CN1744912A - 稳定的含蛋白质的制剂 - Google Patents
稳定的含蛋白质的制剂 Download PDFInfo
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- CN1744912A CN1744912A CNA2004800030798A CN200480003079A CN1744912A CN 1744912 A CN1744912 A CN 1744912A CN A2004800030798 A CNA2004800030798 A CN A2004800030798A CN 200480003079 A CN200480003079 A CN 200480003079A CN 1744912 A CN1744912 A CN 1744912A
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- poloxamer
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Abstract
含有泊洛沙姆作为表面活性剂的蛋白质制剂;以及通过添加泊洛沙姆作为表面活性剂,不添加抗氧化剂而保持蛋白质制剂的生物活性以及抑制不溶性异物形成的方法。
Description
技术领域
本发明涉及稳定的含蛋白质的制剂。更特别地,本发明涉及包含泊洛沙姆作为表面活性剂的稳定的含蛋白质的制剂。
背景技术
随着遗传工程技术的发展,应用生理活性蛋白如抗体、酶、激素及细胞因子作为药物产品已经成为可能。为了以稳定的量高质量提供它们,必需建立能够保持结构和活性的制备条件和储存条件。
通常,蛋白质储存过程中遇到的问题是变质现象,如形成不溶的聚集物,必须防止这种问题。
例如,抗体如免疫球蛋白、单克隆抗体和人源化抗体是不稳定的蛋白质,它们在纯化和制剂加工过程中的过滤、浓缩和加热的应激下以及在储备溶液或制剂存储过程中的热、光和运输的应激下容易发生物理或化学变化例如群丛或群聚。
如果由遗传工程技术得到抗体时,则大量培养并纯化产生抗体的细胞以得到含抗体的溶液,然后冷冻保存该溶液,在制备制剂前解冻。然而,由于在反复的冻/融循环过程中形成抗体二聚体或不溶的颗粒或不溶性异物或者在长期的存储过程中抗体降解形成降解产物,该溶液中剩余的抗体含量降低。
为了抑制此类不溶性异物的形成并获得稳定的含蛋白质的制剂,使用表面活性剂是必不可少的,特别是,这样的表面活性剂如聚山梨酯20和80已被广泛使用。然而对于容易氧化的蛋白质制剂来说,除了聚山梨酯80外还不得不包含抗氧化剂如L-蛋氨酸(JPA No.2000-247903,J.Pharm.Sci.90:3(2001)),因为聚山梨酯80趋向氧化蛋白质(PDA J.Pharm.Sci.Technol.50:3(1996);Formulation,Characterization,and Stability of Protein Drugs.Plenum Press,New Yolk,(1996)),由此降低了抗体制剂的生物活性。加入抗氧化剂需要复杂的操作如严格测定抗氧化剂的规格和含量。
因此,期望提供一种能够不添加抗氧剂而抑制蛋白质氧化并且能够抑制蛋白质制剂中不溶性异物形成的表面活性剂。冻干制剂能够抑制蛋白质的氧化(例如,JPA No.2000-247903),但是对省去重构步骤的便利溶液制剂存在巨大需求并且还将期望提供一种含有蛋白质的制剂,该制剂即使以溶液制剂存在时也是稳定的。
本发明的一个目的是寻找一种表面活性剂(这种表面活性剂能够不添加抗氧化剂而抑制蛋白质氧化以保持蛋白质生物活性,还能够抑制蛋白质制剂中不溶性异物的形成)并且提供一种含有所述表面活性剂的稳定的含蛋白质的制剂。
发明内容
为了实现上述目的我们进行了细致的研究工作,结果发现通过添加泊洛沙姆作为表面活性剂能够在不存在抗氧化剂的情况下保持蛋白质的生物活性而不引起蛋白质的氧化,并且能够抑制含蛋白质的制剂中不溶性异物的形成,在此基础上完成了本发明。
因此,本发明提供:
(1)一种含有泊洛沙姆作为表面活性剂的蛋白质制剂;
(2)上述(1)中定义的蛋白质制剂,其中泊洛沙姆是泊洛沙姆188;
(3)上述(1)或(2)中定义的蛋白质制剂,它是溶液制剂;
(4)上述(1)至(3)任一项中定义的蛋白质制剂,其中所述蛋白质是免疫球蛋白;
(5)上述(4)中定义的蛋白质制剂,其中所述免疫球蛋白是人源化抗体;
