。还可以有益地以相对较小的批量来进行冷冻干燥以使得该埃博霉素类似物与水性介质具有最短的接触时间。
用如上所述的方法所形成溶液的冷冻干燥的主要阶段是在高真空条件下在约-10℃至约-40℃,优选约-25℃的温度下进行一段时间来完成的,其中所说的高真空即约50毫托至约300毫托,优选约200毫托,所说的一段时间即约24小时至约96小时,优选约48小时。在这种温度范围内的冷冻干燥可制备出一种静脉内使用的制剂所需的无定形产品。现有技术中的普通技术人员将意识到可以使用常规方法如粉末X-射线衍射法来确认该冷冻干燥产品的无定形性。
通过第二个干燥阶段来除去该产品中的残余溶剂,该干燥阶段是通过在相对较低的温度即约10℃至约30℃,优选约25℃,在高真空即约50毫托至约300毫托,优选约150毫托的条件下进行一段时间即约24小时至约96小时,优选约48小时来完成的。
已经意外地发现不能通过使用用于提高稳定性目的常用的赋形剂如乳糖、甘露醇、葡聚糖等等来提高这里所述的冷冻干燥的埃博霉素类似物的稳定性。这些赋形剂中的一些竟然对该冷冻干燥产品(亲液胶体)的稳定性具有负面影响。因此,本发明所制备的埃博霉素类似物是单纯的冷冻干燥物,即不含任何赋形剂。
冷冻干燥的式I和II所示的埃博霉素类似物用等份容积的脱水醇,USP和非离子表面活性剂的混合物来进行重组,其中所说的非离子表面活性剂优选的是以Cremophor EL的商标得自GAFCorporation,Mount Olive,新泽西的聚氧乙基化的蓖麻油表面活性剂。将该冷冻干燥的产品和用于重组的赋形剂分别包装于适宜的避光小瓶中。为了将重组溶液中表面活性剂的数量降到最低,仅提供足够数量的赋形剂以形成一种具有约2mg/mL至约4mg/mL埃博霉素类似物的溶液。一旦将药物溶解,则在注射前将所得溶液用一种适宜的非肠道稀释剂进一步进行稀释。该类稀释剂对于现有技术的普通技术人员而言是众所周知的。这些稀释剂一般是可以获得的临床工具。但是,在本发明的范围内,将该主题物质——埃博霉素类似物与第三个包含足够的用于制备给药所需的最终浓度的非肠道稀释剂的小瓶包装到一起。一种优选的稀释剂是乳酸盐林格氏注射液。给药的最终浓度优选地包含约0.1mg/mL至约0.9mg/mL的埃博霉素类似物。
对本发明制剂中重组的埃博霉素类似物的最终稀释可以用其它具有类似用途的制剂来完成,例如可以用5%葡萄糖注射液、乳酸盐林格氏和葡萄糖注射液、无菌的注射用水等等来完成。但是,因为其窄的pH范围,pH6.0至0.5,所以优选乳酸盐林格氏注射液。每100mL乳酸盐林格氏注射液包含氯化钠USP0.6g、乳酸钠0.31g、氯化钾USP0.03g和氯化钙-2H2O USP0.02g。克分渗透压浓度为2750smol/L,其十分接近于等渗。
本发明所形成的制剂,即该埃博霉素类似物在醇-表面活性剂赋形剂中的溶液在进一步进行稀释以进行给药之前可以被存放高至约24小时。已经发现通过将表面活性剂的浓度维持在获得埃博霉素类似物溶液的最小需要量上就可以将由于在制剂中存在表面活性剂而发生的***反应的发生率降到最低。此外,该类反应的发生率大约与其它包含其的非肠道给药制剂例如环胞菌素A的发生率一样。用本发明制剂所观测到的***反应的水平显著低于某些其它肿瘤学物质,如紫杉醇。
本发明还涉及治疗患者癌症和其它过度增生性疾病的方法,该方法包括给患者使用一种或多种治疗有效量的由式I和II所示的化合物。式I和II的化合物可以静脉内给药或口服给药,优选地既进行口服给药又进行静脉内给药。优选地,式I和II的化合物可以与一种或多种其它物质一起进行给药以便于预防恶心、过敏、或胃刺激,其中所说的其它物质如止吐药或H1或H2抗组胺药。
