CN119258013A - 包含抗α4β7抗体的药物制剂 - Google Patents
包含抗α4β7抗体的药物制剂 Download PDFInfo
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- CN119258013A CN119258013A CN202410901386.7A CN202410901386A CN119258013A CN 119258013 A CN119258013 A CN 119258013A CN 202410901386 A CN202410901386 A CN 202410901386A CN 119258013 A CN119258013 A CN 119258013A
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- Prior art keywords
- histidine
- ser
- antibody
- trehalose
- tween
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Abstract
本发明提供了一种稳定的药物制剂，其包含60g/L抗α4β7抗体、112g/L的海藻糖、26.34g/L盐酸精氨酸、0.6g/L的吐温80和50mM的组氨酸‑组氨酸盐酸缓冲液,其中，所述药物制剂的PH值为6.3,所述抗α4β7抗体为维得利珠单抗。
Description
技术领域
本发明涉及生物药物制剂领域，具体而言，本发明涉及一种稳定的包含维得利珠单抗的药物制剂。
背景技术
维得利珠单抗(Vedolizumab)作为一种人源化单克隆抗体，与α4β7整合素特异性结合，阻断α4β7整合素与MAdCAM-1相互作用，抑制记忆T淋巴细胞穿过内皮迁移至胃肠道的炎症组织，从而精准抑制肠道炎症，常用于治疗溃疡性结肠炎和克罗恩病。
目前已上市的药物产品为一种冻干的维得利珠制剂，制剂重构后为60mg/ml抗体、50mM组氨酸、10％(w/v)蔗糖、125mM精氨酸盐酸盐和0.06％(w/v)聚山梨醇酯80，pH为6.3。在此基础上进一步提高制剂中抗体的稳定性，需要确保在将该分子施用给患者时符合剂量和产品安全性的要求，最大程度减少蛋白质降解尤其是蛋白质聚集，以尽量避免严重的免疫原反应。
因此在本领域中，优化维得利珠制剂配方，提高抗体稳定性，提升储存能力，仍然存在需要。
发明内容
本发明的目的在于提供一种优化的包含抗α4β7抗体的制剂，该制剂在长期储存过程中表现出了提高的物理及化学稳定性。
本发明的第一方面提供了一种稳定的药物制剂，其包含抗α4β7抗体和第一稳定剂，其中所述的第一稳定剂为海藻糖。
在一些实施方案中，所述海藻糖的浓度为约99-118g/L。
在一些实施方案中，所述海藻糖的浓度为约99-112g/L。
在一些实施方案中，所述海藻糖的浓度为约112g/L。
在一些实施方案中，所述抗α4β7抗体包含重链可变区(VH)和，所述抗α4β7抗体包含轻链可变区(VL)；其中，所述重链可变区中包含氨基酸序列为SEQ ID NO:1的HCDR1、氨基酸序列为SEQ ID NO:2的HCDR2和/或氨基酸序列为SEQ ID NO:3的HCDR3；所述轻链可变区中包含氨基酸序列为SEQ ID NO:4的LCDR1、氨基酸序列为SEQ ID NO:5的LCDR2和/或氨基酸序列为SEQ ID NO:6的LCDR3。
SEQ ID NO:1：
Ser Tyr Trp Met His
SEQ ID NO:2：
Glu Ile Asp Pro Ser Glu Ser Asn Thr Asn Tyr Asn Gln Lys Phe Lys
SEQ ID NO:3：
Gly Gly Tyr Asp Gly Trp Asp Tyr Ala Ile Asp Tyr
SEQ ID NO:4：
Arg Ser Ser Gln Ser Leu Ala Lys Ser Tyr Gly Asn Thr Tyr Leu Ser
SEQ ID NO:5
Gly Ile Ser Asn Arg Phe Ser
SEQ ID NO:6
Leu Gln Gly Thr His Gln Pro Tyr Thr
在一些实施方案中，所述抗α4β7抗体包含氨基酸序列为SEQ ID NO:7的重链可变区(VH)和氨基酸序列为SEQ ID NO:8的轻链可变区(VL)。
SEQ ID NO:7：
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala SerVal Lys Val Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met His TrpVal Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly Glu Ile Asp Pro Ser GluSer Asn Thr Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Leu Thr Val Asp IleSer Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Gly Gly Tyr Asp Gly Trp Asp Tyr Ala Ile Asp Tyr Trp GlyGln Gly Thr Leu Val Thr Val Ser Ser
