CN1606455A - 包含抗egf受体抗体的冻干制剂 - Google Patents
包含抗egf受体抗体的冻干制剂 Download PDFInfo
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- CN1606455A CN1606455A CNA028256948A CN02825694A CN1606455A CN 1606455 A CN1606455 A CN 1606455A CN A028256948 A CNA028256948 A CN A028256948A CN 02825694 A CN02825694 A CN 02825694A CN 1606455 A CN1606455 A CN 1606455A
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Abstract
本发明涉及包含抗表皮生长因子受体(EGF受体)抗体的冻干药物制剂。该制剂的贮藏稳定性提高,甚至在升高的温度下,并且重构后可经胃肠外使用以治疗肿瘤。
Description
本发明涉及包含抗表皮生长因子受体(EGFR)抗体的稳定的冻干药物制剂,并涉及其制备。
各种体外和体内研究已显示:抗体对EGFR的阻断可在各种水平发挥抗肿瘤作用,例如通过抑制肿瘤细胞增殖、减少肿瘤介导的血管形成、诱导肿瘤细胞凋亡和增强放射治疗和常规化疗的毒性作用。
MAB c225(西妥昔单抗,Cetuximab)是临床上已经被证实与EGF受体结合的抗体。Cetuximab是嵌合抗体,其可变区为鼠源的,恒定区为人源的,并首次在Naramura等人,Cancer Immunol.Immuotherapy.1993,37:343-349和WO 96/40210 A1中述及。
MAB 425最初是在肿瘤细胞中过度表达的鼠源抗体,其对抗EGFR、特别是A431癌细胞的EGFR。其人源化和嵌合形式被公开于例如EP0531472 A1;Kettleborough等人,Protein Engineering 1991,4:773-783;Bier等人,Cancer Chemother.Pharmacol 2001,47:519-524;Bier等人,Cancer Immunol.Immuother 1998,46:167-173。本文中的EMD 72000是处于I/II期临床阶段的抗体(h425),其恒定区由κ和人γ-1链组成。
人抗-EGFR抗体可通过基因转殖鼠(XenoMouse)技术提供,如WO91/10741 A1、WO 94/02602 A1和WO 96/33735 A1所述。已通过该技术制备且目前正在进行临床试验的一种特殊抗体是ABX-EGF(Abgenix,Crit.Rev.Oncol.Hematol.2001,38:17-23;Cancer Research 1999,59:1236-43)。
其它抗EGFR抗体在例如EP 0586002 B1和J.Natl.Cancer Inst.1993,85:27-33中述及(MAB 528)。
和其它抗体一样,EGFR抗体也作为治疗用溶液经胃肠外使用。含有这些抗体的溶液的一个特殊问题是它们的聚集趋势和蛋白多聚体的形成。就可还原多聚体而言,这可归因于通过接近部分之间的相互作用而偶然形成的分子间二硫桥键。疏水性相互作用和随之形成不可还原多聚体也是可能的。此外,随后可导致蛋白质降解反应的脱酰胺反应也可发生。所述的变性反应特别发生于升高温度下的贮藏期间或经受剪切应力期间,如例如运输期间。因此,从各方面而言,液体制剂作为用于广泛使用的药物形式是低稳定性的。
