CN105705139B - 包含水溶性有机染料的液体蛋白质制剂 - Google Patents
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Abstract
本发明已开发出蛋白质的浓缩的低粘度低体积液体药物制剂。此类制剂可通过皮下或肌内注射而不是通过长时间静脉内输注来快速且方便地给药。这些制剂包含低分子量和/或高分子量蛋白质诸如mAb及使粘度降低的水溶性有机染料。
Description
对相关申请的交叉引用
本申请要求2014年7月29日提交的标题为“Low-Viscosity ProteinFormulations Containing Hydrophobic Salts”的美国临时申请62/030,521、2014年7月18日提交的标题为“Low-Viscosity Protein Formulations Containing GRASViscosity-Reducing Agents”的美国临时申请62/026,497、2014年6月5日题为“Low-Viscosity Protein Formulations Containing Ionic Liquids”的美国临时申请62/008,050、2014年5月2日提交的标题为“Low-Viscosity Protein Formulations ContainingOrganophosphates”的美国临时申请61/988,005、2014年2月28日提交的标题为“Concentrated,Low-Viscosity Infliximab Formulations”的美国临时申请61/946,436、2014年2月21日提交的标题为“Concentrated,Low-Viscosity,High-Molecular-Weight-Protein Formulations”的美国临时申请61/943,197、2014年2月14日提交的标题为“Concentrated,Low-Viscosity High-Molecular-Weight Protein Formulations”的美国临时申请61/940,227和2013年9月11日提交的标题为“Concentrated,Low-Viscosity,High-Molecular-Weight Protein Formulations”的美国临时申请61,876,621的优先权和权益,通过引用的方式将其公开的内容明确并入本文。
技术领域
本发明大体为高浓缩蛋白质的注射用低粘度药物制剂领域及其制备和使用的方法。
背景技术
单克隆抗体(mAb)是重要的基于蛋白质的治疗剂,其用于治疗各种人类疾病诸如癌症、感染性疾病、炎症和自身免疫性疾病。超过20种单克隆抗体产品已被美国食品药品监督管理局(FDA)所批准,且目前在临床试验中正在进行评价的全部生物药物中的约20%是单克隆抗体(Daugherty等人,Adv.Drug Deliv.Rev.58:686-706,2006;和Buss等人,Curr.Opinion in Pharmacol.12:615-622,2012)。
基于单克隆抗体的治疗剂通常在延长的时段内反复给药且需要若干种mg/kg剂量。抗体溶液或混悬液可通过胃肠外途径来给药,诸如通过静脉内(IV)输注及皮下(SC)或肌内(IM)注射。与静脉内途径相比,皮下或肌内途径在给药期间降低治疗成本,提高患者顺应性且改善患者和医疗服务提供者的方便性。为了成为有效和在药学上可接受的,胃肠外制剂应当优选是无菌的、稳定的、可注射的(例如经由注射器)且在注射部位无刺激性,从而符合FDA指导方针。因为皮下(通常低于约2mL)和肌内(通常低于约5mL)注射需要小体积,所以用于高剂量蛋白质治疗剂的这些给药途径需要浓缩的蛋白质溶液。这些高浓度通常导致非常粘的制剂,其难以通过注射来给药,在注射部位引起疼痛,通常是不精确的和/或可能具有降低的化学和/或物理稳定性。
这些特征导致可能不易满足的制备、储存和使用要求,特别是对于具有高浓度的高分子量蛋白质诸如单克隆抗体的制剂。所有蛋白质治疗剂在一定程度上都受到物理和化学不稳定性的影响,诸如聚集、变性、交联、脱酰胺、异构化、氧化和剪裁(Wang等人,J.Pharm.Sci.96:1-26,2007)。因此,优化制剂的开发在商业化蛋白质药物的开发中是至关重要的。
高蛋白质浓度造成与蛋白质的物理和化学稳定性相关的挑战及蛋白质制剂的生产、储存和递送困难。一个问题是蛋白质在加工和/或储存期间发生聚集并形成颗粒的倾向,这使进一步加工和/或递送期间的操作变得困难。浓度依赖性降解和/或聚集是开发较高浓度的蛋白质制剂中的主要挑战。除非天然蛋白质聚集和颗粒形成的可能性外,可发生水溶液中的可逆性自缔合,这也促进了使注射递送变得复杂的粘度增加(参见例如StevenJ.Shire等人,J.Pharm.Sci.93:1390-1402,2004)。粘度增加是在浓缩的蛋白质组合物中遇到的主要挑战之一,其使生产工艺和通过常规方法容易地递送此类组合物的能力都受到影响(参见例如J.Jezek等人,Advanced Drug Delivery Reviews 63:1107-1117,2011)。
高粘性液体制剂难以制备、吸到注射器中并皮下或肌内注射。在操作粘性制剂中力的使用可导致过度起泡,这可进一步使治疗活性蛋白质发生变性和失活。高粘度溶液还需要较大直径的注射用针头并在注射部位产生较多的疼痛。
目前市售的通过皮下或肌内注射来给药的单克隆抗体产品通常在含水缓冲液及赋形剂或表面活性剂中配制以防止聚集且改善稳定性,所述含水缓冲液为诸如磷酸盐或L-组氨酸缓冲液,所述赋形剂或表面活性剂为诸如甘露醇、蔗糖、乳糖、海藻糖、(由中央疏水链即聚氧丙烯(聚(环氧丙烷))和位于两侧的两条亲水链即聚氧乙烯(聚(环氧乙烷))构成的非离子型三嵌段共聚物)或80(PEG(80)脱水山梨醇单月桂酸酯)。所报道的如上所述配制的抗体浓度通常高达约100mg/mL(Wang等人,J.Pharm.Sci.96:1-26,2007)。
美国专利7,758,860描述了在低分子量蛋白质的制剂中使用缓冲液和使粘度降低的无机盐诸如氯化钙或氯化镁来降低粘度。然而,这些相同的盐对高分子量抗体(IMA-638)制剂的粘度显示出很小的作用。如美国专利7,666,413所述,高分子量蛋白质的含水制剂的粘度已通过添加浓度大于约100mM的精氨酸盐酸盐、硫氰酸钠、硫氰酸铵、硫酸铵、氯化铵、氯化钙、氯化锌或乙酸钠等盐来降低或如美国专利7,740,842所述通过添加有机酸或无机酸来降低。然而,这些盐没有使粘度降低至所需要的水平并在一些情况下使制剂呈足够的酸性以致很可能在注射部位引起疼痛。
美国专利7,666,413描述了含有特定盐和复溶的抗IgE单克隆抗体的粘度降低的制剂,但是最高抗体浓度至多只有约140mg/mL。美国专利7,740,842描述了含有乙酸盐/乙酸缓冲液的其中抗体浓度高达257mg/mL的E25抗IgE单克隆抗体制剂。盐诸如NaCl、CaCl2或MgCl2的添加被证实降低了高剪切条件下的动态粘度;然而,所述盐在低剪切时产生不合希望且显著的动态粘度增加。此外,无机盐诸如NaCl可降低溶液粘度和/或减少聚集(EP1981824)。
非水性抗体或蛋白质制剂也已有描述。WO2006/071693描述了高达100mg/mL的单克隆抗体在具有粘度增强剂(聚乙烯基吡咯烷酮即PVP)和溶剂(苯甲酸苄酯或PEG 400)的制剂中的非水性混悬液。WO2004/089335描述了含有PVP、四氢呋喃聚乙二醇醚、苯甲酸苄酯、苄醇或PEG 400的100mg/mL非水性溶菌酶混悬液制剂。US2008/0226689A1描述了100mg/mL人生长激素(hGH)单相三种媒介物组分(聚合物、表面活性剂和溶剂)非水性粘性制剂。美国专利6,730,328描述了用于蛋白质制剂的非水性、疏水性、非极性、低反应性媒介物诸如全氟萘烷。这些制剂不是最佳的并具有妨碍加工、制备和注射的高粘度;导致多种媒介物组分在制剂中的存在;并存在与使用FDA尚未批准的聚合物相关的潜在规章挑战。
已描述了使用有机溶剂的可选择的非水性蛋白质或抗体制剂,所述有机溶剂为诸如苯甲酸苄酯(Miller等人,Langmuir 26:1067-1074,2010)、乙酸苄酯、乙醇或甲基乙基酮(Srinivasan等人,Pharm.Res.30:1749-1757,2013)。在这两种情况下,小于50厘泊(cP)的粘度当所配置的蛋白质浓度为至少约200mg/mL时被实现。美国专利6,252,055描述了浓度范围为100mg/mL至高达257mg/mL的单克隆抗体制剂。浓度大于约189mg/mL的制剂显示出显著增加的粘度、低的回收率和加工难度。美国专利申请公开文本2012/0230982描述了浓度为100mg/mL至200mg/mL的抗体制剂。这些制剂都不具有足以使注射变得容易的低粘度。
Du和Klibanov(Biotechnology and Bioengineering 108:632-636,2011)描述了最大浓度高达400mg/mL的牛血清白蛋白和最大浓度高达300mg/mL的牛丙种球蛋白的浓缩水溶液的粘度降低。Guo等人(Pharmaceutical Research29:3102-3109,2012)描述了使用疏水性盐来实现四种模型单克隆抗体的低粘度水溶液。Guo所使用的单克隆抗体制剂在添加盐前具有不大于73cP的初始粘度。此外,多种药学上重要的单克隆抗体在治疗相关浓度时的粘度可超过1,000cP。
在高浓度单克隆抗体溶液中控制聚集和粘度不是无关紧要的事情(EP2538973)。这被目前市场上呈高浓度制剂(>100mg/mL)形式的寥寥几种单克隆抗体产品所证实(EP2538973)。
