CN103347533B - 包含阿那白滞素的无柠檬酸盐药物组合物 - Google Patents
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Abstract
本发明涉及包含阿那白滞素作为活性化合物而不含柠檬酸钠的药物组合物。所述药物组合物可用于治疗IL-1介导的疾病以及用于降低该治疗期间的伤害性疼痛。
Description
技术领域
本发明涉及包含阿那白滞素(anakinra)作为活性化合物而不含柠檬酸钠的药物组合物。所述药物组合物可用于治疗IL-1介导的疾病以及用于降低该治疗期间的伤害性疼痛(nociceptivepain)。
背景技术
适用于肠胃外递送的药物制剂通常包含(a)活性分子;(b)具有足以控制溶液pH之缓冲能力的缓冲剂;和(c)为所述制剂提供等张性的张力剂。此外,根据具体的活性物及其目的用途可以按需要添加其他组分,例如抗氧化剂、特定的稳定剂、表面活性剂、防腐剂等。
制剂组分的选择必须基于评估不同组分在制剂中的功能和最佳稳定能力的全面研究。此外,必须进行其他制剂研究以确定其他溶剂参数,例如对于具体活性分子及其目的用途的最佳pH和离子强度。还进行研究以优化各制剂组分的浓度。在许多情况下,必须考虑最终制剂及其临床用途的其他方面,例如合适的注射体积、与生理流体或组织的相容性、粘度、局部耐受性等。
局部耐受性的一个实例涉及缓冲剂种类的选择。已知特定的缓冲剂种类可能会引发局部不耐受或注射疼痛。一些案例中已报道在皮下注射后柠檬酸钠引起疼痛(Frenken,1993,Laursen,2006)。另外,应该使缓冲剂的浓度最小化以使得不仅对于长期贮存期间药物制剂的pH稳定性来说是最佳的,对注射部位生理条件也具有最小影响(例如,Fransson和Espander-Jansson,1996)。
可以添加到用于肠胃外递送的制剂的组分列表是有限的(Wang和Kowall,1980;Nema,2006)。必须考虑到许多方面:安全性、对于人的以往经验、从供应商的可获得性等。蛋白质药物在体内和体外的稳定性是复杂的问题,其中平行地发生多个降解反应,例如氧化、脱酰胺化、聚集(aggregation)等。一个主要发生的反应是形成聚集体。蛋白质聚集体可以通过共价或非共价途径形成,可具有可溶或不溶的性质。从安全角度来看,蛋白质聚集体的存在是主要问题,这是因为它可能会影响蛋白质的二级和三级结构。特定的非天然蛋白质结构的存在与蛋白质免疫原性的增加相关,潜在地引起效力降低或甚至在体内对天然蛋白质的免疫反应,导致危及生命的情况。
白介素-1介导的疾病包括类风湿性关节炎(rheumatoidarthritis,RA)、炎症性肠病(inflammatoryboweldisease,IBD)、败血症、败血症综合征(sepsissyndrome)、骨质疏松症、缺血性损伤、移植物抗宿主病、再灌注损伤、哮喘、胰岛素糖尿病、骨髓性及其他白血病、银屑病和恶病质(cachexia)。这些以及其他炎症性疾病的特征在于细胞因子(包括白介素-1)的产生。
对于那些IL-1在疾病病理中的作用已知的综合征,可以通过用抗-IL-1药物治疗迅速缓解疾病的临床表现。一种这样的药物是其活性组分阿那白滞素是天然产生的IL-1受体拮抗剂(IL-lra)的重组体形式。阿那白滞素被公开于例如US5,075,222中。
(注射用阿那白滞素)以150mg/ml与10mM柠檬酸钠缓冲剂(pH6-7)和氯化钠(140mM)作为张力剂(tonicityagent)一起配制。此外,0.5mMEDTA和0.1%(w/w)聚山梨酯80被用作稳定剂。选择柠檬酸钠作为阿那白滞素的缓冲组分基于评估阿那白滞素在实时条件下短期和长期稳定性的详细研究。评估了数个可能的缓冲剂成分,磷酸钠为其中之一,并且柠檬酸钠被确定为对于阿那白滞素聚集来说提供最佳的稳定性(Raibekas等,2005)。阿那白滞素的聚集对于缓冲剂组分的选择来说是主要问题。考虑到局部耐受性,尽可能地使柠檬酸钠的浓度最小化。