(6)上述(4)中定义的蛋白质制剂,其中所述免疫球蛋白是一种抗组织因子抗体;
(7)上述(6)中定义的蛋白质制剂,其中所述抗组织因子抗体是一种人源化抗组织因子抗体;
(8)上述(1)至(9)任一项中定义的蛋白质制剂,它不含有作为添加剂的抗氧剂;
(9)一种通过添加泊洛沙姆作为表面活性剂而不添加抗氧剂保持蛋白质制剂中的生物活性以及抑制不溶性异物形成的方法;
(10)上述(1)至(3)任一项中定义的蛋白质制剂,其中所述蛋白质是粒细胞集落刺激因子;以及
(11)上述(1)至(3)任一项中定义的蛋白质制剂,其中所述蛋白质是甲状旁腺激素。
附图简要说明
图1显示含有不同表面活性剂的抗人组织因子抗体溶液制剂中生物活性随时间的变化。
图2表示含有泊洛沙姆188或聚山梨酯80的抗人组织因子抗体溶液制剂的阴离子交换色谱图。
图3显示与添加泊洛沙姆的作用相比,在抗人组织因子抗体中添加L-蛋氨酸对由聚山梨酯80诱导的活性损失的作用。
图4表示显示聚山梨酯80、聚山梨酯20或泊洛沙姆188对粒细胞集落刺激因子氧化作用影响的色谱图。
图5表示显示聚山梨酯80、聚山梨酯20或泊洛沙姆188对甲状旁腺激素氧化作用影响的色谱图。
发明的最优选实施方案
本发明使用的“含蛋白质的制剂”是指一种含有蛋白质,优选作为活性成分的生理活性蛋白质的制剂,它被制备用于给动物如人施用,包括冻干制剂和溶液制剂。
用于本发明制剂中的蛋白质包括但不限定于抗体、酶、细胞因子和激素。特别地,它们包括但不限定于造血因子如粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、促红细胞生成素(EPO)和血小板生成素;细胞因子如干扰素、IL-1和IL-6;免疫球蛋白;单克隆抗体;人源化抗体;组织纤维蛋白溶酶原激活剂(TPA);尿激酶;血清白蛋白;凝血因子VIII;瘦素;胰岛素;干细胞生长因子(SCF)。在这些蛋白质中,优选造血因子如G-CSF和EPO、甲状旁腺激素(PTH)和免疫球蛋白,特别是抗体。在抗体中,特别优选抗组织因子抗体。
用于本发明制剂中的蛋白质具有实质上与哺乳动物特别是人的那些生理活性蛋白相同的生物活性,包括那些衍生自天然来源的蛋白质,优选由遗传工程得到的那些。遗传工程蛋白质可以具有与那些天然蛋白质相同的氨基酸序列,或者可以包含在所述氨基酸序列中的缺失、置换或添加一个或多个氨基酸但是保持所述生物活性。生理活性的蛋白质还包括用PEG或类似物化学修饰的蛋白质。
特别优选具有糖链的蛋白质。糖链可以来自任何来源,但是优选加入哺乳动物细胞的糖链。哺乳动物细胞包括如中国仓鼠卵巢(CHO)细胞、BHK细胞、COS细胞、人衍生的细胞等等,其中最优选CHO细胞。
当蛋白质是EPO时,则EPO可以通过任何方法制备,如它可以被提取自人的尿,用各种技术分离和纯化,或者在中国仓鼠卵巢(CHO)细胞、BHK细胞、COS细胞、人衍生的细胞等中用遗传工程技术生产(例如JPA No.SHO 61-12288),然后用各种技术提取及分离和纯化。也包括用PEG或类似物化学修饰的EPO(参见国际专利申请公开No.WO 90/12874)。也包括没有糖链和用PEG或类似物化学修饰的EPO。也包括EPO类似物,这些类似物中EPO经修饰,以在EPO的氨基酸序列中N连接的糖链结合部位或0连接的糖链结合部位增加一个或多个糖基化位点的数目(例如参见JPA No.HEI 8-151398和JPA No.HEI8-506023)。而且,糖链的数量可以通过增加唾液酸或类似物的含量而不改变糖链结合部位的数目来增加。
当蛋白质是G-CSF时,则可以使用任何高纯度的人G-CSF。本发明中的G-CSF可用任何方法制备,如可以从人肿瘤细胞系的培养物中提取它们,用不同的技术分离和纯化,或者在细菌细胞如E.Coli;酵母细胞;动物培养细胞如中国仓鼠卵巢(CHO)、C127或COS细胞中用遗传工程技术生产,然后用不同的技术提取及分离和纯化。G-CSF优选在E.Coli、酵母或CHO细胞中通过遗传重组,最优选在CHO细胞中通过遗传重组生产。也包括用PEG或类似物化学修饰的G-CSF(参见国际专利申请公开No.WO 90/12874)。
当蛋白质是抗体时,则抗体没有特殊限制,只要其结合到目标抗原上即可,适合时可以使用小鼠抗体、大鼠抗体、兔抗体、绵羊抗体、嵌合抗体、人源化抗体、人抗体等等。抗体可以是多克隆的或单克隆的,但是优选单克隆的,因为同质性抗体能够稳定地生产。多克隆和单克隆抗体可以用本领域技术人员公知的方法制备。