上文引用的参考文献表明虽然多个小组已试图制备单克隆抗体和其它在治疗上重要的蛋白质的低粘度制剂,但是对于多种蛋白质尚未获得真正有用的制剂。值得注意的是,上述多篇报道使用了尚未完全建立安全性和毒性特征的物质。因此,这些制剂与含有已知是安全的化合物的制剂相比在获批前会面临较高的规章负担。事实上,即使化合物被证实大幅降低粘度,所述化合物也可能最终不适用于旨在注射到人体中的制剂。
由于大蛋白质的浓缩溶液的高粘度和其它性质所带来的问题,多种药学上重要的高分子量蛋白质诸如单克隆抗体目前经由静脉内输注来给药以递送治疗有效量的蛋白质。例如,为了在小于约2mL的体积中提供治疗有效量的多种高分子量蛋白质诸如单克隆抗体,通常需要大于150mg/mL的蛋白质浓度。
因此,本发明的目的是提供药学上重要的蛋白质特别是高分子量蛋白质诸如单克隆抗体的浓缩的低粘度液体制剂。
本发明的另一个目的是提供蛋白质特别是高分子量蛋白质诸如单克隆抗体的浓缩的低粘度液体制剂,其能够在可用于皮下和肌内注射的体积中递送治疗有效量的这些蛋白质。
本发明的另一个目的是提供蛋白质特别是高分子量蛋白质诸如单克隆抗体的具有低粘度的浓缩的低粘度液体制剂,所述低粘度可改善可注射性和/或患者顺应性、方便性和舒适性。
本发明的目的还在于提供用于制备和储存蛋白质特别是高分子量蛋白质诸如单克隆抗体的浓缩的低粘度制剂的方法。
本发明的另一个目的是提供给药蛋白质特别是高分子量蛋白质诸如单克隆抗体的浓缩的低粘度液体制剂的方法。本发明的另一个目的是提供用本领域技术人员已知的浓缩和过滤技术加工粘度降低的高浓度生物制剂的方法。
发明内容
已开发出蛋白质的浓缩的低粘度低体积液体药物制剂。此类制剂可通过皮下(SC)或肌内(IM)注射而不是通过长时间静脉内输注来快速且方便地给药。这些制剂包含低分子量和/或高分子量蛋白质诸如单克隆抗体及使粘度降低的水溶性有机染料。
蛋白质的浓度为约10mg/mL至约5,000mg/mL,更优选约100mg/mL至约2,000mg/mL。在一些实施方案中,蛋白质的浓度为约100mg/mL至约500mg/mL,更优选约300mg/mL至约500mg/mL。含有蛋白质和使粘度降低的水溶性有机染料的制剂当在4℃的温度储存时稳定的时间为至少一个月,优选至少两个月且最优选至少三个月。所述制剂的粘度在约25℃小于约75cP,优选低于50cP且最优选低于20cP。在一些实施方案中,所述粘度在约25℃小于约15cP或甚至小于或为约10cP。在一些实施方案中,所述制剂的粘度为约10cP。含有蛋白质和使粘度降低的水溶性染料的制剂当使用锥板式粘度计来测量时通常在约0.6s-1至约450s-1且优选约2s-1至约400s-1的剪切速率测量。含有蛋白质和使粘度降低的水溶性染料的制剂当使用微流体粘度计来测量时通常在约3s-1至约55,000s-1且优选约20s-1至约2,000s-1的剪切速率测量。
蛋白质制剂的粘度由于存在一种或多种使粘度降低的水溶性染料而降低。除非另有明确说明,否则术语“使粘度降低的水溶性染料”包括单一化合物和两种或更多种化合物的混合物。优选的是,存在于制剂中的使粘度降低的水溶性染料的浓度小于约1.0M,优选小于约0.50M,更优选小于约0.30M且最优选小于约0.15M。在一些实施方案中,存在于制剂中的使粘度降低的水溶性染料的浓度低至0.01M。所述制剂所具有的粘度可比在相同条件下除用约相同浓度的适当缓冲剂或盐代替使粘度降低的水溶性染料外的相应制剂的粘度低至少约30%,优选低至少约50%,最优选低至少约75%。在一些实施方案中提供低粘度制剂,其中不含使粘度降低的水溶性染料的相应制剂的粘度大于约200cP,大于约500cP或甚至高于约1,000cP。在优选实施方案中,所述制剂的剪切速率当使用锥板式粘度计来测量时为至少约0.5s-1或当使用微流体粘度计来测量时为至少约1.0s-1。
对于其中蛋白质为“高分子量蛋白质”的实施方案,高分子量蛋白质所具有的分子量可为约100kDa至约1,000kDa,优选约120kDa至约500kDa且最优选约120kDa至约250kDa。高分子量蛋白质可为抗体诸如单克隆抗体或其聚乙二醇化或其它衍生形式。优选的单克隆抗体包括那他珠单抗(natalizumab)西妥昔单抗(cetuximab)贝伐珠单抗(bevacizumab)曲妥珠单抗(trastuzumab)英利昔单抗(infliximab)利妥昔单抗(rituximab)帕尼单抗(panitumumab)奥法木单抗(ofatumumab)及其生物类似物。任选聚乙二醇化的高分子量蛋白质可为酶。也可配制其它蛋白质和蛋白质的混合物以降低其粘度。
在一些实施方案中,将蛋白质和使粘度降低的水溶性染料提供在冻干剂量单元中,其大小适于用无菌水性药用媒介物复溶以产生浓缩的低粘度液体制剂。与不含使粘度降低的水溶性染料的冻干剂量单元相比,一种或多种使粘度降低的水溶性染料的存在有助于和/或加速冻干剂量单元的复溶。
本文提供用于制备高分子量蛋白质诸如单克隆抗体的浓缩的低粘度液体制剂的方法及用于储存低粘度高浓度蛋白质制剂和将其给药于患者的方法。在另一个实施方案中,添加使粘度降低的水溶性染料以通过降低蛋白质溶液的粘度而有助于加工(例如泵送、浓缩和/或过滤)。
具体实施方式
I.定义
本文通常使用的术语“蛋白质”是指氨基酸的聚合物,所述氨基酸通过肽键彼此连接以形成其链长足以产生可检测的至少三级结构的多肽。分子量(以kDa表示,其中“Da”代表“道尔顿”且1kDa=1,000Da)大于约100kDa的蛋白质可被指定为“高分子量蛋白质”,而分子量小于约100kDa的蛋白质可被指定为“低分子量蛋白质”。术语“低分子量蛋白质”不包括以下小肽,所述小肽缺乏被认为是蛋白质所需要的必需条件即至少三级结构。蛋白质分子量可使用本领域技术人员已知的标准方法来确定,包括但不限于质谱(例如ESI、MALDI)或由已知的氨基酸序列和糖基化来计算。蛋白质可为天然存在或非天然存在、合成或半合成的。
“大体纯的蛋白质”和“基本纯的蛋白质”在本文中可互换使用且是指包含至少约90wt%纯蛋白质优选至少约95wt%纯蛋白质的组合物。“大体均质”和“基本均质”在本文中可互换使用且是指以下组合物,其中所存在的蛋白质的至少约90wt%优选至少约95wt%为单体及可逆性二聚和寡聚缔合物(不是不可逆性聚集体)的组合。
本文通常使用的术语“抗体”宽泛地涵盖单克隆抗体(包括具有免疫球蛋白Fc区的全长抗体)、具有聚表位特异性的抗体组合物、双特异性抗体、双抗体和单链抗体分子及抗体片段(例如Fab、Fab’、F(ab’)2和Fv)、单域抗体、多价单域抗体、Fab融合蛋白及其融合体。
本文通常使用的术语“单克隆抗体”或“mAb”是指从基本均质的抗体群中获得的抗体,即构成群的各个抗体是相同的,除了可少量存在的可能的天然存在的突变。单克隆抗体针对单个表位是高度特异性的。例如,这些抗体通常通过如Kohler等人(Nature 256:495,1975)所述那样培养杂交瘤细胞来合成或可通过重组DNA方法(参见例如美国专利4,816,567)来制备或使用Clackson等人(Nature 352:624-628,1991)和Marks等人(J.Mol.Biol.222:581-597,1991)所述的技术从噬菌体抗体库中分离。本文使用的“单克隆抗体”具体包括衍生化抗体、抗体-药物缀合物和“嵌合”抗体(其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而所述链的其余部分与衍生自另一个物种或属于另一个抗体类别或亚类的抗体中的相应序列相同或同源)及这些抗体的片段,只要其展现出所期望的生物学活性(美国专利号4,816,567;Morrison等人,Proc.Natl.Acad.Sci.USA 81:6851-6855,1984)。
“抗体片段”包含完整抗体的一部分,包括完整抗体的抗原结合区和/或可变区。抗体片段的实例包括Fab、Fab’、F(ab’)2和Fv片段;双抗体;线性抗体(参见美国专利号5,641,870;Zapata等人,Protein Eng.8:1057-1062,1995);单链抗体分子;多价单域抗体;和由抗体片段形成的多特异性抗体。
非人类(例如鼠类)抗体的“人源化”形式是大部分人源序列的嵌合免疫球蛋白、免疫球蛋白链或其片段(诸如Fv、Fab、Fab’、F(ab’)2或抗体的其它抗原结合亚序列),其含有衍生自非人类免疫球蛋白的最小序列(参见例如Jones等人,Nature 321:522-525,1986;Reichmann等人,Nature 332:323-329,1988;和Presta,Curr.Op.Struct.Biol.2:593-596,1992)。
“流变学”是指对物质的变形和流动进行的研究。
“粘度”是指物质(通常为液体)对流动的阻力。粘度与剪切力的概念相关;其可被理解为流体的不同层当它们彼此相对移动时彼此施加剪切力或对其它表面施加剪切力的效果。有若干种粘度测量方法。粘度的单位是Ns/m2,称为帕斯卡-秒(Pa-s)。粘度可为“动力的”或“绝对的”。动力粘度是对动量通过流体传递的速率的量度。其以史托(St)进行测量。动力粘度是对流体在重力影响下的阻力性流动的量度。当将体积相等但粘度不同的两种流体置于相同的毛细管粘度计中并使其依靠重力流动时,与较低粘性的流体相比,较高粘性的流体需要较长的时间流动通过毛细管。例如,若一种流体需要200秒(s)完成其流动,而另一种流体需要400s,则称第二种流体的粘度在动力粘度量表上两倍于第一种流体。动力粘度的量纲是长度2/时间。通常,动力粘度以厘史托(cSt)表示。动力粘度的SI单位是mm2/s,其等于1cSt。“绝对粘度”(有时称为“动态粘度”或“单纯粘度”)是动力粘度和流体密度的乘积。绝对粘度以厘泊(cP)为单位表示。绝对粘度的SI单位是毫帕斯卡-秒(mPa-s),其中1cP=1mPa-s。