SEQ ID NO:8：
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly GluPro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Ala Lys Ser Tyr Gly Asn ThrTyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr GlyIle Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly ThrAsp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr CysLeu Gln Gly Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
在一些实施方案中，所述抗α4β7抗体包含氨基酸序列为SEQ ID NO:9的重链和氨基酸序列为SEQ ID NO:10的轻链。
SEQ ID NO:9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala SerVal Lys Val Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met His TrpVal Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly Glu Ile Asp Pro Ser GluSer Asn Thr Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Leu Thr Val Asp IleSer Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Gly Gly Tyr Asp Gly Trp Asp Tyr Ala Ile Asp Tyr Trp GlyGln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe ProLeu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu ValLys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr SerGly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser SerVal Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val AsnHis Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp LysThr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser Val PheLeu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val ThrCys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr ValAsp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn SerThr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly LysGlu Tyr Lys Cys Lys Val SerAsn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr IleSer Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser ArgAsp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr ProSer Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys ThrThr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr ValAsp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu AlaLeu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
SEQ ID NO:10
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly GluPro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Ala Lys Ser Tyr Gly Asn ThrTyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr GlyIle Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly ThrAsp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr CysLeu Gln Gly Thr His Gln Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile LysArg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu LysSer Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala LysVal Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val ThrGlu GlnAsp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser LysAla Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu SerSer Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
在一些实施方案中，所述抗α4β7抗体是维得利珠单抗。
在一些实施方案中，所述抗α4β7抗体的浓度是约50-70g/L。
在一些实施方案中，所述抗α4β7抗体的浓度是约60g/L。
在一些实施方案中，所述药物制剂还包含第二稳定剂，其中所述第二稳定剂选自盐酸精氨酸、甘氨酸和氯化钠。
在一些实施方案中，所述第二稳定剂为盐酸精氨酸。
在一些实施方案中，所述第二稳定剂的浓度为约22g/L-30g/L。
在一些实施方案中，所述第二稳定剂的浓度为约26.34g/L-30g/L。
在一些实施方案中，所述第二稳定剂的浓度为约26.34g/L。
在一些实施方案中，所述药物制剂还包含表面活性剂，其中所述表面活性剂选自吐温80、吐温20和泊洛沙姆188。
在一些实施方案中，所述表面活性剂是吐温80。
在一些实施方案中，所述表面活性剂的浓度是约0.4-0.8g/L。
在一些实施方案中，所述表面活性剂的浓度是约0.6g/L。
在一些实施方案中，所述药物制剂还包含缓冲液，其中所述缓冲液选自组氨酸-组氨酸盐酸和柠檬酸-柠檬酸钠。
在一些实施方案中，所述缓冲液是组氨酸-组氨酸盐酸。
在一些实施方案中，所述缓冲液的浓度是约40mM-约65mM。
在一些实施方案中，所述缓冲液的浓度是约50mM。
在一些实施方案中，所述药物制剂包含抗α4β7抗体、海藻糖、盐酸精氨酸、吐温80和组氨酸-组氨酸盐酸缓冲液。
在一些实施方案中，所述药物制剂包含约50g/L-70g/L抗α4β7抗体、约99g/L-112g/L海藻糖、约22g/L-30g/L盐酸精氨酸、约0.4-0.8g/L吐温80和约40-65mM组氨酸-组氨酸盐酸缓冲液。
在一些实施方案中，所述药物制剂包含约60g/L的抗α4β7抗体、约112g/L海藻糖、约26.34g/L盐酸精氨酸、约0.6g/L吐温80和约50mM组氨酸-组氨酸盐酸缓冲液。
在一些实施方案中，所述药物制剂的PH值为约6.0-约6.6。
在一些实施方案中，所述PH值为6.3。
在一些实施方案中，所述药物制剂为液体制剂或冻干制剂。
在一些实施方案中，所述药物制剂是冻干制剂。
本发明针对抗α4β7抗体提供了一种优化的抗体药物制剂。本发明提供的药物制剂在含有较高浓度的抗α4β7抗体时，具有较高的稳定性，并且以液体制剂存储和以冻干制剂存储时都能够保持相当的稳定性，并且具有低的粘度和接近等渗的渗透压，满足给药需求，提高药物疗效。
定义以及详细说明
以下结合实施例进一步阐明本发明的内容，但并不限制本发明。
本文术语“抗体”是指包括整个抗体及其任意抗原结合部分或单链。自然产生的“抗体”是包含通过二硫键互相连接的至少两个重链(H)和两个轻链(L)的糖蛋白。各重链包含重链可变区(本文缩写为VH)和重链恒定区。重链恒定区包含三个域，CH1、CH2和CH3。各轻链包含轻链可变区(本文缩写为VL)和轻链恒定区。轻链恒定区包含一个域CL。VH和VL区可进一步细分成多个高变区域，称为高变区或互补决定区(CDR)，其间有更保守性地称为骨架区(FR)的区域。VH和VL包含三个CDR和四个FR，从氨基端至羧基端如下排列：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4，即VH包含HCDR1、HCDR2、HCDR3、HFR1、HFR2、HFR3和HFR4，VL包含LCDR1、LCDR2、LCDR3、LFR1、LFR2、LFR3和LFR4。重链和轻链的可变区包含与抗原相互作用的结合域。
