CN110882268A - 包括吉西他滨前药的制剂 - Google Patents
包括吉西他滨前药的制剂 Download PDFInfo
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- CN110882268A CN110882268A CN201911065790.0A CN201911065790A CN110882268A CN 110882268 A CN110882268 A CN 110882268A CN 201911065790 A CN201911065790 A CN 201911065790A CN 110882268 A CN110882268 A CN 110882268A
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- formulation
- phosphate
- gemcitabine
- phenyl
- alaninyl
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Abstract
本发明涉及吉西他滨‑[苯基‑苯甲酰氧基‑L‑丙氨酰基)]‑磷酸酯的药物制剂,其是公知的肿瘤药物吉西他滨的单磷酸酯衍生物。特别地,本发明涉及包含极性非质子溶剂,优选二甲基乙酰胺(DMA)的制剂。包含这些溶剂的制剂提供吉西他滨‑[苯基‑苯甲酰氧基‑L‑丙氨酰基)]‑磷酸酯的治疗上有效的治疗。本发明还涉及使用所述制剂的方法和包含所述制剂的试剂盒。
Description
本申请是国际申请日为2015年6月25日,中国国家申请号为201580034742.9,发明名称为“包括吉西他滨前药的制剂”的发明专利申请的分案申请。
技术领域
本发明涉及是公认的抗肿瘤药物吉西他滨的单磷酸酯衍生物的吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯(化学名:2'-脱氧-2',2'-二氟-D-胞苷-5'-O-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯)的药物制剂。特别地,本发明涉及包含极性非质子溶剂,优选二甲基乙酰胺(DMA)的制剂。包含这些溶剂的制剂提供治疗有效量的吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯。本发明的制剂可以在施用前稀释到所需的浓度。
背景技术
吉西他滨的临床效果受到多种固有耐药机制和获得性耐药机制的限制。细胞水平的耐药取决于三个参数:(i)激活成磷酸化基团所必需的脱氧胞苷激酶的下调;(ii)核苷转运体特别是通过癌细胞摄取所需的hENT1的降低的表达,和(iii)催化酶尤其是降解吉西他滨的胞苷脱氨酶的上调。
WO2005/012327描述了吉西他滨的一系列磷酸酯衍生物和相关的核苷药物分子。其中吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯(NUC-1031;2)被认为是特别有效的化合物。这些化合物似乎避免了很多限制吉西他滨的效果的固有耐药机制和获得性耐药机制(‘Application of ProTide Tech否logy to Gemcitabine:A Successful Approachto Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent(NUC-1031)in Clinical Development’;Slusarczyk et all;J.Med.Chem.;2014,57,1531-1542)。
遗憾的是,NUC-1031非常亲脂,因此难溶于水(通过计算:<0.1mg/mL),此外,可电离基团嘧啶氮和酚羟基的计算所得的pKa值在适于肠胃外施用的pH范围之外。无论盐含量和pH值如何,它基本不溶于水,这对以足以实现有效治疗的高剂量递送化合物的临床可接受方法的发展产生严重影响。有时,可以实现如NUC-1031般亲脂的药物分子的递送,但其疼痛水平于患者来说难以接受。
NUC-1031以在磷酸酯中心差向异构的两种非对映异构体的混合物存在:
本发明的某些实施方案旨在提供递送有效剂量的吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯的药物制剂。
本发明的某些实施方案旨在提供吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯的稳定药物制剂。对于静脉内施用,合适的输注制剂通常应在大于30分钟,并达到48小时内稳定。特别说明的是,对于静脉内施用,制剂的稳定包括对吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯的沉淀和吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯的降解两方面稳定。
本发明的某些实施方案旨在提供静脉内递送有效剂量的吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯的药物制剂。
本发明的某些实施方案旨在提供可以在外周静脉中或经中心管线(centralline)施用的吉西他滨-[苯基(苯甲酰氧基-L-丙氨酰基)]磷酸酯的肠胃外制剂。因此,本发明的某些实施方案旨在提供这样一种制剂,所述制剂的同渗容摩对于经外周静脉施用来说是可接受的。
本发明的某些实施方案满足一些或全部上述目的。
发明内容
根据本发明的第一方面,提供了一种药物制剂,其包含:
吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;
极性非质子溶剂;和
任选的一种或多种药学上可接受的赋形剂。
极性非质子溶剂可以选自二甲基乙酰胺(DMA),二甲基亚砜(DMSO)和N-甲基吡咯烷酮(NMP)。优选地,极性非质子溶剂是DMA。DMA提供了所测试的那些的最佳溶解度曲线。
极性非质子溶剂(例如DMA,DMSO或NMP)可以是药物级的。极性非质子溶剂(例如DMA)可以是施用载体,或者可以是在制剂使用前稀释所使用的提供所需特征的施用载体。因此,制剂可以准备用于输注并且具有极性非质子溶剂(例如DMA)作为主要组分;或者其可以是极性非质子溶剂(例如DMA)作为主要组分并且在施用前稀释以产生准备用于输注并且极性非质子溶剂(例如DMA)仅作为次要组分的制剂的制剂;或者其可以是准备用于输注,具有仅作为次要组分的极性非质子溶剂(例如DMA),并且是由其中极性非质子溶剂(例如DMA)是主要组分的制剂的稀释产生的制剂。因此,极性非质子溶剂(例如DMA)可以占制剂的0.1%v/v至100%v/v。
很少的药学上可接受的溶剂溶解足够量的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯以静脉内递送治疗有效剂量。在那些中,许多是不稳定的,即吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯将倾向于从溶液中沉淀析出。发明人惊奇地发现,确实产生稳定溶液的溶剂通常是极性非质子溶剂,例如DMA,DMSO和NMP。在已经发现能够溶解吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的那些溶剂中,本发明人已经发现某些极性非质子溶剂,特别是DMA,当以水性载体稀释溶液时特别能够以递送所需剂量所必需的浓度将其保持在该溶液中。因此,使用极性非质子溶剂,特别是DMA,提供了优于其它制剂溶剂的双重优点,令人惊讶地,这使其成为将吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯以实用和治疗有效的方式递送至患者的优良介质。
吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯可以作为磷酸酯非对映异构体的混合物存在,或其可以以基本上非对映异构纯的形式作为(S)-差向异构体或作为(R)-差向异构体存在。对于本发明的目的,“基本上非对映异构纯的”被定义为大于约90%的非对映异构纯度。如果以基本上非对映异构纯的形式存在,吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯可以具有大于95%,98%,99%或甚至99.5%的非对映异构纯度。
吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯可以作为磷酸酯非对映异构体的混合物存在。因此,以非对映异构体的混合物施用NUC-1031提供了递送有效治疗的实用且经济的方法。非临床证据表明两种差向异构体之间的生物学效力没有差异。
或者,吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯2可以以基本上非对映异构纯的形式作为(S)-差向异构体3存在。(S)-差向异构体相对于(R)-差向异构体显示令人惊讶和显著的溶解度增加,其允许更方便的配制,增加制剂的稳定性并降低在施用设备(giving set)或中心管线中沉淀的风险。它还可以允许药物以这样的方式递送,即以经稀释的制剂经由外周静脉施用时减少患者不适。
本发明的制剂可以在施用前不久稀释预定量,即在施用前长达48小时(例如长达24、12或2小时)。
所述制剂还可以包含一种或多种药学上可接受的增溶剂,例如,药学上可接受的非离子增溶剂。增溶剂也可以被称为表面活性剂。示例性增溶剂包括聚乙氧基化脂肪酸和脂肪酸酯及它们的混合物。合适的增溶剂包括聚乙氧基化蓖麻油(例如以商品名ELP出售的);或聚乙氧基化硬脂酸(例如以商品名或HS15出售的);或聚乙氧基化(例如聚氧乙烯(20))失水山梨醇单油酸酯(例如以商品名80销售的那些)。
在某些优选的实施方案中,制剂包含多于一种的药学上可接受的增溶剂。
所述制剂还可以包含水性载体。本发明的制剂可以是准备好施用的,在这种情况下,其通常包含水性载体。
该制剂可以用于胃肠外,例如用于静脉内、皮下或肌内施用。优选地,该制剂用于静脉内施用。施用可以通过中心静脉或其可以通过外周静脉。
适合于施用的制剂中的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的总剂量通常为250mg至3g,例如1g至2g,例如约1.5g。
可能的是,极性非质子溶剂(例如DMA)占制剂体积的30%或更多。因此,极性非质子溶剂(例如DMA)占制剂体积的50%或更多,例如60%或更多。极性非质子溶剂(例如DMA)可以占制剂体积的95%或更少,例如90%或更少。制剂还可以包含水性载体(例如盐水)。水性载体可以占制剂体积的50%或更少,例如30体积%或更少。通常,水性载体(例如盐水)将占制剂体积的5%或更多,例如10%或更多。
可能的是,吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯在(多种)制剂溶剂中的浓度为每mL 500mg或更少。可以是每mL 100mg或更多的浓度。优选地,浓度为每mL200mg至300mg,例如225mg至275mg,例如约250mg。
某些优选的制剂包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
每mL 100mg至400mg(例如100mg至300mg)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。
更优选的制剂包含:
70体积%至90体积%的DMA;
10体积%至30体积%的水性载体(例如盐水);和
每mL 200mg至300mg的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。
前四个段落中描述的制剂,其中极性非质子溶剂(例如DMA)作为主要组分存在,可以例如用于施用磷酸酯非对映异构体混合物形式的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。它们还可用于施用基本上非对映异构纯形式的(S)-磷酸酯差向异构体的形式的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。在这些段落中描述的制剂可以通过施用(例如通过输注或注射)制剂使用,而不用在施用前稀释。它们可以通过中心静脉施用。
或者,可以稀释这些制剂以形成适于通过外周静脉施用的制剂。
可能的是,极性非质子溶剂(例如DMA)占制剂体积的10%或更多,例如20%或更多。因此,可能的是极性非质子溶剂(例如DMA)占制剂体积的80%或更少,例如60%或更少。极性非质子溶剂(例如DMA)可占制剂体积的40%或更少。制剂还可以包含一种或多种增溶剂(例如一种或多种聚乙氧基化脂肪酸)。一种或多种增溶剂可占制剂体积的90%或更少,例如80%或更少。通常,一种或多种增溶剂将占制剂体积的30%或更多,例如50%或更多或60%或更多。一种优选的制剂包含作为在30%:70%DMA:增溶剂混合物中的溶液的药物。
可能的是,吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯在(多种)制剂溶剂中的浓度为每mL 200mg或更少,例如150mg或更少或120mg或更少。可能的是,浓度为每mL40mg或更多,例如60mg或更多。优选地,浓度为每mL 70mg至110mg,例如约75mg或约100mg。
某些优选的制剂包含:
20体积%至80体积%的DMA;
30体积%至80体积%的增溶剂或多种增溶剂;和
50mg/mL至150mg/mL的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。所述制剂还可以包含水性载体,例如其量为1体积%至15体积%。
某些特别优选的制剂包含:
20体积%至80体积%的DMA;
20体积%至60体积%的第一增溶剂;
5体积%至40体积%的第二增溶剂;
2%至12%的水性载体;和
50mg/mL至150mg/mL的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。第一增溶剂可以是聚乙氧基化蓖麻油(例如以商品名ELP出售的那些)。第二增溶剂可以是聚乙氧基化脱水山梨糖醇单油酸酯(例如以商品名80销售的那些)。制剂还可以包含水性载体,例如其量为3体积%至15体积%。
所述制剂可以包含:
50体积%至60体积%的DMA;
20体积%至30体积%的第一增溶剂;
8体积%至15体积%的第二增溶剂;
4体积%至10体积%的水性载体;和
75mg/mL至125mg/mL的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。
前五个段落中描述的制剂,其中极性非质子溶剂(例如DMA)作为主要组分存在,可用于例如施用基本上非对映异构纯形式的(S)-磷酸酯差向异构体形式的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。它们也可以用于施用R和S差向异构体的混合物或R差向异构体。在这些段落中描述的制剂通常在施用之前用水性载体稀释。一旦稀释,它们可以通过外周静脉施用。
