CN111375057A - 一种包含抗Her2单克隆抗体的药物配制剂 - Google Patents
一种包含抗Her2单克隆抗体的药物配制剂 Download PDFInfo
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- CN111375057A CN111375057A CN201811628635.0A CN201811628635A CN111375057A CN 111375057 A CN111375057 A CN 111375057A CN 201811628635 A CN201811628635 A CN 201811628635A CN 111375057 A CN111375057 A CN 111375057A
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Abstract
本发明提供了一种包含抗Her2单克隆抗体的药物配制剂,所述药物配制剂包括:抗Her2单克隆抗体、缓冲液、等渗调节剂、蛋白保护剂和表面活性剂等成分。本品在室温条件或较高温度下存储一定时间,经检测表明,主要检测项均无明显变化,且所有检测结果均符合本品现行质量标准要求。本发明所得药物配制剂,在不高于50°C储存条件下,可以保证四周以上的有效期。与原研药物制剂相比,该药物配制剂具有更好的稳定性,更利于抗体稳定。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种包含抗Her2单克隆抗体的药物配制剂。
背景技术
帕妥珠单抗(Pertuzumab,商品名:Perjeta)是一种靶向HER2的重组人源化单克隆抗体。该药物于2012年被美国FDA首次批准上市,用于与曲妥珠单抗和多西紫杉醇联合用药,治疗无既往抗Her2治疗或化疗治疗转移性疾病历史的Her2阳性转移性乳腺癌患者。
蛋白质(单克隆抗体等)类药物制剂通常包括活性成分、缓冲成分、等渗调节剂及稳定剂等。糖类或醇类是常用的药物添加辅料,主要起到稳定剂的作用,具有稳定性好、人体不蓄积、安全等特点,同时可以帮助生物大分子药物维持其分子结构和生物活性,有利于药物的长期稳定性。氯化钠作为等渗调节剂,在蛋白溶液中加入少量氯化钠,会增加蛋白质分子表面的电荷,增强蛋白质分子与水分子的作用,从而增大蛋白质在水溶液中的溶解度。表面活性剂是抗体类药物制剂中常用的药用辅料,可以降低气-液、固-液界面的表面张力,从而减少蛋白在两相界面的聚集,有助于维持生产、运输等过程中的稳定性。
在蛋白质(单克隆抗体等)类药物制剂研究过程中,与药物的稳定性相关的检测技术包括基础的理化性质检测、蛋白质纯度检测、颗粒检测及蛋白质活性检测等。其中基础的理化性质检测项包括外观、pH值、蛋白质浓度及渗透压摩尔浓度等,蛋白质纯度检测包括分子异构体(SEC-HPLC,SDS-PAGE)及电荷异构体(CEX-HPLC,cIEF)检测等,颗粒检测通常使用亚可见颗粒的成像与计数Flowcam、动态光散射DLS及光阻法等。
蛋白质(单克隆抗体等)类药物制剂适合于非肠道给药,包括静脉内、肌肉内、腹膜内或皮下注射等给药方式。液体制剂中蛋白易形成聚体或颗粒,这一直是蛋白类药物制剂的一个难题。通常的药物制剂中,包含的蛋白质特别是单克隆抗体类药物,很难在储藏期内保持良好的物理稳定性、化学稳定性和生物稳定性。
发明内容
为了提供满足制药工业需求的具有良好稳定性的蛋白制剂,本发明提供一种新的包含抗Her2单克隆抗体的药物配制剂。通过高通量筛选和配方优化研究,获得稳定性较高的蛋白制剂。
筛选缓冲液体系,考察其对蛋白稳定性的影响。设计单因素试验,考察不同离子强度、蛋白质浓度、pH值以及稳定剂种类、表面活性剂种类对蛋白稳定性的影响。
为了解决上述技术问题,本发明采取的技术方案之一为:一种包含抗Her2单克隆抗体的药物配制剂,所述药物配制剂包括:抗Her2单克隆抗体、缓冲液、蛋白保护剂和表面活性剂。
其中所述“药物配制剂”为本领域常规药物配制剂,一般是指如下形式的制备物,使得允许活性组分的生物学活性有效,受试者适应性好,满足临床需求且不会引起不良反应,此类配制剂是无菌的。所述药物配制剂还可能包括药学可接受的赋形剂(媒介或添加剂),药学可接受的赋形剂为那些可合理施用于受试哺乳动物以提供有效剂量的辅料组分。
所述药物配制剂的剂型为本领域常规剂型,较佳地包括注射用液体制剂或冻干制剂等。所述注射用液体制剂较佳地包括皮下注射制剂、静脉注射制剂、腹腔给药制剂、肌肉注射制剂、静脉/皮下注射制剂或玻璃体注射制剂等。所述注射用液体制剂较佳地包括水针注射制剂、预充针注射制剂等,优选地为水针注射制剂,该水针注射制剂可以用于静脉注射。
