CN111201042A - 减少粒子形成的方法以及由其形成的组合物 - Google Patents
减少粒子形成的方法以及由其形成的组合物 Download PDFInfo
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- CN111201042A CN111201042A CN201880060396.5A CN201880060396A CN111201042A CN 111201042 A CN111201042 A CN 111201042A CN 201880060396 A CN201880060396 A CN 201880060396A CN 111201042 A CN111201042 A CN 111201042A
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Abstract
本文所公开的生物药物组合物和药物产品表现出减少量的亚可见的粒子形成。本文所公开的组合物和药物产品包含蛋白质和表面活性剂或稳定剂，所述表面活性剂或稳定剂包括高百分比量(例如，至少97％)的长链脂肪酸酯。本文还公开了制备和储存此类组合物和药物产品的方法。
Description
相关申请的交叉参考
本申请要求2017年9月19日提交的美国临时申请号62/560,365的优先权益，所述申请的内容以全文引用的方式并入本文。
技术领域
本公开涉及在储存时形成的亚可见的粒子的量得以减少的生物药物制剂和药物产品，并且涉及其制备及储存方法。具体地，本公开涉及包含蛋白质和表面活性剂或稳定剂的制剂和药物产品，以及其制备和储存方法，所述表面活性剂或稳定剂包含高百分比量的长链单不饱和脂肪酸酯。
背景技术
聚山梨醇酯通常已用于含有蛋白质作为活性成分的药物产品(也称为“DP”)中，以保护蛋白质免受在制造、储存、处理和施用过程中表面诱导的(空气/液体或固体/液体)不稳定性影响。已发现，与感兴趣蛋白(POI)共纯化的脂肪酶当与聚山梨醇酯一起存在于制剂中时，可以将聚山梨醇酯中的脂肪酸酯水解成游离脂肪酸。聚山梨醇酯中脂肪酸酯的非酶水解也可能在制剂中以较慢速率发生。随着时间的流逝，由于水解而形成的游离脂肪酸可能会在含有此类制剂的药物产品中聚集并形成微粒。微粒(可见的和亚可见的)可能会影响产品稳定性，由于其无法满足药典规定的微粒物质规格(例如，美国FDA规格)而缩短药物产品的保质期，并且在施用后可能会产生临床效应，例如免疫原性反应。
POI的疏水性相互作用色谱法(HIC)或亲和色谱法可以减少或去除与POI共纯化的脂肪酶，从而减少脂肪酸酯水解。然而，增加HIC或亲和色谱法步骤来制备蛋白质制剂需要增加例如设备、材料、制备物、方案和制造方法的方案验证，这会导致时间和成本增加。另外，去除酶的HIC或亲和色谱法步骤将无助于预防制剂中脂肪酸酯的非酶水解。因此需要一种例如在不使用增加的HIC或亲和色谱法步骤的情况下减少或预防蛋白质组合物中的亚可见和可见微粒形成的方法。
附图说明
并入本说明书中并且构成本说明书的一部分的附图示出各种示例性实施方案并且连同描述一起用于解释所公开的实施方案的原理。本文所述的实施方案或实施例(例如，组合物、制剂、方法等)的任何特征可与任何其他实施方案或实施例组合，并且涵盖在本公开中。
图1是聚山梨醇酯80中的主要脂肪酸酯聚氧乙烯(20)脱水山梨醇单油酸酯的化学结构图。
图2是示出在包含不同类型的聚山梨醇酯80的蛋白质药物产品中通过膜显微镜方法测量的亚可见的微粒(≥10μm)数目的图表。
图3是示出在包含不同类型的聚山梨醇酯80的蛋白质药物产品中通过微流成像(MFI)测量的亚可见的微粒(≥10μm)数目的图表。
图4是示出在包含不同类型的聚山梨醇酯80的蛋白质药物产品中所测量的游离脂肪酸浓度的图表。
如本文所用，术语“包括(comprises/comprising)”或其任何其他变型意图涵盖非排他性的包括，以使得包括一系列元素的过程、方法、制品或设备不仅包括这些元素，而且可包括未明确列出或此类过程、方法、制品或设备所固有的其他元素。在“实施例”而非“理想”的意义上使用术语“示例性”。除非另外明确说明，否则对于术语“例如”和“诸如”及其语法等效物而言，应理解为其后跟有短语“但不限于”。
如本文所用，术语“约”是为了说明由于实验误差引起的变化。除非另外明确说明，否则将所有本文所报告的测量结果均理解为由术语“约”修饰，不管是否明确使用所述术语。除非上下文另外明确指出，否则如本文所用，单数形式“一个(种)(a/an)”和“所述(the)”包括复数个指代物。
应注意，本文所公开的所有数值(包括所有公开的值、限度和范围)可具有相对于所公开的数值+/-10％的变量(除非指定不同变量)。此外，在权利要求书中，值、限度和/或范围意指+/-10％的值、限度和/或范围。
具体实施方式
本公开不限于本文所公开的具体组合物、制剂、材料制造商、药物产品、方法或实验条件，因为许多变型可能处于本领域普通技术人员的权限内。本文所使用的术语仅仅出于描述具体实施方案的目的，并且不意图是限制性的。
除非另外定义，否则本文使用的所有技术和科学术语都具有与本公开所属领域的普通技术人员通常理解相同的含义。虽然与本文描述的那些方法和材料类似或等效的任何方法和材料可以用于本发明的实践或测试，但现在将描述具体方法和材料。所提及的所有文献特此以引用的方式并入。
如本文所用，术语“蛋白质”是指具有多于约20个通过酰胺键共价连接的氨基酸的任何氨基酸聚合物。蛋白质含有一条或多条本领域通常称为“多肽”的氨基酸聚合物链。因此，多肽可以是蛋白质，并且蛋白质可以含有形成单一构象的单功能生物分子的多个多肽。二硫桥(例如，处于半胱氨酸残基之间以形成胱氨酸)可存在于一些蛋白质中。例如，二硫桥对于胰岛素、免疫球蛋白、鱼精蛋白等的适当结构和功能是必需的。