这些制剂可以通过稀释不含任何增溶剂的制剂来形成。吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯可以在某些增溶剂的存在下降解。
可能的是,极性非质子溶剂(例如DMA)占制剂体积的0.1%或更多,例如0.5%或更多或1%或更多。因此,可能的是DMA占制剂体积的10%或更少,例如5%或更少或3%或更少。极性非质子溶剂(例如DMA)可以占制剂体积的8%或更少或2%或更少。制剂还可以包含水性载体(例如WFI)。水性载体可以以占制剂体积的99.5%或更少存在,例如占制剂体积的99%或98%或更少。通常,水性载体将占制剂体积的85%或更多,例如90%或更多或95%或更多。制剂还可以包含一种或多种增溶剂(例如一种或多种聚乙氧基化脂肪酸)。一种或多种增溶剂可占制剂体积的10%或更少,例如7.5%或更少或5%或更少或3%更少。通常,一种或多种增溶剂将占制剂体积的0.1%或更多,例如0.5%或更多或1%或更多或2%或更多。
可能的是,吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯在(多种)制剂溶剂中的浓度为每mL 12.0mg或更少或每mL 10.0mg或更少,例如每mL7.0mg或更少或4.5mg或更少。可能的是,浓度为每mL 1.0mg或更多,例如2.0mg或更多。优选地,浓度为2.5mg至11mg/mL,例如3mg至7mg/mL,例如约4.5mg/mL。
某些优选的制剂包含:
0.1体积%至15体积%(例如0.5至5体积%)的DMA;
0.1体积%至15体积%(例如0.1%至7.5体积%)的增溶剂或多种增溶剂;
85体积%至99体积%的水性载体;和
每mL 2.0mg至12.0mg(例如2.0mg至10.0mg)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。
某些特别优选的制剂包含:
0.5体积%至10体积%的DMA;
0.2体积%至4体积%的第一增溶剂;
0.1体积%至2体积%的第二增溶剂;
85体积%至99体积%的水性载体;和
每mL 2.0mg至12.0mg(例如2.0mg至10.0mg)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。第一增溶剂可以是聚乙氧基化蓖麻油(例如以商品名ELP出售的那些)。第二增溶剂可以是聚乙氧基化脱水山梨糖醇单油酸酯(例如以商品名80销售的那些)。
所述制剂可以包含:
0.5体积%至6体积%的DMA;
0.5体积%至6体积%的第一增溶剂;
0.2体积%至4体积%的第二增溶剂;
85体积%至99体积%的水性载体;和
每mL 2.0mg至12.0mg(例如2.0mg至10.0mg)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。
前四个段落中描述的制剂,其中极性非质子溶剂(例如DMA)作为主要组分存在,可用于例如施用基本上非对映异构纯形式的(S)-磷酸酯差向异构体形式的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。它们也可以用于施用R和S差向异构体的混合物或R差向异构体。在这些段落中描述的制剂通常通过在施用前长达48小时用水性载体稀释浓缩的极性非质子溶剂(例如DMA)制剂或浓缩的极性非质子溶剂(例如DMA)和增溶剂制剂来制备。所得到的制剂可以通过外周静脉施用。
虽然本发明的制剂优选用于肠胃外施用,但是本发明的某些实施方案也可以口服施用。
在本发明的第二方面,提供了药物制剂,其包含:
吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;
极性非质子溶剂(例如DMA);和
任选的一种或多种药学上可接受的赋形剂;
其中所述制剂用于医疗用途。
在本发明的第三方面,提供了药物制剂,其包含:
吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;
极性非质子溶剂(例如DMA);和
任选的一种或多种药学上可接受的赋形剂;
其中所述制剂用于治疗癌症。
在本发明的第四方面,提供了治疗癌症的方法,所述方法包括对有需要的受试者施用药物制剂,所述药物制剂包含:
吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;
极性非质子溶剂(例如DMA);和
任选的一种或多种药学上可接受的赋形剂。
该方法可以包括以下步骤:
用水性载体稀释包含吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯,极性非质子溶剂(例如DMA)和任选的一种或多种药学上可接受的赋形剂的溶液,以提供用于输注或注射的制剂;和
通过输注或注射对受试者施用用于输注或注射的制剂。
该方法可以包括以下步骤:
用包含极性非质子溶剂(例如DMA)和一种或多种增溶剂的第二溶液稀释包含吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯和极性非质子溶剂(例如DMA)和任选的水性载体的第一溶液以形成第三溶液;
用水性载体稀释所述第三溶液以提供用于输注或注射的制剂;和
通过输注或注射对受试者施用用于输注或注射的制剂。
第二制剂可以包含多于一种增溶剂。通常,第二制剂不包含活性成分。
所述稀释或各稀释可以以预定量。
起始溶液可以是第一方面的制剂。同样地,用于输注或注射的制剂可以是第一方面的制剂。可以是在稀释步骤例如第一或第二稀释步骤后长达48小时(例如长达12或2小时)进行施用步骤。
癌症可以是选自以下的癌症:胰腺癌、乳腺癌、卵巢癌、膀胱癌、结肠直肠癌、肺癌、膀胱癌、前列腺癌、胆管癌、肾癌、子宫颈癌、胸腺癌、未知原发位点的癌症、淋巴瘤或白血病。
该方法可以包括:
用第一制剂的第一部分冲洗中心管线静脉内施用装置,所述第一制剂包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
经由所述施用装置对所述患者施用第二制剂,所述第二制剂包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
每mL 100mg至400mg(例如100mg至300mg)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;和
任选地用第一制剂的第二部分冲洗施用装置。通常,第一制剂不包含活性成分。在本发明的第五方面,提供了制备用于输注或注射的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的药物制剂的方法,所述方法包括:
用水性载体稀释包含吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯,极性非质子溶剂(例如DMA)和任选的一种或多种药学上可接受的赋形剂的溶液,以提供用于输注或注射的制剂。
稀释可以是预定量的。
起始溶液可以是第一方面的制剂。同样地,用于输注或注射的制剂可以是第一方面的制剂。可以是在稀释步骤后长达48小时(例如长达12或2小时)进行施用步骤。
水性载体可选自盐水(例如0.9%盐水或0.45%盐水),葡萄糖溶液和输注用水(WFI)。优选地,水性载体是WFI。WFI的使用提供了与血液基本上等渗的制剂。