其中所述抗Her2单克隆抗体为本领域常规抗Her2单克隆抗体,更佳地为重组的抗Her2全人源单克隆抗体,所述抗Her2单克隆抗体较佳地为帕妥珠单抗(Pertuzumab),优选地为本发明制备所得HLX11单克隆抗体。该单克隆抗体的轻链氨基酸序列如序列表中SEQID NO:1所示,其重链氨基酸序列如序列表中SEQ ID NO:2所示。所述抗Her2单克隆抗体的含量较佳地为5mg/ml-50mg/ml,更佳地为10mg/ml-40mg/ml,优选地为30mg/ml。
所述抗Her2单克隆抗体的制备方法为本领域常规制备方法,其制备方法简述如下:由编码重组抗Her2结构域II人源化单克隆抗体基因的重组质粒转染CHO细胞构建工程细胞系。
生产细胞培养工艺历经种子细胞复苏、摇瓶扩增、WAVE生物反应器扩增及一次性反应器生产细胞培养,采用含HM004的基础培养基和HF001的补料培养基进行生产细胞培养。培养过程中补加谷氨酰胺、补料培养基、葡萄糖和丁酸钠。培养条件:接种后活细胞密度0.7×106±0.1×106cells/mL;搅拌转速90rpm;pH 6.90±0.10;初始时溶氧为饱和浓度,之后稳定在设定的40%附近;初始温度37.0℃;添加丁酸钠6~8h后降温至33.0℃。培养15天或者细胞活性低于60.0%时收获。
蛋白生产纯化工艺流程历经深层过滤、亲和层析、低pH病毒灭活、阴离子层析、阳离子层析、除病毒过滤、超滤浓缩换液,最终获得的蛋白产物制备成表1处方,放置于恒温摇床中,40℃、200rpm条件下振摇2周,于第0、1及2周分别取样,检测分析,检测项目包括蛋白质含量(A280)、分子异构体(SEC-HPLC)以及电荷异构体(CEX-HPLC)。
其中所述缓冲液为本领域常规缓冲液,“缓冲液”一般是指通过其酸-碱配合成分的作用来抵抗pH变化的缓冲溶液。较佳地,本发明所述缓冲液包括:枸橼酸-枸橼酸钠、组氨酸-盐酸组氨酸、醋酸-醋酸钠或枸橼酸-磷酸氢二钠等缓冲液体系中的一种;更佳地为枸橼酸-枸橼酸钠或组氨酸-盐酸组氨酸缓冲液体系;最优选地为组氨酸-盐酸组氨酸缓冲液体系。所述缓冲液的浓度较佳地为:10-30mM,更佳地为15-25mM,优选地为20mM。
本发明所述抗Her2单克隆抗体的制备方法还可以参考Stancovski et al.PNAS(USA)88:8691-8695(1991))以及Fendly et al.Cancer Research 50:1550-1558(1990)等文献公开的内容,该抗Her2单克隆抗体的制备方法是本领域技术人员知晓的技术内容。
其中所述蛋白保护剂为本领域常规蛋白保护剂,或称为“蛋白稳定剂”。所述蛋白保护剂能够保护蛋白质药物的稳定性,并保护蛋白质药物的功能不受条件变化的影响(例如:冷冻、冻干或其他制备条件的变化)。蛋白保护剂较佳地包括糖类、蛋白质、氨基酸、聚合物、盐、胺、表面活性剂等,更佳地包括山梨醇、蔗糖、海藻糖、甘露醇、盐酸精氨酸或甘氨酸中的一种或多种;优选地为山梨醇。所述蛋白保护剂的质量百分比含量较佳地为:1%-5%,更佳地为2%-4%,优选地为3%。
其中所述表面活性剂为本领域常规表面活性作用剂,较佳地为非离子型表面活性剂。本文中的表面活性剂的例子较佳地包括聚山梨酯(例如聚山梨20和聚山梨酯80);泊洛沙姆(例如泊洛沙姆188);Triton;十二烷基硫酸钠(SDS);月桂基硫酸钠;辛基糖苷钠;月桂基-,肉豆蔻基-,亚油基-,或硬脂酰基-磺基甜菜碱;月桂基-,肉豆蔻基-,亚油基-,或硬脂酰基-肌氨酸;亚油基-,肉豆蔻基,或鲸蜡基-甜菜碱;月桂酰氨基丙基-,椰油酰氨基丙基-,亚油酰氨基丙基-,肉豆蔻酰氨基丙基-,棕榈酰氨基丙基-,或异硬脂酰氨基丙基-甜菜碱(例如月桂酰氨基丙基甜菜碱);肉豆蔻酰氨基丙基-,棕榈酰氨基丙基-,或异硬脂酰氨基丙基-二甲胺;甲基椰油基牛磺酸钠或甲基油基牛磺酸二钠;MONAQUATTM系列(MonaIndustries Inc,Paterson,NJ);聚乙二醇,聚丙二醇,及乙二醇和丙二醇共聚物(例如Pluronics,PF68)等。所述表面活性剂更佳地为聚山梨酯20和/或聚山梨酯80,优选地为聚山梨酯20。所述表面活性剂的含量较佳地为0.1mg/mL-0.4mg/mL,更佳地为0.15mg/mL-0.35mg/mL,优选地为0.2mg/mL。
本发明所述药物配制剂的pH值为本领域常规pH值,较佳地为:pH5-7,更佳地为:pH5.5-6.5,优选地为:pH6.0。
本发明所述药物配制剂中可以根据需要含有或不含有等渗调节剂,其中所述等渗调节剂为本领域常规等渗调节剂,较佳地为葡萄糖或氯化钠等,更佳地为氯化钠。