常规的稳定抗体的方法是将含有抗体和助剂的溶液冻干。水的去除可减少分解产物和聚集物的形成。(Hsu等人,Dev.Biol.Stand.1991,74:255-267和Pikal等人,Dev.Biol.Stand.1991,74:21-27)。
WO 93/00807 A1描述了蛋白质冻干制剂,其为了稳定而包含聚乙二醇和糖。然而聚乙二醇在毒理学方面是有争议的,因此如果可能应避免在药物中使用,特别是如果预计将所述药物用于胃肠外施用。
WO 98/22136 A2描述了包含抗体、糖或氨基糖、氨基酸和表面活性剂的冻干制剂。尽管该制剂要求广泛地保护抗体,但是作为工作实施例所公开的制剂仅仅是那些包含抗乙型肝炎病毒(AK HBV)的单克隆抗体的制剂,和每种情况下包含抗L-选择蛋白(抗-L-选择蛋白)抗体的制剂和包含抗抗-L神经生长因子受体(抗-LNGFR)抗体的制剂。然而,包含AK HBV和抗-L-选择蛋白的制剂由最大抗体浓度分别为8mg/ml和7mg/ml的溶液制成,包含抗生长因子抗体即抗-LNGFR的制剂由仅包含0.25mg/ml抗体及另外的相同性质和数量的助剂成分的溶液制成。尽管包含抗-LNGFR的制剂具有低至20倍或更低的抗体含量并因此可预计产生相应较低量的降解产物,但是未公开与包含其它抗体的制剂相对照的稳定性数据。
本发明的目的是提供稳定的抗EGFR抗体的制剂。该制剂不应包含任何毒理学上不可接受的助剂,应当在增加的应力条件如升高的温度和空气湿度下稳定较长时间,并且应当可用水性溶剂重构以提供具有高活性成分含量的备用溶液。
令人惊讶的是,符合这些要求的制剂已通过将水溶液冻干而提供,所述水溶液除包含这些抗-EGFR抗体之一外,还包含糖或氨基糖、氨基酸和表面活性剂。因此本发明涉及包含糖或氨基糖、氨基酸和表面活性剂的稳定的单或多克隆抗体的冻干制剂,其特征在于所述抗体是抗表皮生长因子受体(EGFR)的抗体。
可存在的抗体为任何抗表皮生长因子的抗体,尤其是开篇提到的鼠源、人源或嵌合抗体和已经并可借助所述基因转殖鼠技术制备的人抗-EGFR抗体。本发明制剂中存在的抗-EGFR抗体优选Cetuximab或EMD 72000或与其相对应的鼠源、人源或嵌合抗体类似物之一。特别优选的是包含Cetuximab或EMD 72000作为抗体的制剂。
本发明的制剂在生理上耐受良好、可容易地制备、可精确调剂并且对于检测贮藏期间和反复冷冻和解冻期间的降解产物和聚集物而言是稳定的。其在冷藏温度(2-8℃)和室温(23-27℃,60%相对空气湿度(RAH))条件下贮藏可稳定至少3个月的时间至一到两年的时间。令人惊讶的是,本发明的制剂在升高的温度和较高的空气湿度水平、例如在40℃的温度和75%相对空气湿度下贮藏于所述时间段内也是稳定的。
冻干制剂可通过加入水性溶剂、例如注射用水或等渗水溶液以简单的方法重构,以提供不含可见颗粒的备用溶液。重构的溶液在约5天的时间内是稳定的,但特别优选于4小时内使用。
使用水性溶剂对本发明的制剂进行重构优选使含抗体的溶液制剂的pH为5至8、优选6.0至7.4、特别优选pH为约7.2,且重量克分子渗透浓度为250至350mOsmol/kg。由此,重构的制剂可直接经静脉内、动脉内、还可经皮下施用,基本上无痛觉。此外,还可将所述制剂加入输注溶液中,如例如葡萄糖溶液、等渗盐溶液或林格氏液,所述溶液还可包含其它活性成分,从而也使得能够施用较大量的活性成分。
根据本发明的一个优选实施方案,冻干药物制剂实际上由抗体、糖或氨基糖、氨基酸、缓冲剂和表面活性剂组成。
本发明的制剂使得能够制备浓度符合临床需要的抗体溶液。优选的抗体溶液的抗体浓度为约0.5至25mg/ml、特别优选5至20mg/ml、非常特别优选10至15mg/ml。因此,本发明的制剂使得能够制备备用制剂,其抗体浓度显著高于所述WO 98/22136 A2中制剂的抗体浓度。