在本发明的第六方面,提供了制备吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的药物制剂的方法,所述方法包括:
将吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯溶解在极性非质子溶剂(例如DMA)中以形成溶液;
向溶液中加入一种或多种其它药物赋形剂以形成吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的药物制剂。
发明人已经发现更有效的方法产生于在极性非质子溶剂(例如DMA)中预溶解吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯,然后加入所需的赋形剂,例如增溶剂。
一种或多种药物赋形剂可以包括增溶剂。
在本发明的第七方面,提供了包含吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-(S)-磷酸酯或其药学上可接受的盐或溶剂合物和至少一种药学上可接受的赋形剂的药物制剂。优选地,吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-(S)-磷酸酯基本上是非对映异构纯的形式。
该制剂可以用于胃肠外,例如用于静脉内,皮下或肌内施用。优选地,所述制剂用于静脉内施用。
制剂可以是任选还包含极性有机溶剂的水性制剂。在肠胃外(例如静脉内)施用的情况下,制剂优选还包含极性有机溶剂。该制剂可以包含DMSO或NMP。
制剂还可以包含环糊精。
在本发明的第八方面,提供了包含吉西他滨-[苯基-苯甲酰基-L-丙氨酰基)]-(R)-磷酸酯或其药学上可接受的盐或溶剂合物和至少一种药学上可接受的赋形剂的药物制剂。优选地,吉西他滨-[苯基-苯甲酰基-L-丙氨酰基)]-(R)-磷酸酯是基本上非对映异构纯的形式。
在本发明的第九方面,提供了一种试剂盒,所述试剂盒包括:
第一制剂,其包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
第二制剂,其包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
每mL 100mg至400mg(例如100mg至300mg)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。
第一制剂通常不包含活性成分。因此,其通常不包含吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。第一制剂可以在两个分开的容器中或在单个容器中提供。
本发明第九方面的试剂盒可用于通过中心管线静脉内施用吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。在施用第二制剂之前用第一制剂冲洗中心管线。通过避免活性制剂与水性介质(例如盐水冲洗溶液)的直接接触,这减轻了吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯在静脉内施用装置(即中心管线)中或入口处沉淀的风险。在施用第二制剂后,也可以用第一制剂冲洗中心管线。这进一步防止沉淀。
在本发明的第十方面,提供了一种试剂盒,所述试剂盒包括:
第一制剂,其包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
每mL 100mg至400mg(例如100mg至300mg)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;和
第二制剂,其包含:
20体积%至80体积%的DMA;
20体积%至60体积%的第一增溶剂;
10体积%至40体积%的第二增溶剂。
通常第二制剂不包含任何活性剂。该试剂盒可用于制备适合于外周施用的制剂。施用前长达48小时,例如长达24小时,用第二制剂稀释第一制剂以形成第三制剂。在施用前将第三制剂进一步用水性载体稀释至所需浓度以形成通过输注或注射对患者施用的制剂。为了实现在吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的沉淀方面稳定的外周施用制剂,通常希望包括增溶剂。然而,吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯在这种增溶剂的存在下可能易于降解。因此,在本发明的某些实施方案中,两阶段稀释法是实现用于外周施用的制剂的优选方法。
具体实施方式
在本说明书中,术语S-差向异构体或S-非对映异构体是指吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-(S)-磷酸酯。同样,在本说明书中,术语R-差向异构体或R-非对映异构体是指吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-(R)-磷酸酯。
术语“盐水”旨在表示氯化钠的水溶液。本发明的盐水溶液通常是无菌的,并且通常将是适合于用于肠胃外施用的浓度。合适的浓度为高达2w/v%或高达1w/v%。为了优化渗透压,可以在本发明的制剂中使用不同浓度的盐水,例如0.9%或0.45%。
本发明的制剂可用于治疗人体。它们可以用于治疗动物体。特别地,本发明的化合物可用于治疗商业动物例如家畜。或者,本发明的化合物可用于治疗伴侣动物,例如猫、狗等。
本发明的制剂中的化合物可以以药学上可接受的盐的形式获得、储存和/或施用。合适的药学上可接受的盐包括但不限于药学上可接受的无机酸如盐酸、硫酸、磷酸、硝酸、碳酸、硼酸、氨基磺酸和氢溴酸的盐,或药学上可接受的有机酸例如乙酸、丙酸、丁酸、酒石酸、马来酸、羟基马来酸、富马酸、苹果酸、柠檬酸、乳酸、粘酸、葡萄糖酸、苯甲酸、琥珀酸、草酸、苯乙酸、甲磺酸、甲苯磺酸、苯磺酸、水杨酸、磺胺酸、天冬氨酸、谷氨酸、依地酸(edeticacid)、硬脂酸,棕榈酸,油酸、月桂酸、泛酸、单宁酸、抗坏血酸和戊酸的盐。合适的碱盐由形成无毒盐的碱形成。实例包括铝、精氨酸、苄星、钙、胆碱、二乙胺、二醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨基丁三醇和锌盐。也可以形成酸和碱的半盐,例如半硫酸盐、半草酸盐和半钙盐。在某些实施方案中,特别是适用于s-差向异构体的那些实施方案,化合物是HCl盐或半草酸盐的形式。优选地,本发明的化合物不是盐的形式,即它们是游离碱/游离酸的形式。
对于本发明的上述制剂,所施用的剂量当然将随所使用的化合物,精确的施用模式,所需的治疗和所示的病症而变化。预期本发明化合物的剂量水平,剂量频率和治疗持续时间根据制剂和患者的临床适应症,年龄和共病态医学病症而不同。根据众所周知的药物原理,用于本发明的化合物的治疗目的的剂量大小将根据病症的性质和严重程度,动物或患者的年龄和性别以及施用途径,而自然变化。
药物制剂通常采取组合物的形式,其中活性化合物或其药学上可接受的盐与药学上可接受的佐剂,稀释剂或载体联合。本发明的制剂中的一种这样的药学上可接受的佐剂,稀释剂或载体是极性非质子溶剂。用于选择和制备合适的药物制剂的常规方法描述于例如“Pharmaceuticals-The Science of Dosage Form Designs”,M.E.Aulton,ChurchillLivingstone,1988中。