本发明所述药物配制剂优选地包括:30mg/mL抗Her2单克隆抗体,20mmol/L组氨酸-盐酸组氨酸缓冲液,质量百分比为3%的山梨醇,0.2mg/mL聚山梨酯20,其pH为6.0。
本发明所述药物配制剂,其形式为本领域常规剂型。较佳地包括液体制剂、固体制剂、冻干制剂等;更佳地,所述药物配制剂为注射用液体制剂或冻干制剂。
本发明制备所得药物配制剂在室温条件或更高温度(40℃-50℃)条件下存储一定时间,各项主要检测指标均无明显变化,比原研制剂表现出更好的稳定性。本发明所得包含抗Her2单克隆抗体的药物配制剂,更好地解决了其中蛋白质药物的稳定性问题,该药物配制剂在不高于50℃储存条件下,可以保证四周以上的有效期。
附图说明
图1:HLX11药物配制剂高通量缓冲体系筛选2周纯度变化比较结果。其中,图1(A):不同处方的SEC主峰含量变化对比图;图1(B):不同处方的CEX主峰含量变化对比图。
图2:HLX11药物配制剂缓冲体系筛选4周纯度变化比较结果。其中,图2(A):不同处方的SEC主峰含量变化对比图;图2(B):不同处方的SEC片段含量变化对比图;图2(C):不同处方的CEX主峰含量变化对比图;图2(D):不同处方的CEX酸峰含量变化对比图;图2(E):不同处方的DLS蛋白平均粒径变化对比图。
图3:HLX11药物配制剂辅料筛选4周纯度变化比较结果。其中,图3(A):不同处方的SEC主峰含量变化趋势对比图;图3(B):不同处方的SEC片段含量变化趋势对比图;图3(C):不同处方的CEX主峰含量变化趋势对比图;图3(D):不同处方的CEX酸性峰含量变化趋势对比图;图3(E):不同处方的DLS蛋白平均粒径变化对比图。
图4:HLX11制剂表面活性剂筛选4周纯度变化比较结果。其中,图4(A):不同处方的SEC主峰含量变化对比图;图4(B):不同处方的SEC片段含量变化对比图;图4(C):不同处方的CEX主峰含量变化对比图;图4(D):不同处方的CEX酸峰含量变化对比图。
图5:HLX11药物配制剂初步稳定性研究加速试验SEC和CEX各组分含量变化结果。图5(A):HLX11药物配制剂和Perjeta的SEC主峰含量变化趋势对比图;图5(B):HLX11药物配制剂和Perjeta的SEC片段含量变化趋势图;图5(C):HLX11药物配制剂和Perjeta的SEC主峰含量变化线性拟合趋势图;图5(D):HLX11药物配制剂和Perjeta的SEC片段含量变化线性拟合趋势图。图5(E):HLX11药物配制剂和Perjeta的CEX主峰含量变化趋势图;图5(F):HLX11药物配制剂和Perjeta的CEX酸峰含量变化趋势图;图5(G):HLX11药物配制剂和Perjeta的CEX主峰含量变化线性拟合趋势图;图5(H):HLX11药物配制剂和Perjeta的CEX酸峰含量变化线性拟合趋势图。
具体实施方式
以下的实施例用于为本领域中的普通技术人员提供有关如何实施和使用本发明的完整披露和描述,并且这些例子并非意在对发明人所认为的发明范围进行限制,亦非意指下文的实验是被实施的全部实验而且是仅可实施的实验。
实验例中未注明具体条件的实验方法,通常按照常规条件或按照厂商所建议的条件,实施例中所用化学试剂均为分析纯试剂,抗Her2单克隆抗体可以是按照目前已知任何的方法制备的单抗,以下示例性的抗体制备方法由上海复宏汉霖生物技术股份有限公司提供,该示例性方法并不限制本发明,该单克隆抗体的名称为:HLX11蛋白。将除病毒过滤后的抗Her2单克隆抗体样品(HLX11蛋白),使用超滤浓缩换液,根据缓冲液配方,计算需要补加的置换液,完成稀配,密度默认为1.0g/mL,该制剂的名称为:HLX11制剂。本发明所述HLX11配方制剂产品的制备方法为本领域常规方法,该示例性方法并不限制本发明。
将稀配后的药液经0.22μm除菌过滤器过滤后,无菌分装至20mL西林瓶中,加20mm氯化丁基橡胶塞,轧20mm铝塑组合盖。该配方制剂产品用于下文的长期稳定性试验、加速稳定性试验以及单因素影响试验考察成品的稳定性,确定储存和运输条件。
实施例1 HLX11蛋白的制备
工程细胞系由编码重组抗Her2结构域II人源化单克隆抗体基因的重组质粒转染CHO细胞构建而成。生产细胞培养工艺历经种子细胞复苏、摇瓶扩增、WAVE生物反应器扩增及一次性反应器生产细胞培养,采用含HM004的基础培养基和HF001的补料培养基进行生产细胞培养。培养过程中补加谷氨酰胺、补料培养基、葡萄糖和丁酸钠。培养条件:接种后活细胞密度0.7×106±0.1×106cells/mL;搅拌转速90rpm;pH 6.90±0.10;初始时溶氧为饱和浓度,之后稳定在设定的40%附近;初始温度37.0℃;添加丁酸钠6~8h后降温至33.0℃。培养15天或者细胞活性低于60.0%时收获。