产生单克隆抗体的杂交瘤基本上可由下述已知的技术构建。将目标抗原或表达目标抗原的细胞用作免疫抗原,按照标准免疫技术使宿主细胞免疫,通过标准的细胞融合技术将得到的免疫细胞融合入已知的亲代细胞,然后用标准筛选法筛选融合细胞,选出单克隆抗体产生性细胞(杂交瘤)。可以遵照如Milstein等的方法(Kohler.G.和Milstein,C.,Methods Enzymol.(1981)73:3-46)进行杂交瘤的构建。如果抗原免疫原性低,它可以结合到免疫原性的大分子如白蛋白上并用于免疫。
可以使用重组体抗体,这种重组体是应用遗传工程技术(参见如Carl,A.K.Borrebaeck,James,W.Larrick,THERAPEUTICMONOCLONAL ANTIBODIES.MACMILLAN PUBLISHERS公司在英国出版,1990)用包含从杂交瘤克隆的抗体基因的适当载体转化宿主而生产。特别地,抗体可变区(V区)的cDNA序列是利用逆转录酶由杂交瘤的mRNA合成的。一旦得到编码目的抗体V区的DNA序列,它们就可以结合到编码目的抗体恒定区(C区)的DNA序列上,并且被整合入表达载体。或者,编码抗体V区的DNA序列可以被整合入包含抗体C区的DNA序列的表达载体。它们可以用这样一种方式被整合入表达载体,所述的方式就是它们可以在调节区如增强子和启动子的控制下被表达。然后,宿主细胞可以用这个表达载体转化从而表达抗体。
在本发明中,可以使用重组抗体,即经人工修饰以减少在人中的抗原性或达到其它目的的抗体,如嵌合抗体和人源化抗体。这些经修饰的抗体可以用已知的方法制备。嵌合抗体由从非人哺乳动物如小鼠中得到的抗体重链和轻链可变区和人抗体重链和轻链恒定区组成,可以通过将编码小鼠抗体可变区的DNA序列与人抗体恒定区的DNA序列连接用包含连接序列的表达载体转化宿主,让其产生嵌合抗体而得到。
人源化抗体也被称为重构人抗体,是通过将来自非人哺乳动物如小鼠的抗体的互补决定区(CDRs)移植入人抗体的互补决定区而得到,制备人源化抗体的典型基因重组技术也是已知的。特别的,设计将小鼠抗体的CRDs连接到人抗体的构架区(FRs)上的DNA序列是通过PCR从多个被制备成具有末端重叠区的寡核苷酸合成的。将得到的DNA序列连接到编码人抗体恒定区的DNA序列上,然后整合到表达载体中,这种表达载体被转化到宿主中让它产生重构抗体(参见欧洲专利申请公开No.EP239400,国际专利申请公开No.WO 96/02576)。连接CDRs的人抗体的FRs是以这样的方式进行选择的,即互补决定区形成适当的抗原结合部位。如果必要,重构人源化抗体在可变区的构架区可以具有一些氨基酸变化,以便互补决定区形成适当的抗原结合部位(Sato,K.等,Cancer Res.(1993)53.851-856)。
获得人抗体的方法也是已知的。例如,对目标抗原具有结合活性的目标人抗体可以通过在体外用目标抗原或表达目标抗原的细胞免疫人淋巴细胞并将免疫的淋巴细胞和人骨髓瘤细胞如U266融合而获得(参见JPB No.HEI 1-59878)。目标人抗体也可以通过用抗原免疫具有所有人抗体基因组成成分的转基因动物而获得(参见国际专利申请公开Nos.WO 93/12227,WO 92/03918,WO 94/02602,WO 94/25585,WO96/34096,WO 96/33735)。通过使用人抗体文库淘选而获得人抗体的方法也是已知的。例如,结合到抗原上的噬菌体可以通过用噬菌体展示法将作为单链抗体片段(scFv)的人抗体可变区表达于噬菌体表面上而进行选择。编码与抗原结合的人抗体可变区的DNA序列是通过分析所选的噬菌体的基因而测定的。在与抗原结合的scFv片段的测定DNA序列的基础上,通过制备适当的表达载体可以获得完整的人抗体。这些方法从WO 92/01047,WO 92/20791,WO 93/06213,WO 93/11236.WO 93/19172,WO 95/01438,WO 95/15388中已经是熟知的。
当抗体是通过将初步分离的抗体转化入合适的宿主而制得时,所述适当的宿主可以与表达载体联合使用。作为宿主使用的适当的真核细胞包括动物细胞、植物细胞和真菌细胞。已知的动物细胞包括(1)哺乳动物细胞如CHO、COS、骨髓瘤、BHK(幼仓鼠肾)、HeLa和Vero细胞;(2)两栖动物细胞如非洲蟾蜍属卵母细胞;或者(3)昆虫细胞如sf9、sf21和Tn5。已知的植物细胞包括烟草属的细胞如Nicotiana tabacum,其可以用作愈伤组织培养。已知的真菌细胞包括酵母,例如酵母属物种如saccharomyces serevisiae和丝状真菌如曲霉属物种如黑曲霉(Aspergillus miger)。原核细胞可用作使用菌细胞的生产系统。已知的细菌细胞包括大肠杆菌(E.Coli)和枯草杆菌(Bacillus subtilis)。用目的抗体基因转化这些细胞并在体外培养转化的细胞可以获得抗体。