本发明制剂中所使用的糖可为单糖、二糖和三糖。可提及的单糖的实例有葡萄糖、甘露糖、半乳糖、果糖和山梨糖,可提及的二糖的实例有蔗糖、乳糖、麦芽糖和海藻糖,可提及的三糖的实例有棉子糖。优选蔗糖、乳糖、麦芽糖和海藻糖,特别优选蔗糖。
也可能存在氨基糖,即含有伯、仲或叔氨基或酰化氨基(-NH-CO-R)替代羟基的单糖。用于本发明的目的时,此处特别优选的是葡糖胺、N-甲基-葡糖胺、半乳糖胺和神经氨糖酸。
糖/氨基糖以这样的量存在于本发明的制剂中:其在用建议体积的溶剂重构后得到的溶液中的浓度为约1至200mg/ml。糖在重构溶液中的浓度优选为30至65mg/ml。
根据本发明所使用的适宜的氨基酸为碱性氨基酸,如例如精氨酸、组氨酸、鸟氨酸、赖氨酸,特别地,氨基酸优选以它们的无机盐形式使用(优选以盐酸盐形式即氨基酸盐酸盐)。在使用游离氨基酸的情况下,所需pH通过加入适宜的生理上耐受的缓冲物质而调节,如例如有机或无机酸,如柠檬酸或磷酸、硫酸、乙酸、甲酸或其盐。优选柠檬酸盐和磷酸盐,用它们获得了特别稳定的冻干物质。
优选的氨基酸为精氨酸、赖氨酸和鸟氨酸。此外,也可能使用酸性氨基酸如例如谷氨酸和天冬氨酸,或中性氨基酸如例如异亮氨酸、亮氨酸和丙氨酸,或芳香族氨基酸如例如苯丙氨酸、酪氨酸或色氨酸。本发明制剂中的氨基酸含量为1至100mg/ml、优选1至50mg/ml、特别优选3至30mg/ml(在每种情况下均基于重构溶液)。
可使用的表面活性剂是所有通常用于药物制剂中的表面活性剂,优选聚山梨酯和聚氧乙烯-聚氧丙烯聚合物。特别优选聚氧乙烯(20)山梨糖醇酐单月桂酸酯和聚氧乙烯(20)山梨糖醇酐单油酸酯。根据本发明,制剂包含以重量计0.001至1%、优选以重量计0.005至0.1%并特别优选以重量计约0.01%的表面活性剂(在每种情况下均基于重构溶液)。
如果本发明的制剂包含缓冲剂,则其大体上可为任何生理上耐受的适宜于用来调节所需pH的物质。缓冲物质的量以如下方式选择:例如用注射用水将冻干制剂重构后,所得水溶液的缓冲剂浓度为5mmol/l至20mmol/l、优选约10mmol/l。优选的缓冲剂为柠檬酸盐缓冲剂或磷酸盐缓冲剂。适宜的磷酸盐缓冲剂为磷酸的单-和/或二钠和-钾盐如磷酸氢二钠或磷酸二氢钾的溶液,以及钠盐和钾盐混合物如例如磷酸氢二钠和磷酸二氢钾混合物的溶液。
如果重构溶液通过抗体和起稳定作用的助剂的渗透特性而还未达到等渗,则还可以存在建立等渗性所必需浓度的等渗剂、优选生理上耐受的盐如例如氯化钠或氯化钾,或生理上耐受的多元醇如例如葡萄糖或甘油。
此外,本发明的冻干物质可包含其它生理上耐受的助剂,如例如抗氧化剂如抗坏血酸或谷胱甘肽,防腐剂如苯酚、间甲酚、对羟基苯甲酸甲酯或丙酯、氯代丁醇、硫柳汞或苯扎氯铵,聚乙二醇(PEG)如PEG3000、3350、4000或6000,或环糊精如羟丙基-β-环糊精、磺基丁基乙基-β-环糊精或γ环糊精。
本发明的制剂可如下制备:制备包含Cetuximab或EMD 72000作为活性成分以及糖或氨基糖、氨基酸和表面活性剂作为添加剂、并且如果需要还包含药用助剂的水性配制物,随后将该溶液冻干。
水性配制物可通过将所述助剂加至包含Cetuximab或EMD 72000的溶液中而制备。为此,优选将规定体积的包含规定浓度的所述其它助剂的储备溶液加至所制得的含有规定浓度的Cetuximab或EMD 72000的溶液中,并且如果需要,将该混合物用水稀释至预先计算的浓度。或者,所述助剂也可以以固体形式加至包含Cetuximab的初始溶液中。如果Cetuximab或EMD 72000呈固体形式、例如呈冻干物质的形式,则本发明的制剂可如下制备:首先将各种抗体溶解于水或包含一种或多种其它助剂的水溶液中,随后加入各种情况下所需量的包含其它助剂的储备溶液、固体形式的其它助剂和/或水。Cetuximab或EMD 72000还可有利地直接溶于包含所有其它助剂的溶液中。