蛋白生产纯化工艺流程历经深层过滤、亲和层析、低pH病毒灭活、阴离子层析、阳离子层析、除病毒过滤、超滤浓缩换液,最终获得蛋白产物。确定所得蛋白产物为抗Her2单克隆抗体,其轻链氨基酸序列如序列表中SEQ ID NO:1所示,其重链氨基酸序列如序列表中SEQ ID NO:2所示,将所得蛋白产物命名为HLX11单克隆抗体,或者为HLX11蛋白。HLX11蛋白的制备方法,还可以参照Stancovski et al.PNAS(USA)88:8691-8695(1991))以及Fendlyet al.Cancer Research 50:1550-1558(1990)等文献公开的技术内容。
实施例2缓冲体系的筛选
2.1缓冲体系的首轮筛选
将实施例1所得HLX11蛋白制备成表1处方,放置于恒温摇床中,40℃、200rpm条件下振摇2周,于第0、1及2周分别取样,检测分析,检测项目包括蛋白质含量(A280)、分子异构体(SEC-HPLC)以及电荷异构体(CEX-HPLC)。HLX11药物配制剂高通量筛选研究考察条件详见表2。
通过高通量筛选方法初步筛选出有助于蛋白稳定的潜在缓冲体系类型及pH值范围。选择醋酸-醋酸钠、枸橼酸-枸橼酸钠、组氨酸-盐酸组氨酸、组氨酸-醋酸、磷酸二氢钠-磷酸氢二钠以及枸橼酸-磷酸氢二钠六组常用的缓冲液类型,配制成共23种制剂缓冲液(以下分别称为B1~B23)。其中,B1~B3为20mmol/L醋酸-醋酸钠缓冲体系,pH值分别为5.5、6.0及6.5;B4~B7为20mmol/L枸橼酸-枸橼酸钠缓冲体系,pH值分别为5.0、5.5、6.0及6.5;B8~B12为20mmol/L组氨酸-盐酸组氨酸缓冲体系,B13~B17为20mmol/L组氨酸-醋酸缓冲体系,上述二组缓冲体系的pH值均为5.0、5.5、6.0、6.5以及7.0;B18~B20为20mmol/L磷酸二氢钠-磷酸氢二钠缓冲体系,B21~B23为20mmol/L枸橼酸-磷酸氢二钠缓冲体系,上述二组缓冲体系的pH值均为5.5、6.0以及6.5。上述23种处方中,B13~B17的组氨酸-醋酸缓冲体系为对照处方。首轮研究的药物浓度设为2.0mg/mL。
表1.HLX11制剂高通量缓冲体系筛选研究备选缓冲液信息
表2.HLX11制剂高通量缓冲体系筛选研究考察条件
HLX11高通量缓冲体系筛选研究考察结果详见表3所示。
从表3可以看出,各项检测结果均显示0周时蛋白质量良好,各备选处方之间无明显差异。40℃、200rpm条件下振摇2周后,与2周相比,各处方SEC主峰含量呈下降趋势,主峰含量下降主要表现为片段含量显著增加。HLX11药物配制剂高通量缓冲体系筛选2周纯度变化比较结果如图1所示。其中,图1(A):不同处方的SEC主峰含量变化对比图;图1(B):不同处方的CEX主峰含量变化对比图。
根据图1(A),相比于枸橼酸-枸橼酸钠和磷酸二氢钠-磷酸氢二钠缓冲体系,在醋酸-醋酸钠缓冲体系、组氨酸-盐酸组氨酸缓冲体系、组氨酸-醋酸缓冲体系及枸橼酸-磷酸氢二钠缓冲体系中同pH值条件下的抗体SEC主峰含量下降较少;在醋酸-醋酸钠缓冲体系各pH值条件下抗体SEC主峰变化无差异,在组氨酸-盐酸组氨酸缓冲体系、枸橼酸-磷酸氢二钠缓冲体系及枸橼酸-枸橼酸钠缓冲体系中,pH值为6.0时的缓冲液中抗体SEC主峰含量均比同组缓冲液其它pH值条件下变化略小,且含量变化随着pH值的减小或增加相应减小或增加;在组氨酸-盐酸组氨酸缓冲体系下各pH值条件下,由分子异构体结果可以看出有利于分子异构体稳定的pH值范围为5.5~6.5。
根据表3CEX数据,40℃、200rpm条件下振摇2周后,与0周相比,各处方主峰含量呈下降趋势,主峰含量下降主要表现为酸峰含量显著增加。醋酸-醋酸钠缓冲体系(A55、A60及A65)、组氨酸-盐酸组氨酸缓冲体系(H55、H60及H65)及组氨酸-醋酸缓冲体系(HA55、HA60及HA65)中同pH值条件下的抗体主峰含量下降较少,且pH值为6.0时的缓冲液中抗体主峰含量均比同组缓冲液其它pH值条件下变化略小。根据图1(B)所示纯度对比结果,以及电荷异构体纯度变化数据,判定有助于电荷异构体稳定的最适pH值范围为5.5~6.5。
综上所述,高通量筛选研究显示有助于HLX11蛋白稳定性的缓冲体系为醋酸-醋酸钠缓冲体系及组氨酸-盐酸组氨酸缓冲体系,pH值范围为5.5~6.5,pH值为6.0时稳定性最好。
虽然高通量筛选显示醋酸-醋酸钠缓冲体系及组氨酸-盐酸组氨酸缓冲体系略好,但是醋酸体系容易挥发,且pKa为4.8,在5.5~6.5的pH范围内缓冲能力较弱,故下一轮研究将pH范围调整为5.0~6.0;另外进一步考察枸橼酸-枸橼酸钠缓冲体系的效果;而组氨酸-盐酸组氨酸这种常用的缓冲体系,pH值的筛选范围则固定为5.5~6.5。组氨酸-醋酸缓冲体系作为对照缓冲体系,仅考察稳定性最好的pH值(HA60)。
