CN1774266A - 肿瘤坏死因子结合蛋白的液体制剂 - Google Patents
肿瘤坏死因子结合蛋白的液体制剂 Download PDFInfo
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- CN1774266A CN1774266A CNA2004800103089A CN200480010308A CN1774266A CN 1774266 A CN1774266 A CN 1774266A CN A2004800103089 A CNA2004800103089 A CN A2004800103089A CN 200480010308 A CN200480010308 A CN 200480010308A CN 1774266 A CN1774266 A CN 1774266A
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Abstract
本发明涉及稳定的药学上可接受的TNF－结合蛋白的液体制剂，该制剂含有TNF－结合蛋白、缓冲液和等渗剂。
Description
技术领域
本发明涉及稳定的TNF结合蛋白的液体制剂。
发明背景
肿瘤坏死因子-α(TNF-α)是一种有效力的细胞因子，能诱发大量生物学反应，受TNF-α与细胞表面受体结合而介导。Stauber等“人肿瘤坏死因子-α受体：免疫亲和层析纯化和初步特征鉴定”(J.Biol.Chem.263：19098-19104，1988)从人组织细胞性淋巴瘤细胞系中分离得到了人TNF-α受体。Hohmann等“两种不同的细胞系具有不同的人肿瘤坏死因子(TNF-α)主要受体”(J.Biol.Chem.264：14927-14934，1989)的结论是有两种不同的蛋白质作为TNF-α的主要受体，一种与髓样细胞有关，一种与上皮细胞有关。
利用单克隆抗体，Brockhaus等“用单克隆抗体鉴定人细胞系上两种类型的肿瘤坏死因子受体”(Proc.Nat.Acad.Sci.87：3127-3131，1990)证实有两种不同的TNF-结合蛋白，二者均能特异性结合TNF-α和TNF-β且具有高亲和力。Gray等“人肿瘤坏死因子(TNF)受体cDNA的克隆和重组可溶性TNF-结合蛋白的表达”(Proc.Nat.Acad.Sci.87：7380-7384，1990)分离得到了其中一种受体的cDNA。他们发现此cDNA编码一种455个氨基酸的蛋白质，该蛋白质分成171个残基的胞外结构域和221个残基的胞质结构域。Aggarwal等“人肿瘤坏死因子受体的特征和γ干扰素对其的调节”(Nature.318：665-667，1985)证明肿瘤坏死因子α和β通过结合共同的细胞表面受体发挥它们对细胞功能的作用。TNFA和TNFB受体大小不同，在不同的细胞系中表达有差异性(见Hohmann等，1989和Engelmann等“从人尿液中纯化得到的两种肿瘤坏死因子结合蛋白：与细胞表面肿瘤坏死因子受体免疫交叉反应的证据”(J.Biol.Chem.265：1531-1536，1990)。
TNF-α-R，有些人称为TNFR55，是两种受体中较小的。已克隆了两种受体的cDNA并测定了它们的核酸序列(见Loetscher等“人55kd肿瘤坏死因子受体的分子克隆和表达”(Cell.61：，351-359，1990)；Nophar等“肿瘤坏死因子受体的可溶形式(TNF-Rs)：利用I型TNF-R可溶形式的氨基酸序列数据克隆了其cDNA，可编码该受体的细胞表面和可溶性两种形式”(EMBO J.9：3269-3278，1990)；Schall等“人肿瘤坏死因子受体的分子克隆和表达”(Cell.61：361-370，1990)；Smith等“肿瘤坏死因子受体定义了一个不常见的细胞和病毒蛋白质家族”(Science.248：1019-1023，1990))。
已知这些蛋白质有几种降解途径，特别是脱酰胺、凝聚、肽链的修剪和氧化。除去蛋白质的水份可显著减慢许多这类反应的速度。
然而，开发药物蛋白质的液体制剂好处是，可消除重组误差而提高给药剂量的准确性，及简化该产品的临床使用从而提高病人的接受度。本发明的一个目的是提供一种TNF结合蛋白的液体制剂，该制剂的产品降解控制是可接受的，对强烈搅拌(可导致凝聚)稳定，能抵抗微生物污染(可以“多种用途”或“多个剂量”包装)。
发明内容
本发明的主要目的是一种稳定的药学上可接受的TNF-结合蛋白的液体制剂，该制剂含有人TNF--结合蛋白、缓冲液和等渗剂。