除了二硫键形成，蛋白质可能会经受其他的翻译后修饰。这些修饰包括脂化(例如，豆蔻酰化、棕榈酰化、法尼基化(farnesoylation)、香叶基香叶基化和糖基磷脂酰肌醇(GPI)锚定形成)、烷基化(例如甲基化)、酰化、酰胺化、糖基化(例如，向精氨酸、天冬酰胺、半胱氨酸、羟基赖氨酸、丝氨酸、苏氨酸、酪氨酸和/或色氨酸添加糖基)和磷酸化(即，向丝氨酸、苏氨酸、酪氨酸和/或组氨酸添加磷酸基团)。
如本文所用，术语“蛋白质”包括生物治疗性蛋白质、用于研究或治疗的重组蛋白质、捕获蛋白质和其他Fc-融合蛋白、嵌合蛋白、抗体、单克隆抗体、人源抗体、双特异性抗体、抗体片段、抗体样分子、纳米抗体、重组抗体嵌合体、细胞因子、趋化因子、肽激素等。蛋白质可以使用基于重组细胞的生产系统产生，例如昆虫杆状病毒系统、酵母系统(例如，毕赤酵母属某种(Pichia sp.))、哺乳动物系统(例如，CHO细胞和CHO衍生物，例如CHO-K1细胞)。
如本文所用，术语“抗体”包括免疫球蛋白，其包含通过二硫键相互连接的四条多肽链，即两条重(H)链和两条轻(L)链。通常，根据本公开的抗体具有超过100kDa的分子量，诸如130kDa与200kDa之间，诸如约140kDa、145kDa、150kDa、155kDa、或160kDa。各重链包括重链可变区(文中缩写为HCVR或VH)和重链恒定区。重链恒定区包括三个结构域，即CH1、CH2和CH3。各轻链包括轻链可变区(文中缩写为LCVR或VL)和轻链恒定区。轻链恒定区包括一个结构域，CL。VH和VL区可进一步细分为高变区(称为互补决定区(CDR))，其间散布着较保守的区(称为框架区(FR))。各VH和VL由三个CDR和四个FR构成，以下列顺序由氨基端排列至羧基端：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4(重链CDR可缩写为HCDR1、HCDR2和HCDR3；轻链CDR可缩写为LCDR1、LCDR2和LCDR3。
称为免疫球蛋白G(IgG)的一类免疫球蛋白例如常见于人类血清中并且包含四条多肽链，即两条轻链和两条重链。每条轻链经由胱氨酸二硫键连接至一条重链，并且两条重链经由两个胱氨酸二硫键彼此结合。人类免疫球蛋白的其他类别包括IgA、IgM、IgD和IgE。在IgG的情况下，存在四个子类别：IgG 1、IgG 2、IgG 3和IgG 4。各子类的恒定区不同，并且因此各子类可具有不同的效应子功能。
如本文所用，术语“抗体”也包括完整抗体分子的抗原结合片段。如本文所用，术语抗体的“抗原结合部分”、抗体的“抗原结合片段”等等包括特异性地结合抗原以形成复合物的任何天然存在、可以酶促方法获得、合成或基因工程改造的多肽或糖蛋白。抗体的抗原结合片段可使用任何适合的标准技术例如从完整抗体分子获得，所述标准技术诸如蛋白质水解消化作用或涉及操作和表达编码抗体可变区和任选地恒定结构域的DNA的重组基因工程改造技术。这种DNA为已知的和/或可容易地从例如商业来源、DNA文库(包括，例如噬菌体-抗体文库)获得，或可进行合成。DNA可用化学方法或通过使用分子生物学技术来定序和操作，例如将一个或多个可变结构域和/或恒定结构域排列成适合构型，或引入密码子，产生半胱氨酸残基，修饰、增添或缺失氨基酸等。
如本文所用，术语“人类抗体”意图包括具有来源于人种系免疫球蛋白序列的可变区和恒定区的抗体。本发明的人抗体可包括并非由人种系免疫球蛋白序列所编码的氨基酸残基(例如通过随机或位点特异性体外诱变或通过体内体细胞突变所引入的突变)，例如在CDR中和特别是CDR3中的氨基酸残基。然而，如本文所用，术语“人类抗体”不意图包括其中来源于另外哺乳动物物种(诸如小鼠)的种系的CDR序列已接枝在人框架序列上的抗体。
短语“含Fc蛋白”包括抗体、双特异性抗体、免疫粘附素和包括至少免疫球蛋白CH2和CH3区的功能部分的其他结合蛋白质。“功能部分”是指可以结合Fc受体(例如，FcγR；或FcRn，即新生儿Fc受体)和/或可以参与互补序列活化的CH2和CH3区。如果CH2和CH3区含有缺失、替换和/或插入或导致无法结合任何Fc受体并且还无法活化互补序列的其他修饰，那么CH2和CH3区是没有功能的。
含Fc的蛋白可包含在免疫球蛋白结构域内的修饰，包括修饰影响结合蛋白的一种或多种效应子功能(例如，影响FcγR结合、FcRn结合和由此半衰期和/或CDC活性的修饰)的情况。此类修饰包括但不限于参考免疫球蛋白恒定区的EU编号的以下修饰及其组合：238、239、248、249、250、252、254、255、256、258、265、267、268、269、270、272、276、278、280、283、285、286、289、290、292、293、294、295、296、297、298、301、303、305、307、308、309、311、312、315、318、320、322、324、326、327、328、329、330、331、332、333、334、335、337、338、339、340、342、344、356、358、359、360、361、362、373、375、376、378、380、382、383、384、386、388、389、398、414、416、419、428、430、433、434、435、437、438和439。