2.2缓冲体系次轮筛选
首轮制剂研究通过高通量筛选方法初步筛选出有助于蛋白稳定的候选缓冲液类型及pH值范围。在此基础上,次轮研究通过高温加速试验,采用完整的理化分析手段进一步确定HLX11缓冲体系。
根据首轮研究的结果,本轮研究共选择12种缓冲液(以下分别称为HA60、HA60N、H55、H60、H65、A50、A55、A60、C50、C55、C60及C65),HLX11制剂缓冲体系筛选研究备选缓冲液信息如表4所示。
表4.HLX11制剂缓冲体系筛选研究备选缓冲液组成
取实施例1蛋白产物制备成表4处方。在生物安全柜内采用0.22μm一次性无菌过滤器过滤样品,然后无菌分装至2mL西林瓶中,加13mm胶塞,轧13mm铝塑组合盖。将分装后样品放置于40℃恒温恒湿箱内正置4周,于第0、1、2和4周分别取样,检测分析,检测项目包括外观、蛋白质含量(A280)、pH值、分子异构体(SEC-HPLC)、电荷异构体(CEX-HPLC)、蛋白粒径和PdI(DLS)等。HLX11制剂缓冲体系筛选研究考察条件见表5。
表5.HLX11制剂缓冲体系筛选研究考察条件
HLX11制剂缓冲体系筛选研究考察结果详见表6和表7所示。
从表6可以看出,NaCl的添加导致蛋白溶液的乳光加重,并且枸橼酸-枸橼酸钠缓冲体系(C50~C65)下的各处方溶液的乳光也较另三组缓冲体系下的溶液略明显。
从表7SEC数据可以看出,40℃条件下加速4周后,与0周相比,各处方SEC主峰含量呈下降趋势,主峰含量下降主要表现为片段含量显著增加。使用HA60、HA60N、H55、H60、A55及A60缓冲液的抗体主峰含量下降一致;而使用A50、C55、C60和C65缓冲液的抗体主峰含量下降略快,在酸性最强的C50缓冲液中的抗体主峰含量下降最快。HLX11药物配制剂缓冲体系筛选4周纯度变化比较结果如图2所示。其中,图2(A):不同处方的SEC主峰含量变化对比图;图2(B):不同处方的SEC片段含量变化对比图;图2(C):不同处方的CEX主峰含量变化对比图;图2(D):不同处方的CEX酸峰含量变化对比图;图2(E):不同处方的DLS蛋白平均粒径变化对比图。
根据纯度图2(A)~(B)对比及纯度变化数据,组氨酸-盐酸组氨酸缓冲体系(pH值范围为5.5~6.0)更有助于分子异构体稳定。根据表7的CEX数据,40℃条件下加速4周后,与0周相比,各处方主峰含量呈下降趋势,主峰含量下降主要表现为酸峰含量显著增加。在H60缓冲液中的抗体主峰下降最少,在HA60、HA60N、H55及A60缓冲液中的抗体主峰下降略快,在枸橼酸-枸橼酸钠缓冲体系(C50~C65)下抗体主峰下降比其它三组缓冲体系同pH值条件下均要快。根据纯度对比图2(C)~(D)以及电荷异构体纯度变化数据,组氨酸-盐酸组氨酸缓冲体系(pH值范围为5.5~6.5)更有助于电荷异构体稳定。
由表7和图2(E)可知,在组氨酸-盐酸组氨酸缓冲体系下的蛋白粒径随pH值的升高而减小,但在醋酸-醋酸钠缓冲体系及枸橼酸-枸橼酸钠缓冲体系的蛋白粒径均比组氨酸-盐酸组氨酸缓冲体系下的蛋白粒径大,并且在后两种缓冲体系中的蛋白粒径随pH值的升高而增大,说明pH越高越容易产生聚体。缓冲液中添加NaCl也会导致蛋白粒径明显增加。
综上所述,根据缓冲体系pH值筛选研究加速稳定性试验结果,20mmol/L组氨酸-组氨酸盐酸缓冲体系下可以起到稳定溶液pH值的缓冲作用,当pH值为6.0时,蛋白稳定性最好。因此我们选择20mmol/L pH值为6.0的组氨酸-盐酸组氨酸缓冲体系进行后续研究。
实施例3 HLX11制剂辅料筛选研究和结果
3.1辅料的首轮筛选
根据缓冲液体系筛选研究结果,我们选择了组氨酸-盐酸组氨酸体系,pH值为6.0,作为HLX11药物配制剂的备选缓冲体系。本轮研究共6个备选处方(以下分别称为F1~F6),F1为对照处方,缓冲体系为20mmol/L组氨酸-醋酸,含有4.1%蔗糖以及0.02%聚山梨酯20,pH值为6.0。缓冲体系主要考察组氨酸-盐酸组氨酸缓冲体系,另外将醋酸-醋酸钠以及枸橼酸-枸橼酸钠两种缓冲体系稳定性最好的pH值(A60及CP60)作为对照缓冲体系。稳定剂包括蔗糖和山梨醇;本轮表面活性剂暂定为0.02%的聚山梨酯20。
本轮研究通过单因素试验设计筛选辅料体系,考察不同缓冲液种类、氯化钠以及稳定剂种类对蛋白稳定性的影响。HLX11辅料首轮筛选研究备选处方信息见表8。
表8.HLX11制剂辅料首轮筛选研究备选处方组成