所述溶液的pH值宜通过采用缓冲液保持在6-7之间。所述缓冲液可以是能维持此pH的药学上可接受的任何缓冲液，优选磷酸盐缓冲液。
所述等渗剂可以是药学上可接受的任何试剂，包括中性盐或糖。例如可以是氯化钠或甘露醇。
该制剂中可含有防腐剂以抑制微生物生长，使TNF-结合蛋白可“多种用途”或“多个剂量”包装。防腐剂包括苯酚、苄醇、间甲酚、甲基对羟基苯甲酸酯(paraben)、丙基对羟基苯甲酸酯、苯扎氯铵(benzalconium chloride)、和苯索氯铵(benzethonium chloride)。优选的防腐剂包括间甲酚和苄醇。
本发明的液体制剂如果需要也可冷冻干燥。
本发明的“TNF-结合蛋白”指对于TNF-α或TNF-β-具有亲和力的任何蛋白质，和/或含有属于TNF受体家族的全长或部分胞外可溶性片段的蛋白质。
TNF受体家族成员的一些例子如下：
肿瘤坏死因子受体1(TNFR1)，也称为肿瘤坏死因子受体超家族成员1A(TNFRSF1A)，或肿瘤坏死因子-α受体(NFAR)TNFR 55-KD或TNFR60KD(OMM*191190
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi？db＝OMIM中所述)；
肿瘤坏死因子受体2(TNFR2)，也称为肿瘤坏死因子受体超家族成员1B(TNFRSF1B)，或肿瘤坏死因子-β受体(TNFBR)或TNFR 75-KD或TNFR80-KD(见OMIM*191191中所述)；
OX40抗原(OX40)，也称为肿瘤坏死因子受体超家族成员4(TNFRSF4)，或Tax转录活化糖蛋白1受体(TXGP1L)或淋巴样活化抗原ACT35(ACT35)或CD134(见OMIM*600315中所述)；
CD40L受体(CD40)，也称肿瘤坏死因子受体超家族成员5(TNFRSF5)或B-细胞表面抗原CD40或CDw40或Bp50(见Swiss-Prot Entry No P25942)
FASL受体(FAS)，也称为肿瘤坏死因子受体超家族成员6(TNFRSF6)，或凋亡介导表面抗原FAS或Apo-1抗原或CD95(见Swiss-Prot Entry No.P25445中所述)；
诱骗受体3(DcR3)，也称为肿瘤坏死因子受体超家族成员6B(TNFRSF6B)，或FAS配体的诱骗受体或M68(见Swiss-Prot Entry No.O95407中所述)；
CD27抗原(CD27)，也称为肿瘤坏死因子受体超家族成员7(TNFRSF7)或T-细胞活化抗原S152(S152)(见OMIM*602250中所述)；
淋巴样活化抗原CD30(CD30)也称为肿瘤坏死因子受体超家族成员8(TNFRSF8)(见OMIM*153243所述)；
诱导的By淋巴细胞活化剂(ILA)，也称为肿瘤坏死因子受体超家族成员9(TNFRSF9)或CD137(见OMIM*602250所述)；
死亡受体4(DR4)，也称为肿瘤坏死因子受体超家族成员10A(TNFRSF10A)，或TNF-相关凋亡诱导配基受体1(TRAILR1)或APO2(见OMIM*603611所述)；
死亡受体5(DR5)，也称为肿瘤坏死因子受体超家族成员10B(TNFRSF10B)或TNF-相关凋亡诱导配基受体2(TRAILR2)或杀伤剂/DR5或TRICK2(见OMIM*603612所述)；
诱骗受体1(DCR1)，也称为肿瘤坏死因子受体超家族成员10C(TNFRSF10C)，或TNF-相关凋亡诱导配基受体3(TRAILR3)，或无胞内结构域的TRAIL受体(TRID)(见OMIM*603613所述)；
诱骗受体2(DCR2)，也称为肿瘤坏死因子受体超家族成员10D(TNFRSF10D)，或TNF-相关凋亡诱导配基受体4(TRAILR4)，或含截短死亡结构域的TRAIL受体(TRUNDD)(见OMIM*603014所述)；
NF-KAPPA-B受体激活剂(RANK)，也称为肿瘤坏死因子受体超家族成员11A(TNFRSF11A)，或破骨细胞分化因子受体(ODFR)或PDB2或TRANCER(见OMIM*603499)；
护骨素(Osteoprotegerin，OPG)，也称为肿瘤坏死因子受体超家族成员11B(TNFRSF11B)，或破骨细胞发生抑制因子(OCIF)(见OMIM*602643中所述)；
死亡受体3(DC3)，也称为肿瘤坏死因子受体超家族成员12(TNFRSF12)，或APO3或死亡的淋巴细胞相关受体(LARD)(见OMIM*603366所述)；