粘度可通过使用例如粘度计在给定的剪切速率或多个剪切速率进行测量。“外推零剪切”粘度可如下确定:创建绝对粘度对剪切速率的曲线上的四个最高剪切点的最佳拟合线且线性外推粘度回至零剪切。可选择地,对于牛顿流体,粘度可通过在多个剪切速率的平均粘度值来确定。粘度也可使用微流体粘度计在单个或多个剪切速率(也称为流速)进行测量,其中绝对粘度得自液体流经通道时压力的变化。粘度等于剪切应力比剪切速率。在一些实施方案中,用微流体粘度计测量的粘度可直接与外推零剪切粘度例如由使用锥板式粘度计在多个剪切速率测量的粘度外推的那些粘度进行比较。
“剪切速率”是指一层流体在相邻层上经过时粘度的变化率。速度梯度是速度随着与板的距离的变化率。该简单的情况显示了其中单位为(cm/秒)/(cm)的剪切速率(v1-v2)/h=1/秒的均匀速度梯度。因此,剪切速率的单位为倒数秒或通常为倒数时间。对于微流体粘度计,压力和流速的变化与剪切速率相关。“剪切速率”是指使材料发生变形的速度。当使用锥板式粘度计和本领域技术人员所适当选择的梭杆进行测量时,含蛋白质和使粘度降低的水溶性染料的制剂通常在剪切速率为约0.5s-1至约200s-1时测量以在感兴趣的样品的粘度范围内精确地测量粘度(即20cP的样品用固定于DV2T粘度计(Brookfield)的CPE 40梭杆最精确地测量);当使用微流体粘度计进行测量时,剪切速率大于约20s-1至约3,000s-1。
对于本文通常使用的经典“牛顿”流体,粘度与剪切速率基本无关。然而,对于“非牛顿流体”,粘度随着剪切速率增加而降低或增加,例如流体分别是“剪切稀化”或“剪切增稠”的。在浓缩的(即高浓度)蛋白质溶液的情况下,这可表现为假塑性剪切稀化行为,即粘度随着剪切速率而降低。
本文通常使用的术语“化学稳定性”是指制剂中的蛋白质组分抵抗化学途径诸如氧化、脱酰胺或水解所致降解的能力。若小于约5%的组分在4℃保存24个月后发生降解,则蛋白质制剂通常被认为是化学稳定的。
本文通常使用的术语“物理稳定性”是指蛋白质制剂抵抗物理变质诸如聚合的能力。物理稳定的制剂仅形成可接受的百分比的生物活性蛋白质的不可逆性聚集体(例如二聚体、三聚体或其它聚集体)。聚集体的存在可通过多种方式来评价,包括通过借助动态光散射来测量制剂中蛋白质的平均粒度。若所形成的不可逆性聚集体在4℃保存24个月后小于约5%,则制剂被认为是物理稳定的。聚集的杂质的可接受的水平理想地应小于约2%。虽然低至约0.2%的水平是可以实现的,但是约1%是较典型的。
本文通常使用的术语“稳定的制剂”是指既化学稳定又物理稳定的制剂。稳定的制剂可为以下制剂,其中制剂中超过约95%的生物活性蛋白质分子在4℃储存24个月后或在高温等效处理条件下诸如在40℃储存1个月后仍然保留生物活性。用于测量蛋白质稳定性的各种分析技术在本领域中是可得到的并参见例如Peptide and Protein DrugDelivery,247-301,Vincent Lee,Ed.,Marcel Dekker,Inc.,New York,N.Y.(1991)和Jones,A.,Adv.Drug Delivery Revs.10:29-90,1993。稳定性可在所选择的温度测量一定的时段。例如,为了进行快速筛选,可将制剂在40℃保存2周至1个月,然后测量剩余的生物活性并与初始条件进行比较以评价稳定性。当制剂在2℃-8℃储存时,制剂通常应当在30℃或40℃稳定至少1个月和/或在2℃-8℃稳定至少2年。当制剂在室温即约25℃储存时,制剂通常应当在约25℃稳定至少2年和/或在40℃稳定至少约6个月。冻干和储存后聚集的程度可用作蛋白质稳定性的指标。在一些实施方案中,稳定性通过测量制剂中蛋白质的粒度来评价。在一些实施方案中,稳定性可如下评价:使用本领域技术人员已知的标准生物学活性或结合测定来测量制剂的活性。
本文通常使用的术语“蛋白质粒度”是指当通过使用已知的粒度仪例如动态光散射、SEC(尺寸排阻色谱)或本领域技术人员已知的其它方法来测定时,制剂中生物活性分子颗粒的主要群体的平均直径或其粒度分布。
本文通常使用的术语“浓缩的”或“高浓度”描述了以下液体制剂,其所具有的蛋白质的最终浓度大于约10mg/mL,优选大于约50mg/mL,更优选大于约100mg/mL,更优选大于约200mg/mL或最优选大于约250mg/mL。
本文通常使用的“复溶制剂”是指如下制备的制剂:将干燥粉末即冻干、喷雾干燥或由溶剂析出的蛋白质溶解在稀释剂中,从而将蛋白质溶解或分散在用于给药的水溶液中。
“冻干保护剂”是以下物质,其当与蛋白质组合时在冻干和/或后续储存过程中显著降低蛋白质的化学和/或物理不稳定性。示例性冻干保护剂包括糖及其相应的糖醇,诸如蔗糖、乳糖、海藻糖、葡聚糖、赤藓醇、阿糖醇、木糖醇、山梨醇和甘露醇;氨基酸,诸如精氨酸或组氨酸;易溶盐,诸如硫酸镁;多元醇,诸如丙二醇、甘油、聚(乙二醇)或聚(丙二醇);及其组合。其它示例性冻干保护剂包括明胶、糊精、改性淀粉和羧甲基纤维素。优选的糖醇是通过对单糖和二糖诸如乳糖、海藻糖、麦芽糖、乳果糖和麦芽酮糖进行还原而得到的那些化合物。糖醇的其它实例是葡萄糖醇、麦芽糖醇、乳糖醇和异麦芽酮糖。通常以“冻干保护量”向预冻干制剂中添加冻干保护剂。这是指在冻干保护量的冻干保护剂存在下对蛋白质进行冻干后,蛋白质基本保留其物理和化学稳定性及完整性。
本文通常使用的“稀释剂”或“载体”是药学上可接受的(即就向人类或其它哺乳动物给药而言是安全且无毒的)且可用于制备液体制剂(诸如冻干后复溶的含水制剂)的成分。示例性稀释剂包括无菌水、注射用抑菌水(BWFI)、pH缓冲溶液(例如磷酸盐缓冲盐水)、无菌盐水溶液、林格溶液或葡萄糖溶液及其组合。
“防腐剂”是以下化合物,可将其添加到本发明制剂中以减少由细菌、真菌或其它感染原所引起的污染和/或作用。例如,防腐剂的添加可有助于生产多次使用(多剂量)制剂。潜在的防腐剂的实例包括十八烷基二甲基苄基氯化铵、氯己双铵、苯扎氯铵(氯化烷基苄基二甲基铵的混合物,其中所述烷基为长链的)和苄索氯铵。其它类型的防腐剂包括芳族醇,诸如苯酚、丁醇和苄醇;对羟基苯甲酸烷基酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚。
本文通常使用的“填充剂”是以下化合物,其增加冻干混合物的质量并促成冻干饼的物理结构(例如有助于产生基本均匀的保持开孔结构的冻干饼)。示例性填充剂包括甘露醇、甘氨酸、乳糖、改性淀粉,聚(乙二醇)和山梨醇。
“治疗有效量”是实现任何症状或特定病症或障碍的可测量的改善或预防、实现预期寿命的可测量的延长或大体改善患者生活质量所需要的最小浓度。治疗有效量取决于具体生物活性分子和待治疗的具体病症或障碍。多种蛋白质诸如本文所述的单克隆抗体的治疗有效量是本领域已知的。尚未确定的蛋白质的治疗有效量或已知的蛋白质诸如单克隆抗体用于治疗特定障碍和临床用于治疗其它障碍的治疗有效量可通过本领域技术人员诸如医师已知的标准技术来确定。
本文通常使用的术语“可注射性”或“通针性”是指药物制剂通过配备有任选薄壁的18-32号针头的注射器的注射性能。可注射性取决于多种因素诸如注射所需要的压力或力量、流动的均匀性、吸入量和堵塞的避免。液体药物制剂的可注射性可通过对粘度降低制剂的注射力与没有添加使粘度降低的水溶性染料的标准制剂的注射力进行比较来评价。含使粘度降低的水溶性染料的制剂的注射力的降低反映了该制剂的改善的可注射性。当与在相同条件下除用约相同浓度的适当缓冲液代替使粘度降低的水溶性染料外的具有相同蛋白质浓度的标准制剂相比注射力降低至少10%、优选至少30%、更优选至少50%和最优选至少75%时,粘度降低制剂具有改善的可注射性。可选择地,液体药物制剂的可注射性可如下评价:比较当用相同力量按压注射器时注射相同体积诸如0.5mL或更优选约1mL的不同液体蛋白质制剂所需要的时间。
本文通常使用的术语“注射力”是指以给定的注射速度推动给定的液体制剂通过配备有给定大小的针头的给定的注射器所需要的力。注射力通常以牛顿报道。例如,可将注射力测量为以250mm/min的注射速度推动液体制剂通过内径为0.25英寸的配备有0.50英寸27号针头的1mL塑料注射器所需要的力。测试设备可用于测量注射力。当在相同条件下测量时,具有较低粘度的制剂通常将需要整体较低的注射力。
本文使用的“粘度梯度”是指蛋白质溶液的粘度当蛋白质浓度增加时的变化率。粘度梯度可由以下曲线图来近似,所述曲线图为粘度对其它方面相同但蛋白质浓度不同的一系列制剂的蛋白质浓度的函数。随着蛋白质浓度增加,粘度以近似指数的方式增加。特定蛋白质浓度时的粘度梯度可由以下曲线图的切线的斜率来近似,所述曲线图为粘度对蛋白质浓度的函数。粘度梯度可由以下曲线图的线性近似来近似,所述曲线图为粘度对任何蛋白质浓度的函数或蛋白质浓度的窄窗口处的曲线图。在一些实施方案中,当粘度对蛋白质浓度的函数近似为指数函数时,若所述指数函数的指数小于就其它方面相同但不含使粘度降低的水溶性染料的制剂所得到的指数,则认为制剂具有降低的粘度梯度。以类似的方式,当与第二种制剂比较时,若制剂的指数低于/高于第二种制剂的指数,则认为制剂具有较低/较高的粘度梯度。粘度梯度可通过熟练的制剂研究人员所已知的其它方法由粘度对蛋白质浓度的函数的曲线图进行数值近似。
本文通常使用的术语“粘度降低制剂”是指具有高浓度的高分子量蛋白质诸如单克隆抗体或低分子量蛋白质的液体制剂,所述液体制剂与不含一种或多种使粘度降低的添加剂的相应制剂相比通过存在一种或多种使粘度降低的添加剂来改性。
本文通常使用的术语“摩尔渗透压浓度”是指每升中所溶解的组分的总数。摩尔渗透压浓度类似于摩尔浓度,但是包括溶液中所溶解的各种物质的摩尔总数。1Osm/L的摩尔渗透压浓度是指在每升溶液中有1摩尔所溶解的组分。一些溶质诸如在溶液中离解的离子性溶质将在溶液中贡献超过1摩尔所溶解的组分/摩尔溶质。例如,NaCl在溶液中离解成Na+和Cl-且由此在溶液中提供2摩尔所溶解的组分/1摩尔所溶解的NaCl。生理学摩尔渗透压浓度通常为约280mOsm/L至约310mOsm/L。