制备方法:采用实施例所得HLX11蛋白,经三步层析纯化,超滤换液后加辅料、调节蛋白浓度制备成表8处方。在生物安全柜中分别用0.22μm一次性无菌过滤器过滤样品,无菌分装1.0mL样品至2mL无菌西林瓶中,加13mm胶塞,轧13mm铝塑组合盖。分别将上述分装后的样品在40℃(75%RH)恒温恒湿箱内正置4周,于第0、2周和4周分别取样,检测分析,检测项目包括外观、蛋白质含量(A280)、pH值、分子异构体(SEC-HPLC)、蛋白粒径和PdI(DLS)、电荷异构体(CEX-HPLC)等。HLX11制剂辅料筛选研究考察条件详见表9。
表9.HLX11辅料首轮筛选研究考察条件
HLX11辅料首轮筛选研究考察结果详见表10所示。
从表10可以看出,处方HSuN中NaCl的添加导致蛋白溶液的乳光较重,并且处方C60蛋白溶液的乳光也较另两组缓冲体系下的溶液略明显。HLX11药物配制剂辅料筛选4周纯度变化比较结果如图1所示。其中,图3(A):不同处方的SEC主峰含量变化趋势对比图;图3(B):不同处方的SEC片段含量变化趋势对比图;图3(C):不同处方的CEX主峰含量变化趋势对比图;图3(D):不同处方的CEX酸性峰含量变化趋势对比图;图3(E):不同处方的DLS蛋白平均粒径变化对比图。
结合表10及图3(A)~(B)SEC数据可以看出,40℃条件下加速4周后,与0周相比,各处方SEC主峰含量呈下降趋势,主峰含量下降主要表现为片段含量显著增加。处方HASu及HSuN中的抗体主峰含量下降较其它处方下降较快,而处方HSu、HSo、ASu和CSu中的抗体主峰含量下降接近;处方HSo抗体主峰含量下降略慢于HSu。
结合表10及图3(C)~(D)CEX数据,40℃条件下加速4周后,与0周相比,各处方主峰含量呈下降趋势,主峰含量下降主要表现为酸峰含量显著增加。处方HASu及CSu中的抗体主峰含量下降较其它处方下降较快,处方HSuN抗体主峰含量下降略慢,而处方HSu、HSo及ASu中的抗体主峰含量下降一致且最慢。
由表10及图3(E)可知,处方HSuN中添加NaCl也会导致蛋白粒径明显增加;处方ASu及CSu相比于组氨酸-盐酸组氨酸缓冲体系下的蛋白粒径较大,进一步说明醋酸-醋酸钠缓冲体系及枸橼酸-枸橼酸钠缓冲体系容易产生聚体。
综上所述,根据辅料筛选首轮研究加速稳定性试验结果,20mmol/L组氨酸-组氨酸盐酸缓冲体系pH值为6.0时,添加3.0%山梨醇作为稳定剂,蛋白稳定性最好。因此我们选择20mmol/L pH值为6.0的组氨酸-盐酸组氨酸缓冲体系且3.0%山梨醇作为稳定剂进行后续表面活性剂种类及含量研究。
3.2辅料次轮筛选
本轮研究进一步通过单因素试验设计筛选辅料体系,考察不同表面活性剂种类及含量的影响。HLX11辅料筛选次轮研究备选处方信息见表11。
表11.HLX11制剂辅料次轮筛选研究备选处方组成
制备方法:采用实施例1所得HLX11蛋白,经三步层析纯化,超滤换液后加辅料、调节蛋白浓度制备成表11处方。在生物安全柜中分别用0.22μm一次性无菌过滤器过滤样品,无菌分装1.0mL样品至2mL无菌西林瓶中,加13mm胶塞,轧13mm铝塑组合盖。分别将上述分装后的样品在40℃(75%RH)恒温摇床内正置200rpm振摇4周,于第0、1周、2周和4周分别取样,检测分析,检测项目包括外观、蛋白质含量(A280)、pH值、分子异构体(SEC-HPLC)、电荷异构体(CEX-HPLC)及蛋白粒径和PdI(DLS)等。HLX11制剂辅料筛选次轮研究考察条件详见表12。
表12.HLX11辅料次轮筛选研究考察条件
HLX11辅料次轮筛选研究考察结果详见表13所示。
表13.HLX11制剂辅料次轮筛选研究加速稳定性试验(40℃ 200rpm)数据汇总表
如表13所示,各项检测结果均显示0周时,蛋白质量良好,各备选处方无明显差异。40℃、200rpm的加速条件下考察4周后,各处方的基础理化性质(外观、蛋白质含量以及pH值)与蛋白平均粒径和PdI无明显变化。
SEC数据显示各处方抗体SEC主峰含量均呈下降趋势,聚体无明显变化,主峰含量下降主要表现为片段含量显著增加,其中处方F1(不含聚山梨酯20或80)和F2(含0.02%聚山梨酯20)抗体SEC主峰下降最少,而F3(含0.05%聚山梨酯20)和F4(含0.02%聚山梨酯80)抗体SEC主峰下降略快。
CEX数据显示各处方CEX抗体主峰含量均呈下降趋势,碱峰无明显变化,CEX主峰含量下降主要表现为酸峰含量显著增加,其中处方F1(不含聚山梨酯20或80)抗体主峰下降最少,F2(含0.02%聚山梨酯20)抗体主峰下降略快,而F3(含0.05%聚山梨酯20)和F4(含0.02%聚山梨酯80)抗体主峰下降最快。HLX11制剂表面活性剂筛选4周纯度变化比较结果如图4所示。其中图4(A):SEC主峰含量变化对比图;图4(B):SEC片段含量变化对比图;图4(C):CEX主峰含量变化对比图;图4(D):CEX酸性峰含量变化对比图。