跨膜激活剂和Caml相互作用因子(TACI)也称为肿瘤坏死因子受体超家族成员13B(TNFRSF13B)(见OMIM*604907中所述)；
BAFF受体(BAFFR)，也称为肿瘤坏死因子受体超家族成员13C(TNFRSF13C)，或B细胞激活因子受体(见OMIM*606269所述)；
疱疹病毒进入介质(HVEM)，也称为肿瘤坏死因子受体超家族成员14(TNFRSF14)，或疱疹病毒进入介质A(HVEA)或TR2(见OMIM*602746所述)；
神经生长因子受体(NGFR)，也称为肿瘤坏死因子受体超家族成员16(TNFRSF16)，或p75(NTR)(见OMIM*162010所述)；
B细胞成熟因子(BCMA)，也称为肿瘤坏死因子受体超家族成员17(TNFRSF17)，或BCM(见OMIM*109545)；
糖皮质素诱导的TNFR-相关基因(GITR)，也称为肿瘤坏死因子受体超家族成员18(TNFRSF18)，或活化可诱导的TNFR家族成员(AITR)(见OMIM*603905所述)；
TRADE，也称为肿瘤坏死因子受体超家族成员19(TNFRSF19)，或毒性和JNK诱导剂或TROY或TAJ(见Swiss-Prot Entry No，Q9NS68)；
X-连接的致外胚层发育不良因子-A2受体(XEDAR)，也称为EDA-A2受体(见Swiss-Prot Entry No，Q9HAV5)；
死亡受体6(DR6)，也称为肿瘤坏死因子受体超家族成员21(TNFRSF21)(见OMIM*605732)。
按照本发明的优选实施方式，TNF--结合蛋白选用重组的h-TBP-1(人TNF受体-1的重组胞外可溶性片段，含有对应于Nophar等的20-180氨基酸片段的氨基酸序列，其国际商品名(INN)是“onercept”)和重组的h-TBP-2(TNF受体2的重组胞外可溶性片段，含有对应于Smith等的23-257的氨基酸序列)。最优选重组的hTBP-1(r-hTBP-1)。所有其它蛋白的可溶性胞外域见于相关的Swiss-Prot entry中。
在尝试制备稳定的液体制剂时，评估了pH/缓冲液、离子强度和赋形剂的作用。下面描述用TBP-1(onercept)获得的实验报告。
附图说明
图1是用10mM磷酸盐缓冲液制备的5mg/ml和50mg/ml的onercept制剂原液的线性回归曲线(+40±2℃时的稳定性数据)，PHO＝磷酸钠缓冲液；
图2是用10mM乙酸盐缓冲液制备的5mg/ml和50mg/ml的onercept制剂原液的线性回归曲线(+40±2℃时的稳定性数据)，ACE＝乙酸钠缓冲液；
图3是用10mM柠檬酸盐缓冲液制备的5mg/ml和50mg/ml的onercept制剂原液的线性回归曲线(+40±2℃时的稳定性数据)，CITR＝柠檬酸钠缓冲液；
图4是不同离子强度的5mg/ml onercept制剂原液的线性回归曲线(+40±2℃时的稳定性数据)，PHO＝磷酸钠缓冲液；
图5是不同离子强度的50mg/ml onercept制剂原液的线性回归曲线(+40±2℃时的稳定性数据)，PHO＝磷酸钠缓冲液；
图6是含赋形剂的5mg/ml onercept制剂原液的线性回归曲线(+40±2℃时的稳定性数据)；
图7是含赋形剂的50mg/ml onercept制剂原液的线性回归曲线(+40±2℃时的稳定性数据)。
具体实施方式
材料
Onercept药物原料(由Istituto di Ricerca Cesare Serono，Ardea，IT提供)
乙腈(Merck)
冰醋酸(Merck)
硫酸铵(Merck)
柠檬酸(Merck)
一水合D(+)葡萄糖(Merck)
D(+)甘露醇(Merck)
正磷酸(Merck)
蔗糖(Merck)
叠氮钠(Merck)
氯化钠(Merck)
氢氧化钠(Merck)
无水硫酸钠(Merck)
一水合磷酸二氢钠(Merck)
二水合磷酸氢二钠(Merck)
三氟乙酸(Baker)
设备
HPLC系统(Waters)
校准的移液器(Gilson)
不锈钢支架(Sartorius)
pH计(nod，713。Metrohm)
渗压计(Osmomat 030-D，Gonotec)
过滤膜0.45μm和0.22μm(cod.HVL P04700GWVP04700，Millipore)
TSK G2000 SWXL凝胶柱(cod，08540，TosoHass)
TSK苯基-5PW玻璃凝胶柱，0.8ID×7.5cm(cod 08804，TosoHass)
主要包装材料
硼硅酸盐1型玻璃小瓶(DIN 2R，Nuova Ompi)