在临床使用10mM柠檬酸钠中的阿那白滞素期间,发现了制剂引起皮下注射部位的局部耐受性问题(Thaler,2009)。注射部位的反应在蛋白质药物皮下递送中并不少见,其是普遍问题(Haller,2008)并且与临床上使用的大量蛋白质药物相关。50%以上的使用注射用阿那白滞素的患者在进行第一次注射时会经历一定程度的注射部位反应。已经研究局部反应的性质和机制且已得出一些结论(Bendele,1995)。总结出注射位点反应有多个原因,包括阿那白滞素分子本身和制剂组分,柠檬酸钠具有非常大的影响。
因此,需要适用于注射的阿那白滞素组合物,所述阿那白滞素组合物稳定且避免包含柠檬酸钠的阿那白滞素组合物所具有的缺点。
附图说明
图1示出多种阿那白滞素组合物(命名为E、G、H、O、R、S、T和U)每毫升的亚可见(sub-visible)颗粒(尺寸大于5、7.5和10μm)数目。
图2示出所述阿那白滞素组合物在+25℃保存1个月后,如图1中的颗粒数目。
图3示出所述阿那白滞素组合物在+5℃保存3个月后,如图1中的颗粒数目。
图4表示在施用多种阿那白滞素组合物后的雄性Sprague-Dawley大鼠中如增加的爪体积所表示的炎症。
发明内容
根据本发明,令人惊奇地发现适用于注射的阿那白滞素可以在不使用柠檬酸钠的情况下足够稳定。与Raibekas等(2005)的发现相反,阿那白滞素可与适当的张力剂和另外的稳定剂配制为水溶液,但不含柠檬酸钠作为缓冲剂。在适当的制备条件下,阿那白滞素将固有地控制溶液pH。即使不添加缓冲剂的溶液也可足够稳定。
因此,在第一个方面,本发明提供了包含有效量阿那白滞素的药物制剂,其中所述药物制剂不含柠檬酸盐。
本发明的另一个方面是用于治疗或预防IL-1介导之疾病的方法,其包括向需要该治疗的哺乳动物(包括人)施用包含有效量阿那白滞素的药物制剂,其中所述药物制剂不含柠檬酸盐。
根据本发明,所述制剂在无柠檬酸盐的情况下是稳定的,其中术语“稳定”意指,例如,没有聚集和/或pH稳定性至少为大约等于相似的包含10mM柠檬酸钠(pH6-7)的阿那白滞素制剂。
特别地,术语“阿那白滞素”意指具有如NCBI参考序列NP_776214.1中的26-177位所示152个氨基酸之序列的IL-1受体拮抗剂(IL-1ra)(www.ncbi.nlm.nih.gov)。此外,术语“阿那白滞素”应被理解为包括经修饰形式的阿那白滞素,例如与阿那白滞素的氨基酸序列具有至少90%、95%、97%或99%同一性的氨基酸变体。本领域技术人员将理解在阿那白滞素的氨基酸序列内可以进行缺失、插入、倒位和替换的许多组合,前提是所得分子(“阿那白滞素变体”)是生物活性的(例如,其具有抑制IL-1的能力)。特定的阿那白滞素变体描述于例如美国专利No.5,075,222、6,858,409和6,599,873中。
术语“阿那白滞素”还包括包含阿那白滞素的融合蛋白。阿那白滞素可以被设计为具有更大的水动力学尺寸,例如,通过连接聚亚烷基二醇基团(例如聚乙二醇(PEG)基团)、血清白蛋白、转铁蛋白、转铁蛋白受体或至少其转铁结合部分、抗体Fc区域,或者通过与抗体结构域缀合。
术语“有效量”指的是对治疗对象产生治疗效果的量。治疗效果可以是客观的(即,可以通过一些测试或标记物测量)或主观的(即,对象给出效果指征或感觉到效果)。
优选地,阿那白滞素以每天0.1至100mg/kg的剂量施用,优选每天0.1至1mg/kg。优选的用于治疗IL-1介导之疾病的剂量应产生血液阿那白滞素浓度1至1000ng/ml。因此,优选地初始施用的剂量产生大于5ng/ml血浆的阿那白滞素循环水平。
根据本发明的药物制剂优选包含20至200mg/ml之量的阿那白滞素,更优选100至200mg/ml,例如150mg/ml。