作为实例而并不作为限制，结合蛋白质为含Fc蛋白并且可以表现出增强的血清半衰期(与不具有所述修饰的相同含Fc蛋白相比)，并且可具有在位置250(例如，E或Q)；250和428(例如，L或F)；252(例如，L/Y/F/W或T)、254(例如，S或T)，以及256(例如，S/R/Q/E/D或T)处的修饰；或在428和/或433(例如，L/R/SI/P/Q或K)和/或434(例如，H/F或Y)处的修饰；或在250和/或428处的修饰；在307或308(例如，308F、V308F)和434处的修饰。在另一个实例中，修饰可包括428L(例如M428L)和434S(例如N434S)修饰；428L、259I(例如V259I)和308F(例如V308F)修饰；433K(例如H433K)和434(例如434Y)修饰；252、254和256(例如252Y、254T和256E)修饰；250Q和428L修饰(例如T250Q和M428L)；或307和/或308修饰(例如308F或308P)。
术语“细胞”包括任一种适于表达重组核酸序列的细胞。细胞包括原核生物与真核生物的细胞(单细胞或多细胞)、细菌细胞(例如大肠杆菌、杆菌属某些种、链霉菌属某些种等的菌株)、分枝杆菌细胞、真菌细胞、酵母菌细胞(例如酿酒酵母(S.cerevisiae)、粟酒裂殖酵母(S.pombe)、巴氏毕赤酵母(P.pastoris)、嗜甲醇酵母菌(P.methanolica)等)、植物细胞、昆虫细胞(例如SF-9、SF-21、杆状病毒感染的昆虫细胞、粉斑夜蛾(Trichoplusiani)等)、非人动物细胞、人细胞或细胞融合物，例如像融合瘤或四价体瘤。在一些实施方案中，所述细胞为人、猴、猿、仓鼠、大鼠或小鼠细胞。在一些实施方案中，所述细胞为真核细胞并选自以下细胞：CHO(例如CHO K1、DXB-11CHO、Veggie-CHO)、COS(例如COS-7)、视网膜细胞、Vero、CV1、肾脏(例如HEK293、293EBNA、MSR 293、MDCK、HaK、BHK)、HeLa、HepG2、WI38、MRC 5、Colo205、HB 8065、HL-60(例如BHK21)、Jurkat、Daudi、A431(上皮)、CV-1、U937、3T3、L细胞、C127细胞、SP2/0、NS-0、MMT 060562、足细胞、BRL 3A细胞、HT1080细胞、骨髓瘤细胞、肿瘤细胞以及来源于上述细胞的细胞系。在一些实施方案中，所述细胞包含一个或多个病毒基因，例如表达病毒基因的视网膜细胞(例如PER.C6TM细胞)。
术语“脂肪酸酯”意指含有经由酯键连接至头部基团的脂肪酸链的任何有机化合物。当羟基(例如，醇或羧酸)被烷氧基替代时，形成酯键。如本文所用，羟基可为羧酸(更确切地说为脂肪酸)和/或醇(诸如甘油、山梨醇、脱水山梨糖醇、异山梨醇或其类似物)的一部分。醇基团通常在本文中被称为头部基团。
脂肪酸酯的实例通常包括磷脂、脂质(例如，头部基团为甘油，包括甘油单酯、甘油二酯和甘油三酯)以及表面活性剂和乳化剂，包括例如聚山梨醇酯，像聚山梨醇酯20、聚山梨醇酯60和聚山梨醇酯80，其为非离子型洗涤剂。表面活性剂和乳化剂适用作助溶剂和稳定剂。它们通过与亲水性表面和亲脂性表面缔合以维持成分像蛋白质的分散性和结构稳定性来起作用。表面活性剂主要添加到蛋白质制剂中以增强蛋白质针对机械应激的稳定性，所述机械应激诸如气体/液体界面诱导和固体/液体界面诱导的部分展开和自身缔合。在没有表面活性剂的情况下，蛋白质在一些情况下可变得在溶液中在结构上不稳定，并且形成多聚体聚集物，其最终变成亚可见的粒子。
术语“脂肪酸”或“脂肪酸链”意指具有脂肪族尾部的羧酸。脂肪族尾部为简单烃链，其包含碳和氢并且在一些情况下包含氧、硫、氮和/或氯取代。脂肪族尾部可为饱和的(如在饱和脂肪酸中)，这意味着所有碳-碳键均为单键(即，烷烃)。脂肪族尾部可为不饱和的(如在不饱和脂肪酸中)，其中一个或多个碳-碳键为双键(烯烃)或三键(炔烃)。
脂肪酸通常指定为在其脂肪族尾部具有少于六个碳的短链脂肪酸、具有六个至十二个碳的中链脂肪酸、具有十三个至二十一个碳的长链脂肪酸和具有二十二个碳和更长链的脂肪族尾部的极长链脂肪酸。如上文所提及，脂肪酸也根据其饱和度来分类，所述饱和度与硬度和熔点相关。常见脂肪酸包括辛酸(8个碳:0个双键；8:0)、癸酸(10:0)、月桂酸(12:0)、肉豆蔻酸(14:0)、肉豆蔻脑酸(14:1)、棕榈酸(16:0)、棕榈烯酸(16:1)、顺-6-十六碳烯酸(sapienic acid)(16:1)、硬脂酸(18:0)、油酸(18:1)、反油酸(18:1)、异油酸(18:1)、亚油酸(18:2)、反式亚油酸(linelaedic acid)(18:2)、α-亚麻酸(18:3)、花生酸(20:0)、花生四烯酸(20:4)、二十碳五烯酸(20:5)、山萮酸(22:0)、芥酸(22:1)、二十二碳六烯酸(22:6)、二十四酸(24:0)和蜡酸(26:0)。
如上文所述，聚山梨醇酯为适用作非离子表面活性剂和蛋白质稳定剂的脂肪酸酯。聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60和聚山梨醇酯80在医药、化妆品和食品工业中广泛用作稳定剂和乳化剂。聚山梨醇酯20主要包含聚氧乙烯(20)脱水山梨糖醇的单月桂酸酯。聚山梨醇酯40主要包含聚氧乙烯(20)脱水山梨糖醇的单棕榈酸酯。聚山梨醇酯60主要包含聚氧乙烯(20)脱水山梨糖醇的单硬脂酸酯。聚山梨醇酯80主要包含聚氧乙烯(20)脱水山梨糖醇的单油酸酯(图1中所示)。
聚山梨醇酯的商业品级的品质因供应商不同而不同。聚山梨醇酯通常为各种化学实体的混合物，其主要由聚氧乙烯(20)脱水山梨糖醇单酯(如上文所述)以及在一些情况下异山梨醇酯污染物组成。它们还可包括例如聚乙二醇(PEG)、中间体结构和脂肪酸反应物。头部基团(在此情况下为聚氧乙烯(20)脱水山梨糖醇)包含在其醇基团中的三个处被取代以与三个聚氧乙烯基团形成醚键的脱水山梨糖醇(脱水山梨醇的混合物，包括1,4-酐山梨醇、1,5-酐山梨醇和1,4,3,6-二酐山梨醇)。第四醇基团被脂肪酸取代以形成脂肪酸酯。