本发明的稳定制剂中包含的抗体包括但不限定于,抗IL-6受体抗体、抗HM1.24抗原单克隆抗体、抗甲状旁腺激素相关肽抗体(抗PTHrP抗体)、抗组织因子抗体,等等。
用于本发明的优选的重构人源化抗体包括人源化抗IL-6受体抗体(hPM-1)(参见国际专利申请公开No.WO 92-19759)、人源化抗HM1.24抗原单克隆抗体(参见国际专利申请公开No.WO 98-14580)和人源化抗甲状旁腺激素相关肽抗体(抗PTHrP抗体)(参见国际专利申请公开No.WO 98-13388)。
我们制备了人/小鼠的嵌合抗体,该抗体由对抗人组织因子的小鼠单克隆抗体的可变区(V区)和人抗体的恒定区(C区)组成,以及由被转移到人抗体中的抗人组织因子的小鼠单克隆抗体的轻链(L链)可变区和重链(H链)可变区中的互补决定区组成,并报道这些将可被期望成为DIC、动脉血栓形成和静脉血栓形成的优良治疗剂(WO 99/51743,WO 01/24626)。特别优选的是WO 99/51743中描述的包含人源化H链形式i和人源化L链形式b2的组合的人源化抗人组织因子抗体,它是由CHO细胞产生的重组抗体。许多抗人组织因子抗体已经被报道(WO 99/51743,WO 88/07543,WO 96/40921,WO 98/40408,WO 01/70984)。它们可以由本领域技术人员公知的方法制备,因为它们的抗原组织因子是已知的(Ito T等,J.Biochem.114.691-696,(1993))。这些抗人组织因子抗体也是用于本发明的优选抗体。
本发明制剂中包含的抗体可以属于任意免疫球蛋白类,优选IgG,如IgG1、IgG2、IgG3和IgG4。
本文中使用的“含抗体的溶液”可以是包含任何抗体的溶液,不论是生物衍生的还是重组的,优选在其中培养包含抗体的哺乳动物细胞如CHO细胞的培养基,或者通过将这样的培养基进行一定的处理如部分纯化(本体溶液)而得到的溶液,或者如上所述制备的给动物如人施用的溶液制剂。
本文中使用的“不溶性异物”是指很容易检测到的溶液制剂中不应该含有的不溶性异物,并当按照日本药典中一般检测、方法和装置部分中关于注射剂的不溶性异物检测一节中所定义的,将溶液制剂放在容器中在白炽灯下用肉眼在光线强度大约为1000勒克司的位置观察时,所述溶液制剂是澄清的。
本文中使用的“抗体的生物活性”是指抗体结合与其抗原的能力,可以用抗原中和活性试验测定。当抗体是人源化抗人组织因子抗体时,保留抗体生物活性的制剂是指在25℃加速试验6个月后,制剂保留抗体原种生物活性的60%或更多,优选70%或更多;还更加优选80%或更多,最优选90%或更多。
在本发明中,抗体制剂的纯度检查可以用下述的凝胶过滤色谱法和阴离子交换色谱法来进行。
本发明的含蛋白质的制剂中,通过添加泊洛沙姆作为表面活性剂,在不存在抗化氧剂的情况下,可以维持制剂的高生物活性,不引起蛋白质的氧化并且能够抑制不溶性异物的形成。
泊洛沙姆是非离子型表面活性剂,由一系列的环氧乙烷和1,2-环氧丙烷的嵌段共聚物组成,其通式如下:
HO(C2H4O)a(C3H6O)b(C2H4O)aH
泊洛沙姆包括USP(美国药典)中描述的泊洛沙姆124、188、237、338和407,其中本发明特别优选泊洛沙姆188。USP中描述的泊洛沙姆188是上述通式的化合物,其中a是80,b是27,平均分子量为7680-9510,BP(英国药典)中描述的泊洛沙姆188是上述通式的化合物,其中a为大约75,b为大约30,平均分子量为8350。另外,EP(欧洲药典)描述了泊洛沙姆182、184和331。Pluronics(可由BASF获得的泊洛沙姆的商标)如Pluronics L35,L43,L44,L61,L62,L64,F68,L81,P84,P85,F87,F88,L92,F98,L101,P103,P104,P105,F108,L121,P123和F127也包括在本发明的泊洛沙姆的范围内。
在药物制剂中泊洛沙姆以前被用作静脉内注射的脂肪乳剂的乳化剂或保持酏剂或糖浆剂澄清的增溶剂,但是没有被用作含蛋白质制剂的稳定剂。