氟化橡胶塞(S2F452，D777-1，B2-40，Daiky Seiko)
硼硅酸盐1型玻璃注射器(HYPAK SCF注射器针筒，有固定的针头和针套-SCF，1.0ml长，W7974灰色-Becton Dickinson)
氟化塞，1ml-1BG B2-40Cflt 4023/50gr(Daykio)
溴丁基塞(HYPAK SCF活塞-BSCF 1.0ml L4023/50，灰色(BectonDickinson)
分析试验和方法
采用以下分析试验和方法
·pH(电势计)
·外观(颜色、澄清/不透明、颗粒)(肉眼观察)
·用SE-HPLC测纯度和含量(操作规程TF08/01)
·用HI-HPLC测纯度(操作规程TF09/01)
·渗透压摩尔浓度(冰点法测定)，只测0时
·生物鉴定
首先评估pH/缓冲液、离子强度和赋形剂的作用及其与瓶塞(有涂层和无涂层)的相容性，一旦选择出最好的条件，对以下三种浓度的预充注射器进行试验：
·10mg/ml
·50mg/ml
·60mg/ml
在+5±3□；+25±2℃和+40±2℃贮存3个月后进行稳定性研究，包括以下检验：
·pH
·外观(颜色、澄清/不透明、颗粒；肉眼观察)
·试验(用SE-HPLC)
·纯度(用SE-HPLC)
·纯度(用HI-HPLC)
·渗透压摩尔浓度(只测0时)
·生物鉴定
pH的作用
为了测试pH/缓冲液的作用，用以下不同pH值的10mM缓冲液稀释药物制备5mg/ml和50mg/ml的onercept溶液：
1.pH4，5和6的乙酸钠
2.pH4，5和6的柠檬酸钠
3.pH5，6，7和8的磷酸钠
将上述溶液(每批约20ml)装入3ml玻璃小瓶(1ml装量体积)，加盖，加塞，贮存在+5±3℃；+25±2℃和+40±2℃，每周分析一次直到1个月。
结果见图1，2和3及表1：
表1
以10mM缓冲液配制的5mg/ml和50mg/ml的onercept制剂原液(+40±2℃贮存，用SE-HPLC测定纯度损失)
| 制剂 | 斜率(％度/周) | 1个月后纯度损失(％) | ||||
| PHO* | CITR* | ACE* | PHO* | CITR* | ACE* | |
| 5mg/ml pH4.0 | / | -0.07 | -0.10 | / | -0.3％ | -0.4％ |
| 5mg/ml pH5.0 | -0.33 | -0.24 | -0.32 | -1.3％ | -0.9％ | -1.3％ |
| 5mg/ml pH6.0 | -0.17 | -0.10 | -0.17 | -0.7％ | -0.4％ | -0.7％ |
| 5mg/ml pH7.0 | -0.40 | -0.15 | / | -1.6％ | -0.6％ | / |
| 5mg/ml pH8.0 | -8.45 | / | / | -33.8％ | / | / |
| 50mg/ml pH4.0 | / | -0.68 | -1.56 | / | -2.7％ | -6.2％ |
| 50mg/ml pH5.0 | -1.79 | -0.95 | -1.79 | 7.2％ | -3.8％ | -7.2％ |
| 50mg/ml pH6.0 | -0.65 | -0.50 | -0.70 | -2.6％ | -2.0％ | -2.8％ |
| 50mg/ml pH7.0 | -0.86 | -0.78 | / | -3.4％ | -3.1％ | / |
| 50mg/ml pH8.0 | -10.88 | / | / | -43.5％ | / | / |
*PHO＝磷酸钠缓冲液；CITR＝柠檬酸钠缓冲液；ACE＝乙酸钠缓冲液
如上表和图所示，5mg/ml和50mg/ml时均观察到pH依赖性；这两种浓度的纯度％最小损失见于pH6.0和pH7.0。pH4.0的柠檬酸钠和乙酸钠缓冲液对成分的凝聚也有正面作用，而在pH8.0的磷酸钠缓冲液中观察到迅速降解作用。
+40±2℃贮存1个月后用HI-HPLC没有观察到氧化或pH及外观的变化。
离子强度的作用
为了测定不同离子强度的作用，分别以pH6.0、6.5和7.0的三种不同摩尔浓度(10mM、50mM和100mM)磷酸盐缓冲液制备了5mg/ml和50mg/ml的onercept溶液。将上述溶液(每批约20ml)装入3ml玻璃小瓶(1ml装量体积)，加盖，加塞，贮存在+5±3℃；+25±2℃和+40±2℃，每周分析一次直到1个月。
表2
以不同离子强度缓冲液配制的5mg/ml和50mg/ml的onercept制剂原液(+40±2℃贮存，用SE-HPLC测定纯度损失)