本文通常使用的术语“张力”是指通过半透膜使两种溶液分离所引起的渗透压梯度。具体地,张力用于描述当细胞暴露于外部溶液时在细胞膜两侧产生的渗透压。可穿过细胞膜的溶质不促成最终的渗透压梯度。只有那些不能穿过细胞膜的所溶解的物质将促成渗透压差及由此促成张力。
本文通常使用的术语“高张性”是指溶液所具有的溶质浓度高于在细胞内侧存在的溶质浓度。当将细胞浸入到高张性溶液中时,趋势是水从细胞中流出以平衡溶质的浓度。
本文通常使用的术语“低张性”是指溶液所具有的溶质浓度低于在细胞内侧存在的溶质浓度。当将细胞浸入到低张性溶液中时,水流到细胞中以平衡溶质的浓度。
本文通常使用的术语“等张性”是指其中在细胞膜两侧的渗透压梯度基本平衡的溶液。等张性制剂是具有与人类血液基本相同的渗透压的制剂。等张性制剂通常将具有约250mOsm/kg至350mOsm/kg的渗透压。
本文使用的术语“液体制剂”是在可接受的药物稀释剂中提供的蛋白质或向患者给药前在可接受的药物稀释剂中复溶的蛋白质。
术语“品牌”和“参照”当用于指蛋白质或生物制品时在本文中可互换使用且是指根据美国公共卫生服务法案(42U.S.C.§262)第351(a)条所许可的单个生物制品。
本文使用的术语“生物类似物”通常与“一般等价物”或“第二代产品”互换使用。例如,“生物类似物单克隆抗体”是指创新者的单克隆抗体的通常由另一家公司生产的后续变体。“生物类似物”当用于指品牌蛋白质或品牌生物制品时可指相对于品牌蛋白质或品牌生物制品进行评价并根据美国公共卫生服务法案(42U.S.C.§262)第351(k)条所许可的生物制品。生物类似物单克隆抗体可为满足由欧洲药品监督管理局人用药品委员会(CHMP)在2012年5月30日正式通过且由欧盟公开为“Guideline on similar biological medicinalproducts containing monoclonal antibodies-non-clinical and clinical issues”的一个或多个指导方针(参考文献EMA/CHMP/BMWP/403543/2010)的生物类似物单克隆抗体。
生物类似物可通过微生物细胞(原核、真核)、人类或动物来源(例如哺乳动物、鸟类、昆虫)的细胞系或衍生自动物或植物的组织来产生。所提出的生物类似物产物的表达构建体通常将编码与其参照产物相同的主要氨基酸序列。可存在小的修改诸如不会对安全性、纯度或效力产生影响的N-或C-末端截短。
生物类似物单克隆抗体在安全性和有效性方面与参照单克隆抗体是物理化学或生物学类似的。生物类似物单克隆抗体可相对于参照单克隆抗体使用包括细节如下的测定在内的一种或多种体外研究来评价:结合于一种或多种目标抗原;结合于Fcγ受体(FcγRI、FcγRII和FcγRIII)、FcRn和补体(C1q)的同工型;Fab相关功能(例如可溶性配体的中和、受体活化或阻断);或Fc相关功能(例如抗体依赖性由细胞介导的细胞毒性、补体依赖性细胞毒性、补体活化)。体外比较可与使药物动力学、药效学和/或安全性的相似性得以证实的体内数据组合。相对于参照单克隆抗体对生物类似物单克隆抗体进行的临床评价可包括比较药物动力学性质(例如AUC0-inf、AUC0-t、Cmax、tmax、Ctrough);药效学终点;或临床效果的相似性(例如使用随机平行组比较性临床试验)。生物类似物单克隆抗体和参照单克隆抗体之间的质量比较可使用已确定的程序来评价,包括“Guideline on similar biologicalmedicinal products containing biotechnology-derived proteins as activesubstance:Quality issues”(EMEA/CHMP/BWP/49348/2005)和“Guideline ondevelopment,production,characterization and specifications for monoclonalantibodies and related substances”(EMEA/CHMP/BWP/157653/2007)所述的那些程序。
生物类似物单克隆抗体与参照单克隆抗体之间的差异可包括翻译后修饰,例如通过使其它生化基团诸如磷酸酯、各种脂质和碳水化合物接附到单克隆抗体;通过在翻译后进行蛋白质水解裂解;通过改变氨基酸的化学性质(例如甲酰化);或通过多种其它机制。其它翻译后修饰可为制备过程操作的结果,例如糖基化可在产物暴露于还原性糖的情况下发生。在其它情况下,储存条件可允许一些降解途径诸如氧化、脱酰胺或聚集。所有这些产物相关变体都可包含在生物类似物单克隆抗体中。
本文使用的术语“药用盐”是指由药用无毒酸和碱(包括无机酸和碱及有机酸和碱)制备的盐。合适的无毒酸包括无机和有机酸诸如乙酸、苯磺酸、苯甲酸、樟脑磺酸、枸橼酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘液酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。合适的带正电荷的抗衡离子包括钠、钾、锂、钙和镁。
本文使用的术语“离子性液体”是指以下结晶性或无定形的盐、两性离子或其混合物,其在大多数常规盐是固体的温度或在该温度附近是液体,所述温度小于200℃,优选小于100℃或更优选小于80℃。一些离子性液体具有在室温附近的熔融温度例如10℃至40℃或15℃至35℃。术语“两性离子”在本文中用于描述以下电荷总体为中性的分子,其在分子的不同化学基团上带有形式为正的电荷和形式为负的电荷。离子性液体的实例参见Riduan等人,Chem.Soc.Rev.,42:9055-9070,2013;Rantwijk等人,Chem.Rev.,107:2757-2785,2007;Earle等人,Pure Appl.Chem.,72(7):1391-1398,2000;和Sheldon等人,GreenChem.,4:147-151,2002。
本文使用的术语“有机磷酸酯”是指含有一个或多个磷酰基的化合物,所述磷酰基中的至少一个通过磷酸酯键而共价连接到有机基团。
本文使用的“水溶性有机染料”可与“水溶性染料”互换使用且是以下有机分子,其在25℃和pH 7的情况下具有至少0.001M的摩尔溶解度且吸收一些波长的光优选电磁波谱的可见光至红外线部分同时可透射或反射其它波长的光。
本文使用的术语“硫族元素”是指第16族元素,包括呈任何氧化态的氧、硫和硒。例如,除非另有说明,否则术语“硫族元素”还包括SO2。
本文使用的术语“烷基”是指直链、支链和环状烃基。除非另有说明,否则术语“烷基”包括含有一个或多个双键或叁键的烃基。含有至少一个环系的烷基是“环烷基”。含有至少一个双键的烷基是“烯基”,且含有至少一个叁键的烷基是“炔基”。
本文使用的术语“芳基”是指包括稠环系统在内的芳族碳环系统。在“芳基”中,形成环的每个原子都为碳原子。
本文使用的术语“杂芳基”是指包括稠环系统在内的芳族环系统,其中形成环的至少一个原子为杂原子。
本文使用的术语“杂环”是指包括稠环系统在内的非芳族环系统,其中形成环的至少一个原子为杂原子。
本文使用的术语“杂原子”为任何非碳或非氢原子。优选的杂原子包括氧、硫和氮。示例性杂芳基和杂环基环包括苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、3H-吲哚基、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、十氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噻噁基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡唑并噁唑基、吡唑并咪唑基、吡唑并噻唑基、吡啶基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基和呫吨基。
II.制剂
生物相容性低粘度蛋白质溶液诸如单克隆抗体的那些生物相容性低粘度蛋白质溶液可用于以皮下(SC)和肌内(IM)注射所适用的体积递送治疗有效量的蛋白质,通常对于皮下注射小于或为约2mL且对于肌内注射小于或为约5mL,更优选对于皮下注射小于或为约1mL且对于肌内注射小于或为约3mL。蛋白质通常可具有任何分子量,虽然在一些实施方案中,高分子量蛋白质是优选的。在其它实施方案中,蛋白质是低分子量蛋白质。
制剂所具有的蛋白质浓度可为约10mg/mL至约5,000mg/mL。包括单克隆抗体制剂在内的制剂所具有的蛋白质浓度可大于100mg/mL,优选大于150mg/mL,更优选大于约175mg/mL,更优选大于约200mg/mL,更优选大于约225mg/mL,更优选大于约250mg/mL且最优选大于或为约300mg/mL。在不存在使粘度降低的水溶性染料的情况下,蛋白质制剂的粘度随着浓度增加而以指数方式增加。此类蛋白质制剂在不存在使粘度降低的水溶性染料的情况下当在25℃测量时所具有的粘度可大于100cP,大于150cP,大于200cP,大于300cP,大于500cP或甚至大于1,000cP。此类制剂通常不适于皮下或肌内注射。一种或多种使粘度降低的水溶性染料的使用允许制备当在25℃测量时粘度小于或为约100cP、优选小于或为约75cP、更优选小于或为约50cP、更优选小于或为约30cP、更优选小于或为约20cP或最优选小于或为约10cP的制剂。
虽然使粘度降低的水溶性染料可用于降低浓缩的蛋白质制剂的粘度,但是其也可用于浓缩程度较小的制剂。在一些实施方案中,制剂所具有的蛋白质浓度可为约10mg/mL至约100mg/mL。制剂所具有的蛋白质浓度可大于约20mg/mL,大于约40mg/mL或大于约80mg/mL。