综上所述,结合SEC纯度以及CEX纯度变化对比图(图4(A)~(D)),当处方中添加0.02%PS20比添加0.02%PS80时蛋白稳定性略好。当处方中添加PS20浓度为0.00%、0.02%及0.05%(处方F1~F3)时,蛋白稳定性无明显差异,所有备选处方稳定性良好。因此HLX11制剂处方中PS20的含量可以控制在0.20±0.2mg/mL的范围内。
通过制剂处方开发,我们筛选出了有助于HLX11蛋白稳定的缓冲体系和辅料,确定了HLX11药物配制剂的处方组成为:30mg/mLHLX11单克隆抗体,1.51mg/mL组氨酸,2.15mg/mL盐酸组氨酸(组氨酸-盐酸组氨酸缓冲液的摩尔浓度为:20mmol),30.0mg/mL山梨醇,0.2mg/mL聚山梨酯20(聚山梨酯20的体积百分比含量为0.02%),pH值为6.0。
实施例4 HLX11制剂与Perjeta初步稳定性对照研究
根据实施例1所述内容,使用最终培养和纯化工艺获得的HLX11蛋白换液稀配至最终处方,使用同样的内包材及规格,将HLX11药物配制剂与Perjeta(购买自罗氏公司)在生物安全柜中分别用0.22μm一次性无菌过滤器过滤样品,无菌分装1.0mL样品至2mL无菌西林瓶中,加13mm胶塞,轧13mm铝塑组合盖。
Perjeta原研制剂的配方为:30mg/mL Pertuzumab、20mM L-组氨酸醋酸盐、120mM蔗糖和0.02%聚山梨醇酯20,pH值为6.0。
考察条件为50℃,正置1个月,于0周、1周、2周和4周分别取样检测,检测项目包括外观、蛋白质含量、渗透压摩尔浓度以及纯度(SEC-HPLC、CEX-HPLC、CE-SDS)等。HLX11药物配制剂与Perjeta初步稳定性对照试验考察条件见表14。
表14.HLX11药物配制剂与Perjeta初步稳定性对照试验考察条件
HLX11与Perjeta初步稳定性对照结果详见表15所示。
表15.HLX11药物配制剂与Perjeta初步稳定性对照研究结果
HLX11药物配制剂初步稳定性研究加速试验SEC和CEX各组分含量变化结果如图5所示。其中图5(A):SEC主峰含量变化趋势图;图5(B):SEC片段含量变化趋势图;图5(C):SEC主峰含量变化线性拟合趋势图;图5(D):SEC片段含量变化线性拟合趋势图;图5(E):CEX主峰含量变化趋势图;图5(F):CEX酸性峰含量变化趋势图;图5(G):CEX主峰含量变化线性拟合趋势图;图5(H):CEX酸峰含量变化线性拟合趋势图。
结合表15及图5(A)~(D)SEC数据显示各处方抗体SEC主峰含量均呈下降趋势,聚体略有增加,主峰含量下降主要表现为片段含量显著增加。HLX11与Perjeta的SEC主峰含量变化线性拟合方程分别为y=-2.25x+102.2和y=-2.20x+102.2,HLX11的主峰下降斜率-2.25与Perjeta的主峰下降斜率-2.2差异很小,因而HLX11与Perjeta的SEC主峰下降趋势一致。HLX11与Perjeta的SEC片段含量变化线性拟合方程分别为y=2.05x+2.4和y=1.85x+1.95,HLX11的SEC片段增加斜率2.05大于Perjeta的片段增加斜率1.85,因而HLX11的SEC片段增加趋势比Perjeta的片段增加趋势略快。但50℃条件下考察4周后,SEC片段分别增加了6.4%(HLX11)和5.5%(Perjeta),两者间的差异可以忽略。
表15及图5(E)~(H)CEX数据显示各处方CEX抗体主峰含量均呈下降趋势,碱峰无明显变化,CEX主峰含量下降主要表现为酸峰含量显著增加。HLX11与Perjeta CEX主峰含量变化线性拟合方程分别为y=-16.39x+92.9和y=-17.27x+90.55,HLX11的主峰下降斜率-16.39略大于Perjeta的主峰下降斜率-17.27,因而HLX11CEX主峰下降趋势略慢于Perjeta的主峰下降趋势。HLX11与Perjeta的CEX酸峰含量变化线性拟合方程分别为y=15.89x+3.55和y=18.59x-4.95,HLX11的酸峰增加斜率15.89明显小于Perjeta的酸峰增加斜率18.59,因而HLX11的酸峰增加趋势明显慢于Perjeta的酸峰增加趋势。