细胞表面分子“α4β7整合素”或“α4β7”是α4链(CD49D，ITGA4)与β7链(ITGB7)的杂二聚体。人α4及β7基因(分别为GenBank(National Center for Biotechnology Information，Bethesda，MD)RefSeq寄存编号NM_000885和NM_000889)由B和T淋巴细胞、特别是记忆CD4+淋巴细胞表达。作为许多整合素的典型，α4β7可以静止或活化状态存在。α4β7的配体包括血管细胞粘着分子(VCAM)、纤维结合蛋白(fibronectin)和粘膜地址素(MAdCAM(例如MAdCAM—1))。
术语“抗α4β7抗体”意指与人α4β7特异性结合的人抗体或其抗原结合片段。
本文使用“液体制剂”，也称液体药物组合物，表示并非自冻干物复溶的水性组合物，其包含至少一种抗α4β7抗体或其抗原结合片段(例如维得利珠单抗)和至少一种赋形剂(例如稳定剂等)。该液体药物组合物可包含其他赋形剂(缓冲液、表面活性剂)和其他活性成分。这种制剂也称为“即用型”液体制剂。
术语“稳定的制剂”是指其中的抗体在储存时保持其物理稳定性和/或化学稳定性和/或生物学活性的制剂。可使用各种分析方法来评估给定组合物的稳定性，例如可使用CEX-HPLC来评估本公开液体组合物中的抗体纯度(主峰的含量)，可使用SEC-HPLC评估本公开液体组合物中的聚集水平。
本文描述为“包括”或“包含”一个或多个命名的要素或步骤的组合物或方法是开放式的，意味着所述命名的元件或步骤是必要的，但可在所述组合物或方法的范围内添加其他元件或步骤。在本文公开的任何组合物或方法中，任何命名的基本元件或步骤的已知或公开的等同物可取代所述元素或步骤。
具体实施方式
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药物原料、试剂材料等，如无特殊说明，均为市售购买产品，或是按照本领域公知技术可以制得的。
本文使用尺寸排阻色谱法SEC-HPLC，可用于评估抗α4β7抗体(如维得利珠单抗)的物理稳定性。SEC被用于根据非变性条件下的尺寸将单体抗α4β7抗体(包括维得利珠单抗)从聚集体和片段中分离。本文使用“SEC纯度”表示SEC中单体的百分比，用于评估抗α4β7抗体(包括维得利珠单抗)的稳定性。在主峰之前洗出的峰之和报告为聚集产物百分比(聚体，AP-SEC)，在主峰之后洗出的峰之和报告为降解产物百分比(片段，DP-SEC)。根据中国药典2015年版三部通则<0512>测定。本发明中具体步骤为：SEC-HPLC检测采用沃特世厂家的E2695-2489的高效液相色谱仪器进行检测，流动相是25％甲醇和150mM磷酸钠溶液，检测波长280nm，将供试品稀释至约2mg/mL抗体浓度，作为供试品溶液，取供试品溶液20μL注入液相色谱仪，利用面积归一化法计算，单体相对含量：报告数值，聚体相对含量：报告数值，片段含量：报告数值。
本文中阳离子交换高效液相色谱CEX-HPLC可用于评估抗α4β7抗体(包括维得利珠单抗)的化学稳定性。使用CEX通过测定酸性和碱性变体的百分比来评价维得利珠单抗的电荷异质性(参考中国药典2015版三部附录IIIB)。具体步骤为：使用岛津公司高效液相色谱仪，赛默飞ProPacTM WCX-10色谱柱，以20mM MES为流动相，波长为280nm，样品稀释至浓度为2mg/ml，然后进行检测。按面积归一化法计算。
十二烷基硫酸钠-毛细管凝胶电泳(CE-SDS)用于评估抗α4β7抗体(如维得利珠单抗)的纯度(参考中国药典2015版第三部)。本发明中采用SCIEX厂家的CESI 8000Plus的毛细管电泳仪进行检测，将供试品稀释至10g/L，上样体积20ul，采用面积归一化法计算。
实施例中使用的维得利珠单抗为实验室利用常规生物技术自制的维得利珠单抗，序列(重链可变区氨基酸序列为SEQ ID NO:7，轻链可变区氨基酸序列为SEQ ID NO:8)与市面上所售的维得利珠单抗序列一致。制备维得利珠单抗的方法为：应用DNA重组技术构建表达抗α4β7抗体的CHO(中国仓鼠卵巢)细胞：将α4β7编码序列克隆至真核表达载体中，得到重组表达载体；将获得的重组表达载体转入CHO-GS细胞，经筛选和鉴定获得表达抗α4β7抗体的细胞株。本发明实施例中的CHO-GS细胞(中国仓鼠卵巢细胞)购自默克公司；抗α4β7抗体重链和轻链的氨基酸序列分别为SEQ ID NO:9和SEQ ID NO:10。接种表达抗α4β7抗体的CHO细胞至基础培养基中发酵培养12-18天收获，利用常规生物技术分离纯化得到抗α4β7抗体。得到与具有相同理化性质的抗α4β7抗体产品。
通过以上已知的常规重组蛋白技术制备得到维得利珠单抗，然后将药物活性成分维得利珠单抗与不同赋形剂通过以下所述的配制方法进行制剂配制：
置换缓冲液配制方法：