对于一些蛋白质,不具有使粘度降低的水溶性染料的制剂所具有的粘度可大于约20cP,大于约50cP或大于约80cP。一种或多种使粘度降低的水溶性染料的使用允许制备当在25℃测量时粘度小于或为约80cP、优选小于或为约50cP、更优选小于约20cP或最优选小于或为约10cP的制剂。
在一些实施方案中,当在相同条件下测量时,所述含水蛋白质制剂的粘度比不含一种或多种使粘度降低的水溶性染料的类似制剂低至少约30%。在其它实施方案中,所述制剂的粘度比不含一种或多种使粘度降低的水溶性染料的类似制剂低40%,低50%,低60%,低70%,低80%,低90%或甚至低90%以上。在优选实施方案中,制剂在小于约2mL、优选小于约1mL或更优选小于约0.75mL的体积中含有治疗有效量的一种或多种高分子量蛋白质诸如单克隆抗体。
与其它条件相同但不含使粘度降低的水溶性染料(例如在磷酸盐缓冲液中)的类似制剂相比,粘度降低制剂具有改善的可注射性且需要较小的注射力。在一些实施方案中,与其它条件相同但不含一种或多种使粘度降低的水溶性染料的标准制剂相比,注射力降低超过约20%,超过约30%,超过约40%,超过约50%或超过约2倍。在一些实施方案中,所述制剂具有“牛顿流动特性”,其被定义为具有与剪切速率基本无关的粘度。可容易地将所述蛋白质制剂注射通过大小为约18-32号的针头。用于递送所述低粘度制剂的优选针头大小包括27、29和31号,任选薄壁的。
所述制剂可含有一种或多种其它赋形剂诸如缓冲剂、表面活性剂、糖和糖醇、其它多元醇、防腐剂、抗氧化剂和螯合剂。所述制剂具有适于给药但不引起显著不良副作用的pH和摩尔渗透压浓度。在一些实施方案中,浓缩的低粘度制剂的pH为5至8、5.5至7.6、6.0至7.6、6.8至7.6或5.5至6.5。
低粘度蛋白质制剂可在制剂开发中允许较大的灵活性。与其它方面相同但不含使粘度降低的水溶性染料的制剂相比,低粘度制剂可展现出较少依赖于蛋白质浓度的粘度变化。低粘度蛋白质制剂可允许增加蛋白质的浓度并降低蛋白质的给药频率。在一些实施方案中,低粘度蛋白质制剂含有2种或更多种、3种或更多种或4种或更多种不同的蛋白质。例如,可将2种或更多种单克隆抗体的组合提供在单一低粘度蛋白质制剂中。
因为可按比其它方面类似但不含使粘度降低的水溶性染料的蛋白质制剂高的蛋白质浓度向患者给药蛋白质(诸如单克隆抗体)制剂,所以可降低蛋白质的给药频率。例如,当蛋白质与使粘度降低的水溶性染料一起配制时,先前需要每天给药一次的蛋白质可每两天给药一次,每三天给药一次或甚至更不频繁地给药。目前需要在同一天(在一天的同一时间或不同时间)多次给药的蛋白质可按每天较少次的注射来给药。在一些情况下,频率可减少至每天一次单次注射。通过使每次注射给药的剂量增加多倍,可降低给药频率,例如由每2周一次降低至每6周一次。
在一些实施方案中,所述液体制剂所具有的生理学摩尔渗透压浓度为例如约280mOsm/L至约310mOsm/L。在一些实施方案中,所述液体制剂所具有的摩尔渗透压浓度大于约250mOsm/L,大于约300mOsm/L,大于约350mOsm/L,大于约400mOsm/L或大于约500mOsm/L。在一些实施方案中,所述制剂所具有的摩尔渗透压浓度为约200mOsm/L至约2,000mOsm/L或约300mOsm/L至约1,000mOsm/L。在一些实施方案中,所述液体制剂与人类血液是基本等张的。在一些情况下,所述液体制剂可为高张的。
可按任何量引入包括使粘度降低的水溶性染料在内的添加剂以实现液体制剂的所需粘度水平,只要所述量不是有毒或有害的且基本不干扰制剂的化学和/或物理稳定性。在一些实施方案中,一种或多种使粘度降低的水溶性染料可按以下浓度独立存在:小于约1.0M,优选小于约0.50M,小于或等于约0.30M或小于或等于0.15M。尤其优选的浓度包括约0.01M和约0.10M。对于一些具有两种或更多种使粘度降低的水溶性染料的实施方案,所述物质优选但不必须以相同浓度存在。
使粘度降低的水溶性染料允许冻干剂量单元的较快复溶。剂量单元是蛋白质、使粘度降低的水溶性染料和其它赋形剂的冻干饼,向所述冻干饼中添加水、盐水或其它药用流体。在不存在使粘度降低的水溶性染料的情况下,通常需要10分钟或更长时间以使高蛋白质浓度的冻干饼完全溶解。当冻干饼含有一种或多种使粘度降低的水溶性染料时,使冻干饼完全溶解所需要的时间通常减少为原来的二分之一、五分之一或十分之一。在一些实施方案中,使蛋白质浓度大于或为约150、200或甚至300mg/mL的冻干饼完全溶解需要不到1分钟。
低粘度蛋白质制剂在制剂开发中允许较大的灵活性。与其它方面相同但不含一种或多种使粘度降低的水溶性染料的制剂相比,低粘度制剂展现出当蛋白质浓度增加时改变较少的粘度。与其它方面相同但不含使粘度降低的水溶性染料的制剂相比,低粘度制剂展现出降低的粘度梯度。
与其它方面相同但不含一种或多种使粘度降低的水溶性染料的蛋白质制剂的粘度梯度相比,所述蛋白质制剂的粘度梯度可为其二分之一、三分之一或甚至低于三分之一。对于蛋白质浓度为10mL/mg至2,000mL/mg的蛋白质制剂,所述蛋白质制剂的粘度梯度可小于2.0cPmL/mg,小于1.5cPmL/mg,小于1.0cPmL/mg,小于0.8cPmL/mg,小于0.6cPmL/mg或小于0.2cPmL/mg。通过降低制剂的粘度梯度,可在观察到粘度的指数增加前将蛋白质浓度增加至较高的水平。
一些水溶性有机染料含有酸性或碱性官能团。这些官能团是否完全或部分离子化取决于其所处制剂的pH。除非另有说明,否则具有可离子化的官能团的水溶性有机染料的母体化合物和任何可能的离子化状态均可存在于制剂中。
A.蛋白质
可配制任何蛋白质,包括重组、分离或合成的蛋白质、糖蛋白或脂蛋白。这些蛋白质可为抗体(包括抗体片段和重组抗体)、酶、生长因子或激素、免疫调节因子、抗感染因子、抗增殖因子、疫苗或其它治疗性、预防性或诊断性蛋白质。在一些实施方案中,蛋白质所具有的分子量大于约150kDa,大于160kDa,大于170kDa,大于180kDa,大于190kDa或大于200kDa。
在一些实施方案中,蛋白质可为聚乙二醇化蛋白质。本文使用的术语“聚乙二醇化蛋白质”是指具有一种或多种聚(乙二醇)或其它隐形聚合物基团的蛋白质,所述一种或多种聚(乙二醇)或其它隐形聚合物基团共价接附到所述蛋白质,任选通过可与所述一种或多种聚合物基团不同的化学连接基。聚乙二醇化蛋白质的特征在于其通常降低的肾滤过、减少的网状内皮系统摄取和减弱的酶降解,从而导致例如延长的半衰期和提高的生物利用度。隐形聚合物包括聚(乙二醇);聚(丙二醇);聚(氨基酸)聚合物,诸如聚(谷氨酸)、聚(羟基乙基-L-天冬酰胺)和聚(羟基乙基-L-谷氨酰胺);聚(甘油);聚(2-噁唑啉)聚合物,诸如聚(2-甲基-2-噁唑啉)和聚(2-乙基-2-噁唑啉);聚(丙烯酰胺);聚(乙烯基吡咯烷酮);聚(N-(2-羟基丙基)甲基丙烯酰胺);及其共聚物和混合物。在优选实施方案中,聚乙二醇化蛋白质中的隐形聚合物是聚(乙二醇)或其共聚物。聚乙二醇化蛋白质可为随机聚乙二醇化的即具有一种或多种共价接附在蛋白质上的一个或多个非特异性位点的隐形聚合物或可按位点特异性方式通过使隐形聚合物共价接附到蛋白质上的一个或多个特异性位点来聚乙二醇化。位点特异性聚乙二醇化可例如使用具有一种或多种反应性官能团的活化隐形聚合物来实现。实例参见例如Hoffman等人,Progress in Polymer Science,32:922-932,2007。
在优选实施方案中,蛋白质为高分子量的且为抗体(最优选单克隆抗体)且在缓冲水溶液中当浓缩到足以就皮下注射而言按不超过1.0至2.0mL的体积和就肌内注射而言按不超过3.0至5.0mL的体积来注射治疗有效量时具有高粘度。高分子量蛋白质可包括以下文献所述的那些高分子量蛋白质:Scolnik,mAbs 1:179-184,2009;Beck,mAbs 3:107-110,2011;Baumann,Curr.Drug Meth.7:15-21,2006;或Federici,Biologicals 41:131-147,2013。用于本文所述制剂的蛋白质优选是大体纯和大体均匀的(即基本不含其污染性蛋白质和/或不可逆性聚集物)。
本文优选的单克隆抗体包括那他珠单抗西妥昔单抗贝伐珠单抗曲妥珠单抗英夫利昔单抗利妥昔单抗帕尼单抗奥法木单抗及其生物类似物。示例性高分子量蛋白质可包括托珠单抗阿仑单抗(alemtuzumab)(以几种商品名销售)、brodalumab(由Amgen,Inc.(“Amgen”)开发)、denosumab(和)及其生物类似物。
本文所述抗体的示例性分子靶标包括CD蛋白,诸如CD3、CD4、CD8、CD19、CD20和CD34;HER受体家族成员,诸如EGF受体、HER2、HER3或HER4受体;细胞粘附分子,诸如LFA-1、Mo1、p150,95、VLA-4、ICAM-1、VCAM和αv/β3整联蛋白,包括其α或β亚基(例如抗CD11a、抗CD18或抗CD11b抗体);生长因子,诸如VEGF;IgE;血型抗原;flk2/flt3受体;肥胖(OB)受体;蛋白C;PCSK9等。
目前市场上的抗体治疗剂
目前市场上的多种蛋白质治疗剂尤其是本文所定义的抗体由于需要高剂量而经由静脉内输注来给药。制剂可包含目前市场上的抗体治疗剂之一或其生物类似物。目前市场上的一些蛋白质治疗剂不是高分子量的,但是由于疗效需要高剂量而仍然经由静脉内输注来给药。在一些实施方案中提供本文所定义的这些低分子量蛋白质的液体制剂,其浓度就皮下或肌内注射而言适于递送治疗有效量。