在每次IV输注或口服、或同时输注和口服时,式I和II所示的化合物的给药数量是由现有技术中普通技术人员所决定的,用于人的剂量的实例为约0.01mg/kg/天至约200mg/kg/天,其可以以一个单剂量的形式来进行给药,或者可以以各个分割剂量的形式来进行给药,如每天给药1至约4次。优选地,该化合物以少于约100mg/kg/天,并且更优选地少于约25mg/kg/天的剂量以单剂量或约2至约4个分割剂量的形式来进行给药。应当清楚的是,任何特定主题物质的特定剂量水平和给药频率都不同,其将取决于许多因素,这些因素包括所用特定化合物的活性、该化合物的代谢稳定性和作用时间长度、个体的种属、年龄、体重、一般健康状况、性别和饮食情况、给药的方式和时间、***速率、药物合用情况、以及特定情况的严重程度。治疗的优选个体包括患有上述病症的动物,最优选地是哺乳动物类如人、以及家畜如狗、猫等等。
式I和II的化合物一般给药至患者出现一种反应例如肿瘤体积减小时或直至出现限制给药的毒性时为止,当病人出现反应时或当病人出现限制给药的毒性时现有技术中的人员或普通技术人员将很容易的知道。通常的限制给药的毒性与式I和II的化合物有关,非限制性的包括疲劳、关节痛/肌痛、厌食、过敏、中性白细胞减少、血小板减少、以及神经毒性。
当静脉内给药时,式I和II的化合物优选地用本发明的制剂来进行给药。一般而言,式I和II的化合物是通过在约10分钟至约3小时,优选约30分钟至约2小时,更优选约45分钟至约90分钟,并且最优选约1小时的时间内IV输注来进行给药的。该化合物一般是以约0.5mg/m2至65mg/m2,优选约1mg/m2至50mg/m2,更优选约2.5mg/m2至30mg/m2,并且最优选约25mg/m2的剂量来进行静脉内给药的。
只要给出患者的高度和重量,现有技术中的普通技术人员将很容易的知道如何将剂量从mg/kg转换成mg/m2(参见例如,http://www.fda.gov/cder/cancer/animalframe.htm)。
当口服给药时,式I和II的化合物优选地与可药用的酸中和缓冲剂一起进行给药。该缓冲剂可中和患者胃中的酸以足够降低式I和II的化合物的降解速率,从而使其在胃肠道内可以存在足够的时间以被吸收。式I和II的化合物还可以与抗酸剂如铝和镁的氢氧化物;碳酸盐,如碳酸钠和碳酸钙;硅酸盐;以及磷酸盐一起进行给药以在式I和II的化合物给药前、给药期间或给药后中和胃中的酸。
正如这里所用的这样,“可药用的酸中和缓冲剂”的定义指的是当将其加入到一种溶液中时可提供一种当向该溶液中加入酸或碱时对pH改变的抵抗性比不含该缓冲剂的溶液更强的溶液的可药用无毒的酸和该酸可药用无毒的盐的组合物。“可药用的酸中和缓冲剂”还包括当将其加入到一种酸性溶液中时可中和酸并使该溶液的pH值增加的化合物。
在本发明的一个实施方案中,式I和II的化合物以及可药用的酸缓冲剂是以单剂量口服剂型的形式提供的并且被同时给药。包含式I和II的化合物的单一组合物可以以固体口服剂型(例如片剂、胶囊剂、或粉剂)或液体口服剂型(例如溶液、混悬液、或酏剂)的形式来进行给药。该溶液和混悬液可以就在使用之前才用适宜的溶剂或共溶剂溶解埃博霉素和缓冲剂组分来进行配制。
例如,式I和II的化合物以及可药用的酸中和缓冲剂可以以溶解于一种液体中的式I或II的埃博霉素溶液的形式同时口服给药,其中所说的液体包含各自的比例分别为约58:12:30的丙二醇:乙醇:磷酸盐缓冲剂(例如1M,大约为8的pH)。