在聚山梨醇酯的一些可商购获得的批料中，聚山梨醇酯含有异山梨醇单酯。异山梨醇为葡萄糖的杂环衍生物，其也通过对山梨醇脱水来制备。其为二醇，即具有可以参与形成一个或两个酯键的两个醇基团。因此，例如一些批次的聚山梨醇酯80可以含有大量的异山梨醇油酸酯单酯和二酯。
除了头部基团变化，聚山梨醇酯的制备物含有可变量的其他脂肪酸酯。例如，对聚山梨醇酯80的一个特定来源的分析揭示了<5％肉豆蔻酸、<16％棕榈酸、>58％油酸、<6％硬脂酸和<18％亚油酸。对聚山梨醇酯80的另一个来源的分析揭示了约70％油酸，其余部分为其他脂肪酸酯和杂质。对聚山梨醇酯80的另一个来源的分析揭示了约86％-87％油酸。对聚山梨醇酯80的另一个最新开发的来源的分析揭示了≥99％油酸。
非离子型洗涤剂像聚山梨醇酯20或聚山梨醇酯80有助于使大分子像抗体和其他蛋白质稳定，并且有助于预防形成寡聚物或其他聚集物。聚集物可以变成10至100微米范围或2至100微米范围的纳米粒子或亚可见的粒子，并且干扰药物产品稳定性和半衰期，并且可诱导免疫原性。因此，在一些情况下，蛋白质制剂的稳定性取决于非离子型洗涤剂添加剂的稳定性。然而并如本文进一步讨论，在一些情况下，聚山梨醇酯20和聚山梨醇酯80可促使形成聚集物、纳米粒子和亚可见的粒子。
根据本公开的短语“亚可见的粒子”(SVP)和“亚可见的微粒”是指裸眼不可见的粒子，尤其是在液体中。换言之，含有SVP而非可见粒子的溶液或其他液体将不会出现混浊。SVP通常包括直径100微米或更小的那些粒子，但在一些情况下包括150微米以下的粒子(Narhi等人,“A critical review of analytical methods for subvisible andvisible particles,”Curr Pharm Biotechnol 10(4):373–381(2009))。SVP可为污染物、蛋白质聚集物或DP的其他组分的聚集物的结果。SVP可尤其包含硅油液滴(油状液滴)、脂肪酸(无定形粒子和/或油状液滴)、聚集的蛋白质(无定形粒子)和/或蛋白质/脂肪酸复合物(无定形粒子)。
SVP可以通过多种方法中的任一者或多者来检测。USP标准指定光阻法(lightobscuration)和光学显微镜法方案。其他方法包括微流成像(MFI)分析、库尔特计数和亚微米粒子追踪方法。SVP的若干种测量和表征方法(例如，光阻法、流式显微镜法、电敏感区法和流式细胞术)例如在Narhi等人,“Subvisible(2–100μm)Particle Analysis DuringBiotherapeutic Drug Product Development:Part 1,Considerations and Strategy,”J.Pharma.Sci.104:1899–1908(2015)中讨论。
光阻法由于低估蛋白质聚集物和其他无定形结构而不受青睐。流成像分析诸如微流成像(MFI)(Brightwell Technologies,Ottawa,Ontario)为检测不规则形状的、易碎的和透明蛋白质SVP并将那些类型的粒子与硅酮微液滴、气泡和其他外来污染物区分开来的更敏感方法(Sharma等人,“Micro-flow imaging:Flow microscopy applied to sub-visible particulate analysis in protein formulations,”AAPS J.12(3):455-464(2010))。一般而言，因为通过光阻法分析进行SVP测量和表征不如MFI敏感，所以通过MFI检测的粒子计数将倾向于高于通过光阻法分析检测到的粒子计数。简言之，MFI为流式显微镜法，其中获得连续明场像并实时分析。图像分析算法应用于这些图像以辨别气泡、硅油液滴和蛋白质聚集物。可以分析低至约250微升至高至数十微升的体积。根据所使用的系统，可以检测2至300微米或1至70微米范围内的粒子。(同上)
FDA和其他政府管理机构已限制胃肠外药物制剂中允许的SVP的量。主要关注问题为与在接受所述药物的患者中的潜在免疫原性和下游负面作用相关的不确定性(Singh等人,“An industry perspective on the monitoring of subvisible particles as aquality attribute for protein therapeutics,”J.Pharma.Sci.99(8):3302-21(2010))。对于小体积胃肠外药物(例如，100mL或更低)，在通过光阻法分析测定时，药典将大于或等于10微米的SVP限制为每个容器不多于6,000个SVP，并且将大于或等于25微米的SVP限制为每个容器不多于600个；在通过膜显微镜测试测定时，将大于或等于10微米的SVP限制为每个容器不多于3,000个SVP，并且将大于或等于25微米的SVP限制为每个容器不多于300个。(美国药典和国家处方集(USP 40-NF 28)，<787>治疗性蛋白质注射液中的亚可见的微粒物质。)对于眼用药物，SVP限度为50个/mL的10微米或更大、5个/mL的25微米或更大和2个/mL的50微米或更大(在<789>眼用溶液中的微粒物质处，同上)。管理机构越来越多考虑制造商建立2微米或更大的SVP的规格(参见Singh等人,“An industry perspective onthe monitoring of subvisible particles as a quality attribute for proteintherapeutics,”J.Pharm.Sci.99(8):3302-21(2010))。