本发明制剂中存在的一种或多种助剂可有利地已在特定EGFR抗体的制备方法过程中或结束时被加入。这可优选通过将Cetuximab或EMD72000在其制备后所进行的纯化的最后一步中直接溶解于包含一种、多于一种或所有其它助剂的水溶液中进行。为制备所述制剂,则各种其它一种或多种成分在各种情况下仅需以较小的量加入和/或根本无需加入。特别优选将各种成分在其制备后所进行的纯化的最后一步中直接溶解于包含所有其它助剂的水溶液中,直接得到待冻干的溶液。
将包含各个抗体和助剂的溶液的pH调节至5至8、无菌过滤并冻干。
实施例阐述本发明而非对其进行限制。
如果使用10mmol/l pH 7.2的磷酸钠缓冲剂或磷酸钾缓冲剂,则其包含2.07g/l的磷酸氢二钠七水合物和0.31g/l的磷酸二氢钠一水合物,或1.220g/l的磷酸氢二钾和0.4050g/l的磷酸二氢钾。
实施例1
自水溶液得到冻干物质,所述水溶液包含:
10mg/ml的EMD 72000
10mmol/l的磷酸钾缓冲剂pH7.2
17mmol/l的精氨酸
以重量计3%的蔗糖
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单月桂酸酯
以重量计0.4%的PEG 6000
通过将规定体积的包含规定浓度的各种助剂的水溶液混合而进行制备。使用了以下溶液:
溶液A(活性成分溶液),包含:
20mg/ml的EMD 72000
10mmol/l的磷酸钾缓冲剂pH7.2
溶液B(缓冲剂/盐溶液):
10mmol/l的磷酸钾缓冲剂pH7.2
以重量计6%的蔗糖
以重量计0.02%的聚氧乙烯(20)山梨糖醇酐单月桂酸酯
34mmol/l的精氨酸
以重量计0.8%的聚乙二醇6000
为制备本发明的制剂,将相同体积的溶液A和溶液B彼此合并。
将所制备的溶液在包装前无菌过滤。每瓶填装2ml溶液。随即用塞子将瓶不完全密封并冻干。冻干后,将瓶密封并卷边。
实施例2
自水溶液得到冻干物质,所述水溶液包含:
10mg/ml的EMD 72000
10mmol/l的磷酸钾缓冲剂pH7.2
14mmol/l的精氨酸
以重量计3%的蔗糖
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单月桂酸酯
通过将规定体积的包含规定浓度的各种助剂的水溶液混合而进行制备。使用了以下溶液:
溶液A(活性成分溶液),包含:
20mg/ml的EMD 72000
10mmol/l的磷酸钾缓冲剂pH7.2
溶液B(缓冲剂/盐溶液):
10mmol/l的磷酸钾缓冲剂pH7.2
以重量计6%的蔗糖
以重量计0.02%的聚氧乙烯(20)山梨糖醇酐单月桂酸酯
34mmol/l的精氨酸
为制备本发明的制剂,将相同体积的溶液A和溶液B彼此合并。
将所制备的溶液在包装前无菌过滤。每瓶填装20ml溶液。随即用塞子将瓶不完全密封并冻干。冻干后,将瓶密封并卷边。
实施例3
自水溶液得到冻干物质,所述水溶液包含:
15mg/ml的Cetuximab
5mmol/l的柠檬酸盐
100mmol/l的精氨酸
以重量计4%的甘露醇
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单油酸酯
通过将规定体积的包含规定浓度的各种助剂的水溶液混合而进行制备。使用了以下溶液:
溶液A(活性成分溶液),包含:
19mg/ml的Cetuximab
5mmol/l的柠檬酸盐
127mmol/l的精氨酸
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单油酸酯溶液B(缓冲剂/盐溶液):
5mmol/l的柠檬酸盐
以重量计19.05%的甘露醇
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单油酸酯
为制备本发明的制剂,将7.9ml溶液A和2.1ml溶液B彼此合并。
将所制备的溶液在包装前用无菌过滤器过滤。每瓶用移液管填装2ml溶液。随即用塞子将瓶不完全密封并冻干。冻干后,将瓶密封并卷边。
实施例4
自水溶液得到冻干物质,所述水溶液包含:
15mg/ml的Cetuximab
5mmol/l的柠檬酸盐
100mmol/l的精氨酸
以重量计1.5%的蔗糖
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单月桂酸酯
通过将规定体积的包含规定浓度的各种助剂的水溶液混合而进行制备。使用了以下溶液:
溶液A(活性成分溶液),包含:
19mg/ml的Cetuximab
5mmol/l的柠檬酸盐
127mmol/l的精氨酸
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单油酸酯溶液B(缓冲剂/盐溶液):
5mmol/l的柠檬酸盐
7.1%的蔗糖
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单油酸酯
为制备本发明的制剂,将7.9ml溶液A和2.1ml溶液B彼此合并。
将所制备的溶液在包装前用无菌过滤器过滤。每瓶用移液管填装2ml溶液。随即用塞子将瓶不完全密封并冻干。冻干后,将瓶密封并卷边。
实施例5
自水溶液得到冻干物质,所述水溶液包含:
15mg/ml的Cetuximab
10mmol/l的磷酸钾缓冲剂pH 7.2
14mmol/l的L-精氨酸盐酸盐
88mmol/l的蔗糖
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单月桂酸酯
用磷酸调节pH至7.5
通过将规定体积的包含规定浓度的各种助剂的水溶液混合而进行制备。使用了以下溶液:
溶液A(活性成分溶液),包含:
25mg/ml的Cetuximab
10mmol/l的磷酸钾缓冲剂pH7.2
注射用水
溶液B(缓冲剂/盐溶液):
10mmol/l的磷酸钾缓冲剂pH7.2
35.6mmol/l的L-精氨酸盐酸盐
219mmol/l的蔗糖
以重量计0.025%的聚氧乙烯(20)山梨糖醇酐单月桂酸酯
用磷酸调节pH至7.5
为制备本发明的制剂,将6ml溶液A和4ml溶液B彼此合并。
将所制备的溶液在包装前用无菌过滤器过滤。每瓶用移液管填装2ml溶液。随即用塞子将瓶不完全密封并冻干。冻干后,将瓶密封并卷边。
实施例6(对比制剂1)
水溶液,包含:
5mg/ml的Cetuximab
10mmol/l的磷酸钠缓冲剂pH7.2
145mmol/l的氯化钠
通过将规定体积的包含规定浓度的各种助剂的水溶液混合而进行制备。使用了以下溶液:
溶液A(活性成分溶液),包含:
10mg/ml的Cetuximab
10mmol/l的磷酸钠缓冲剂pH7.2
145mmol/l的氯化钠
(该溶液通过在活性成分制备后进行的活性成分色谱纯化的最后一步中用溶液B自色谱柱中将活性成分洗脱而获得。)
溶液B(缓冲剂/盐溶液):
和溶液A一致,但不包含活性成分。
为制备该对比制剂,将溶液A和B各10ml彼此合并。
实施例7(对比制剂2)