根据本发明的药物制剂优选地适于阿那白滞素的皮下注射。优选地,药物制剂包含螯合剂,如乙二胺四乙酸(EDTA)。制剂中EDTA的量优选为0.05至1mM,更优选约0.5mM。乳化剂,优选非离子型表面活性剂如聚山梨酯80(也称为聚氧乙烯脱水山梨醇单油酸酯或吐温80TM),可添加到制剂中以减少聚集和变性以及用于增加溶解度。聚山梨酯80的量优选为0.01至1%,更优选约0.1%。因此,根据本发明的药物制剂优选形式包含150mg/ml阿那白滞素、0.5mMEDTA和0.1%的聚山梨酯80。
此外,根据本发明的药物制剂可以包含张力剂(例如NaCl),其量足以为制剂提供等张性。优选的张力剂是浓度120至240mM的NaCl,优选约120-180mM,例如约120-150mM,或最优选约140mM。
或者,所述张力剂可以是NaCl与选自单糖、二糖和糖醇的第二张力剂的混合物。优选地,第二张力剂选自蔗糖、甘露醇、山梨醇、甘油、肌醇和海藻糖。更优选地,所述第二张力剂是甘露醇、山梨醇或甘油。最优选地,第二张力剂是量为1至100mg/ml的甘露醇,优选5至50mg/ml。
本发明包括药物制剂,其中活性蛋白质(即,阿那白滞素)足以作为缓冲物质并能够将pH保持在期望水平,优选地约pH6.5。因此,根据本发明的制剂无需添加另外的缓冲物质。但是,在本发明还包括包含阿那白滞素以及至少一种另外的缓冲物质的药物制剂,前提是所述另外的缓冲物质不是柠檬酸盐缓冲剂。所述另外的缓冲物质例如可以是磷酸盐缓冲剂或组氨酸。更具体地,所述另外的缓冲剂可以是量为1至50mM的磷酸钠,优选为约10mM,或者量为5至50mM的组氨酸,优选约10mM。
特别优选的制剂是包含与甘露醇组合之磷酸盐缓冲剂的那些。在该制剂中,磷酸盐(如磷酸钠)的浓度优选1至50mM(更优选约10mM),甘露醇浓度优选5至50mg/ml(更优选约10mg/ml)。所述制剂的pH优选为6至7,例如6.3至6.6,或者更优选为约6.5。
因此,根据本发明的优选制剂包括这样的制剂,其包含:
(a)阿那白滞素(100至200mg/ml);
(b)EDTA(0.05至1mM);
(c)聚山梨酯80(0.01至1%);
(d)NaCl(120至180mM);
(e)磷酸钠,pH为6至7(1至50mM);和
(d)甘露醇(5至50mg/ml)。
特别优选的制剂包含:
(a)阿那白滞素(150mg/ml):
(b)EDTA(0.5mM);
(c)聚山梨酯80(0.1%);
(d)NaCl(120至150mM,优选140mM);
(e)磷酸钠,pH6.3至6.6,优选pH6.5(10mM);和
(d)甘露醇(10mg/ml)。
根据本发明的药物制剂可以优选地用于治疗至少一种IL-1介导的疾病。本发明还包括用于治疗IL-1介导之疾病的方法,其包括向有该治疗需要的哺乳动物(包括人)施用如本文所定义的药物制剂。术语“治疗”包括预防(prevention)(预防(prophylaxis))IL-1介导的疾病,或者改善或消除已发生的疾病。
如果自发的或实验性的疾病或医学病症与体液或组织中IL-1的高水平相关,或者如果从身体取出的细胞或组织在培养物中产生高水平的IL-1,那么疾病或医学病症就会被认为是“IL-1介导的疾病”。在许多情况下,这样的白介素1介导的疾病还通过下面的另外两种条件识别:(1)与疾病或医学病症相关的病理现象可以通过施用IL-1在动物中实验性模拟;和(2)疾病或医学病症的实验动物模型中诱导的病理可以通过用抑制IL-1作用之试剂的治疗来抑制或消除。在大多数白介素-1介导的疾病中至少符合三种条件的两种,以及在很多白介素-1介导的疾病中所有三个条件均符合。
IL-1介导的疾病包括:
●淀粉样蛋白A淀粉样变性(amyloidAamyloidosis)
●成人期发作斯蒂尔病(adultonsetStill′sdisease,AOSD)
●哮喘