式I和II的化合物以及可药用的酸中和缓冲剂还可以以各自不同的药物组合物的形式被供给并分别单独给药。它们各自可以以固体口服剂型或液体口服剂型的形式进行给药。当式I和II的化合物以及可药用的酸中和缓冲剂分别单独给药时,该可药用的酸中和缓冲剂可以在式I和II的化合物给药之前、之后或之前和之后进行口服给药。优选地,该可药用的酸中和缓冲剂在式I和II的化合物给药之前和之后都以足够中和胃酸的数量进行给药。当该可药用的酸中和缓冲剂在式I和II的化合物之前进行给药时,其在式I和II的化合物给药之前约5小时内,优选约3小时内,更优选约1小时内,并且最优选约10分钟内进行给药。当该可药用的酸中和缓冲剂在式I和II的化合物之后进行给药时,其在式I和II的化合物给药之后约5小时内,优选约3小时内,更优选约1小时内,并且最优选约10分钟内进行给药。
式I和II的化合物还可以以包肠衣的丸剂或胶囊剂的形式进行给药以将埃博霉素的释放延迟至该有效的药用酸中和缓冲剂给药之后。肠衣片和胶囊是用能在胃液中抵抗溶液但在小肠中可崩解的物质进行了包衣的胶囊。
该可药用的酸中和缓冲剂一般是以足够传递至少约20微当量酸中和能力,优选至少约30微当量的酸中和能力,更优选至少约40微当量的酸中和能力,并且最优选至少约50微当量的酸中和能力的数量来进行给药的。该可药用的酸中和缓冲剂一般是以具有约5至9,优选约6至8.5,并且更优选约7至8的pH的水性溶液的形式来进行给药的。在本发明的方法中可以使用可提供具有所需pH范围的溶液的任何可药用的酸中和缓冲剂。优选地,该可药用的酸中和缓冲剂是一种二元磷酸盐-单碱磷酸盐缓冲剂或一种二元磷酸盐缓冲剂-枸橼酸-枸橼酸盐缓冲剂。
例如,式I和II的化合物的口服给药可以包括首先给患者口服使用约150mL pH约7.4的包含无水磷酸二氢钠(约0.2M)、枸橼酸钠二水合物(约0.07M)、以及无水枸橼酸(约0.008M)的水性溶液形式的可药用的酸中和缓冲剂;然后给患者口服在比例为约80:20的丙二醇:乙醇体系中的液体剂型形式的式I和II的化合物;然后再口服约150mL pH约7.4的包含无水磷酸二氢钠(约0.2M)、枸橼酸钠二水合物(约0.07M)、以及无水枸橼酸(约0.008M)的水性溶液。
正如上面所讨论的那样,式I和II的化合物可以口服给药、静脉内给药、或既进行口服给药又进行静脉内给药。本发明的方法特别地包含一些给药剂量方案,如每天给药一次,连续给药2至10天,优选每3至9天,更优选每4至8天并且最优选每5天进行一次该种给药。在一个实施方案中,在各给药周期之间有3天5周,优选4天至4周,更优选5天至3周,并且最优选1周至2周不进行治疗的时间间隔。在另一个实施方案中,式I或II的化合物可以每天给药一次,连续3天口服给药、静脉内给药或既进行口服给药又进行静脉内给药,在各周期之间存在一个优选1周至3周不进行治疗的时间间隔。还是在另一个实施方案中,式I或II的化合物可以每天给药一次,连续5天口服给药、静脉内给药或既进行口服给药又进行静脉内给药,在各周期之间存在一个优选1周至3周不进行治疗的时间间隔。
在一个优选的实施方案中,式I或II的化合物给药的治疗周期为每天一次,连续给药5天,在各治疗周期之间有2至10天,优选1周的时间间隔。
式I和II的化合物还可以每1至10周给药一次,优选每2至8周,更优选每3至6周,并且最优选每3周给药一次,其可以口服给药、静脉内给药或既进行口服给药又进行静脉内给药。
在本发明的另一种方法中,式I和II的化合物可以以一种28天的给药周期来进行给药,在该给药周期中式I和II的化合物在第1、7和14天进行静脉内给药并在第21天进行口服给药。式I和II的化合物可以以另一种供选择的28天的给药周期来进行给药,在该给药周期中,式I和II的化合物在第1天进行口服给药,在第7、14和28天进行静脉内给药。