目前市场上的抗体治疗剂包括贝利木单抗(belimumab)戈利木单抗(golimumab)(Simponi )、阿昔单抗(abciximab)以销售的托西莫单抗(tositumomab)和碘-131托西莫单抗的组合、阿仑单抗帕利珠单抗(palivizumab)巴利昔单抗(basiliximab)ado-trastuzumabemtansine帕妥珠单抗(pertuzumab)卡罗单抗喷地肽(capromabpendetide)(ProstaScint )、caclizumab替伊莫单抗(ibritumomabtiuxetan)艾库组单抗(eculizumab)依匹木单抗(ipilimumab)莫罗单抗(muromonab)-CD3(Orthoclone )、瑞西巴库单抗(raxibacumab)、尼妥珠单抗(nimotuzumab)贝伦妥单抗维多汀(brentuximab vedotin)阿达木单抗(adalimumab)戈利木单抗帕利珠单抗奥马珠单抗(omalizumab)和优特克单抗(ustekinumab)
那他珠单抗作为针对细胞粘附分子α4-整联蛋白的人源化单克隆抗体用于治疗多发性硬化和克罗恩病。那他珠单抗先前以商品名上市且目前由BiogenIdec(“Biogen”)和Elan Corp.(“Elan”)以共同上市。在鼠类骨髓瘤细胞中产生。每15mL剂量含有300mg那他珠单抗;123mg氯化钠USP;17.0mg磷酸二氢钠一水合物USP;7.24mg磷酸氢二钠七水合物USP;3.0mg聚山梨醇酯80USP/NF;在静脉内注射用水USP pH 6.1中。那他珠单抗通常通过每月静脉内(IV)输注来给药且已被证实可有效治疗多发性硬化和克罗恩病的症状及用于预防复发、视力减退、认知衰退且显著改善患者生活质量。
本文使用的术语“那他珠单抗”包括以国际非专有名称“NATALIZUMAB”已知的针对细胞粘附分子α4-整联蛋白的单克隆抗体或其抗原结合部分。那他珠单抗包括在美国专利5,840,299、美国专利6,033,665、美国专利6,602,503、美国专利5,168,062、美国专利5,385,839和美国专利5,730,978中所述的抗体。那他珠单抗包括由Biogen Idec和ElanCorporation以商品名上市的产品中的活性剂或其生物类似物产品。
西妥昔单抗是用于治疗转移性结直肠癌和头颈癌的表皮生长因子受体(EGFR)抑制剂。西妥昔单抗是通常通过静脉内输注来给药的嵌合(鼠类/人类)单克隆抗体。西妥昔单抗以商品名由Bristol-Myers Squibb Company(North America;“Bristol-Myers Squibb”)、Eli Lilly和Company(North America;“Eli Lilly”)和Merck KGaA上市仅供静脉内使用。在哺乳动物(鼠类骨髓瘤)细胞培养物中产生。的每个单次使用的50mL小瓶含浓度为2mg/mL的100mg西妥昔单抗并配制在含8.48mg/mL氯化钠、1.88mg/mL磷酸氢二钠七水合物、0.42mg/mL磷酸二氢钠一水合物和静脉内注射用水USP的不含防腐剂的溶液中。
西妥昔单抗适用于与化学疗法联合治疗患有表达表皮生长因子受体(EGFR)的KRAS野生型转移性结直肠癌(mCRC)的患者并在用基于奥沙利铂和伊立替康的疗法不能治疗或不耐受伊立替康的患者中作为单一药物。西妥昔单抗适用于与用于一线治疗复发性和/或转移性疾病的基于铂的化学疗法联合和与用于局部晚期疾病的放射疗法联合治疗患有头颈鳞状细胞癌的患者。患有转移性结直肠癌的患者中的约75%具有表达EGFR的肿瘤且由此根据FDA指导方针据信适于用西妥昔单抗或帕尼单抗治疗。
本文使用的术语“西妥昔单抗”包括以国际非专有名称“CETUXIMAB”已知的单克隆抗体或其抗原结合部分。西妥昔单抗包括在美国专利6,217,866中所述的抗体。西妥昔单抗包括以商品名上市的产品中的活性剂及其生物类似物产品。的生物类似物可包括目前正在由Amgen,AlphaMab Co.,Ltd.(“AlphaMab”)和Actavis plc(“Actavis”)开发的那些生物类似物。
贝伐珠单抗即一种抑制血管内皮生长因子A(VEGF-A)的人源化单克隆抗体作为抗血管生成剂发挥作用。其以商品名由Genentech,Inc.(“Genentech”)和F.Hoffmann-La Roche,LTD(“Roche”)上市。其被许可用于治疗多种癌症,包括结直肠癌、肺癌、乳腺癌(美国除外)、成胶质细胞瘤(仅在美国)、肾癌和卵巢癌。在2004年被FDA批准当与标准化学疗法(作为一线治疗)一起使用时用于转移性结直肠癌及当与基于5-氟尿嘧啶的疗法一起使用时用于二线转移性结直肠癌。FDA在2006年批准与卡铂/紫杉醇化学疗法联合用于一线晚期非鳞状非小细胞肺癌。以15mg/kg或7.5mg/kg的剂量通过静脉内输注每三周给药一次。较高的剂量通常与基于卡铂的化学疗法一起给药,而较低的剂量与基于顺铂的化学疗法一起给药。FDA在2009年批准用于转移性肾细胞癌(肾癌的一种形式)。FDA在2009年还允许加速批准用于治疗复发性多形性成胶质细胞瘤。对初始生长的治疗仍处于III期临床试验中。
美国国家综合癌症网络(“NCCN”)推荐贝伐珠单抗与任何基于铂的化学疗法联合作为标准一线疗法,然后保持贝伐珠单抗直到疾病进展。NCCN在2010年更新了其针对乳腺癌的肿瘤学临床实践指南(NCCN指南)以肯定关于在治疗转移性乳腺癌中使用贝伐珠单抗(Genentech/Roche)的建议。
本文使用的术语“贝伐珠单抗”包括以国际非专有名称/通用名称“BEVACIZUMAB”已知的抑制血管内皮生长因子A(VEGF-A)的单克隆抗体或其抗原结合部分。贝伐珠单抗参见美国专利6,054,297。贝伐珠单抗包括以商品名上市的产品中的活性剂及其生物类似物产品。的生物类似物可包括目前正在由Amgen、Actavis、AlphaMab和Pfizer,Inc(“Pfizer”)开发的那些生物类似物。的生物类似物可包括已知为BCD-021的由Biocad生产且目前在美国进行临床试验的生物类似物。
曲妥珠单抗是干扰HER2/neu受体的单克隆抗体。曲妥珠单抗以商品名由Genentech,Inc上市。由哺乳动物细胞(中华仓鼠卵巢(CHO))系产生。是无菌的白色至淡黄色的不含防腐剂的用于静脉内给药的冻干粉末。每个小瓶含有440mg曲妥珠单抗、9.9mg L-组氨酸HCl、6.4mgL-组氨酸、400mg a,a-海藻糖二水合物和1.8mg聚山梨醇酯20USP。用20mL水复溶得到含21mg/mL曲妥珠单抗的多剂量溶液。目前以每周一次的频率且以约2mg/kg至约8mg/kg的剂量经由静脉内输注来给药。
曲妥珠单抗主要用于治疗一些乳腺癌。HER2基因在20-30%的早期乳腺癌中是扩增的,这使其在细胞膜中过表达表皮生长因子(EGF)受体。曲妥珠单抗对于患有HER2阳性乳腺癌的患者通常作为维持疗法来给药,通常在化学疗法后持续一年。曲妥珠单抗目前以每周一次的频率且以约2mg/kg至约8mg/kg的剂量经由静脉内输注来给药。
本文使用的术语“曲妥珠单抗”包括以国际非专有名称/通用名称“TRASTUZUMAB”已知的干扰HER2/neu受体的单克隆抗体或其抗原结合部分。曲妥珠单抗参见美国专利5,821,337。曲妥珠单抗包括以商品名上市的产品中的活性剂及其生物类似物。术语“曲妥珠单抗”包括以商品名由Mylan,Inc.(“Mylan”)上市和以商品名由Biocon,Ltd.(“Biocon”)上市的生物类似物产品中的活性剂。曲妥珠单抗可包括正在由Amgen和PlantForm Corporation,Canada开发的生物类似物产品中的活性剂。
英利昔单抗是用于治疗自身免疫性疾病的针对肿瘤坏死因子α(TNF-α)的单克隆抗体。其以商品名由Janssen Global Services,LLC(“Janssen”)(美国)、Mitsubishi Tanabe Pharma(日本)、Xian Janssen(中国)和Merck&Co(“Merck”)(其它国家和地区)上市。英利昔单抗是高分子量即约144kDa的嵌合小鼠/人类单克隆抗体。在一些实施方案中,制剂含有的生物类似物诸如REMSIMATM或INFLECTRATM。由Celltrion,Inc.(“Celltrion”)开发的REMSIMATM和由Hospira Inc.,UK开发的INFLECTRATM都已在欧洲被推荐行政批准。Celltrion已向FDA提交REMSIMATM。英利昔单抗目前以约3mg/kg至约10mg/kg的剂量经由静脉内输注来给药。
英利昔单抗含有约30%鼠可变区氨基酸序列,其赋予对人TNFα的抗原结合特异性。剩余70%对应于人IgG1重链恒定区和人κ轻链恒定区。英利昔单抗对人TNFα具有高亲和力,而人TNFα为具有包括介导炎症应答和调节免疫系统在内的多种生物作用的细胞因子。
英利昔单抗是通常由小鼠骨髓瘤细胞(SP2/0细胞)产生和分泌的重组抗体。所述抗体目前通过连续预灌注细胞培养物来生产。英利昔单抗使用构成如下的嵌合抗体基因来表达:由鼠抗TNFα杂交瘤细胞A2克隆的可变区序列及由质粒表达载体提供的人抗体恒定区序列。鼠抗TNFα杂交瘤的产生通过用纯化的重组人TNFα使BALB/c小鼠免疫来进行。对重链和轻链载体构建体进行线性化并通过电穿孔而转染到Sp2/0细胞中。标准纯化步骤可包括色谱纯化、病毒灭活、纳米过滤及超滤/渗滤。
本文使用的术语“英利昔单抗”包括以国际非专有名称“INFLIXIMAB”已知的嵌合小鼠/人类单克隆抗体或其抗原结合部分。英利昔单抗通过以高亲和力与TNFα的可溶性跨膜形式结合来中和TNFα的生物活性并抑制TNFα与其受体的结合。英利昔单抗参见美国专利5,698,195。术语“英利昔单抗”包括以商品名由多家公司、以REMSIMATM由Celltrion和以INFLECTRATM由Hospira,Inc(“Hospira”)上市或拟上市的产品中的活性剂。英利昔单抗以用于复溶和稀释的无菌冻干饼形式提供。英利昔单抗的每个小瓶含有100mg英利昔单抗和赋形剂诸如磷酸二氢钠一水合物、磷酸氢二钠二水合物、蔗糖和聚山梨醇酯80。