●白塞氏病(Behcet′sdisease)
●布劳综合征(Blausyndrome)
●恶病质
●二水焦磷酸钙疾病(Calciumpyrophosphatedihydratedisease,CPPD)
●卡斯尔曼病(Castleman′sdisease)
●冷吡啉相关周期性综合征(cryopyrin-associatedperiodicsyndrome,CAPS)
●白介素-1受体拮抗剂缺陷(deficiencyoftheinterleukin-1-receptorantagonist,DIRA)
●皮肌炎
●埃德海姆-切斯特病(Erdheim-Chester′sdisease)
●侵蚀性骨关节炎
●家族性地中海热
●泛发性脓疱型银屑病(generalisedpustularpsoriasis)
●痛风和假性痛风
●移植物抗宿主病
●化脓性汗腺炎
●高IgD综合征(hyperIgDsyndrome,HIDS)
●先天性寒冷性荨麻疹
●包涵体肌炎(inclusion-bodymyositis)
●炎症性肠病(inflammatoryboweldisease,IBD)
●缺血性损伤
●巨噬细胞活化综合征
●马吉德综合征(Majeedsyndrome)
●甲羟戊酸激酶缺乏症
●骨髓性及其他白血病,
●嗜中性脂膜炎
●骨质疏松症
●伴有口疮性口炎、咽炎和淋巴结炎的周期性发热(Periodicfeverswithaphthousstomatitis,pharyngitis,andadenitis,PFAPA)
●多发性肌炎
●银屑病
●坏疽性脓皮病、聚会性痤疮和无菌性关节炎(pyodermagangrenosum,acneconglobata,andasepticarthritis,PAPA)
●复发性先天性心包炎
●复发性多软骨炎
●再灌注损伤
●类风湿性关节炎(RA)
●施尼茨勒综合征(Schnitzler′ssyndrome)
●败血症;败血症综合征
●郁积型骨髓瘤(smolderingmyeloma)
●滑膜炎痤疮脓疱病骨质增生性骨炎(SynovitisAcnePustulosisHyperostosisOsteitis,SAPHO)综合征
●全身型特发性幼年型关节炎(Systemiconsetidiopathicjuvenilearthritis,SoIJA)
●肿瘤坏死因子受体相关周期性综合征(tumournecrosisfactorreceptor-associatedperiodicsyndrome,TRAPS)
●1型糖尿病
●2型糖尿病
●荨麻疹性血管炎
●葡萄膜炎
在本发明的优选形式中,药物制剂通过皮下注射向需要其的哺乳动物(包括人类)施用。根据本发明,皮下注射部位的伤害性疼痛被避免或降低。术语“伤害性疼痛”意指由伤害感受器(疼痛受体)发起的神经活动。
实施例
实施例1:关于可见聚集的稳定性
使用MilliporeProFluxTMM12系统使从AmgenManufacturing获得的在10mM柠檬酸钠、140mMNaCl和0.5mMEDTA中的大量冷冻阿那白滞素溶液解冻并渗滤,所述系统包含0.1m2MilliporePellicon2TM微盒,其含有10kDa的复合再生纤维素PLC10膜TM(www.millipore.com)。所得溶液根据标准方法经超滤浓缩。
表I中所述的组合物由上述所获得的渗滤浓缩溶液制备。除了表I中所示的成分,所有组合物含有150mg/ml阿那白滞素、0.5mMEDTA和0.1%聚山梨酯80。将溶液填充到硅化玻璃注射器(1ml)中,将其贮存1个月(+5℃或+25℃)或3个月(+5℃)。
表I:研究的阿那白滞素组合物
S | 240 | 柠檬酸钠 | 6.5 |
T | 120 | 磷酸钠 | 6.5 |
U | 120 | 磷酸钠 | 6.8 |