根据本发明的方法,式I和II的化合物可以给药至病人出现反应例如肿瘤体积缩小或给药至出现限制给药的毒性。
许多抗癌剂具有神经毒性,例如已知它们可造成中枢神经和外周神经***的副作用。本发明还进一步包含式I和II的化合物在以前用使用抗癌剂时出现了神经毒性的患者中的应用。虽然本发明的化合物在某些剂量时也会引起神经毒性,但是可以用这里的方法来减少或避免这类毒性。
实施例
用下面的非限制性实施例来对本发明的实践进行说明。
实施例1:IV剂型
将[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-二羟基-8,8,10,12,16-五甲基-3-[1-甲基-2-(2-甲基-4-噻唑基)乙烯基]-4-氧杂-17-氧杂二环[14.1.0]十七烷-5,9-二酮,9.86g,用已经预先冷却至5℃的600mL叔丁醇和USP注射用水9:1的混合物润湿或部分溶解。一旦药物粉末已经被完全润湿,则通过添加同样已经预先冷却至5℃的600mL1:9的叔丁醇和注射用水混合物以及7661:1的叔丁醇和注射用水混合物来完全溶解,从而制得最终溶液——一种1:1的混合物。该溶解是在避光的条件下完成的。
在避光的条件下将上面所形成的溶液迅速在Virtis INOTOP冷冻干燥器中在-16℃冷冻干燥48小时。然后将所得的冷冻干燥产品(亲液胶体)在15℃下,在高真空下进一步干燥48小时。在这些过程中没有观察到药物的降解现象。在无菌的条件下将该亲液胶体包装到30mL小瓶中,各小瓶包含10mg的药物和用于弥补小瓶/针/注射器损失的标准余额。
将该亲液胶体用5.5mL USP脱水醇和Cremophor EL1:1体积的混合物进行重组,所说脱水醇USP和Cremophor EL的混合物一般在一个单独的小瓶中与药物一起供给。一旦通过轻轻涡旋该小瓶完成溶解后,通过向每毫升所制备的药品中加入9mL注射用乳酸盐林格氏溶液将所得的溶液进行稀释以获得0.2mg/mL的浓度。
实施例2:化合物II的IV给药
一共24名癌症患者(12名男性和12名女性)通过IV给药接受了化合物II从而对最大耐受剂量(MTD)、限制给药的毒性(DLT)、药物动力学和药效学进行评估并评估了化合物II的抗肿瘤活性。患者的中间年龄(范围)为57岁(34岁-74岁)。5名患者患有乳癌,5名患者患有头和颈部的癌症,2名患者患有肉瘤,2名患者患有结肠直肠癌症,2名患者患有UPT癌症,2名患者患有黑素瘤,2名患者患有食管肿瘤,1名患者患有肾癌,1名患者患有***,1名患者患有甲状腺癌,1名患者患有***癌。21名患者之前接受了化疗(18名患者使用了神经毒性物质并且有18名患者接受了放疗)。之前进行的包含辅助剂的化疗治疗的中间数目(范围)是2次(1-3次)。
在第1天给患者口服化合物II(以20mg/m2及更高的剂量进行给药)后从第7天开始每周进行30分钟式II化合物的IV输注。将化合物II以1、2.5、5、10、20、25、和30mg/m2的剂量对患者进行给药。在治疗期间对患者进行剂量限制毒性(DLT)的监测。该研究的结果表明式II的化合物可以以高至30mg/m2的剂量每周给药一次而不会出现严重的毒性。