综上所述,本发明所得HLX11药物配制剂比Perjeta制剂乳光略浅,渗透压更加接近于人体血液渗透压;HLX11制剂的SEC纯度变化趋势与Perjeta制剂SEC纯度变化趋势趋于一致;HLX11CEX主峰下降趋势略慢于Perjeta的主峰下降趋势,并且HLX11CEX酸峰增加趋势明显弱于Perjeta酸峰增加趋势。与原研药物Perjeta制剂相比,HLX11药物配制剂更利于抗体稳定,在不高于50℃储存条件下,可以保证四周以上的有效期。
应理解,在阅读了本发明的上述内容之后,本领域技术人员可以对本发明作各种改动或修改,而这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 上海复宏汉霖生物技术股份有限公司
上海复宏汉霖生物制药有限公司
<120> 一种包含抗Her2单克隆抗体的药物配制剂
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 3
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Claims (10)
1.一种包含抗Her2单克隆抗体的药物配制剂,其特征在于,所述药物配制剂包括:抗Her2单克隆抗体、缓冲液、蛋白保护剂和表面活性剂。
2.如权利要求1所述的药物配制剂,其特征在于,所述缓冲液为:枸橼酸-枸橼酸钠缓冲液、组氨酸-盐酸组氨酸缓冲液、醋酸-醋酸钠缓冲液和枸橼酸-磷酸氢二钠缓冲液中的一种或多种,所述缓冲液的浓度为10-30 mM。
3.如权利要求2所述的药物配制剂,其特征在于,所述缓冲液为组氨酸-盐酸组氨酸,其浓度为20mM。
4.如权利要求1所述的药物配制剂,其特征在于,所述蛋白保护剂为:蔗糖、海藻糖、甘氨酸、甘露醇、山梨醇和/或盐酸精氨酸中的一种或多种;其质量百分比含量为1%-5 %。
5.如权利要求1所述的药物配制剂,其特征在于,所述表面活性剂为聚山梨酯、聚山梨酯20和/或泊洛沙姆中的一种或多种,表面活性剂含量为0.1 mg/mL -0.4 mg/mL。
6.如权利要求5所述的药物配制剂,其特征在于,所述抗Her2单克隆抗体的轻链氨基酸序列如序列表中SEQ ID NO:1所示,其重链氨基酸序列如序列表中SEQ ID NO:2所示。
7.如权利要求1所述的药物配制剂,其特征在于,所述药物配制剂的pH值为5-7。
8.如权利要求1所述的药物配制剂,其特征在于,所述抗Her2单克隆抗体的蛋白浓度为5mg/ml-50mg/ml。
9.如权利要求1~8任一项所述的药物配制剂,其特征在于,所述药物配制剂包括:30mg/mL 抗Her2单克隆抗体,20 mmol/L组氨酸-盐酸组氨酸缓冲液,质量百分比为3%的山梨醇,0.2mg/mL聚山梨酯20,其pH为6.0。
10.如权利要求1~9任一项所述的药物配制剂,其特征在于,所述药物配制剂为注射用液体制剂或冻干制剂。
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CN112798720A (zh) * | 2021-01-11 | 2021-05-14 | 苏桥生物(苏州)有限公司 | 组氨酸缓冲液在减少蛋白聚体中的应用 |
WO2022017401A1 (zh) * | 2020-07-22 | 2022-01-27 | 三生国健药业(上海)股份有限公司 | 抗her2/pd1双特异性抗体冻干制剂及其制备方法 |
CN117224689A (zh) * | 2023-11-16 | 2023-12-15 | 上海复宏汉霖生物技术股份有限公司 | 联合抗her2抗体和化疗剂治疗胃癌的用途 |
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WO2022017401A1 (zh) * | 2020-07-22 | 2022-01-27 | 三生国健药业(上海)股份有限公司 | 抗her2/pd1双特异性抗体冻干制剂及其制备方法 |
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CN112798720B (zh) * | 2021-01-11 | 2022-04-19 | 苏州药明生物技术有限公司 | 组氨酸缓冲液在减少蛋白聚体中的应用 |
CN117224689A (zh) * | 2023-11-16 | 2023-12-15 | 上海复宏汉霖生物技术股份有限公司 | 联合抗her2抗体和化疗剂治疗胃癌的用途 |
CN117224689B (zh) * | 2023-11-16 | 2024-02-23 | 上海复宏汉霖生物技术股份有限公司 | 联合抗her2抗体和化疗剂治疗胃癌的用途 |
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