所述制剂可以适合于局部施用(例如皮肤或膀胱),用于口服施用或用于肠胃外(例如静脉内施用)。
本发明的药物制剂中使用的任何溶剂应当是药物级的,这意味着它们具有使得它们适于对人施用(例如静脉内施用)的杂质分布。
对于口服施用,本发明的制剂可以包括与佐剂或载体混合的活性化合物,所述佐剂或载体例如乳糖、蔗糖、山梨醇、甘露醇;淀粉,例如马铃薯淀粉、玉米淀粉或支链淀粉;纤维素衍生物;粘合剂,例如明胶或聚乙烯吡咯烷酮;和/或润滑剂,例如硬脂酸镁、硬脂酸钙、聚乙二醇、蜡、石蜡等,然后压制成片剂。如果需要包衣片剂,可以用浓缩的糖溶液包衣如上所述制备的芯,所述浓缩的糖溶液可以含有例如阿拉伯树胶、明胶、滑石粉和二氧化钛。或者,片剂可以用溶解在易挥发的有机溶剂中的合适的聚合物包衣。
对于软明胶胶囊的制备,活性化合物可以与例如植物油或聚乙二醇混合。硬明胶胶囊可以含有使用上述片剂赋形剂的化合物颗粒。也可将活性化合物的液体或半固体制剂填充入硬明胶胶囊中。
用于口服应用的液体制剂可以是糖浆或悬浮液的形式,例如含有本发明化合物的溶液,其余是糖以及乙醇、水、甘油和丙二醇的混合物。任选地,这样的液体制剂可以含有着色剂、调味剂、甜味剂(例如糖精)、防腐剂和/或羧甲基纤维素作为增稠剂或本领域技术人员已知的其它赋形剂。
然而,优选地,本发明的制剂用于肠胃外(例如静脉内)施用或用于稀释以形成用于胃肠外(例如静脉内)施用的制剂。对于肠胃外(例如静脉内)施用,活性化合物可以作为无菌水性或油性溶液施用。优选地,活性化合物作为无菌水溶液施用。
本发明的药物组合物将优选包含0.05-99%w(重量百分比)的吉西他滨-[苯基-苯甲酰基-L-丙氨酰基)]-磷酸酯,更优选0.05-80%w吉西他滨-[苯基-苯甲酰基-L-丙氨酰基)]-磷酸酯,还更优选0.10至70%w吉西他滨-[苯基-苯甲酰基-L-丙氨酰基)]-磷酸酯,甚至更优选0.10至50%w吉西他滨-[苯基-苯甲酰基-L-丙氨酰基)]-磷酸酯,所有重量百分比均基于总组合物。
已经显示环糊精在药物递送中具有广泛的应用(Rasheed等人,Sci.Pharm.,2008,76,567-598)。环糊精是环状寡糖的家族。它们充当“分子笼”,其封装药物分子并改变那些药物分子的性质,例如溶解性。环糊精包含(α-1,4)-连接的α-D-吡喃葡萄糖单元。环糊精可以含有6,7或8个吡喃葡萄糖单元(分别称为α-,β-和γ-环糊精)。用于药物制剂中的环糊精通常是β-环糊精。侧挂羟基可以用C1-C6取代或未取代的烷基烷基化。环糊精的实例是α-环糊精、β-环糊精、γ-环糊精、2-羟丙基-β-环糊精(HP-β-CD)、磺丁基醚β-环糊精钠盐、部分甲基化的β-环糊精。本发明的制剂还可以包括至少一种环糊精。
本发明还包括化合物的所有药学上可接受的同位素标记形式的制剂,其中一个或多个原子被具有相同原子序数但原子质量或质量数不同于自然界中通常存在的主要同位素的原子质量或质量数的原子替换。
适合包括在本发明化合物中的同位素的实例包括氢的同位素,例如2H和3H,碳的同位素,例如11C、13C和14C,氯的同位素,例如36Cl,氟的同位素,例如18F,碘的同位素,例如123I和125I,,氮的同位素,例如13N和15N,氧的同位素,例如15O、17O和18O,磷的同位素,例如32P,和硫的同位素,例如35S。
某些同位素标记的化合物,例如掺入放射性同位素的那些可用于药物和/或底物组织分布研究。放射性同位素氚,即3H,和碳-14,即14C,鉴于其易于掺入和现成的检测手段,特别可用于此目的。
用更重的同位素例如氘,即2H,进行的取代可以提供由更大的代谢稳定性例如增加的体内半衰期或降低的剂量需求带来的某些治疗优势,因此在一些情况下可能是优选的。
同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过类似于使用适当的同位素标记的试剂代替之前使用的非标记试剂所描述的那些方法的方法制备。
除了本发明的制剂之外,用于治疗癌症、淋巴瘤或白血病的治疗方法或制剂可以涉及常规外科手术或放射疗法或化疗。这种化疗可以包括施用一种或多种其它活性剂。
当另外的活性剂作为本发明的治疗方法的一部分施用时,这种组合治疗可以通过各个治疗组分的同时,相继或分开配量来实现。这种组合产品使用在上文所述的治疗有效剂量范围内的本发明化合物和在其批准的剂量范围内的一种或多种其它药物活性剂。
因此,本发明的药物制剂可以包含另一种活性剂。
一种或多种其他活性剂可以是一种或多种以下类别的抗肿瘤剂:
(i)抗增殖/抗肿瘤药及其组合,例如烷化剂(例如环磷酰胺、氮芥、苯达莫司汀(bendamustin)、美法仑(melphalan)、苯丁酸氮芥、白消安(busulphan)、替莫唑胺(temozolamide)和亚硝基脲);抗代谢药(例如吉西他滨和抗叶酸药如氟嘧啶如5-氟尿嘧啶和喃氟啶、雷替曲塞、甲氨蝶呤、培美曲塞、阿糖胞苷和羟基脲);抗生素(例如蒽环类药物如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、更生霉素和光神霉素);抗有丝分裂剂(例如长春花生物碱如长春新碱、长春花碱、长春地辛和长春瑞滨和紫杉烷类如紫杉醇和泰素帝和polo激酶(polokinase)抑制剂);蛋白酶体抑制剂,例如卡非佐米和硼替佐米;干扰素治疗;和拓扑异构酶抑制剂(例如表鬼臼毒素如依托泊苷和替尼泊苷、安吖啶、拓扑替康、米托蒽醌和喜树碱);
(ii)细胞静止素如抗雌激素(例如他莫昔芬,氟维司群,托瑞米芬,雷洛昔芬,屈洛昔芬和碘氧芬(iodoxyfene)),抗雄激素(例如比卡鲁胺、氟他胺、尼鲁米特和乙酸环丙孕酮),LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林),孕激素(例如醋酸甲地孕酮),芳香酶抑制剂(例如阿那曲唑、来曲唑、伏罗唑和依西美坦)和5α-还原酶抑制剂如非那雄胺;
(iii)抗侵入剂,例如达沙替尼和博舒替尼(SKI-606),和金属蛋白酶抑制剂,尿激酶纤溶酶原激活物受体功能抑制剂或类肝素酶抗体;
(ⅳ)生长因子功能的抑制剂:例如此类抑制剂包括生长因子抗体和生长因子受体抗体,例如抗erbB2抗体曲妥单抗[赫赛汀TM],抗EGFR抗体帕尼单抗,抗erbB1抗体西妥昔单抗,酪氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,例如吉非替尼、厄洛替尼和6-丙烯酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)-喹唑啉-4-胺(CI 1033)、erbB2酪氨酸激酶抑制剂如拉帕替尼);肝细胞生长因子家族的抑制剂;胰岛素生长因子家族的抑制剂;细胞凋亡的蛋白质调节器的调节剂(例如Bcl-2抑制剂);血小板衍生生长因子家族的抑制剂如伊马替尼和/或尼罗替尼(AMN107);丝氨酸/苏氨酸激酶的抑制剂(例如Ras/Raf信号传导抑制剂如法尼基转移酶抑制剂,例如索拉非尼、替吡法尼和洛那法尼),细胞通过MEK和/或AKT激酶信号传导的抑制剂,c-kit抑制剂,abl激酶抑制剂,PI3激酶抑制剂,Plt3激酶抑制剂,CSF-1R激酶抑制剂,IGF受体,激酶抑制剂;极光激酶抑制剂和细胞周期蛋白依赖性激酶抑制剂如CDK2和/或CDK4抑制剂;
(v)抗血管生成剂,例如抑制血管内皮生长因子的作用的那些,[例如抗血管内皮细胞生长因子抗体贝伐单抗(AvastinTM)];沙利度胺;来那度胺;和例如,VEGF受体酪氨酸激酶抑制剂如凡德他尼、瓦他拉尼、舒尼替尼、阿西替尼和帕唑帕尼;
(vi)基因治疗方法,包括例如替代异常基因如异常p53或异常BRCA1或BRCA2的方法;