在第二种研究中,给12癌症患者(5名男性和7名女性)在第1天口服化合物II,然后从第7天开始每周以25mg/m2的剂量每周进行30分钟式II化合物的IV输注以对化合物II的神经毒性进行评估。患者的中间年龄(范围)为51岁(30岁-65岁)。4名患者患有结肠直肠癌,3名患者患有乳癌,2名患者患有黑素瘤,1名患者患有肾癌,1名患者患有肉瘤,1名患者患有卵巢癌。10名患者之前接受了化疗(6名患者使用来神经毒性物质并且18名患者接受了放疗)。之前进行的包含辅助剂的化疗治疗的中间数目(范围)是2次(0-3次)。这种研究表明化合物II可以用于以前进行过包括使用神经毒性抗癌物质的化疗方面治疗的患者。但是,在之前进行过使用神经毒性的抗癌物质的化疗方法的患者中,每个周期中化合物II的累积剂量不能超过约200mg/m2。
该研究进一步表明之前用化疗进行过治疗的患者的***肿瘤和结肠肿瘤对于用化合物II进行的治疗有反应。之前用阿霉素和taxotere与环磷酰胺、5-氟尿嘧啶、甲氨蝶呤辅助治疗;阿霉素和taxotere与环磷酰胺、5-氟尿嘧啶、甲氨蝶呤辅助治疗;或阿霉素、环磷酰胺、5-氟尿嘧啶对转移性癌症进行过治疗的乳癌患者对化合物II有特定反应。用紫杉酚和卡铂;5-氟尿嘧啶和亚叶酸;或伊立替康进行治疗的患有转移性结肠癌的患者对于化合物II的治疗有反应。
实施例3:给癌症患者口服给药的化合物II的药物动力学
每周一次地以30分钟输注的形式给患有进行性恶性肿瘤的患者使用化合物II(一个疗程=3次每周一次的静脉内给药)。患者使用的给药剂量为1、2.5、5、10、20、25、或30mg/m2。从20mg/m2的剂量水平开始,在第3天给予在80%丙二醇和20%乙醇(v/v)的赋形剂中的化合物II的单一口服剂量,之后在疗程1之前进行枸橼酸盐/磷酸盐缓冲剂(22.5gm)的给药,从而对化合物II的绝对生物利用度进行评估。在第6天化合物II的口服给药剂量与第1天化合物II的IV给药剂量相匹配。在该疗程的第6天和第1天采取系列血浆样品,通过LC/MS/MS对药物动力学进行评估。
血浆样品是通过向0.2mL血浆药品中加入内标,用丙酮进行沉淀,然后用1-氯丁烷对上清液进行提取来进行分析的。除去有机层然后将其蒸发干燥。将残余物重新溶解并将其注射到LC/MS/MS***中。用YMC ODS-AQ柱(4.6x50mm,3:m),用乙腈:0.01M醋酸铵,pH5.0(65:35)恒速洗脱来完成色谱分离。用阴离子电扫描串连质谱来进行检测。适用于所有分析物的范围为2至500ng/ml的标准曲线与一种1/x权重的平方的回归模型相适配。
用于口服给药的化合物II是以“瓶装药”的形式被提供的,25mg/瓶。用于化合物II的重组的赋形剂(缓冲剂)是80%丙二醇和20%乙醇(v/v)的混合物,25mg/瓶,。该丙二醇/乙醇混合物是通过将80份体积的丙二醇和20份体积的乙醇在适宜容器中进行混合并将该容器轻轻涡动直至该溶液被完全混合为止来进行制备的。
在使用化合物II后用于口服给药的枸橼酸盐/磷酸盐缓冲剂是在一个独立的小瓶中被供给的。与化合物II结合使用的缓冲剂是用注射用水(WFI)来进行制备的。
给患者使用的化合物II是通过根据患者的给药剂量,用适宜的注射器缓慢地分别将2.5、5、或10mL丙二醇/乙醇混合物注射到该包含化合物II的25mg/瓶的20cc的小瓶中以分别获得10、5、或2.5mg/mL的浓度来进行制备的。将注射器除去,然后将该小瓶剧烈振荡10分钟。将该小瓶房子超声浴中,超声至该溶液变为透明。根据剂量来对小瓶进行合并。
用于与化合物II一起进行给药的缓冲剂是以盛放在8oz.透明玻璃瓶中的形式被供给的,并且是用注射用水(WFI)来进行制备的。从缓冲剂瓶上除去儿童打不开的帽,然后向其中加入约140mL的注射用水(WFI)。将该瓶剧烈振荡并结合使用超声与间歇振荡直至获得一种澄清的溶液。