| 制剂 | 斜率(％度/周) | 1个月后纯度损失(％) | ||||
| pH6.0 | pH7.0 | pH8.0 | pH6.0 | pH7.0 | pH8.0 | |
| 5mg/ml 10ml磷酸缓冲液 | -0.18/ | -0.17 | -0.48 | -0.7％ | -0.7％ | -1.9％ |
| 5mg/ml 50ml磷酸缓冲液 | -0.15 | -0.17 | -0.33 | -0.6％ | -0.7％ | -1.3％ |
| 5mg/ml 100ml磷酸缓冲液 | -0.13 | -0.16 | -0.37 | -0.5％ | -0.6％ | -1.5％ |
| 50mg/ml 50ml磷酸缓冲液 | -0.53 | -0.57 | -1.07 | -2.1％ | -2.3％ | -4.3％ |
| 50mg/ml 100ml磷酸缓冲液 | -0.39 | -0.50 | -1.21 | -1.6％ | -2.0％ | -4.5％ |
如上表和图所示，缓冲液的的浓度对凝聚的程度没有影响；在各浓度缓冲液中pH7.0对纯度％均有负面影响，而pH6.0和6.5条件下观察到的纯度损失较小。+40±2℃贮存1个月后用HI-HPLC没有观察到氧化或pH及外观的变化。
不同赋形剂(稳定剂)的作用
为了测试不同赋形剂的作用，用pH6.0和6.5的40mM磷酸盐缓冲液制备5mg/ml和50mg/ml的onercept溶液，并用氯化钠、甘露醇、葡萄糖和蔗糖调节至等渗。将上述溶液(每批约20ml)装入3ml玻璃小瓶(1ml装量体积)，加盖，加塞，贮存在+5±3℃；+25±2℃和+40±2℃，每周分析一次直到1个月。
结果见图6和7及表3：
表3
含赋形剂的5mg/ml和50mg/ml的onercept制剂原液(+40±2℃贮存，用SE-HPLC测定纯度损失)
| 制剂 | 斜率(％度/周) | 1个月后纯度损失(％) | ||
| pH＝6.0 | pH＝6.5 | pH＝6.0 | pH＝6.5 | |
| 5mg/ml加氯化钠 | -0.10 | -0.10 | -0.4％ | -0.4％ |
| 5mg/ml加甘露醇 | -0.10 | -0.08 | -0.4％ | -0.3％ |
| 5mg/ml加蔗糖 | -0.17 | -0.20 | -0.7％ | -0.8％ |
| 5mg/ml加葡萄糖 | -1.09 | -2.7 | -4.4％ | -10.8％ |
| 50mg/ml加氯化钠 | -0.44 | -0.42 | -1.8％ | -1.7％ |
| 50mg/ml加甘露醇 | -0.48 | -0.43 | -1.9％ | -1.7％ |
| 50mg/ml加蔗糖 | -0.63 | -0.54 | -2.5％ | -2.2％ |
| 50mg/ml加葡萄糖 | -4.66 | -6.97 | -18.6％ | -27.9％ |
如上表和图所示，氯化钠和甘露醇的作用与等渗剂相同，因此选择采用在该药物溶液中已有的氯化钠。此外+40±2℃贮存一个月后pH不变，而用HI-HPLC观察到含葡萄糖和蔗糖稳定剂的onercept制剂层析图谱有变化。
从以上三种结果得出令人惊奇的结论，即最稳定的液体制剂是那些将通常用作稳定剂的物质作为赋形剂的配方。因此，那些只含有稀释活性物质的适当缓冲液和等渗剂的制剂是最稳定的。
在这些条件下，稳定性良好的pH范围是6.0-7，优选6-6.5。加入足够量的氯化钠或甘露醇，优选氯化钠达到等渗。
另外，类似实验已证实，对浓度高达170mg/ml的TBP-l和TBP-2结果基本上相同。
药物产品实施例
材料
r-h TBP-1药物原料；氯化钠(Merck)；二水合磷酸氢二钠(Merck)；一水合磷酸二氢钠(Merck)；正磷酸85％(Merck)；WFI(注射用水)。
容器/包装物
主要容器是带有不锈钢针头和橡胶活塞的玻璃注射器。容器内装有注射器和柱塞，其中
注射器
说明：SCF 1.0ml长W7974灰色(Becton Dickinson)
材料、组成
注射器：硼硅酸玻璃1型
针头：钢
润滑剂：DC360，硅油-二甲基硅氧烷
针头套：合成橡胶
柱塞
说明：HYPAK SCF活塞；BSCF 1.0mLL 4023/50灰色(Becton Dickinson)
材料，组成：
合成橡胶：溴丁基，惰性矿物盐，非常规(橡胶)硫化系统
润滑剂：DC360，硅氧烷油-二甲基硅氧烷
制备含0.1M磷酸钠缓冲液，pH＝6.5，氯化钠0.025M的r-h TBP-1溶液实施
例
A)14.3mg/ml的r-h TBP-1溶液