(vii)免疫治疗方法,包括例如抗体治疗,例如阿仑珠单抗、利妥昔单抗、替伊莫单抗(ibritumomab tiuxetan)和奥法木单抗;干扰素如干扰素α;白细胞介素如IL-2(阿地白介素);白细胞介素抑制剂,例如IRAK4抑制剂;癌症疫苗,包括预防和治疗疫苗,例如HPV疫苗,例如加德西、希瑞适(Cervarix)、Oncophage和Sipuleucel-T(普罗文奇(Provenge));和toll样受体调节剂,例如TLR-7或TLR-9激动剂;
(viii)细胞毒性剂,例如氟达拉滨(fludara)、克拉屈滨、喷司他丁(NipentTM);(ⅸ)类固醇例如皮质类固醇,包括糖皮质激素和盐皮质激素,例如阿氯米松(aclometasone)、二丙酸阿氯米松、醛固酮、安西奈德、倍氯米松、二丙酸倍氯米松、倍他米松、二丙酸倍他米松、倍他米松磷酸钠、戊酸倍他米松、布地奈德、氯倍他松、丁酸氯倍他松、丙酸氯倍他索、氯泼尼醇、可的松、醋酸可的松、可的伐唑(cortivazol)、去氧皮甾酮、地奈德、去羟米松(desoximetasone)、地塞米松、地塞米松磷酸钠、地塞米松异烟酸酯、二氟可的松、氟氯奈德(fluclorolone)、氟甲松、氟尼缩松、氟轻松、醋酸氟轻松(fluocinoloneacetonide)、氟轻松醋酸酯(fluocinonide)、氟可丁(fluocortin butyl)、氟可的松、氟可龙(fluorocortolone)、氟可龙己酸酯、氟可龙三甲基乙酸酯、氟米龙、氟泼尼定、醋酸氟泼尼定、氟氢缩松、氟替卡松、丙酸氟替卡松、哈西奈德、氢化可的松、醋酸氢化可的松、丁酸氢化可的松、醋丙氢可的松、氢化可的松丁丙酸酯、戊酸氢化可的松、艾可米松、醋丁艾可米松、甲泼尼松、甲基强的松龙、莫米松、帕拉米松、糠酸莫米松一水合物、泼尼卡酯、泼尼松龙、泼尼松、替可的松、新戊酸替可的松、曲安西龙(triamcinolone)、曲安奈德(triamcinolone acetonide)、曲安西龙醇和它们各自的药学上可接受的衍生物。可以使用类固醇的组合,例如两种或更多种本段落中提及的类固醇的组合;
(x)靶向治疗,例如PI3Kd抑制剂,例如伊达利塞(idelalisib)和哌立福辛;或抑制PD-1,PD-L1和CAR T的化合物。
一种或多种其它活性剂也可以是抗生素。
作为说明性实例,吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的非对映异构体混合物可以根据WO2005/012327中描述的合成方法或在‘Application of ProTideTech否logy to Gemcitabine:A Successful Approach to Overcome th Key CancerResistance Mechanisms Leads to a New Agent(NUC-1031)in Clinical Development’;Slusarczyk et all;J.Med.Chem.;2014,57,1531-1542中描述的那些制备。
在以下条件下通过HPLC分离吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的(R)和(S)同分异构体:
设备:Agilent 1200TM系列,带DAD检测器
流速:1.0mL/min
柱:Chiralpak ADTM;250x 4.6mm ID(正相)
温度:环境
粒径:20μm
进料:溶于MeOH;10g/L
溶剂:正庚烷/IPA 10->50%IPA
(S)-差向异构体在8.6分钟洗脱,(R)-差向异构体在10.3分钟洗脱。
使用下面的表征方法可以表征各个同分异构体:在Bruker Avance 500光谱仪上在25℃下记录质子(1H),碳(13C),磷(31P)和氟(19F)NMR光谱。将光谱自动校准到氘代溶剂峰,并且所有13C NMR和31P NMR都是质子去耦的。通过HPLC分析,使用Varian Polaris C18-A(10μM)作为分析柱,在35分钟内进行从100/0至0/100的H2O/MeOH梯度洗脱,证实最终化合物的纯度>95%。HPLC分析通过Varian Prostar(LC Workstation-Varian prostar 335LC检测器)进行。
2'-脱氧-2′,2′-二氟-D-胞苷-5'-O-[苯基(苯甲酰氧基-L-丙氨酰基)]-(S)-磷酸酯3(ES+)m/z,实测值:(M+Na+)603.14。C25H27F2N4O8NaP理论值:(M+)580.47。
31P NMR(202MHz,MeOD):δP 3.66
1H NMR(500MHz,MeOD):δH 7.58(d,J=7.5Hz,1H,H-6),7.38–7.32(m,7H,ArH),7.26–7.20(m,3H,ArH),6.24(t,J=7.5Hz,1H,H-1’),5.84(d,J=7.5Hz,1H,H-5),5.20(AB系统,JAB=12.0Hz,2H,OCH2Ph),4.46–4.43(m,1H,H-5’),4.36–4.31(m,1H,H-5’),4.25–4.19(m,1H,H-3’),4.07–4.00(m,2H,H-4’,CHCH3),1.38(d,J=7.2Hz,3H,CHCH3)。
19F NMR(470MHz,MeOD):δF–118.0(d,J=241Hz,F),–120.24(宽d,J=241Hz,F)。
13C NMR(125MHz,MeOD):δC 174.61(d,3JC-P=5.0Hz,C=O,酯),167.63(C-NH2),157.74(C=O基),152.10(d,2JC-P=7.0Hz,C-Ar),142.40(CH-基),137.22(C-Ar),130.90,129.63,129.39,129.32,126.32(CH-Ar),124.51(d,1JC–F=257Hz,CF2),121.47,121.43(CH-Ar),96.67(CH-基),85.92(宽信号,C-1′),80.31(C-4′),71.27(明显t,2JC–F=23.7Hz,C-3′),68.03(OCH2Ph),65.73(d,2JC–P=5.30Hz,C-5’),51.66(CHCH3),20.42(d,3JC–P=6.25Hz,CHCH3)。
反相HPLC,用H2O/MeOH从100/0至0/100在35分钟内洗脱,显示非对映异构体的一个峰,tR=22.53min。
2'-脱氧-2′,2′-二氟-D-胞苷-5'-O-[苯基(苯甲酰氧基-L-丙氨酰基)]-(R)-磷酸酯4。
(ES+)m/z,实测值:(M+Na+)603.14。C25H27F2N4O8NaP理论值:(M+)580.47。
31P NMR(202MHz,MeOD):δP 3.83
1H NMR(500MHz,MeOD):δH 7.56(d,J=7.5Hz,1H,H-6),7.38–7.31(m,7H,ArH),7.23–7.19(m,3H,ArH),6.26(t,J=7.5Hz,1H,H-1’),5.88(d,J=7.5Hz,1H,H-5),5.20(s,2H,OCH2Ph),4.49–4.46(m,1H,H-5’),4.38–4.34(m,1H,H-5’),4.23–4.17(m,1H,H-3’),4.07–4.01(m,2H,H-4’,CHCH3),1.38(d,J=7.2Hz,3H,CHCH3).
19F NMR(470MHz,MeOD):δF–118.3(d,J=241Hz,F),–120.38(宽d,J=241Hz,F).