在第6天的口服给药后,根据如下的时间表(以从口服给药开始的小时:分钟来进行表达)向带有作为抗凝剂的K3EDTA的BectonDickinson Vacutainer管中收集7mL的血样:给药前、00:15、00:30、00:45、1:00、1:30、2:00、3:00、4:00、6:00、8:00、24:00、48:00、以及72:00。在第1天IV给药后,,根据如下的时间表(以从口服给药开始的小时:分钟来进行表达)向带有作为抗凝剂的K3EDTA的Becton Dickinson Vacutainer管中收集7mL的血样:给药前、00:15、00:30(输注结束)、00:45、1:00、1:30、2:00、3:00、4:00、6:00、8:00、24:00、48:00、以及72:00。
在收集血样后立即将该Vacutainer管反转几次以确保其与抗凝剂进行混合,然后立即将其放置在碎冰上。在收集后30分钟内,在约2000xg和0至5℃的条件下将样品离心5分钟。然后将血浆转移至独立的预先贴有标签的螺旋帽的聚丙烯管中并在-70℃下进行储存直至进行生物学分析。
用LC/MS/MS分析来对化合物II的血浆浓度进行分析。用非隔室法对血浆浓度与时间数据进行分析。所测得的化合物II的药物动力学参数包括所观测到的最大血浆浓度(Cmax)、达到Cmax的时间(Tmax)、从0时间点到最后的取样时间点T的血浆浓度时间曲线下面积(AUC(0-T))。
一共18名患者在第6天口服使用溶液形式的化合物II并且在第1天通过IV使用化合物II。将由这些病人所获得的药物动力学结果概括地列于表1中。
表1.口服和静脉内给予化合物II后患者药物动力学的概述
a均值(SD)
b中值(最小,最大)
c代表AUC(0-T)
本发明上述的实施方案仅仅是用于进行示范性的说明,现有技术中的技术人员将意识到或将能确定所用的常规实验、许多同等的特定化合物、物质、以及方法。认为所有这些等同都属于本发明的范围并且包含在所附的权利要求中。
Claims (11)
2.一种形成用于非肠道给药的药物组合物的方法,该方法包括将如权利要求1所述的药物制剂小瓶的内容物进行混合从而获得所说的冷冻干燥的埃博霉素类似物的溶液,然后将所得的溶液用一定数量适宜的非肠道的稀释剂进行稀释,从而使得其中所说类似物的浓度为0.1mg/mL至0.9mg/mL。
3.权利要求2的方法,其中所说的稀释剂是乳酸盐林格氏注射液。
4.式II所示的埃博霉素类似物在制备用于治疗有需要的患者的药物中的用途,所述药物通过静脉内注射或输注给患者施用有效量的权利要求2或3的药物组合物,其中所述埃博霉素类似物是冷冻干燥的,形成所述埃博霉素类似物的冷冻干燥用溶液的介质是叔丁醇和注射用水的混合物,所述混合物包含至少50%v/v的叔丁醇。
6.式II所示的埃博霉素类似物在制备用于治疗患者癌症的药物中的用途,其中所述药物是以1至65mg/m2的剂量每三周一次静脉内施用给患者的,其中所述埃博霉素类似物是冷冻干燥的,形成所述埃博霉素类似物的冷冻干燥用溶液的介质是叔丁醇和注射用水的混合物,所述混合物包含至少50%v/v的叔丁醇,
7.权利要求6的用途,其中所述剂量为30-50mg/m2。
8.权利要水6的用途,其进一步包括给患者施用一种或几种另外的药剂,以预防恶心、呕吐、过敏或胃部刺激。
9.权利要求8的用途,其中所述一种或几种另外的药剂是H1或H2抗组胺药。
10.权利要求6的用途,其中癌症是抗癌的化疗难以治疗的癌症。
11.权利要求6的用途,其中式II化合物在10分钟至3小时的时间内通过静脉内注射或输注给药。
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