术语“酯酶”意指催化酯键水解以形成酸和醇的酶。酯酶为不同类别的酶，包括乙酰酯酶(例如，乙酰胆碱酯酶)、磷酸酶、核酸酶、硫代酯酶、脂肪酶和其他羧基酯水解酶(EC3.1。如其名称暗示，羧基酯水解酶(又称为羧基酯酶、羧酸酯水解酶和EC 3.1.1.1)使用水将羧酸酯水解为醇和羧酸盐。脂肪酶为催化脂质(包括甘油三酯、脂肪和油)水解为脂肪酸和醇头部基团的羧基酯水解酶。例如，甘油三酯由脂肪酶像胰腺脂肪酶水解以形成单酰基甘油和两条脂肪酸链。
磷脂酶为将磷脂水解为脂肪酸和其他产物的脂肪酶。磷脂酶属于以下四个广泛类别：磷脂酶A(包括磷脂酶A1和磷脂酶A2)、磷脂酶B和磷酸二酯酶磷酸二酯酶C和磷酸二酯酶D。除了典型磷脂酶，驻留在溶酶体腔处的磷脂酶B样酶被认为参与脂质催化。例如，假设磷脂酶B样2(PLBL2)基于序列同源性和亚细胞定位而具有酯酶活性(Jensen等人,“Biochemical characterization and liposomal localization localization of themannose-6-phosphate protein p76,”Biochem.J.402:449-458(2007))
已发现与聚山梨醇酯(包括聚山梨醇酯20和聚山梨醇酯80)的去稳定性相关的酶促活性。已发现该活性与酯酶诸如包含表1的胺基酸序列的多肽相关。那些肽序列的BLAST搜索揭示了与假定的磷脂酶B样2(PLBL2)的同一性。PLBL2在仓鼠、大鼠、小鼠、人类和牛中为高度保守的。申请人设想的是，PLBL2在某些过程下与一些类别的在哺乳动物细胞系中制造的感兴趣蛋白(POI)共纯化，其具有负责水解聚山梨醇酯20和80的酯酶活性。申请人设想的是，根据特定感兴趣蛋白和/或宿主细胞的遗传/表观遗传背景，其他酯酶种类(其中PLBL2为一个实例)可导致聚山梨醇酯不稳定。
最近报告了聚山梨醇酯80的酯水解(参见Labrenz,S.R.,“Ester hydrolysis ofpolysorbate 80in mAb drug product:evidence in support of the hypothesizedrisk after observation of visible particulate in mAb formulations,”J.Pharma.Sci.103(8):2268-77(2014))。该论文报告了含有IgG的制剂中可见粒子的形成。作者假设胶体IgG粒子由于酶促水解聚山梨醇酯80的油酸酯而形成。尽管未直接鉴别酯酶，但是作者推测与IgG共纯化的脂肪酶或tweenase负责降解聚山梨醇酯80。(在7处同上。)如该论文所述，由于存在聚山梨醇酯80而形成粒子引起了关注，因为此类粒子可能影响IgG药物产品的稳定性和功效。
表1
如本文所用，短语“脂肪酸酯水解百分比”意指已经水解的脂肪酸酯的摩尔比例。由于脂肪酸酯水解导致游离脂肪酸释放，所以脂肪酸酯水解百分比可以通过测量样品中的游离脂肪酸来确定。因此，脂肪酸酯水解百分比可以通过计算游离脂肪酸摩尔数除以游离脂肪酸摩尔数加上脂肪酸酯摩尔数之和来确定。在聚山梨醇酯80或聚山梨醇酯20的水解百分比的情况下，该数值可以通过计算游离脂肪酸的摩尔数并除以其余聚山梨醇酯加上游离脂肪酸摩尔数的总摩尔数来确定。
术语“酯酶抑制剂”意指减少、抑制或阻断酯酶活性的任何化学实体。申请人假设在含有脂肪酸酯表面活性剂的蛋白质制剂中包含酯酶抑制剂可有助于维持蛋白质稳定性并且有助于减少SVP形成。本领域已知的常见酯酶抑制剂包括奥利司他(四氢利普司他汀；羧基酯酶2和脂蛋白脂肪酶的抑制剂)、二乙基伞形酮磷酸酯(胆甾醇酯酶[脂肪酶A]抑制剂)、URB602([1-1’-联苯基]-3-tl-氨基甲酸环己酯；单酰基甘油脂肪酶抑制剂)和2-丁氧基苯基硼酸(激素敏感性脂肪酶抑制剂)。在感兴趣蛋白质纯化期间或在最终制剂中包含酯酶抑制剂可以预防或减慢非离子型洗涤剂如聚山梨醇酯80的水解，这进而预期预防或减少亚可见的粒子形成。然而，包含酯酶抑制剂也可负面影响最终制剂中的活性成分或其他成分的功能。
术语“缓冲液”意指使溶液的pH稳定的缓冲溶液或缓冲剂。缓冲液通常包含弱酸及其共轭碱或弱碱及其共轭酸。使蛋白质溶液缓冲在最佳pH下或接近最佳pH有助于确保适当蛋白质折叠和功能。最佳缓冲液可以在加速储存/温育之后例如通过测量热力学稳定性(DSC)以及在不同pH下蛋白质(例如抗体)溶液的高分子量变体(SEC)和电荷变体(CEX)来鉴别。测量在不同pH下蛋白质(例如抗体)溶液的圆二色性也可以帮助鉴别缓冲液。圆二色性(CD)为用于确定蛋白质的结构变化(展开)的一种方法(S.Beychok,“Circular dichroismof biological macromolecules,”Science 154(3754):1288-99(1966)；Kemmer和Keller,“Nonlinear least-squares data fitting in Excel spreadsheets,”Nat Protoc.5(2):267-81(2010))。一些蛋白质具有充当缓冲液的能力(即，所谓“自身缓冲”)并且因此可不需要添加外来缓冲液来维持稳定pH(Gokarn等人,“Self-buffering antibodyformulations,”J Pharm Sci.97(8):3051-66(2008))。常用缓冲液的实例在表2中列出。关于生物溶液中的缓冲液的更完整讨论，参见Irwin H.Segel,Biochemical Calculations(第2版，1976)或Remington,The Science and Practice of Pharmacy 244(PaulBeringer等人编，第21版，2006)。