置换缓冲液A:按处方量称量缓冲液、第一稳定剂和第二稳定剂，注射用水定至总体积7000ml，搅拌混合均匀，pH至约6.0-6.6，此为最终置换缓冲液。
液体制剂和冻干制剂配制方法：
1.将纯化后的样品(活性成分是维得利珠单抗)进行超滤，超滤速度为20～30ml/min，压力小于2bar。
2.超滤完成后进行蛋白浓度测定，浓度为40mg/ml时，进行等比换液；置换操作过程中进行透过端液体的电导率，PH测定，透过端测得的PH，渗透压与置换缓冲液一致时，停止换液。
3.将置换缓冲液后的样品(活性成分是维得利珠单抗)进行超滤过浓缩至100-120mg/ml，收集样品并记录体积。然后，用置换缓冲液进行系统的冲洗并加入到过浓缩的样品中，使样品浓度为60mg/ml。
4.在60mg/ml的样品(活性成分是维得利珠单抗)中加入表面活性剂，使表面活性剂的最终浓度为0.02％，从而得到最终制剂。
5.将最终制剂在无菌环境下用0.22μm滤膜过滤并分装至预灌封注射器中，分装体积为1ml/支，共1000支，贴好标签，得到液体制剂。
或者将最终制剂进行终端除菌，并进行罐装至西林瓶中(5.50ml/支)，共100支。然后进行冻干、贴签，包装至最终的外包材中，得到冻干制剂。
实施例
配制制剂
按照前述液体制剂配制方法配制，得到如下制剂：
实施例1：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH 6.3，液体制剂。
实施例2：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH 6.0，液体制剂。
实施例3：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH 6.2，液体制剂。
实施例4：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH6.6，液体制剂。
按照前述冻干制剂配制方法配制，得到如下制剂：
实施例5：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH 6.3，冻干制剂，以上为冻干制剂复溶后的浓度。
对比例1-14制剂配制
按照前述液体制剂配制方法配制，得到如下对比例的液体制剂：
对比例1：维得利珠单抗60mg/ml，蔗糖100mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例2：维得利珠单抗60mg/ml，蔗糖100mg/ml，甘氨酸17.02mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例3：维得利珠单抗60mg/ml，蔗糖100mg/ml，氯化钠6.95mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80
0.6mg/ml，pH 6.3，液体制剂。
对比例4：维得利珠单抗60mg/ml，山梨醇59mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例5：维得利珠单抗60mg/ml，海藻糖99mg/ml，盐酸精氨酸30mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例6：维得利珠单抗60mg/ml，海藻糖118mg/ml，盐酸精氨酸22.36mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例7：维得利珠单抗60mg/ml，海藻糖127mg/ml，盐酸精氨酸18.28mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例8：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，柠檬酸0.8mg/ml，柠檬酸钠14.0mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例9：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，冰醋酸0.08mg/ml，三水醋酸钠6.60mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例10：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，磷酸二氢钠10.5mg/ml，磷酸氢二钠3.20mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例11：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，柠檬酸2.40mg/ml，磷酸氢二钠7.00mg/ml，吐温80 0.6mg/ml，pH 6.3，液体制剂。