denosumab(和)是人单克隆抗体且是第一个被批准用于具有骨质疏松症风险的绝经后妇女和患有实体瘤的骨转移的患者的RANKL抑制剂。denosumab针对治疗类风湿性关节炎正在进行II期临床试验。
帕尼单抗是FDA批准用于对伴随疾病进展的表达EGFR的转移性癌症进行治疗的完整人单克隆抗体。帕尼单抗以商品名由Amgen上市。以20mg/ml帕尼单抗浓缩物形式包装在5ml、10ml和15ml小瓶中用于静脉内输注。当根据包装说明书进行配制时,帕尼单抗的最终浓度不超过10mg/ml。以6mg/kg的剂量通过静脉内输注每14天给药一次。本文使用的术语“帕尼单抗”包括以国际非专有名称“PANITUMUMAB”已知的抗人表皮生长因子受体。术语“帕尼单抗”包括以商品名由Amgen上市的产品中的活性剂及其生物类似物。术语“帕尼单抗”包括美国专利6,235,883所述的单克隆抗体。术语“帕尼单抗”包括生物类似物产品,包括正在由BioXpress,SA(“BioXpress”)开发的生物类似物。
贝利单抗是分子量为约151.8kDa的抑制B细胞活化因子(BAFF)的人单克隆抗体。贝利单抗在美国、加拿大和欧洲被批准用于治疗系统性红斑狼疮。贝利单抗目前以10mg/kg的剂量通过静脉内输注向狼疮患者给药。高分子量低粘度蛋白质制剂可包含贝利单抗,优选浓度为约400mg/mL至约1,000mg/mL。优选的范围基于40-100kg(约80-220磅)的体重在1mL的体积中计算。
阿昔单抗由Janssen Biologics BV制造且由Eli Lilly&Company(“Eli Lilly”)分销。阿昔单抗是嵌合人类/鼠类单克隆抗体7E3的Fab片段。阿昔单抗结合于人血小板的糖蛋白(GP)IIb/IIIa受体并通过防止纤维蛋白原、von Willebrand因子和其它粘附分子的结合来抑制血小板聚集。其还结合于在血小板、血管壁内皮细胞和平滑肌细胞上发现的玻连蛋白(αvβ3)受体。阿昔单抗是主要在冠状动脉程序期间和之后使用的血小板聚集抑制剂。阿昔单抗经由静脉内输注来给药,首先以0.25mg/kg推注,随后以0.125mcg/kg/分钟连续静脉内输注12小时。
托西莫单抗是用于治疗滤泡性淋巴瘤的药物。其是得自永生化小鼠细胞的IgG2a抗CD20单克隆抗体。托西莫单抗通过相继输注来给药:冷的单克隆抗体,随后是碘(131I)托西莫单抗即与放射性核素碘-131共价结合的相同抗体。临床试验已在患有复发性难治性滤泡性淋巴瘤的患者中确定了托西莫单抗/碘托西莫单抗给药方案的功效。目前以450mg的剂量经由静脉内输注来给药。
阿仑单抗(以或上市且目前还以进行开发)是用于治疗慢性淋巴细胞性白血病(CLL)、皮肤T细胞淋巴瘤(CTCL)和T细胞淋巴瘤的单克隆抗体。其根据临床试验方案也用于治疗一些自身免疫性疾病诸如多发性硬化。阿仑单抗的分子量为约145.5kDa。其对于患有B细胞慢性淋巴细胞性白血病的患者每天静脉内输注给药30mg。
帕利珠单抗是针对呼吸道合胞病毒的F蛋白的A抗原性位点中的表位的人源化单克隆抗体。在就儿科群体进行的两项III期临床试验中,帕利珠单抗使呼吸道合胞病毒感染所致住院的风险减少55%和45%。帕利珠单抗经由15mg/kg肌内注射每月给药一次。
奥法木单抗是似乎抑制早期B淋巴细胞活化的人抗CD20单克隆抗体。奥法木单抗以商品名由GlaxoSmithKline,plc(“GlaxoSmithKline”)上市。以含用于静脉内输注的100mg/5mL和1,000mg/50mL奥法木单抗的单次使用的小瓶形式分销。奥法木单抗被FDA批准用于治疗慢性淋巴细胞性白血病并还已在治疗滤泡性非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、类风湿性关节炎和复发性缓解型多发性硬化中显示出潜力。奥法木单抗的分子量为约149kDa。其目前以300mg的初始剂量通过静脉内输注来给药,随后通过每周一次静脉内输注2,000mg来给药。本文使用的术语“奥法木单抗”包括以国际非专有名称“OFATUMUMAB”已知的抗CD20单克隆抗体。术语“奥法木单抗”包括以商品名上市的产品中的活性剂及其生物类似物。术语“奥法木单抗”包括正在由BioExpress开发的生物类似物产品中的活性剂。高分子量低粘度液体蛋白质制剂可包含奥法木单抗,优选浓度为约300mg/mL至约2,000mg/mL。
trastuzumab emtansine(在美国,ado-trastuzumab emtansine,以上市)是由与细胞毒剂mertansine连接的单克隆抗体曲妥珠单抗构成的抗体-药物缀合物。上述曲妥珠单抗通过结合于HER2/neu受体使癌细胞的生长停止,而mertansine进入细胞并通过结合于微管蛋白而破坏细胞。trastuzumab emtansine在美国被批准特别用于治疗复发性HER2阳性转移性乳腺癌。在2014年计划或正在进行多项关于trastuzumabemtansine的III期临床试验。trastuzumab emtansine目前通过静脉内输注3.6mg/kg来给药。高分子量低粘度液体制剂可包含trastuzumab emtansine,优选浓度为约144mg/mL至约360mg/mL。
帕妥珠单抗是抑制HER2二聚化的单克隆抗体。帕妥珠单抗在2012年被FDA批准用于治疗HER2阳性转移性乳腺癌。帕妥珠单抗的目前推荐剂量为静脉内输注420mg至840mg。高分子量低粘度液体制剂可包含帕妥珠单抗,优选浓度为约420mg/mL至约840mg/mL。
达克珠单抗(daclizumab)是人源化抗CD25单克隆抗体并用于预防器官移植特别是肾移植中的排斥。也在研究所述药物用于治疗多发性硬化。达克珠单抗的分子量为约143kDa。达克珠单抗在美国以由Hoffmann-La Roche,Ltd.(“Roche”)上市并通过静脉内输注1mg/kg来给药。达克珠单抗高产方法(DAC HYP;BIIB019;Biogen Idec(“Biogen”)和AbbVie,Inc.(“AbbVie”))处于针对每月皮下注射一次150mg用于治疗复发性缓解型多发性硬化的III期临床试验中。高分子量低粘度液体制剂可包含达克珠单抗,优选浓度为约40mg/mL至约300mg/mL。
艾库组单抗是被批准用于治疗罕见血液病诸如阵发性夜间血红蛋白尿和非典型溶血性尿毒综合征的人源化单克隆抗体。分子量为约148kDa的艾库组单抗由Alexion Pharmaceuticals,Inc(“Alexion”)开发。其以约600mg至约1,200mg的量通过静脉内输注来给药。高分子量低粘度液体制剂可包含艾库组单抗,优选浓度为约500mg/mL至约1,200mg/mL。
托珠单抗是针对白细胞介素-6受体的人源化单克隆抗体。其是主要用于治疗类风湿性关节炎(RA)和系统性青少年特发性关节炎(一种儿童中严重形式的类风湿性关节)的免疫抑制药物。托珠单抗通常以约6mg/kg至约8mg/kg的剂量通过静脉内输注来给药。高分子量低粘度液体制剂可包含托珠单抗,优选浓度为约240mg/mL至约800mg/mL。
利妥昔单抗是用于对以过多数量的B细胞、过度活化的B细胞或功能失常的B细胞为特征的多种疾病进行治疗的嵌合抗CD20单克隆抗体。利妥昔单抗用于治疗白细胞系统的癌症诸如白血病和淋巴瘤,包括霍奇金淋巴瘤及其以淋巴细胞为主的亚型。已显示其为有效的类风湿性关节炎疗法。利妥昔单抗在说明书外广泛用于治疗多发性硬化、系统性红斑狼疮和自身免疫性贫血的疑难病例。
利妥昔单抗在美国以商品名由Biogen和Genentech联合上市且在美国以外以商品名由Roche上市。以含100mg/10mL和500mg/50mL的单次使用的小瓶形式分销。通常通过静脉内输注约375mg/m2来给药。本文使用的术语“利妥昔单抗”包括以国际非专有名称/通用名称“RITUXIMAB”已知的抗CD20单克隆抗体。利妥昔单抗包括美国专利5,736,137所述的单克隆抗体。利妥昔单抗包括以商品名和上市的产品中的活性剂及其生物类似物。
高分子量低粘度液体制剂可包含利妥昔单抗,优选浓度为约475mg/mL至约875mg/mL(使用就5英尺40kg至6英尺100kg的人由Mosteller公式得到的体表面积范围即1.3至2.3平方米来近似)。浓度就1mL制剂来计算。
依匹木单抗是由Bristol-Myers Squibb Company(“Bristol-Myers Squibb”)开发的人单克隆抗体。其以上市且用于治疗黑色素瘤且正在进行关于治疗非小细胞肺癌(NSCLC)、小细胞肺癌(SCLC)和转移性激素难治性前列腺癌的临床试验。依匹木单抗目前通过静脉内输注3mg/kg来给药。高分子量低粘度液体制剂可包含依匹木单抗,优选浓度为约120mg/mL至约300mg/mL。
瑞西巴库单抗是旨在预防和治疗吸入性炭疽的人单克隆抗体。其目前通过静脉内输注来给药。超过50kg的成人和儿童中的建议剂量为40mg/kg。高分子量低粘度液体制剂可包含瑞西巴库单抗,优选浓度为约1,000mg/mL至约4,000mg/mL。
尼妥珠单抗(BIOMAB )是分子量为约151kDa的用于对头颈鳞状细胞癌、复发性或难治性高级恶性神经胶质瘤、间变性星形细胞瘤、成胶质细胞瘤、扩散性内因性脑桥神经胶质瘤进行治疗的人源化单克隆抗体。尼妥珠单抗通常通过每周静脉内输注约200mg来给药。高分子量低粘度液体制剂可包含尼妥珠单抗,优选浓度为约200mg/mL。