添加的泊洛沙姆的量取决于使用的泊洛沙姆的类型和蛋白质的类型和浓度,但泊洛沙姆188的量典型地是0.001-100mg/mL,优选0.005-50mg/mL,更优选0.01-10mg/mL。
本发明的含蛋白质的制剂中,使用泊洛沙姆作为表面活性剂,消除了当使用聚山梨酯时所需要的添加抗氧剂如L-蛋氨酸的需要。
本发明的含蛋白质的制剂可以包含氨基酸作为稳定剂。氨基酸包括但不限定于亮氨酸、色氨酸、丝氨酸、谷氨酸、精氨酸、组氨酸和赖氨酸和它们的盐。
为了抑制在冻/融循环过程中二聚体的形成,本发明的制剂还可以包含糖醇如甘露糖醇和山梨糖醇;以及非还原性低聚糖,如非还原性二糖例如蔗糖和海藻糖或非还原性三糖例如棉子糖。尤其优选非还原性低聚糖。优选的非还原性低聚糖是非还原性二糖,更优选蔗糖和海藻糖。
优选地,本发明的含抗体的溶液制剂实质上不含有蛋白质如人血清白蛋白或作为稳定剂的纯明胶。
本发明的抗体制剂的pH优选4-8,更优选5-7.5,然而,pH取决于所包含的抗体,并且不限于这些数值。
本发明的制剂还可以含有等渗剂,如聚乙二醇;以及糖,例如葡聚糖、甘露糖醇、山梨糖醇、肌醇、葡萄糖、果糖、乳糖、木糖、甘露糖、麦芽糖、蔗糖、海藻糖和棉子糖。
如果需要,本发明的含抗体的溶液制剂还可以包括稀释剂、增溶剂、赋形剂、pH调节剂、缓和剂、缓冲剂、含硫还原剂、抗氧化剂等等。例如,含硫的还原剂包括N-乙酰半胱氨酸、N-乙酰高半胱氨酸、硫辛酸、硫二甘醇、硫代乙醇胺、硫代甘油、硫代山梨糖醇、巯基乙酸(thioglycolic acid)和其盐、硫代硫酸钠、谷胱甘肽和含巯基的化合物如具有1至7个碳原子的硫代链烷酸。抗氧化剂包括异抗坏血酸、二丁基羟基甲苯、丁基羟基茴香醚、α-生育酚、乙酸生育酚、L-抗坏血酸或其盐、L-抗坏血酸棕榈酸酯、L-抗坏血酸硬脂酸酯、亚硫酸氢钠、亚硫酸钠、没食子酸三戊酯、没食子酸丙酯或螯合剂如乙二胺四乙酸二钠(EDTA)、焦磷酸钠和偏磷酸钠。也可以包含其它常用的添加剂,如无机盐,例如氯化钠、氯化钾、氯化钙、磷酸钠、磷酸钾和碳酸氢钠;以及有机盐,例如柠檬酸钠、柠檬酸钾和醋酸钠。
可以如下制备本发明的制剂:将这些组分溶解于溶液制剂领域已知的含水缓冲溶液中,如磷酸盐缓冲液(优选磷酸一氢钠-磷酸二氢钠体系)和/或柠檬酸盐缓冲液(优选柠檬酸钠缓冲液),制成溶液制剂。缓冲液的浓度典型地是1-500mM,优选5-100mM,更优选10-50mM。
本发明含有抗体的溶液制剂通常是通过胃肠道外途径给药,如注射(例如皮下、静脉内、肌内或腹膜内注射)或者经皮、经粘膜、鼻腔或肺给药,也可以口服给药。
本发明的含蛋白质的制剂可以是冻干制剂或者是溶液制剂,优选溶液制剂。溶液制剂通常在密封并灭菌的具有确定容积的塑料或玻璃容器,如小瓶、安瓿或注射器或者大容积如瓶中被供应。从方便的角度,优选预填充的注射器。
本发明制剂中所含抗体的量一般为0.1-200mg/ml,优选1-120mg/ml,取决于所治疗的疾病的种类、疾病严重程度和患者的年龄以及其它因素。
如下面实施例所示,本发明的溶液制剂通过添加泊洛沙姆作为表面活性剂,不添加抗氧化剂能够以高水平保持抗体制剂的生物活性,并抑制不溶性异物的形成。
下述的实施例进一步阐述了本发明,但是不限定本发明的范围。本领域技术人员可以根据本说明书而做出各种变化和修改,这些变化和修改也包含在本发明的范围之内。
实施例
样品
1.抗体样品
WO 99/51743中描述的人源化抗人组织因子抗体,其包含人源化H链形式i和人源化L链形式b2的组合,被用作抗人组织因子抗体。用在下述实施例中的抗人组织因子抗体是由CHO细胞产生并属于IgG4类的重组抗体。
2.粒细胞集落刺激因子(G-CSF)
使用的粒细胞集落刺激因子是在中国仓鼠卵巢(CHO)细胞中使用基因重组方法通过遗传工程技术而制得以及提取并分离/纯化的。
3.甲状旁腺激素(PTH)
具有1-84个残基的甲状旁腺激素是由WO9014415中描述的方法制备的。
试验方法
(1)TF中和活性试验
组织因子(TF)是在细胞表面上表达的凝血因子VII受体并被定位为凝血反应的实质触发物。组织因子通过与凝血因子VII形成复合物而激活凝血因子IX和X。因此,人源化的抗人组织因子抗体的生物活性可以通过下面描述的使用凝血因子VIIa溶液和凝血因子X溶液的的方法测定。
1.制备下列溶液。
1)A.B.(测试缓冲液):TBS(pH 7.6)包含5mmol/L CaCl2,0.1%BSA。