表2
术语“热稳定剂”意指包含在生物药物制剂中以提供对蛋白质的保护使其免于热降解、变性和生物活性侵蚀的赋形剂或其他添加剂。一般而言，热稳定剂有助于维持蛋白质(例如抗体)的天然构象并且预防在热应激条件下聚集。热应激可藉由冷冻-解冻循环、暴露于高温或长储存时间发生。热稳定剂包括糖和其他碳水化合物、糖醇和多元醇像聚乙二醇以及胺基酸像甘氨酸。适用作热稳定剂的糖或糖醇的实例包括蔗糖、海藻糖和甘露醇。
术语“疏水性相互作用介质”意指支撑结构和疏水性部分的组合，其中疏水性部分附连至支撑结构。介质可以是呈色谱介质形式(例如保持在填充的床柱形式中的珠粒或其他粒子)、呈膜形式或呈可容纳包含感兴趣蛋白质和污染物的液体的任何形式。因此，支撑结构包括琼脂糖珠粒(例如，琼脂糖凝胶)、二氧化硅珠粒、纤维素膜、纤维素珠粒、亲水性聚合物珠粒等。疏水性部分结合至疏水性分子和蛋白质的疏水性表面。介质的疏水性程度可以通过选择疏水性部分来控制。疏水性相互作用介质用于称为疏水性相互作用色谱法(HIC)的方法中并且用于分离感兴趣蛋白质与产品和方法相关污染物。当在宿主细胞中制造感兴趣蛋白质并且/或者从宿主细胞纯化感兴趣蛋白质时，产品和方法相关污染物被称为宿主细胞蛋白质(HCP)。来自常见生物治疗性制造宿主细胞中国仓鼠卵巢(CHO)细胞的HCP可以被称为CHOP(中国仓鼠卵巢蛋白)。在一些情况下，含有感兴趣蛋白质(POI)和HCP的混合物应用于缓冲液中的HIC介质，所述缓冲液被设计为促进POI中的疏水性基团与HIC介质的疏水性部分结合。POI通过结合疏水性部分来粘合至HIC介质，并且一些HCP未能结合并且在洗涤缓冲液中析出。然后使用促进POI与HIC疏水性部分解离的缓冲液洗脱POI，从而使POI与不合需要的HCP分离。
在一些情况下，HIC疏水性部分结合一些污染物诸如HCP，并且POI从HIC溢流中收集。
在一些情况下，使用结合具有亲脂性属性的特异性蛋白质的亲和色谱法来代替HIC或与HIC一致。由于一些酯酶诸如一般而言脂肪酶或具体地说磷脂酶结合至甘油三酯或磷脂，所以模拟那些脂质的分子可以用于捕获酯酶。例如，“豆蔻酰化ADP核糖基化因子1”(又称为“myrARF1”)可以用于捕获脂肪酶并允许POI保持未结合并使其流过。
如本文所用，术语“容器”意指主要包装组件诸如注射器(如在预填充注射器中)、小瓶(例如用于储存生物药物制剂的2.5mL玻璃小瓶)或容纳固体、液体或气体物质的任何器皿或装置。在此，术语“容器”尤其用于指代容纳生物药物制剂的器皿，因为该术语由FDA和USP以其关于亚可见的粒子的限度的指南使用(美国药典和国家处方集(USP 40-NF 28)，<787>治疗性蛋白质注射液中的亚可见的微粒物质)。
如本公开中所用，术语“组合物”、“制剂”和“配制的药物物质”(FDS)是指包含在药物产品中的两种或更多种药物成分的组合。组合物、制剂或FDS可为例如液体组合物，其包含活性药物成分，诸如抗体，以及赋形剂，诸如稳定剂或表面活性剂。组合物、制剂或FDS可包含多种赋形剂。组合物、制剂或FDS还可包含其他组成，诸如与抗体共纯化的蛋白质。
如本公开中所用，术语“药物产品”(DP)是指包含一定量的FDS并用于包装、运输或施用的剂型。例如，药物产品可以是保持一定体积的FDS以用于向患者施用的预填充注射器。
如上文所讨论，假设与一些POI共纯化的HCP诸如PLBL2对用于具有那些POI的制剂和药物产品中的聚山梨醇酯的脂肪酸酯表现出酯酶样活性。此酯酶样行为被认为导致游离脂肪酸形成，所述游离脂肪酸然后可以聚集以形成SVP。虽然HIC和/或亲和色谱法可以用于纯化POI并从药物产品或制剂中去除HCP，从而减少对脂肪酸酯的酯酶样行为，但是增加HIC或亲和色谱法步骤需要增加装置(例如，疏水性相互作用介质)、材料、制备物、方案和药物产品制造方法的方案验证，这意味着增加时间、资源、实验和成本。因此，希望具有减少包含POI、聚山梨醇酯和共纯化HCP的制剂和药物产品中的SVP形成的替代性方法。
已发现随着时间的推移，包含POI和具有高百分比(例如，>98％)油酸酯含量的聚山梨醇酯80的FDS和药物产品与例如包含具有相对更低百分比(例如，70％或86％-87％)油酸酯含量的聚山梨醇酯80的FDS和药物产品相比表现出更少可测量的SVP形成。甚至在POI未经历HIC或亲和色谱法来去除对脂肪酸酯具有酯酶样行为的HCP时，也是这样情况。
本公开的实施方案涉及包含POI(诸如抗体)和具有>98％油酸酯含量的聚山梨醇酯80的FDS和药物产品，其中POI未经历HIC或亲和色谱法步骤来去除具有酯酶样行为的HCP。在本公开的一些实施方案中，当在容器中在例如约5℃下储存至少6个月时，FDS和药物产品表现出少于3,000个具有10μm或更大直径的粒子的形成。在一些实施方案中，当在容器中在例如约5℃下储存至少6个月时，FDS和药物产品表现出少于2,000、1,500、1,000、800、600、500、400、300、290、275、270或250个具有10μm或更大直径的粒子的形成。在一些方面中，本公开的实施方案涉及制备此类FDS和药物产品的方法。
在本公开的实施方式中，FDS或药物产品包含POI。在一些实施方案中，POI为抗体，诸如人类单克隆抗体。在一些实施方案中，POI为免疫球蛋白，诸如IgG。在一些实施方案中，蛋白质为IgG 1、IgG2、IgG 3或IgG 4。在一些实施方案中，FDS或药物产品包含多于一种POI(例如，FDS或药物产品包括两种或更多种POI的共制剂)。