对比例12：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH至5.8，液体制剂。
对比例13：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH至6.8，液体制剂。
按照前述冻干制剂配制方法配制，得到
对比例14：维得利珠单抗60mg/ml，蔗糖100mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3，冻干制剂。
试验例1：第一稳定剂的选择
评价不同第一稳定剂在长期(4℃)、高温(40℃)储存条件下，储存期间对维得利珠单抗物理稳定性(SEC-HPLC(SEC高分子蛋白：中国药典2015版通则)、化学稳定性(CEX-HPLC赖氨酸变体，参考中国药典2015版三部附录IIIB)的影响。在预灌封注射器中评价第一稳定剂(蔗糖、海藻糖和山梨醇)的影响，具体处方如下：
对比例1：维得利珠单抗60mg/ml，蔗糖100mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3。
实施例1：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3。
对比例4：维得利珠单抗60mg/ml，山梨醇59mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3。
结果见表1-4。根据加速和4℃长期稳定性24周结果，从SEC结果可以看出实施例1的聚体相较对比例1低，且CEX结果可以看出实施例1酸性变体最低，综合以上，海藻糖作为第一稳定剂，相较于蔗糖和山梨醇，抗体制剂稳定性较优。
表1SEC-HPLC检测结果(40℃)
表2CEX-HPLC检测结果(40℃)
表3SEC-HPLC检测结果(4℃)
表4CEX-HPLC检测结果(4℃)
试验例2：第二稳定剂的选择
评价不同第二稳定剂在高温(40℃)储存条件下，储存期间对维得利珠单抗物理稳定性(SEC-HPLC(SEC高分子蛋白：中国药典2015版通则；CE-SDS毛细管电泳法：中国药典2020年版第四部)、化学稳定性(CEX-HPLC赖氨酸变体，参考中国药典2015版三部附录IIIB)的影响。
在预灌封注射器中评价稳定剂种类(盐酸精氨酸、甘氨酸、氯化钠)的影响。具体处方如下：
对比例1：维得利珠单抗60mg/ml，蔗糖100mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3；
对比例2：维得利珠单抗60mg/ml，蔗糖100mg/ml，甘氨酸
17.02mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3；
对比例3：维得利珠单抗60mg/ml，蔗糖100mg/ml，氯化钠6.95mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80
0.6mg/ml，pH 6.3。
结果见表5-7。根据加速24周结果， 从SEC结果可以看出对比例1聚体最低，且从CE结果可以看出对比例1抗体纯度较高，从CEX结果可以看出对比例1酸性变体最低，综合以上盐酸精氨酸作为第二稳定剂时，相较于甘氨酸、氯化钠，抗体制剂稳定性较优。
表5 SEC-HPLC检测结果(40℃)
表6 CE-SDS检测结果(40℃)
表7 CEX-HPLC检测结果(40℃)
试验例3：第一稳定剂和第二稳定剂含量的选择
评价不同含量稳定剂第一稳定剂和第二稳定剂在长期(4℃)、高温(40℃)储存条件下，储存期间对维得利珠单抗物理稳定性(SEC-HPLC，SEC高分子蛋白：中国药典2015版通则)、化学稳定性(CEX-HPLC赖氨酸变体，参考中国药典2015版三部附录IIIB)的影响。在预灌封注射器中评价稳定剂含量的影响，具体处方如下：对比例5：维得利珠单抗60mg/ml，海藻糖99mg/ml，盐酸精氨酸30mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温800.6mg/ml，pH 6.3
实施例2：维得利珠单抗60mg/ml，海藻糖110mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3
对比例6：维得利珠单抗60mg/ml，海藻糖118mg/ml，盐酸精氨酸22.36mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3
对比例7：维得利珠单抗60mg/ml，海藻糖127mg/ml，盐酸精氨酸18.28mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3