根据美国药典-国家处方集(USP-NF),905章(www.usp.org)但调整到小样本体积,通过光阻技术测试了表I中溶液的亚可见颗粒。在每个时间点,来自3个注射器的样品被合并成汇集物(pool)并测试。在每个汇集物中,确定尺寸大于5、7.5和10μm的颗粒数目。结果示于表II和图1-3。肠胃外产品中的亚可见颗粒典型结果为少于6000个大于10μm的颗粒。
表II:阿那白滞素制剂的亚可见颗粒
测量的亚可见颗粒的量表明阿那白滞素的可见聚集是比较低的,随着时间略有增加,而且不依赖于缓冲剂的存在。该数据表明,阿那白滞素可以在不含柠檬酸钠的情况下配制且具有相当的稳定性。
实施例2:聚集稳定性
阿那白滞素组合物如实施例1所描述地进行制备和贮存。通过尺寸排阻色谱(SEC)测量单体含量。用10mM柠檬酸钠、140mMNaCl、0.5mMEDTA将每个样品稀释至阿那白滞素浓度为5mg/mL。经稀释的样品负载于TSK-GelG2000SWXL柱,7.8mm×30cm(ToSohBiosciences08450)并用流速为0.5mL/分钟的10mM柠檬酸钠、140mMNaCl、0.5mMEDTA进行洗脱。记录280nm的吸光度,并由各自的峰面积计算出单体%。
结果(表III)显示所有所研究的阿那白滞素组合物中的阿那白滞素单体水平在3个月内保持稳定。
表III:多种阿那白滞素制剂的稳定性
实施例3:pH稳定性
阿那白滞素组合物如实施例1中所描述地进行制备和贮存。pH根据标准程序进行测量。结果(表IV)显示所有所研究的阿那白滞素组合物中的pH在3个月内保持稳定。
表IV:多种阿那白滞素制剂的pH稳定性
实施例4:包含磷酸盐和甘露醇的阿那白滞素组合物的稳定性
使用MilliporeProFluxTMM12系统使内部获得的在10mM柠檬酸钠,140mMNaCl和0.5mMEDTA中的大量冷冻阿那白滞素溶液解冻并渗滤,所述系统包含0.1m2MilliporePellicon2TM微盒,其含有10kDa的复合再生纤维素PLC10膜TM(www.millipore.com)。所得溶液根据标准方法经超滤浓缩。
表V中描述的组合物由以上所获得的渗滤浓缩溶液制备。除了表V中所示的成分,所有组合物含有150mg/ml阿那白滞素。将溶液填充入硅化玻璃注射器(1ml)中,将其贮存在不同温度下以测试这些制剂中阿那白滞素的稳定性。将样品贮存在+30℃1个月,在+25℃2个月和4个月。
表V:所研究的阿那白滞素组合物
在各温度贮存后通过尺寸排阻色谱(SEC)测量单体含量。用10mM柠檬酸钠、140mMNaCl、0.5mMEDTA将每个样品稀释至阿那白滞素浓度为5mg/mL。经稀释的样品负载于TSK-GelG2000SWXL柱,7.8mm×30cm(ToSohBiosciences08450)并用流速为0.5mL/分钟的10mM柠檬酸钠、140mMNaCl和0.5mMEDTA进行洗脱。记录280nm的吸光度并由各自的峰面积计算出单体%。显示在表VI中的尺寸排阻色谱(SEC)分析的结果表明所有所研究的阿那白滞素组合物中的阿那白滞素单体水平在长达4个月内保持稳定。
表VI:所研究的阿那白滞素制剂的稳定性
此外,如阿那白滞素的蛋白质通常对pH变化敏感。为了评估pH对阿那白滞素的任何影响,已进行的研究中记录了制剂的pH值。结果示于表VII中,显示出随着时间pH增加,但该变化不依赖于制剂,并且表VI显示的单体含量差异不是由pH差异引起的。
表VII:所研究的阿那白滞素制剂的溶液pH
实施例5:阿那白滞素组合物在哈格里夫斯(Hargreaves)测试中的作用
这些研究的目的是比较不同的阿那白滞素制剂(柠檬酸盐缓冲剂或磷酸盐/甘露醇缓冲剂)对雄性Sprague-Dawley大鼠的热痛觉阈值和后爪体积的影响(Hargreaves等,1988)。