在本公开的实施方案中，可能已通过本领域已知的纯化步骤来纯化POI。例如，如果POI是免疫球蛋白，则可能已使用蛋白A或蛋白G亲和纯化步骤来对其进行纯化。在一些实施方案中，在所述纯化步骤期间，一种或多种HCP或其他杂质可能已与POI共纯化。例如，在一些实施方案中，FDS或药物产品包含与POI共纯化的酯酶。在一些实施方案中，所述酯酶是磷脂酶B样蛋白，例如PLBL2。
在本公开的实施方案中，FDS或药物产品中POI的浓度范围可为约40mg/mL至约250mg/mL，例如像在约50mg/mL与约160mg/mL之间、约80mg/mL与100mg/mL之间、约100mg/mL与160mg/mL之间、约125mg/mL与155mg/mL之间。
在实施方案中，FDS或药物产品包含一定量的表面活性剂或稳定剂。在一些实施方案中，表面活性剂或稳定剂是包含脂肪酸酯混合物的聚山梨醇酯80，并且其具有至少97％、98％或99％的油酸酯含量。在一些实施方案中，表面活性剂或稳定剂是包含脂肪酸酯混合物的聚山梨醇酯80，并且其具有>98％的油酸酯含量。在其他施方案中，表面活性剂或稳定剂是包含脂肪酸酯混合物的聚山梨醇酯80，并且其具有至少≥99％的油酸酯含量。在实施方案中，FDS或药物产品中表面活性剂或稳定剂的浓度为0.005％与1.00％(w/v)之间，诸如0.5％(w/v)。
在一些实施方案中，FDS或药物产品的体积为约0.25mL与3mL之间，诸如0.25mL、0.5mL、1mL、1.5mL、2mL、2.25mL、2.5mL或3mL。在一些实施方案中，药物产品包含包装在容器中的一定体积的FDS。
在一些实施方案中，FDS或药物产品包含额外赋形剂，例如缓冲剂、热稳定剂或酯酶抑制剂。
在一些实施方案中，FDS或药物产品在约2℃-8℃温度下储存至少6个月。在其他实施方案中，FDS或药物产品储存在例如约5℃、15℃、22℃、24℃或30℃-50℃，诸如约35℃、40℃、45℃或50℃的温度下。
在一些实施方案中，FDS或药物产品储存多达例如2-4周、2个月、3个月、4个月、5个月、6个月、12个月、18个月、24个月或36个月。例如，在一些实施方案中，FDS或药物产品在约5℃温度下储存长达24个月。在其他实施方案中，FDS或药物产品在约30℃-50℃温度下储存长达5个月。
实施例
实施例1
在不同DP样品中评估了由于由共纯化的宿主细胞蛋白(HCP)脂肪酶导致的聚山梨醇酯降解而易于形成基于游离脂肪酸的亚可见的微粒的IgG4抗体药物产品的储存稳定性。每个DP样品的体积为2.136mL，含有相同浓度的IgG4抗体(150mg/mL)和0.2％(w/v)的若干批次PS80之一。PS80批次中的每个批次具有三个不同百分比含量的油酸酯(70％、87％和≥99％)之一。下表总结了每个FDS样品中PS80的油酸酯百分比含量。
表3
将DP样品在2℃-8℃的玻璃预填充注射器中储存长达24个月。通过显微镜方法和微流成像(MFI)，每六个月测量每个DP样品中的微粒，总共24个月。
图2以图表形式示出了通过显微镜方法测量的具有≥10μm直径的每容器内SVP数目。图3以图表形式示出了通过MFI测量的具有≥10μm直径每容器内SVP数目。如图2和图3所示，DP B和DP C(含有具有≥99％油酸酯含量的PS80的两个DP样品)在整个24个月时间段内显示出最低数目的SVP，如通过显微镜法(图2)和MFI(图3)所测量。含有具有87％油酸酯含量的PS80的DP A在24个月时间段内显示出次最低数目的亚可见的微粒(特别是在24个月内显示800与1200个之间的粒子)。DP D、DP E和DP F在标记至少18个月时全部都显示每个容器超过3000个粒子(如通过两种方法所测量)。
假设DP A、DP B和DP C中的较低粒子数目(与DP D、DP E和DP F中的更多数目粒子相比)是由于使用了具有更高百分比油酸(或长链脂肪酸)酯含量的PS80。油酸是具有一个不饱和键的长链脂肪酸(参见图1)。因此，它具有约13℃的低于室温的熔化温度。亚可见和可见游离脂肪酸(FFA)微粒形成的前体是单个FFA链团聚成聚集物，然后以粒子形式沉淀。在制剂储存在5℃下期间可通过例如酶促水解聚山梨醇酯80中的脂肪酸酯来产生油酸。这种油酸可能会形成SVP，但由于其熔化温度较低，因此在进行分析的室温(约22℃)下，此类粒子更可能以油状液体形式存在于蛋白质制剂中，并且因此在室温下不会以亚可见的微粒形式持久存在。相反，制剂中较高量的非油酸酯含量将导致在水解时形成其相应的FFA，并且由于其熔化温度较高，因此形成的亚可见和可见无定形微粒在分析期间在环境温度下持续存在。
另外，由于油酸酯具有较高的疏水性，因此它们(油酸酯)是比短链脂肪酸酯更好的增溶剂/稳定剂，这使油酸酯能够溶解游离脂肪酸和蛋白质微粒，从而维持产品稳定性。因此，与具有较低油酸酯含量的聚山梨醇酯80相比，具有较高油酸酯含量(＞98％)的聚山梨醇酯80可以为蛋白质制剂和药物产品提供改善的稳定性。
实施例2
在将样品在5℃下储存18个月后，评估每个样品DP(DP A-F)中每种类型的游离脂肪酸的浓度(以微克/mL计)。如实施例1中所述制备样品DP A-F。在18个月时通过LC-MS测量游离脂肪酸浓度。图4以图表形式显示结果。如图所示，DP B和DP C(含有具有≥99％油酸酯含量的PS80的两个DP样品)显示出最高浓度的油酸和最低浓度的其他FFA。这表明DP B和DPC中FFA(即油酸)的均质性。
序列表
<110> 里珍纳龙药品有限公司(Regeneron Pharmaceuticals, Inc.)