2)因子VIIa&Thromborel S的混合溶液:因子VIIa和Thromborel S分别用A.B.稀释至0.1PEU/mL和0.42mg/mL。
3)因子X溶液:因子X用A.B.稀释至0.25PEU/mL。
4)混合的Testzyme显色底物S-2222溶液:1.5mg/mL显色底物S-2222溶液与水及1,5-二甲基-1,5-二氮十一亚甲基聚溴化物水溶液以1∶1∶2的比例混合。
2.将因子VIIa和Thromborel S的混合溶液以60μL/孔分配于板中并允许在室温下放置60分钟。
3.将抗人组织因子抗体储备溶液(标准溶液)和用因子X溶液稀释的样品溶液以40μL/孔分配于板中并允许在室温下放置30分钟。
4.通过添加10μL/孔0.5mol/L的EDTA溶液结束反应,然后将混合的Testzyme显色底物S-2222溶液以50μL/孔分配于板中并允许在室温下放置30分钟。
5.测定在405nm-655nm处的吸光度。
6.每个测试样品的生物活性基于标准曲线分析被计算为标准溶液的百分数。
缩略语
TBS:三羟甲基氨基甲烷缓冲盐水
BSA:牛血清白蛋白
EDTA:乙二胺四乙酸
(2)离子交换柱色谱法(IEC)
分析条件如下
柱:DEAE-NPR(4.6mm I.D.x3.5cm)
流动相:
A:50mmol/L Tris缓冲液,pH 8.0
B:50mmol/L Tris缓冲液+500mmol/L NaCl,pH 8.0
梯度:
0-5min溶液B0%
5-40min溶液B 0→50%
流速:1.0mL/min
检测:在280nm处的UV吸收
样品载荷:相当于100μg
(3)分析不溶性异物
按照日本药典中一般检测、方法和装置部分中关于注射剂的不溶性异物检测一节中所定义的,在白炽灯下在光线强度大约为1000勒克司的位置以肉眼观察装在容器中的溶液制剂。
实施例1:添加表面活性剂对生物活性的影响
测试了含有不同表面活性剂的抗人组织因子抗体溶液制剂的生物活性随时间的变化。测试了在5℃下保存14天和在40℃下保存14天后,含2.3mg/mL抗人组织因子抗体的醋酸盐缓冲液和0.5mg/mL的聚山梨酯20或80(均是A公司制造)或泊洛沙姆188(B公司制造)作为表面活性剂的样品(pH6.0)的生物活性(TF-中和活性)。为了比较,也以相同方式测试了不含表面活性剂的组。结果如图1所示。
和含有聚山梨酯80制剂形成对比,该制剂显示抗人组织因子抗体的生物活性明显损失,含有泊洛沙姆188的制剂保持与不含表面活性剂的制剂的类似活性。在包含本领域中被称为可注射表面活性剂的聚山梨酯20的制剂中也观察到了活性损失。
实施例2:表面活性剂对生物活性和纯度的影响
测试了添加表面活性剂对抗人组织因子抗体溶液制剂的生物活性和纯度的影响。在25℃加速试验6个月后,通过TF-中和活性试验测试了含10mg/mL抗人组织因子抗体的醋酸盐缓冲液和0.5mg/mL的聚山梨酯80(C公司制造)或泊洛沙姆188(D公司制造)作为表面活性剂的样品(pH5.5)的生物活性,通过离子交换色谱法(IEC)测定其纯度。为了比较,也以相同的方式测试了不经加速试验的抗人组织因子抗体储备溶液(本体)。结果如图2所示。
含有泊洛沙姆188作为表面活性剂的制剂的生物活性是抗人组织因子抗体储备溶液生物活性的92%,而含有聚山梨酯80的制剂的生物活性为52%。
在离子交换色谱法中,含有聚山梨酯80的抗人组织因子抗体溶液制剂中的主峰降低,在主峰的前面立即出现一个新的峰(在图2中用箭头指示)。在主峰前立即出现的峰部分是含有一些氧化的氨基酸残基的衍生物造成的。然而,含有泊洛沙姆188的制剂保持与抗人组织因子抗体储备溶液的相似色谱图。
这些结果显示,泊洛沙姆188在生物活性和纯度方面都优于聚山梨酯80。
实施例3:与添加泊洛沙姆的影响比较,添加L-蛋氨酸对由聚山梨酯80诱导的抗人组织因子抗体活性损失的影响
测试了添加L-蛋氨酸对由聚山梨酯80诱导的抗人组织因子抗体活性损失的影响,并与含有泊洛沙姆的制剂作比较。制备了含有10mg/mL抗人组织因子抗体醋酸盐缓冲液以及
1)0.5mg/mL聚山梨酯80,
2)0.5mg/mL聚山梨酯80和5mg/mL的L-蛋氨酸,或者
3)0.5mg/mL泊洛沙姆188的样品(pH 5.5)。
在25℃加速试验6个月后,通过TF-中和活性试验测定每个样品的生物活性,并与抗人组织因子抗体储备溶液(本体)的生物活性比较。