为制备每批1L的成品，采用以下量的：
r-h TBP-1 14.3g
氯化钠 1.46g
二水合磷酸氢二钠 10.5g
一水合磷酸二氢钠 5.68g
B)71.4mg/ml的r-h TBP-1溶液
为制备每批1L的成品，采用以下量的：
r-h TBP-1 71.4g
氯化钠 1.46g
二水合磷酸氢二钠 10.5g
一水合磷酸二氢钠 5.68g
C)1429mg/ml的r-h TRP-1溶液
为制备每批1L的成品，采用以下量的：
r-h TBP-1 142.9g
氯化钠 1.46g
二水合磷酸氢二钠 10.5g
一水合磷酸二氢钠 5.68g
制备方法
·冻干含r-h TBP-1的液体药物，收集产生的粉末作浓度测定。
·在大约800g WFI中溶解所需量的氯化钠、二水合磷酸氢二钠和一水合磷酸二氢钠。计算它们的量时要考虑冻干药物中的盐。
·核查pH，用稀释(1∶10)的85％正磷酸调pH到6.5±0.2值。
·在搅拌条件下缓慢加入所需量的冻干药物，并加入WFI至最终重量(考虑该溶液的最终密度作计算)，在混合过程的不同阶段，核查pH，用稀释的85％正磷酸调pH到6.5±0.2。
·先通过0.45微米滤膜预过滤r-h TBP-1溶液，然后用0.22微米滤膜(DURAPORE)在1.0atm氮气压下除菌过滤(14.3mg/ml的溶液不作预过滤)。将除菌溶液收集到玻璃瓶中。
Claims (13)
1.一种稳定的药学上可接受的TNF-结合蛋白的液体制剂，其特征在于，所述制剂含有TNF-结合蛋白、缓冲液和等渗剂。
2.如权利要求1所述的制剂，其中所述缓冲液是磷酸盐缓冲液。
3.如上述任一权利要求所述的制剂，其中所述缓冲液保持溶液的pH在6-7之间。
4.如权利要求1或2所述的制剂，其中所述等渗剂是氯化钠。
5.如权利要求1或2所述的制剂，其中所述等渗剂是甘露醇。
6.如上述权利要求任何一项所述的制剂，其中所述TNF-结合蛋白是TBP-1。
7.如上述权利要求任何一项所述的制剂，其中所述TNF-结合蛋白是TBP-2。
8.如上述权利要求任何一项所述的制剂，其中所述TNF-结合蛋白的浓度在5-170mg/ml之间。
9.如上述权利要求任何一项所述的制剂，其中所述缓冲液的浓度为5-150mM。
10.如上述权利要求任何一项所述的制剂，其中所述等渗剂的浓度为5-50mM。
11.如上述权利要求任何一项所述的制剂，它包含TBP-1、pH＝6.5的0.1M磷酸钠缓冲液和0.025M的氯化钠。
12.制备如权利要求1-11任何一项所述液体药物制剂的方法，其特征在于，该方法包括用含赋形剂的溶液稀释TNF-结合蛋白。
13.如权利要求1-11任何一项所述的液体药物制剂的剂型，其中所述剂型使用前无菌条件下密封于适当的容器中贮存。
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| US8883146B2 (en) | 2007-11-30 | 2014-11-11 | Abbvie Inc. | Protein formulations and methods of making same |
| NZ602498A (en) * | 2007-11-30 | 2014-08-29 | Abbvie Inc | Protein formulations and methods of making same |
| NZ595694A (en) * | 2009-05-04 | 2013-09-27 | Abbvie Biotechnology Ltd | Stable high protein concentration formulations of human anti-tnf-alpha-antibodies |
| TWI603739B (zh) | 2010-11-11 | 2017-11-01 | 艾伯維生物技術有限責任公司 | 具有增進高濃度之抗－ＴＮＦα抗體之液體調配物 |
| CN103930124B (zh) | 2011-07-01 | 2021-05-11 | 生物基因Ma公司 | 无精氨酸的tnfr：fc-融合多肽组合物及使用方法 |
| AR088383A1 (es) | 2011-10-18 | 2014-05-28 | Coherus Biosciences Inc | Formulaciones de etanercept estabilizadas con combinaciones de azucares y polioles |