13C NMR(125MHz,MeOD):δC 174.65(d,3JC-P=5.0Hz,C=O,酯),167.65(C-NH2),157.75(C=O基),152.10(d,2JC-P=7.0Hz,C-Ar),142.28(CH-基),137.50(C-Ar),130.86,129.63,129.40,129.32,126.31(CH-Ar),124.50(d,1JC–F=257Hz,CF2),121.44,121.40(CH-Ar),96.67(CH-基),85.90(宽信号,C-1′),80.27(C-4′),71.30(明显t,2JC–F=23.7Hz,C-3′),68.02(OCH2Ph),65.50(C-5’),51.83(CHCH3),20.22(d,3JC–P=7.5Hz,CHCH3)。
反相HPLC,用H2O/MeOH从100/0至0/100在35分钟内洗脱,显示非对映异构体的一个峰,tR=21.87min
在本说明书的整个说明书和权利要求书中,词语“包括”和“含有”及其变体意味着“包括但不限于”,并且它们不旨在(并且不)排除其他部分、添加剂、组分、整数或步骤。在本说明书的整个说明书和权利要求书中,单数包括复数,除非上下文另有要求。特别地,在使用不定冠词时,除非上下文另有要求,否则说明书应被理解为考虑复数以及单数。
结合本发明的特定方面、实施方案或实施例描述的特征、整数、特性、化合物、化学部分或基团应理解为可应用于本文所述的任何其它方面、实施方案或实施例,除非与其不相容。在本说明书(包括任何所附权利要求,摘要和附图)中公开的所有特征,和/或如此公开的任何方法或过程的所有步骤可以以任何组合进行组合,除了其中至少一些这样的特征和/或步骤是相互排斥的组合。本发明不限于任何前述实施方案的细节。本发明延伸到本说明书(包括任何所附权利要求,摘要和附图)中公开的特征的任何新颖的一个或任何新颖的组合,或如此公开的任何方法或过程的步骤的任何新颖的一个或任何新颖的组合。
读者的注意力指向与本申请所关联的本说明书同时或先于本说明书提交的,并且用本说明书对公众公开的所有论文和文献,并且所有这些论文和文献的内容通过引用并入本文。
在本说明书中使用以下缩写:
API-活性药物成分,即吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯
DMA-二甲基乙酰胺 DMF-N,N-二甲基甲酰胺
DMSO-二甲基亚砜 IPA-异丙醇
NMP-N-甲基吡咯烷酮 PEG-聚乙二醇
实施例1-开发第一代制剂
通过WO2005/012327中描述的方法获得作为磷酸酯非对映异构体的混合物的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯(NUC-1031;2)。
实施例1的实验都使用作为磷酸酯非对映异构体的混合物的NUC-1031进行。
在一系列药学上可接受的溶剂系统中测定NUC-1031的溶解度。采用的方案如下:
制备小体积,1-2mL的每种溶剂体系,并加入一定量的所述化合物。将溶液搅拌约4小时,然后0.45μL膜过滤。然后通过HPLC测定确定滤液中所述化合物的浓度。
基于用于治疗胰腺癌的吉西他滨剂量方案,NUC-1031的分子量调整剂量为约3200mg,每周一次输注。作为所需溶解度水平的指示,采用500mL输注体积的名义目标,NUC-1031的所需溶解度在输注液中将>6mg/ml。然而,这种溶解度水平仅仅是一种指示,并且较低的溶解度仍然可以提供有效的疗法。
表1显示了吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯2在适于静脉内施用的一系列溶剂内的溶解度。
DMSO,DMA和NMP,所有这些都是极性非质子溶剂,提供稳定的溶液。
用水或盐水稀释1:1后,NMP和DMA没有显示任何沉淀的迹象。附录1显示NUC-1031在一系列稀释溶剂中的溶解度。DMA提供了足够的溶解性以施用所需的剂量。
表2显示了在稀释时NUC-1031在一系列溶剂中的溶解度
*含有0.13%Tween 80的0.9%盐水
稀释对DMA溶解度的影响
表2给出了水稀释对DMA溶解度的影响
表2
溶液 | 含量测定(mg/ml) | 沉淀>24小时 |
100%DMA | 592 | 否 |
95:5DMA:0.9%盐水 | 518 | 否 |
90:10DMA:0.9%盐水 | 483 | 否 |
80:20DMA:0.9%盐水 | 386 | 是 |
70:30DMA:0.9%盐水 | 339 | 是 |
60:40DMA:0.9%盐水 | 293 | 是 |
50:50DMA:0.9%盐水 | 66 | 是 |
进一步在更长时间内评价这些DMA溶液的物理稳定性,结果在表2a中给出
表2a
在上述实验之后,在临床测试中使用在5ml小瓶中的250mg NUC-1031在80:20DMA:0.9%盐水溶液中的制剂。该制剂在临床研究中提供了成功的治疗,但由于注射时疼痛,需要通过中心管线施用。
然后寻求允许通过外周静脉施用的制剂。
实施例2
实施例2至6的实验都使用NUC-1031的(S)-差向异构体进行。
混合
使用如表3所述的DMA和共赋形剂将NUC-1031混合成九种不同的制剂。
表3:NUC-1031制剂
使用以下方法混合API:
1.将DMA加入到在玻璃闪烁小瓶中的NUC-1031中。观察到API的即时溶解。
2.随后加入共赋形剂并使用涡旋混合器(Whirlmixer,Fisher brand)短暂混合(小于1分钟)。
发现这提供了比将NUC-1031溶解在DMA和共赋形剂的混合物中更有效的混合API的方法。在混合物中溶解NUC-1031仍然提供混合的API,但是该方法效率较低。
所有制剂是澄清的溶液,其保持稳定(通过眼睛)几天(>7天)。
观察到API有助于制剂体积。本研究中的典型制剂的体积为10.6-10.7mL(API浓度93-94mg/mL)。
实施例3-输注溶液研究
研究了NUC-1031制剂在输注溶液中的溶解度。
在临床中,其旨在将2g的API溶解在500mL的输注溶液(4mg/mL)中。将上述制剂稀释以产生具有稍高的API浓度(4.6-4.7mg/mL)的输注溶液,以表示最坏的情况。结果示于表4中。
表4:NUC-1031制剂在输注溶液中的溶解度(p=沉淀;c=澄清溶液)
选择制剂B和F用于输注袋研究。
实施例4-输注袋研究
表5:WFI输注袋中制剂B和F的溶解度(p=沉淀;c=澄清溶液)
上述结果显示可以产生包含DMA的制剂,其在用水性载体稀释时能够保持稳定足够长时间以施用于患者。可以稀释制剂直到DMA是相对较少的组分(1-2%),其中溶剂的大部分剩余物是水,而没有吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯从溶液中沉淀出来。
实施例5-进一步的制剂稳定性研究
制备和研究吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的(S)-同分异构体的一系列其他制剂(表6)。
表6.其它(S)-同分异构体制剂
*API的效力99.1%时作为因素考虑的实际API重量
过滤和填充
将制剂通过注射器过滤器手动过滤到2mL透明玻璃小瓶中。
在用13mm West塞密封之前用氮气冲洗填充的小瓶的顶部空间,并用铝外壳卷边。
所有小瓶在2-8℃下储存3天,之后进行T=0测试并进入稳定状态。在任何小瓶中没有观察到沉淀形成或胶凝。
稳定性
对于每种制剂,在25℃下评价四个小瓶的稳定性,在2-8℃下评价四个小瓶的稳定性。
外观-批次1-3和5-7在所有储存条件下在T=0和1个月符合描述“澄清无色溶液,不含可见颗粒”。批次4和8在所有储存条件下在T=0和1个月符合描述“澄清的黄色溶液,不含可见颗粒”。
含量测定和相关物质-使用NUC-1031的含量测定和相关物质方法ADP173vs.04分析样品。对于100mg/mL样品,使用容积式移液器将200μl转移至20mL容量瓶中,并用稀释剂稀释至体积。对于75mg/mL样品,使用容积式移液器将250μl转移到20mL容量瓶中,并用稀释剂稀释至体积。
表7含量测定2-8℃
表8含量测定25℃/60%相对湿度
然后将制剂稀释在0.45%盐水中,如表9所示评价稳定性。
表9制剂在0.45%盐水中的稳定性
结果表明,在0.45%盐水中稀释至3mg/mL的75mg/mL制剂(J-M)物理稳定24小时。在0.45%盐水中稀释至5mg/mL的100mg/mL制剂(N-Q)物理稳定长达6小时。通过不同的操作者在不同的日子评价制剂L和O,并且获得相同的结果。
输注溶液评价
在制剂如表10所示储存1个月后,通过用0.45%盐水稀释来评价制剂的长期稳定性。
表10.在0.45%盐水中的制剂T=1个月
结果表明,已经储存1个月,然后在0.45%盐水中稀释至3mg/mL的75mg/mL制剂(J-M)和100mg/mL制剂(N-Q)在24小时后是物理稳定的。
以表11所示的多种浓度在过滤的0.45%盐水中评价已经在25℃储存(2个月)和含有Kolliphor ELPTM的制剂。
表11在0.45%盐水中的NUC-1031制剂,T=2个月,25℃