在右后爪足底内施用组胺(50μl/爪,3mg/ml),含或不含阿那白滞素(150mg/ml)的柠檬酸盐缓冲剂(10mM,pH6.3)或磷酸盐缓冲剂(10mM,pH6.3,加甘露醇10mg/ml)。2小时后测量为爪体积增加的水肿形成表明,柠檬酸盐缓冲剂和柠檬酸盐缓冲的阿那白滞素以及磷酸盐/甘露醇缓冲的阿那白滞素引起急性炎症(图4)。磷酸盐/甘露醇缓冲剂不引起急性炎症。用作阳性对照的组胺(0.15mg/爪)诱导热痛觉过敏和水肿形成。
总之,单独的柠檬酸缓冲剂和磷酸盐/甘露醇缓冲剂之间,2小时后爪肿胀有明显的区别。此外,注射2小时后爪体积测量表明与柠檬酸缓冲的阿那白滞素相比,磷酸盐/甘露醇缓冲的阿那白滞素具有引起更少水肿形成的趋势。
实施例6:阿那白滞素组合物对大鼠中伊文思蓝(EvansBlue)通透性的影响
用异氟烷麻醉雄性大鼠,使用剪刀将背部和侧面的毛仔细地剃掉,小心避免创伤。用标记笔在背部和侧面暴露的皮肤上绘制具有8个方格的网格。伊文思蓝溶液(1mg/kg;Sigma-Aldrich)通过侧尾静脉注射施用,随后在方格内以随机的方式皮下注射阿那白滞素测试溶液(1000μl)。注射后,动物返回到它们的笼子中,并让其从麻醉中恢复。注射后6小时,将动物暴露于二氧化碳中安乐死。从背部除去皮肤并清理脂肪和结缔组织,毛茸面朝下安装在板上。以毫米为单位渗出的伊文思蓝染料区域的大小通过厘米标尺测量,并且基于染料染色强度,赋予外渗反应个0至4的主观得分。
施用多种阿那白滞素组合物,包括“CSEP”(10mM柠檬酸钠,0.5mMEDTA,0.1%聚山梨酯80和140mMNaCl,pH6.5)中的阿那白滞素,以及磷酸盐缓冲盐水(PBS)作为对照。测量的渗透率变化表明,单独注射1mlPBS导致仅有少量伊文思蓝染料从注射部位渗出。与此相反,注射以100mg/ml溶解在CSEP中的阿那白滞素,显著提高渗透性。
实施例7:阿那白滞素组合物对小鼠伤害性行为的影响
为了评估不同阿那白滞素组合物在注射部位的疼痛作用(algesiogenicaction),使用小鼠后爪舔舐模型(Piovezan等,1998)。将动物单个放置在室(透明玻璃圆筒)内,适应环境至少20分钟,然后足底(sub-plantar)注射多种测试阿那白滞素组合物,包括CSEP中的阿那白滞素(见实施例6)以及PBS作为对照。在刺激(challenge)后,将小鼠单个地观察15-30分钟。用秒表测量舔舐爪子花费的时间量作为伤害性行为的指标。
实施例8:阿那白滞素组合物在热板试验中的作用
为了评估不同阿那白滞素组合物在注射部位产生的疼痛作用,使用小鼠热痛觉过敏模型(Kanaan等,1996)。在测试前1-2天,动物适应预热至30℃的热板装置(UgoBasil,意大利)。测试当天,动物接受足底注射多种测试的阿那白滞素组合物,其包括CSEP中的阿那白滞素(见实施例6)以及PBS作为对照。实验者对处理不知情,小鼠在设为+52℃的热板上进行测试。响应延迟由舔舐后肢或跳跃所花费的时间确定。
实施例9:不同阿那白滞素制剂在体外对肥大细胞脱颗粒的作用
A23187(钙离子载体)和剂量-响应IgE抗IgE作为肥大细胞活化的阳性对照。分离来自10个不同个体(5个来自脐血,5来自成年个体)的肥大细胞。肥大细胞通过CD34-选择(流式细胞仪)从造血细胞中分离,随后在6-8周期间将其培养于37℃、5%CO2、血清剥夺的条件,在人重组干细胞因子和IL-6的存在下(Gulliksson,M.等,2010)。在使细胞遭遇不同的阿那白滞素制剂后,通过测量组胺和PGD2来评估肥大细胞脱颗粒的程度。肥大细胞脱颗粒的变化是肥大细胞活化水平之改变的测量,其为急性炎症性疼痛机制的标识。
实施例10:使用微透析方法的皮下注射阿那白滞素对在注射位点细胞外疼痛介质释放的影响