结果如图3所示。由聚山梨酯80诱导的活性损失被添加L-蛋氨酸抑制。含有泊洛沙姆188样品显示了与含有聚山梨酯80和L-蛋氨酸的样品的类似的或者更高的生物活性。
实施例4:表面活性剂对不溶性异物的影响
测试了添加表面活性剂对抗人组织因子抗体溶液制剂中不溶性异物形成的影响。在制备后立即和在5℃储存24个月后,测试了含有10mg/mL抗人组织因子抗体醋酸盐缓冲液和0.5mg/mL聚山梨酯80(C公司制造)或泊洛沙姆188(D公司制造)作为表面活性剂的样品(pH6.0)的不溶性异物。为了比较,也以相同的方式测试了不含表面活性剂的组。结果显示在表1中。显示的是在5个样品瓶中观察到有不溶性异物的瓶的数目。在不含表面活性剂的样品中制备后立即观察到了不溶性异物。然而,在含有泊洛沙姆188和聚山梨酯80的样品中没有观察到不溶性异物的形成。
表1
表面活性剂 | 不含 | 泊洛沙姆188 | 聚山梨酯80 |
最初5℃-24个月 | 5/55/5 | 0/50/5 | 0/50/5 |
(4)泊洛沙姆对蛋白质稳定作用的实验
将不同的表面活性剂加入上述的粒细胞集落刺激因子溶液制剂和甲状旁腺激素溶液制剂中,评价它们对粒细胞集落刺激因子和甲状旁腺激素氧化作用的影响。
实施例5:表面活性剂对粒细胞集落刺激因子氧化作用的影响
测试了表面活性剂对粒细胞集落刺激因子溶液制剂的影响。在25℃加速试验5周后,用反相色谱法(RPC)测定含有0.25mg/mL集落刺激因子磷酸盐缓冲液和0.05%聚山梨酯80(A公司制造)、聚山梨酯20(A公司制造)或泊洛沙姆188(B公司制造)作为表面活性剂的样品(pH6.5)的粒细胞集落刺激因子的氧化衍生物的含量。
分析条件如下。
柱:DAISOPAK SP-300-5-C4-P(4.6mm I.D.x25cm)
流动相:
A乙腈∶水∶三氟醋酸=400∶600∶1
B腈∶水∶三氟醋酸=800∶200∶1
梯度:
0-25min 溶液B 20→90%
25-40min 溶液B 90→90%
40-41min 溶液B 90→20%
41-60min 溶液B 20%
流速:0.3mL/min
载荷:10μL
柱温:35℃
检测波长:在215nm处的UV吸收
结果如图4所示。
反相色谱法显示,在包含不同表面活性剂的粒细胞集落刺激因子溶液制剂的主峰前立即出现氧化的衍生物(在图4中用箭头表示)。这些峰部分是由于包含一些氧化的氨基酸残基的粒细胞集落刺激因子的衍生物而形成的。
在包含聚山梨酯20的样品中氧化衍生物的含量最高,其次是聚山梨酯80,再次是泊洛沙姆188。
实施例6:表面活性剂对甲状旁腺激素的氧化作用的影响
测定表面活性剂对甲状旁腺激素溶液制剂的影响。在40℃加速试验2周后,用反相色谱法(RPC)测定含有0.25mg/mL甲状旁腺激素柠檬酸盐缓冲液和0.05%聚山梨酯80(A公司制造)、聚山梨酯20(A公司制造)或泊洛沙姆188(B公司制造)作为表面活性剂的样品(pH5.0)的甲状旁腺激素的氧化衍生物的含量。
分析条件如下。
柱:YMC-Pack ODS A-312(4.6mm I.D.x15cm)
流动相:
A腈∶水∶三氟醋酸=0∶1000∶1
B乙腈∶水∶三氟醋酸=600∶40O∶1
梯度:
0-40min 溶液B 40→60%
40-42min 溶液B 60→60%
42-42.5min 溶液B 60→40%
42.5-60min 溶液B 40%
流速:1.0mL/min
载荷:10μL
柱温:25℃
检测波长:在215nm处的UV吸收
结果如图5所示。
反相色谱法显示,在包含不同表面活性剂的甲状旁腺激素溶液制剂的主峰前立即出现氧化的衍生物(在图5中用箭头表示)。这些峰部分是由于包含一些氧化的氨基酸残基的甲状旁腺激素的衍生物而形成的。
在包含聚山梨酯20样品中的氧化衍生物的含量最高,其次是聚山梨酯80,再次是泊洛沙姆188。
这些结果显示,泊洛沙姆188在对蛋白质溶液制剂的抗氧化作用方面优于聚山梨酯。
工业实用性
本发明稳定的含蛋白质制剂在显示,即使长期储存后既没有生物活性损失,也没有形成不溶性异物。它们是稳定的制剂,其中蛋白质的氧化衍生物的产生被有效地抑制。
Claims (11)
1.一种含有泊洛沙姆作为表面活性剂的蛋白质制剂。
2.权利要求1的蛋白质制剂,其中所述泊洛沙姆是泊洛沙姆188。
3.权利要求1或2的蛋白质制剂,它是溶液制剂。
4.权利要求1至3任一项的蛋白质制剂,其中所述蛋白质是免疫球蛋白。
5.权利要求4的蛋白质制剂,其中所述免疫球蛋白是人源化抗体。