水溶液,包含:
5mg/ml的Cetuximab
10mmol/l的磷酸钠缓冲剂pH7.2
45mmol/l的氯化钠
以重量计0.01%的聚氧乙烯(20)山梨糖醇酐单油酸酯
通过将规定体积的包含规定浓度的各种助剂的水溶液混合而进行制备。使用了以下溶液:
溶液A(活性成分溶液),包含:
9.7mg/ml的Cetuximab
10mmol/l的磷酸钠缓冲剂pH7.2
145mmol/l的氯化钠
(该溶液通过在活性成分制备后进行的活性成分色谱纯化的最后一步中用溶液B自色谱柱中将活性成分洗脱而获得。)
溶液B(缓冲剂/盐溶液)
和溶液A一致,但不包含活性成分。
溶液C(聚氧乙烯山梨糖醇酐脂肪酸酯溶液)
和溶液B一致,但另外包含以重量计1%的聚氧乙烯(20)山梨糖醇酐单油酸酯
为制备该对比制剂,将10ml溶液A、9.8ml溶液B和0.2ml溶液C彼此合并。
将所制备的溶液在包装前用无菌过滤器过滤。每瓶用移液管填装2ml溶液。随即用塞子将瓶不完全密封并冻干。冻干后,将瓶密封并卷边。
制剂的稳定性研究
用应力实验对实施例1和2的本发明制剂的稳定性进行检验。为此,将所制备的冻干物质在40℃和75%相对空气湿度(RAH)下贮藏。将所述制剂贮藏一定时间并用适宜的分析方法进行分析。抗体中可能的不稳定性主要体现在聚集物的形成和降解产物的形成。降解产物优选通过凝胶电泳(十二烷基硫酸钠/聚丙烯酰胺凝胶电泳(SDS-PAGE)和等离子聚焦(IEF))进行检测,而目测和浊度测量用于检测可见聚集物,采用空间排阻色谱法(HPLC-SEC)检测可溶聚集物。ELISA(酶联免疫吸附试验)实验同样被用于评价所述制剂,其用以检验完整性和结合受体的能力。
表1和2中的结果清楚地证实了所制备制剂的性质和稳定性,甚至证实了在升高的贮藏温度和升高的相对空气湿度下(40℃/75%RAH)的性质和稳定性。
贮藏时间(月) | pH | ELISA(相对滴度) | SDS-PAGE[IG单体%] | SE-HPLC | |
非还原 | 还原 | ||||
温度2-8℃ | |||||
0 | 7.11 | 1.00 | 100 | 100 | 100 |
6 | 7.14 | 1.01 | 99.3 | 100 | 99.6 |
12 | 7.15 | 1.04 | 99.9 | 99.1 | 99.7 |
24 | 7.16 | 1.03 | 100 | 100 | 100 |
温度25℃,60%相对湿度 | |||||
6 | 7.17 | 1.03 | 99.1 | 99.0 | 99.5 |
12 | 7.15 | 1.01 | 98.7 | 99.1 | 99.6 |
24 | 7.16 | 1.03 | 100 | 100 | 99.5 |
温度40℃,75%相对湿度 | |||||
6 | 7.17 | 1.10 | 98.8 | 98.2 | 99.3 |
12 | 7.15 | n.m. | n.m. | n.m. | n.m. |
24 | 7.16 | 0.98 | 100 | 100 | 99.3 |
表1:实施例1的制剂的稳定性
贮藏时间(周) | pH | ELISA(相对滴度) | SDS-PAGE[IG单体%] | SE-HPLC | |
非还原 | 还原 | ||||
温度2-8℃ | |||||
0 | 7.20 | 0.97 | 100 | 100 | 99.33 |
13 | 7.23 | 1.00 | n.m. | n.m. | 99.24 |
26 | 7.21 | 1.02 | 99.47 | 99.57 | 99.27 |
温度25℃,60%相对湿度 | |||||