为了研究注射多种阿那白滞素组合物(包括CSEP中的阿那白滞素(见例6))以及PBS作为对照的急性反应,使用用于测定细胞外生化疼痛介质(例如,神经递质,神经调质,急性炎症细胞因子和趋化因子)浓度的众所周知的微透析方法。动物在实验过程中经吸入异氟烷麻醉。微透析探针插入到每只动物的颈上部皮肤的真皮层中。微透析探针的入口管连接到微灌注泵并且Krebs-Ringer溶液以1-10ml/分钟的流速泵送。收集样品并对各个单独实验的疼痛介质进行分析(例如,通过ELISA)(WeidnerC.等,2000和YoshitakeT.等,2012)。
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Claims (6)
1.适用于注射的药物制剂,其包含有效量的阿那白滞素和甘露醇,其中所述药物制剂不含柠檬酸盐,并且所述药物制剂的pH为6至7,所述药物制剂包含:
(a)阿那白滞素,其为100至200mg/ml;
(b)EDTA,其为0.05至1mM;
(c)聚山梨酯80,其为0.01至1%;
(d)NaCl,其为120至180mM;
(e)磷酸钠,其为1至50mM;以及
(f)甘露醇,其为5至50mg/ml。
2.根据权利要求1所述的药物制剂,其中所述药物制剂的pH为6.5,所述药物制剂包含:
(a)阿那白滞素,其为150mg/ml;
(b)EDTA,其为0.5mM;
(c)聚山梨酯80,其为0.1%;
(d)NaCl,其为145mM;
(e)磷酸钠,其为10mM;以及
(f)甘露醇,其为10mg/ml。
3.根据权利要求1或2所述的药物制剂,其适于阿那白滞素的皮下注射。
4.根据权利要求1或2中任一项所述的药物制剂,其用于治疗IL-1介导的疾病。
5.根据权利要求4所述的药物制剂,其中所述IL-1介导的疾病是类风湿性关节炎。
6.根据权利要求1或2中任一项所述的药物制剂,其中皮下注射部位的伤害性疼痛被避免或降低。
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PCT/SE2012/050124 WO2012108828A1 (en) | 2011-02-11 | 2012-02-09 | Citrate free pharmaceutical compositions comprising anakinra |
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AU2016256217B2 (en) | 2015-04-28 | 2020-04-16 | Swedish Orphan Biovitrum Ab (Publ) | Compositions comprising anakinra |
SG11201805598WA (en) | 2015-12-30 | 2018-07-30 | Green Cross Corp | Methods and compositions for treating hunter syndrome |
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US5075222A (en) | 1988-05-27 | 1991-12-24 | Synergen, Inc. | Interleukin-1 inhibitors |
US6858409B1 (en) | 1988-05-27 | 2005-02-22 | Amgen Inc. | Nucleic acids encoding interleukin-1 inhibitors and processes for preparing interleukin-1 inhibitors |
US5656730A (en) * | 1995-04-07 | 1997-08-12 | Enzon, Inc. | Stabilized monomeric protein compositions |