| US10493151B2 (en) | 2011-10-18 | 2019-12-03 | Coherus Biosciences, Inc. | Etanercept formulations stabilized with sodium chloride |
| LT3091029T (lt) * | 2011-10-31 | 2023-02-27 | F. Hoffmann-La Roche Ag | Anti-il13 antikūno kompozicijos |
| EP2869816A4 (en) | 2012-07-09 | 2016-04-20 | Coherus Biosciences Inc | FORMANTS OF ETANERCEPT HAVING A REDUCTION MARKED IN INVISIBLE PARTICLES IN THE NU |
| AU2013315750B9 (en) | 2012-09-11 | 2018-11-15 | Coherus Biosciences, Inc. | Correctly folded etanercept in high purity and excellent yield |
| JP6431844B2 (ja) | 2012-10-26 | 2018-11-28 | ルピン アトランティス ホールディングス エスエーＬｕｐｉｎ Ａｔｌａｎｔｉｓ Ｈｏｌｄｉｎｇｓ Ｓａ | Ｔｎｆｒ：ｆｃ融合プロテインの安定な医薬組成物 |
| JP5684954B1 (ja) | 2014-06-26 | 2015-03-18 | 丸石製薬株式会社 | 安定性を改善したロクロニウム製剤 |
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| MXPA05009135A (es) | 2005-10-20 |
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| ATE394123T1 (de) | 2008-05-15 |
| CA2515539A1 (en) | 2004-09-10 |
| US9512215B2 (en) | 2016-12-06 |
| RS51041B (sr) | 2010-10-31 |
| US20170020960A1 (en) | 2017-01-26 |
| BRPI0407649A (pt) | 2006-02-21 |
| AR043418A1 (es) | 2005-07-27 |
| PL378290A1 (pl) | 2006-03-20 |
| ES2304602T3 (es) | 2008-10-16 |
| RS20050662A (en) | 2007-11-15 |
| US20070053906A1 (en) | 2007-03-08 |
| PL213501B1 (pl) | 2013-03-29 |
| EP1603596A1 (en) | 2005-12-14 |
| JP2006519210A (ja) | 2006-08-24 |
| AU2004216483A1 (en) | 2004-09-10 |
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| NO20054440L (no) | 2005-09-26 |
| EA200501230A1 (ru) | 2006-04-28 |
| ZA200506504B (en) | 2006-12-27 |
| HK1085677A1 (en) | 2006-09-01 |
| JP4980048B2 (ja) | 2012-07-18 |
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| IL170414A (en) | 2009-11-18 |
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| US20150098950A1 (en) | 2015-04-09 |
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| UA82503C2 (uk) | 2008-04-25 |
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