13 | 7.24 | 1.05 | n.m. | n.m. | 99.22 |
26 | 7.24 | 0.97 | 99.47 | 99.64 | 99.21 |
温度40℃,75%相对湿度 | |||||
13 | 7.23 | 1.04 | n.m. | n.m. | 99.08 |
26 | 7.25 | 0.97 | 99.61 | 99.62 | 98.85 |
表2:实施例2的制剂的稳定性
实施例3至7的本发明制剂的稳定性同样用应力实验进行检验。为此,将含有实施例3至5的溶液的瓶和用于对照目的的含有实施例6至7的溶液的瓶贮藏于25℃和60%相对空气湿度(RAH)和40℃和75%RAH条件下。贮藏前和规定的贮藏时间后,每种情况下取3瓶在冷光源直接照明下进行目测评价,并且测定溶液在350和550nm处的吸收,其代表浊度的量度。此外,每种情况各取3瓶并借助HPLC凝胶过滤对Cetuximab和分解产物的含量进行分析。
用乙腈/水95/5(v/v)梯度(B)和pH2.5的缓冲溶液/乙腈95/5(v/v)(A)作为洗脱剂进行HPLC色谱研究。色谱柱:LiChroCHART125-2 HPLCcartridge;Super-spher60 RP-select B,流速:0.3ml/min,在210nm处检测。
所述稳定性研究的结果见表3。
实验溶液 | 在40℃/75%RAH下贮藏[周] | Cetuximab[%] | 聚集物[%] | 分解产物[%] | 浊度λ=350nm | 浊度λ=550nm | 目测评价 |
实施例3 | 0 | 99.30 | 0.20 | 0.51 | 0.0200 | 0.0055 | 澄清 |
实施例3 | 4 | 99.04 | 0.62 | 0.34 | 0.0214 | 0.0029 | 澄清 |
实施例3 | 8 | 98.54 | 1.12 | 0.34 | 0.0224 | 0.0020 | 澄清 |
实施例3 | 13 | 98.43 | 1.18 | 0.40 | 0.0246 | 0.0019 | 澄清 |
实施例4 | 0 | 99.33 | 0.19 | 0.48 | 0.0198 | 0.0045 | 澄清 |
实施例4 | 4 | 99.11 | 0.40 | 0.50 | 0.0174 | 0.0025 | 澄清 |
实施例4 | 8 | 99.19 | 0.44 | 0.38 | 0.0181 | 0.0021 | 澄清 |
实施例4 | 13 | 99.20 | 0.45 | 0.36 | 0.0172 | 0.0014 | 澄清 |
实施例5 | 0 | 99.58 | 0.19 | 0.04 | 0.0195 | 0.0050 | 澄清 |
实施例5 | 4 | 99.51 | 0.24 | 0.25 | 0.0165 | 0.0028 | 澄清 |
实施例5 | 8 | 99.56 | 0.22 | 0.22 | 0.0156 | 0.0023 | 澄清 |
实施例5 | 13 | 99.52 | 0.28 | 0.20 | 0.0187 | 0.0045 | 澄清 |
实施例6 | 0 | 99.69 | 0.62 | 0.15 | 0.0130 | 0.0021 | 澄清 |
实施例6 | 4 | 92.00 | 0.84 | 7.38 | 0.0232 | 0.0047 | 浑浊 |
实施例6 | 8 | 89.94 | 1.39 | 8.68 | 0.0338 | 0.0044 | 浑浊 |
实施例6 | 13 | 86.66 | 3.26 | 10.11 | 0.0403 | 0.0061 | 浑浊 |