NZ503548A (en) * | 1996-02-09 | 2001-09-28 | Amgen Inc | A fusion protein comprising an IL-1ra receptor antagonist with a constant domain of human immunoglobulin at the carboxy terminus |
US7619066B2 (en) * | 2004-04-02 | 2009-11-17 | Amgen Inc. | IL-1ra variants |
JP2009512710A (ja) * | 2005-10-21 | 2009-03-26 | アムジエン・インコーポレーテツド | Il−1阻害剤を用いて血管石灰化を抑制する方法 |
WO2009015345A1 (en) * | 2007-07-25 | 2009-01-29 | Amgen Inc. | Pharmaceutical compositions comprising fc fusion proteins |
CN101584857A (zh) * | 2008-05-23 | 2009-11-25 | 西藏诺迪康药业股份有限公司 | 一种眼用制剂及其制备方法 |
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US20160045568A1 (en) | 2016-02-18 |
RU2599848C2 (ru) | 2016-10-20 |
SI2672985T1 (sl) | 2016-09-30 |
EP2672985A4 (en) | 2014-07-30 |
BR112013020195B1 (pt) | 2020-01-07 |
PT2672985T (pt) | 2016-07-25 |
LT2672985T (lt) | 2016-10-10 |
PL2672985T3 (pl) | 2016-11-30 |
HRP20160928T1 (hr) | 2016-10-07 |
CY1117795T1 (el) | 2017-05-17 |
NZ613111A (en) | 2014-06-27 |
AU2012214879B2 (en) | 2016-05-19 |
CN103347533A (zh) | 2013-10-09 |
RU2013141548A (ru) | 2015-03-20 |
BR112013020195A2 (pt) | 2016-08-30 |
WO2012108828A1 (en) | 2012-08-16 |
DK2672985T3 (en) | 2016-06-27 |
HK1189355A1 (zh) | 2014-06-06 |
US9198954B2 (en) | 2015-12-01 |
SMT201600243B (it) | 2016-08-31 |
US10179162B2 (en) | 2019-01-15 |
AU2012214879A1 (en) | 2013-07-25 |
JP2014505099A (ja) | 2014-02-27 |
JP5937622B2 (ja) | 2016-06-22 |
HUE029809T2 (en) | 2017-03-28 |
EP2672985B1 (en) | 2016-04-27 |
US20140018298A1 (en) | 2014-01-16 |
CA2824578A1 (en) | 2012-08-16 |
ES2582928T3 (es) | 2016-09-16 |
RS54968B1 (sr) | 2016-11-30 |
EP2672985A1 (en) | 2013-12-18 |
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