6.权利要求4的蛋白质制剂,其中所述免疫球蛋白是抗组织因子抗体。
7.权利要求6的蛋白质制剂,其中所述抗组织因子抗体是人源化抗组织因子抗体。
8.权利要求1至9任一项的蛋白质制剂,它不含作为添加剂的抗氧化剂。
9.一种通过添加泊洛沙姆作为表面活性剂,不添加抗氧化剂而保持蛋白质制剂中的生物活性以及抑制不溶性异物形成的方法。
10.权利要求1至3任一项的蛋白质制剂,其中所述蛋白质是粒细胞集落刺激因子。
11.权利要求1至3任一项的蛋白质制剂,其中所述蛋白质是甲状旁腺激素。
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EP (1) | EP1598074B1 (zh) |
JP (2) | JP4607010B2 (zh) |
KR (1) | KR101235507B1 (zh) |
CN (1) | CN100353997C (zh) |
AU (1) | AU2004216298B2 (zh) |
CA (1) | CA2517310C (zh) |
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CN104906053A (zh) * | 2015-06-12 | 2015-09-16 | 北京四环生物制药有限公司 | 注射用重组人粒细胞刺激因子冻干粉针剂 |
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CN112516291A (zh) * | 2019-09-17 | 2021-03-19 | 通化安睿特生物制药股份有限公司 | 含人白蛋白的制剂及其制备方法 |
WO2021051807A1 (zh) * | 2019-09-17 | 2021-03-25 | 通化安睿特生物制药股份有限公司 | 含人白蛋白的制剂及其制备方法 |
CN112516291B (zh) * | 2019-09-17 | 2023-07-14 | 通化安睿特生物制药股份有限公司 | 含人白蛋白的制剂及其制备方法 |
RU2801099C1 (ru) * | 2019-09-17 | 2023-08-01 | Тунхуа Анрейт Биофармасьютикал Ко., Лтд | Препарат, содержащий человеческий альбумин, и способ его получения |
CN114544926A (zh) * | 2021-12-02 | 2022-05-27 | 浙江鑫科医疗科技有限公司 | 一种血清蛋白稳定剂 |
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AU2004216298B2 (en) | 2009-04-23 |
CN100353997C (zh) | 2007-12-12 |
WO2004075913A1 (ja) | 2004-09-10 |
EP1598074A4 (en) | 2011-10-26 |
JP4607010B2 (ja) | 2011-01-05 |
US8765124B2 (en) | 2014-07-01 |
EP1598074B1 (en) | 2019-01-02 |
EP1598074A1 (en) | 2005-11-23 |
US20060159653A1 (en) | 2006-07-20 |
HK1084340A1 (en) | 2006-07-28 |
AU2004216298A1 (en) | 2004-09-10 |
US9968677B2 (en) | 2018-05-15 |
CA2517310C (en) | 2015-11-24 |
KR101235507B1 (ko) | 2013-02-20 |
US20090264629A1 (en) | 2009-10-22 |
KR20050113199A (ko) | 2005-12-01 |
JP2010215664A (ja) | 2010-09-30 |
JPWO2004075913A1 (ja) | 2006-06-01 |
CA2517310A1 (en) | 2004-09-10 |
JP5377431B2 (ja) | 2013-12-25 |
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