结果表明,在0.45%盐水中稀释的制剂直至4.5mg/mL的浓度是物理稳定的。
实施例7-增溶剂的组合
制备其中存在增溶剂的组合的样品。
首先,通过将S-差向异构体溶解在DMA中,制备S-差向异构体在DMA中的250mg/mL溶液。然后根据表12通过加入所需的增溶剂组合将其稀释至100mg/mL溶液。
将制剂各自在0.45%盐水(pH 5.9)中稀释,得到4mg/mL,6mg/mL,8mg/mL和10mg/mL的溶液。搅拌后和在环境温度下储存3小时,6小时和24小时后检查溶液的外观。所有溶液,包括10mg/mL的溶液,在24小时后保持澄清无色溶液。然而,制剂3的10mg/mL溶液在26小时后显示出一些浑浊和颗粒形成。其它10mg/mL溶液的HPLC分析显示活性物质在溶液中的浓度和活性物质的纯度保持在预期水平。
因此,使用多于一种增溶剂的组合可以允许在更高浓度下形成NUC-1031的稳定溶液。
实施例8
用于配制NUC-1031的优选制剂系统如下:
在DMA和0.9%盐水的80:20(体积)混合物中形成NUC-1031(S-差向异构体,R差向异构体或其混合物)的250mg/mL溶液。该系统对于NUC-1031的长期储存和运输是足够稳定的。
该制剂可以经由中心管线(例如Hickman管线,PICC管线,Portacath)对患者静脉内施用。在施用包含NUC-1031的制剂之前和之后,通常用80:20(按体积)的DMA和0.9%盐水的混合物冲洗静脉内施用装置。这有助于减轻在与盐水冲洗接触时静脉内施用装置中NUC-1031的任何潜在沉淀的风险。
或者,当静脉内施用到外周静脉中是优选的施用方法时,将该第一制剂用DMA:80:ELP的40%:40%:20%混合物稀释至100mg/mL(例如将6.9mL的在80:20DMA:0.9%盐水中的250mg/mL NUC-1031加入到10.35mL的DMA:80:ELP稀释剂中)。对于S-差向异构体和R和S差向异构体的混合物,所得(第二)制剂已显示稳定长达5天。
然后通过用盐水将该第二制剂稀释至所需浓度来制备最终施用制剂。在pH范围(4.5,6.0和7.0)下在0.45%和0.9%盐水中稀释该制剂后48小时,4、8和10mg/mL的R和S差向异构体的混合物的溶液已经显示出稳定(对于NUC-1031的沉淀和对于NUC-1031的降解两者),条件是不搅拌混合物。所有这些溶液的摩尔渗透压浓度也已显示对于外周施用是可接受的。
Claims (25)
1.一种药物制剂,其包含:
吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;
极性非质子溶剂;和
任选的一种或多种药学上可接受的赋形剂。
2.权利要求1的制剂,其中所述极性非质子溶剂选自二甲基乙酰胺(DMA),二甲基亚砜(DMSO)和N-甲基吡咯烷酮(NMP)。
3.权利要求1的制剂,其中所述极性非质子溶剂是DMA。
4.权利要求1至3中任一项的制剂,其中所述制剂还包含水性载体。
5.权利要求4的制剂,其中所述水性载体是盐水。
6.权利要求4的制剂,其中所述水性载体是WFI。
7.权利要求1至6中任一项的制剂,其中所述制剂还包含增溶剂。
8.权利要求7的制剂,其中所述制剂包含两种或更多种增溶剂。
9.权利要求7或8的制剂,其中所述增溶剂或每种增溶剂是聚乙氧基化脂肪酸或其混合物。
10.权利要求1的制剂,其中所述制剂包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
100mg/mL至300mg/mL的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;任选地其中吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯是磷酸酯非对映异构体的混合物的形式。
11.权利要求1的制剂,其中所述制剂包含:
20体积%至80体积%的DMA;
30体积%至80体积%的增溶剂或多种增溶剂;和
50mg/mL至150mg/mL的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;任选地其中吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯是基本上非对映异构纯形式的(S)-磷酸酯差向异构体的形式。
12.权利要求11的制剂,其中所述制剂包含:
20体积%至80体积%的DMA;
20体积%至60体积%的第一增溶剂;
10体积%至40体积%的第二增溶剂;和
50mg/mL至150mg/mL的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。
13.权利要求1所述的制剂,其中所述制剂包含:
0.5体积%至7.5体积%的DMA;
0.5体积%至7.5体积%的增溶剂或多种增溶剂;
85体积%至99体积%的水性载体和
2.0mg/mL至12.0mg/mL的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;任选地其中吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯是基本上非对映异构纯形式的(S)-磷酸酯差向异构体的形式。
14.权利要求1至10,13和14中任一项的制剂,其用于静脉内施用。
15.权利要求1至4,7至9,11和12中任一项的制剂,其用于用水性载体稀释以形成用于静脉内施用的制剂。
16.根据前述任一项权利要求的制剂,其用于医疗用途。
17.权利要求1至15中任一项的制剂,其用于治疗癌症。
18.一种治疗癌症的方法,所述方法包括对有需要的受试者施用药物制剂,所述药物制剂包含:
吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;和
极性非质子溶剂。
19.权利要求18的方法,所述方法还包括以下步骤:
用水性载体稀释包含吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯和极性非质子溶剂的溶液,以提供用于输注或注射的制剂;和
通过输注或注射对受试者施用用于输注或注射的制剂。
20.权利要求19的方法,其中在稀释步骤后长达48小时进行施用步骤。
21.一种制备用于输注或注射的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的药物制剂的方法,所述方法包括:
用水性载体稀释包含吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯和极性非质子溶剂的溶液,以提供用于输注或注射的制剂。
22.一种制备吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的药物制剂的方法,所述方法包括:
将吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯溶解在极性非质子溶剂中以形成溶液;
向溶液中加入一种或多种其它药物赋形剂以形成吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯的药物制剂。
23.权利要求18至22中任一项的方法,其中所述极性非质子溶剂是DMA。
24.一种试剂盒,其包括:
第一制剂,其包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
第二制剂,其包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
100mg/mL至400mg/mL(例如100mg/mL至300mg/mL)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯。
25.一种试剂盒,其包括:
第一制剂,其包含:
30体积%至95体积%的DMA;
5体积%至50体积%的水性载体;和
100mg/mL至400mg/mL(例如100mg/mL至300mg/mL)的吉西他滨-[苯基-苯甲酰氧基-L-丙氨酰基)]-磷酸酯;和
第二制剂,其包含:
20体积%至80体积%的DMA;
20体积%至60体积%的第一增溶剂;
10体积%至40体积%的第二增溶剂。
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WO2005012327A2 (en) * | 2003-07-21 | 2005-02-10 | University College Cardiff Consultants Limited | Nucleotide phosphoramidates as anticancer agents |
CN102740833A (zh) * | 2009-11-20 | 2012-10-17 | 克拉维斯制药公司 | 吉西他滨衍生物的肠胃外制剂 |
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