结果见表8-11。根据加速24周结果，从SEC结果可以看出实施例2(海藻糖浓度为110mg/ml，盐酸精氨酸浓度为26.34mg/ml时)聚体最低，且从CEX结果可以看出,实施例2(海藻糖浓度为110mg/ml，盐酸精氨酸浓度为26.34mg/ml时)酸性变体与其他处方差异不大；且从4℃、24周结果可知，实施例2(海藻糖为110mg/ml)和对比例5(海藻糖为99mg/ml)的SEC聚体和酸峰结果相当且均较优；综上，海藻糖浓度为约99mg/L-约118mg/mL,优选地海藻糖浓度为约99mg/L-约112mg/mL，更优选地海藻糖浓度为约110-112mg/mL，抗体制剂具有较优的稳定性；盐酸精氨酸约22mg/ml-约30mg/ml，优选地约26.34mg/ml-约30 mg/ml，更优选地为约26.34mg/ml时，具有较优的稳定性；其中海藻糖浓度为约110-112mg/ml，盐酸精氨酸浓度为26.34mg/ml时抗体制剂稳定性最优。
表8 SEC-HPLC检测结果(40℃)
表9 CEX-HPLC检测结果(40℃)
表10 SEC-HPLC检测结果(4℃)
表11 CEX-HPLC检测结果(4℃)
实验例4：缓冲液的选择
评价不同缓冲液在长期(4℃)、高温(40℃)储存条件下，储存期间对维得利珠单抗物理稳定性(SEC-HPLC(SEC高分子蛋白：中国药典2015版通则)、化学稳定性(CEX-HPLC赖氨酸变体，参考中国药典2015版三部附录IIIB)的影响。在预灌封注射器中评价不同缓冲对(组氨酸、柠檬酸、乙酸、磷酸等)的影响，具体处方如下：实施例1：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温800.6mg/ml，pH 6.3
对比例8：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，柠檬酸0.8mg/ml，柠檬酸钠14.0mg/ml，吐温80 0.6mg/ml，pH 6.3
对比例9：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，冰醋酸0.08mg/ml，三水醋酸钠6.60mg/ml，吐温80 0.6mg/ml，pH 6.3
对比例10：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，磷酸二氢钠10.5mg/ml，磷酸氢二钠3.20mg/ml，吐温80 0.6mg/ml，pH 6.3
对比例11：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，柠檬酸2.40mg/ml，磷酸氢二钠7.00mg/ml，吐温80 0.6mg/ml，pH 6.3
结果见表12-15。根据加速(40℃)、8周结果，从SEC结果可以看出实施例1(缓冲液为组氨酸)聚体最低，纯度最高，且从CEX结果可以看出实施例1(缓冲液为组氨酸)酸性变体最低，纯度较高；其次是对比例8(即柠檬酸缓冲液)；根据长期(4℃)、8周试验结果，从SEC结果可以看出实施例1(缓冲液为组氨酸)聚体最低，纯度最高，且从CEX结果可以看出实施例1(缓冲液为组氨酸)酸性变体与其他对比例相当，纯度均较高；综合以上，实施例1(即组氨酸缓冲液)和对比例8(即柠檬酸缓冲液)中的抗体制剂稳定性均较优，其中实施例1的抗体制剂稳定性最优。
表12 SEC-HPLC检测结果(40℃)
表13 CEX-HPLC检测结果(40℃)
表14 SEC-HPLC检测结果(4℃)
表15 CEX-HPLC检测结果(4℃)
试验例5：不同pH的影响
用盐酸或氢氧化钠调节不同pH，并在长期(4℃)、高温(40℃)条件下储存，储存期间对维得利珠单抗物理稳定性(SEC-HPLC，SEC高分子蛋白：中国药典2015版通则)、化学稳定性(CEX-HPLC赖氨酸变体，参考中国药典2015版三部附录IIIB)的影响。在预灌封注射器中评价pH对抗体稳定性的影响，具体处方如下：
对比例12：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH至5.8。
实施例2：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH至6.0。
实施例3：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH至6.2。
实施例4：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH至6.6。
对比例13：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，用盐酸或氢氧化钠调节pH至6.8。
结果见表16-19。根据加速(40℃)和长期(4℃)、12周结果，从SEC结果可以看出pH为6.0-6.6时，聚体较低，纯度较高，且从CEX可以看出pH为6.0-6.6时，纯度最高；综合以上，pH为6.0-6.6时稳定性较优。
表16 SEC-HPLC检测结果(40℃)
表17 CEX-HPLC检测结果(40℃)
表18 SEC-HPLC检测结果(4℃)
表19 CEX-HPLC检测结果(4℃)
试验例6：冻干制剂中不同第一稳定剂的影响