<120> METHODS OF REDUCING PARTICLE FORMATION AND COMPOSITIONS FORMEDTHEREBY
<130> 00166-11-304
<140> PCT/US2018/046183
<141> 2018-08-10
<150> US 62/560,365
<151> 2017-09-19
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Claims (25)
1.一种减少药物产品中的亚可见和可见粒子形成的方法，所述方法包括：
在所述药物产品中包含至少100mg/mL的IgG抗体；以及
在所述药物产品中包含聚氧乙烯脱水山梨糖醇的脂肪酸酯的混合物，其中所述混合物中油酸酯的含量大于所述混合物中所有脂肪酸酯的98％。
2.如权利要求1所述的方法，其还包括将所述药物产品在30℃至50℃之间的温度下储存1至5个月之间，此后在所述药物产品中可检测到少于3000个具有10微米或更大直径的粒子，如通过流成像显微镜法或膜显微镜法之一所检测到的。
3.如权利要求1所述的方法，其还包括将所述药物产品在2℃至8℃之间的温度下储存18至36个月之间，此后在所述药物产品中可检测到少于3000个具有10微米或更大直径的粒子，如通过流成像显微镜法或膜显微镜法之一所检测到的。
4.如权利要求1所述的方法，其还包括添加一种试剂以减小所述药物产品的粘度。
5.如权利要求1所述的方法，其中所述IgG抗体为IgG4抗体。
6.如权利要求1所述的方法，其中所述IgG抗体能够与脂肪酶共纯化，并且所述药物产品包含所述脂肪酶。
7.如权利要求1所述的方法，其中所述IgG抗体在包含于所述药物产品中之前已使用亲和纯化步骤来纯化。
8.如权利要求1所述的方法，其中在所述药物产品中包含至少100mg/mL的所述IgG抗体的步骤包括在所述药物产品中包含至少150mg/mL的所述IgG抗体。
9.如权利要求1所述的方法，其中所述IgG抗体在包含于所述药物产品中之前尚未使用疏水相互作用色谱法(HIC)纯化。
10.如权利要求1所述的方法，其中所述IgG抗体为IgG4抗体，并且所述药物产品包含磷脂酶B样2蛋白。
11.如权利要求1所述的方法，其还包括在将所述IgG抗体包含于所述药物产品中之前使用蛋白A纯化步骤纯化所述IgG抗体。
12.如权利要求1所述的方法，其中所述混合物中油酸酯的所述含量为所述混合物中所有脂肪酸酯的至少99％。
13.如权利要求1所述的方法，其中所述药物产品还包含酯酶。
14.一种药物产品，其根据权利要求1所述的方法制备。
15.如权利要求1所述的方法，其中所述混合物中油酸酯的所述含量通过气液色谱法、液相色谱法、比色测定法或荧光测定法之一来确定。
16.如权利要求1所述的方法，其中所述药物产品被配置用于胃肠外施用。
17.一种减少包含IgG抗体和酯酶的药物产品中的微粒形成的方法，所述方法包括：
在所述药物产品中包含聚氧乙烯脱水山梨糖醇脂肪酸酯的混合物，其中所述混合物中油酸酯的含量大于所述混合物中所有脂肪酸酯的98％，
其中所述方法不包括使用疏水相互作用色谱法来纯化所述IgG抗体。
18.如权利要求17所述的方法，其中所述IgG抗体为IgG4抗体，并且所述酯酶为磷脂酶B样2蛋白。
19.一种制剂，其包含：
至少100mg/mL的IgG抗体；以及
脂肪酸酯混合物，其中所述混合物中油酸酯的含量大于所述混合物中所有脂肪酸酯的98％。
20.如权利要求19所述的制剂，其包含至少150mg/mL的所述IgG抗体。
21.如权利要求19所述的制剂，其中所述脂肪酸酯混合物为聚山梨醇酯80。
22.如权利要求19所述的制剂，其中所述IgG抗体为IgG4抗体，并且所述制剂包含磷脂酶B样2蛋白。
23.一种药物产品，其包含如权利要求19所述的制剂。
24.如权利要求23所述的药物产品，其中在已将所述药物产品在30℃与50℃之间的温度下储存1至5个月之间之后，通过流成像显微镜法或膜显微镜法之一在所述药物产品中可检测到少于3000个具有10微米或更大直径的粒子。
25.如权利要求23所述的药物产品，其中在已将所述药物产品在2℃与8℃之间的温度下储存18至36个月之间之后，通过流成像显微镜法或膜显微镜法之一在所述药物产品中可检测到少于3000个具有10微米或更大直径的粒子。
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| US20220042954A1 (en) | 2019-03-29 | 2022-02-10 | Bristol-Myers Squibb Company | Methods of measuring hydrophobicity of chromatographic resins |
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