实施例7 | 0 | 99.72 | 0.17 | 0.11 | 0.0128 | 0.0016 | 澄清 |
实施例7 | 4 | 98.60 | 0.56 | 0.84 | 0.0200 | 0.0022 | 澄清 |
实施例7 | 8 | 96.49 | 2.21 | 1.32 | 0.0280 | 0.0033 | 澄清 |
实施例7 | 13 | 86.46 | 4.84 | 8.73 | 0.0382 | 0.0036 | 浑浊 |
表3
此外,图1至5显示了实施例4的本发明制剂和对比制剂1和2在40℃和75%RAH下贮藏规定时间后的各种稳定性研究的结果对比。在进行每次试验前,将实施例4的冻干制剂用注射用水重构以获得水溶液,所述水溶液与用于经冻干制备冻干制剂的起始溶液相比包含三倍量的水。
图1显示对比制剂1和2与实施例4的本发明制剂相比活性成分含量的降低,以HPLC-SEC中的单体含量测量。
图2显示对比制剂1和2与实施例4的本发明制剂相比降解产物的增加,以HPLC-SEC测量。
图3显示对比制剂1和2与实施例4的本发明制剂相比聚合物的增加,以HPLC-SEC测量。
图4显示对比制剂1和2与实施例4的本发明制剂相比在λ=350nm处的光密度的增加。
图5显示对比制剂1和2与实施例4的本发明制剂相比在λ=550nm处的光密度的增加。
结果清楚地显示:与液体对比溶液相比,本发明组合物的稳定性显著增强。
Claims (15)
1.包含糖或氨基糖、氨基酸和表面活性剂的单或多克隆抗体的冻干药物制剂,其特征在于:所述抗体是抗表皮生长因子受体(EGF受体)抗体。
2.权利要求1的冻干药物制剂,其特征在于:所述抗体是Cetuximab或EMD 72000或与其相对应的鼠源、人源或嵌合抗体类似物之一。
3.权利要求2的冻干药物制剂,其特征在于:所述抗体是Cetuximab或EMD 72000。
4.权利要求1至3的一项或多项的冻干药物制剂,其基本上由抗体、糖或氨基糖、氨基酸、缓冲剂和表面活性剂组成。
5.权利要求1至4的一项或多项的冻干药物制剂,其特征在于:所述糖是单糖、二糖或三糖,优选蔗糖、麦芽糖或海藻糖。
6.权利要求1至5的一项或多项的冻干药物制剂,其特征在于:所述氨基糖是葡糖胺、N-甲基-葡糖胺、半乳糖胺或神经氨糖酸。
7.权利要求1至6的一项或多项的冻干药物制剂,其特征在于:所述氨基酸是碱性、酸性或中性氨基酸,优选精氨酸、赖氨酸或鸟氨酸。
8.权利要求1至7的一项或多项的冻干药物制剂,其特征在于:所述表面活性剂是聚山梨酯或聚氧乙烯-聚氧丙烯聚合物。
9.权利要求8的冻干药物制剂,其特征在于:所述表面活性剂是聚氧乙烯山梨糖醇酐脂肪酸酯聚氧乙烯(20)山梨糖醇酐单油酸酯或聚氧乙烯(20)山梨糖醇酐单月桂酸酯。
10.权利要求1至9的一项或多项的冻干药物制剂,其特征在于:还存在建立等渗性所必需浓度的等渗剂。
11.权利要求10的冻干药物制剂,其特征在于:氯化钠作为等渗剂存在。
12.通过将权利要求1至11的一项或多项的冻干物质用水性溶剂重构可获得的单或多克隆抗体的水性药物制剂。
13.权利要求12的水性药物制剂,其特征在于:所述溶液的pH为5至8、优选6至7.4。
14.权利要求13的水性药物制剂,其特征在于:所述溶液的pH为约7.2。
15.制备权利要求1至11的一项或多项的冻干药物制剂的方法,其特征在于:制备包含Cetuximab或EMD 72000作为活性成分并包含糖或氨基糖、氨基酸和表面活性剂作为添加剂、并且如果需要还包含其它药用助剂的水性配制物,随后将溶液冻干。
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