评价不同第一稳定剂在长期(4℃)、高温(40℃)储存条件下，储存期间对维得利珠单抗物理稳定性(SEC-HPLC(SEC高分子蛋白：中国药典2015版通则)、化学稳定性(CEX-HPLC赖氨酸变体，参考中国药典2015版三部附录IIIB)的影响。在西林瓶中冻干后评价含有不同稳定剂(蔗糖和海藻糖)的制剂的稳定性，具体处方如下：对比例14：维得利珠单抗60mg/ml，蔗糖100mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温800.6mg/ml，pH 6.3
实施例5：维得利珠单抗60mg/ml，海藻糖112mg/ml，盐酸精氨酸26.34mg/ml，组氨酸4.6mg/ml，组氨酸盐酸4.28mg/ml，吐温80 0.6mg/ml，pH 6.3
结果见表20-23。根据加速(40℃)和长期(4℃)、24周结果，从SEC结果可以看出实施例5在存储过程中产生的聚体相较对比例14更低，且从CEX结果可以看出实施例5在存储过程中产生的酸性变体也最低，综合以上，实施例5抗体冻干制剂的稳定性较优，即海藻糖作为第一稳定剂时，稳定性更优。
表20 SEC-HPLC检测结果(40℃)
表21 CEX-HPLC检测结果(40℃)
表22 SEC-HPLC检测结果(4℃)
表23 CEX-HPLC检测结果(4℃)
本发明已经通过上述实施例进行了说明，但应当理解的是，上述实施例只是用于举例和说明的目的，而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是，本发明并不局限于上述实施例，根据本发明的教导还可以做出更多种的变型和修改，这些变型和修改均落在本发明所要求保护的范围以内。本发明的保护范围由附属的权利要求书及其等效范围所界定。
Claims (10)
1.一种稳定的药物制剂，其包含抗α4β7抗体和第一稳定剂，其中所述的第一稳定剂为海藻糖；优选地，所述海藻糖的浓度为约99-118g/L,更优选地所述海藻糖的浓度为约99-112g/L，最优选地，所述海藻糖的浓度为约112g/L。
2.根据权利要求1所述的药物制剂，其中，所述抗α4β7抗体包含重链可变区(VH)和，所述抗α4β7抗体包含轻链可变区(VL)；其中，所述重链可变区中包含氨基酸序列为SEQ IDNO:1的HCDR1、氨基酸序列为SEQ ID NO:2的HCDR2和/或氨基酸序列为SEQ ID NO:3的HCDR3；所述轻链可变区中包含氨基酸序列为SEQ ID NO:4的LCDR1、氨基酸序列为SEQ IDNO:5的LCDR2和/或氨基酸序列为SEQ ID NO:6的LCDR3；优选地，所述抗α4β7抗体包含氨基酸序列为SEQ ID NO:7的重链可变区(VH)和氨基酸序列为SEQ ID NO:8的轻链可变区(VL)；更优选地，所述抗α4β7抗体包含氨基酸序列为SEQ ID NO:9的重链和氨基酸序列为SEQ IDNO:10的轻链；最优选地，所述抗α4β7抗体是维得利珠单抗；
进一步优选地，所述抗α4β7抗体的浓度是约50-70g/L；更进一步优选地，所述抗α4β7抗体的浓度是约60g/L。
3.根据权利要求1-2任一项所述的药物制剂，其中，所述药物制剂还包含第二稳定剂，其中所述第二稳定剂选自盐酸精氨酸、甘氨酸和氯化钠；优选地，所述第二稳定剂为盐酸精氨酸。
4.根据权利要求3所述的药物制剂，其中，所述第二稳定剂的浓度为约22g/L-30g/L，优选地所述第二稳定剂的浓度为约26.34g/L-
30g/L，更优选地所述第二稳定剂的浓度为约26.34g/L。
5.根据权利要求1-4任一项所述的药物制剂，所述药物制剂还包含表面活性剂，其中所述表面活性剂选自吐温80、吐温20和泊洛沙姆188；优选地，所述表面活性剂是吐温80；更优选地，所述表面活性剂的浓度是约0.4-0.8g/L；最优选地，所述表面活性剂的浓度是约0.6g/L；和/或
所述药物制剂还包含缓冲液，其中所述缓冲液选自组氨酸-组氨酸盐酸和柠檬酸-柠檬酸钠；优选地，所述缓冲液是组氨酸-组氨酸盐酸；更优选地，所述缓冲液的浓度是约40mM-65mM；最优选地，所述缓冲液的浓度是约50mM。
6.根据权利要求1-5任一项所述的药物制剂，其中，所述药物制剂包含抗α4β7抗体、海藻糖、盐酸精氨酸、吐温80和组氨酸-组氨酸盐酸缓冲液。
7.根据权利要求1-6任一项所述的药物制剂，其中，所述药物制剂包含约50-70g/L抗α4β7抗体、约99-112g/L海藻糖、约22g/L-30g/L盐酸精氨酸、约0.4-0.8g/L吐温80和约40-65mM组氨酸-组氨酸盐酸缓冲液。
8.根据权利要求1-7任一项所述的药物制剂，所述药物制剂包含约60g/L抗α4β7抗体、约112g/L海藻糖、约26.34g/L盐酸精氨酸、约0.6g/L吐温80和约50mM组氨酸-组氨酸盐酸缓冲液。
9.根据权利要求1-8中任一项所述的药物制剂，其中，所述药物制剂的PH值为约6.0-6.6，优选地所述PH值为6.3。
10.根据权利要求1-9中任一项所述的药物制剂,其中所述制剂为液体制剂或冻干制剂。
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