贝伦妥单抗维多汀是针对在经典霍奇金淋巴瘤和系统性间变性大细胞淋巴瘤中表达的蛋白质CD30的抗体-药物缀合物。其通过静脉内输注约1.8mg/kg来给药。高分子量低粘度液体制剂可包含贝伦妥单抗维多汀,优选浓度为约80mg/mL至约200mg/mL。
itolizumab是由Biocon开发的人源化IgG1单克隆抗体。itolizumab在患有中度至重度牛皮癣的患者中成功完成了III期临床试验。itolizumab已在印度获得上市许可;尚未向FDA提交许可申请。
最初由Roche开发并根据与Biogen的合作协议正在进一步开发的obinutuzumab是被批准用于治疗慢性淋巴细胞性白血病的人源化抗CD20单克隆抗体。其还在针对患有各种淋巴瘤的患者的III期临床试验中正在进行研究。约1,000mg的剂量经由静脉内输注来给药。
聚乙二醇化赛妥珠单抗(certolizumab pegol)是对人肿瘤坏死因子α(TNFα)具有特异性的与约40kDa的聚乙二醇(PEG2MAL40K)缀合的重组人源化抗体Fab’片段。聚乙二醇化赛妥珠单抗的分子量为约91kDa。
可与使粘度降低的水溶性染料一起配制的其它抗体治疗剂包括来自Celltrion,Inc.(Celltrion)的CT-P6。
后期试验和开发中的抗体治疗剂
进行至后期临床开发和行政审批的抗体治疗剂以迅猛步伐向前发展。在2014年有超过300种单克隆抗体处于临床试验中且有30种商业上发起的抗体治疗剂正在进行后期研究评价。最近向FDA提交了两种单克隆抗体(维多珠单抗(vedolizumab)和雷莫芦单抗(ramucirumab))的第一次上市申请。Amgen目前正在发起多项针对在患有斑块状银屑病的患者中使用brodalumab而进行的具有额外试验计划或患者招募的III期试验。XBiotech,Inc.已发起了两项MABp1(Xilonix)针对患有晚期癌症或2型糖尿病的患者的I期临床试验。关于MABp1的其它试验正在招募患者。针对用moxetumomab pasudotox治疗白血病,多项试验由MedImmune,LLC(“MedImmune”)发起并正在进行或招募患者。针对使用tildrakizumab治疗慢性斑块状银屑病的长期安全性和有效性而正在进行研究。最近已完成针对使用rilotumumab治疗多种癌症的多项II期试验。
目前针对治疗炎性或免疫性病症、癌症、高胆固醇、骨质疏松症、阿尔茨海默病和感染性疾病正在进行或最近完成III期研究的至少28种单克隆抗体为高分子量蛋白质。目前正在进行或最近完成III期试验的单克隆抗体包括AMG145、elotuzumab、依帕珠单抗(epratuzumab)、farletuzumab(MORAb-003)、gantenerumab(RG1450)、gevokizumab、伊珠单抗奥佐米星(inotuzumab ozogamicin)、itolizumab、ixekizumab、lebrikizumab、美泊利单抗(mepolizumab)、naptumomab estafenatox、necitumumab、nivolumab、ocrelizumab、onartuzumab、racotumomab、ramucirumab、reslizumab、romosozumab、sarilumab、secukinumab、sirukumab、solanezumab、tabalumab和vedolizumab。单克隆抗体混合物(actoxumab和bezlotoxumab)也正在进行III期试验评价。参见例如Reichert,MAbs 5:1-4,2013。
维多珠单抗是由Millennium Pharmaceuticals,Inc(“Millennium”;TakedaPharmaceuticals Company,Ltd.(“Takeda”)的子公司)开发的单克隆抗体。发现维多珠单抗在患有中度至重度溃疡性结肠炎的患者中就诱导和保持临床缓解而言是安全和高度有效的。III期临床试验表明其在克罗恩病和溃疡性结肠炎患者中实现了诱导临床应答和保持缓解的目的。评价长期临床结果的研究表明接近60%的患者实现了临床缓解。维多珠单抗的常用剂量为静脉内输注6mg/kg。
雷莫芦单抗是被开发用于治疗实体瘤的人单克隆抗体。针对治疗乳腺癌、转移性胃腺癌、非小细胞肺癌和其它类型的癌症正在进行III期临床试验。雷莫芦单抗在一些III期试验中以约8mg/kg通过静脉内输注来给药。
rilotumumab是对肝细胞生长因子/分散因子的作用进行抑制的人单克隆抗体。其由Amgen开发且处于针对治疗实体瘤的III期试验中。针对在晚期或转移性食管癌患者中用rilotumumab进行治疗的开放式III期研究将经由静脉内输注以约15mg/kg来给药rilotumumab。
evolocumab(AMG 145)也由Amgen开发且是结合于PCSK9的单克隆抗体。evolocumab的适应症为高胆固醇血症和高脂血症。
alirocumab(REGN727)是来自Regeneron Pharmaceuticals,Inc.(“Regeneron”)和Sanofi-Aventis U.S.LLC(“Sanofi”)的人单克隆抗体,其适应症为高胆固醇血症和急性冠状动脉综合征。
来自Active Biotech AB(“Active Biotech”)的naptumomab estafenatox即ABR-217620是适用于肾细胞癌的单克隆抗体。
来自CIMAB,SA(“CIMAB”);Laboratorio Elea S.A.C.I.F.y A.的racotumomab是适用于非小细胞肺癌的单克隆抗体。
可与使粘度降低的水溶性染料一起配制的其它抗体包括bococizumab(PF-04950615)和tanezumab;来自Amgen的ganitumab、blinatumomab、trebananib;来自CangeneCorporation的炭疽免疫球蛋白;来自MacroGenics,Inc.的teplizumab;来自Merck&Co(“Merck”)的MK-3222、MK-6072;来自Wilex AG的girentuximab;来自NavideaBiopharmaceuticals(“Navidea”)的RIGScan;来自Pfizer的PF-05280014;来自ChugaiPharmaceutical Co.Ltd.(“Chugai”)的SA237;来自Janssen/Johnson and JohnsonServices,Inc.(“J&J”)的guselkumab;来自Kyowa的抗凝血酶γ(KW-3357);和来自Celltrion的CT-P10。
早期临床试验中的抗体
多种单克隆抗体最近已经进入或正在进入临床试验。其可包括目前经由静脉内输注来给药的蛋白质,优选分子量大于约120kDa的那些蛋白质,通常约140kDa至约180kDa。其还可包括也正在进入临床试验或已被FDA批准的高分子量蛋白质诸如与白蛋白缀合的药物或肽。多种来自Amgen的单克隆抗体目前处于临床试验中。这些单克隆抗体可为高分子量蛋白质例如AMG 557,其是由Amgen和AstraZeneca联合开发的人单克隆抗体且目前处于针对治疗狼疮的I期试验中。类似地,AMG 729是由Amgen开发的人源化单克隆抗体且目前处于针对治疗狼疮和类风湿性关节炎的I期试验中。此外,AMG 110是针对上皮细胞粘附分子的单克隆抗体;由Amgen和AstraZeneca联合开发的AMG 157是目前处于针对治疗哮喘的I期试验中的人单克隆抗体;AMG 167是已在多项针对治疗骨质疏松症的I期试验中进行评价的人源化单克隆抗体;已完成I期给药研究且目前处于针对治疗偏头痛和潮热的II期研究中的AMG334是对降钙素基因相关肽进行抑制的人单克隆抗体;AMG 780是对内皮细胞选择性Tie2受体与其配体Ang1和Ang2的相互作用进行抑制的人抗血管生成素单克隆抗体且最近完成了作为癌症疗法的I期试验;AMG 811是抑制干扰素γ且作为用于系统性红斑狼疮的疗法正在被研究的人单克隆抗体;AMG 820是抑制c-fms并降低肿瘤相关巨噬细胞(TAM)功能并作为癌症疗法正在被研究的人单克隆抗体;由Amgen和AstraZeneca联合开发的AMG 181是抑制α4/β7的作用且作为用于溃疡性结肠炎和克罗恩病的疗法处于II期试验中的人单克隆抗体。
多种单克隆抗体目前处于针对治疗自身免疫性病症的临床试验中。这些单克隆抗体可包含在低粘度高分子量液体制剂中。RG7624是被设计为特异性且选择性与人白细胞介素-17家族的细胞因子结合的完整人单克隆抗体。针对自身免疫性疾病评价RG7624的I期临床试验正在进行。BIIB033是由Biogen开发的目前处于针对治疗多发性硬化的II期试验中的抗LINGO-1单克隆抗体。
高分子量蛋白质还可包括AGS-009即由Argos Therapeutics,Inc.开发的靶向于IFN-α的单克隆抗体,其最近完成了针对治疗狼疮的I期试验。经由静脉内输注向患者给药至多30mg/kg的AGS-009。由AbbVie开发的BT-061处于针对类风湿性关节炎患者的II期试验中。聚乙二醇化赛妥珠单抗是处于针对强直性脊柱炎和青少年类风湿性关节炎的II期试验中的单克隆抗体。clazakizumab是处于由Bristol-Myers Squibb进行的II期试验中的抗IL6单克隆抗体。
CNTO-136(sirukumab)和CNTO-1959是最近已由Janssen完成II期和III期试验的单克隆抗体。达克珠单抗(先前以由Roche上市)由AbbVie目前进行或最近已完成多项针对治疗多发性硬化的III期试验。依帕珠单抗是处于针对治疗狼疮的III期试验中的人源化单克隆抗体。卡那单抗(canakinumab)是靶向于白细胞介素-1β的人单克隆抗体。其被批准用于治疗cryopyrin相关周期综合征。卡那单抗作为用于慢性阻塞性肺病、痛风和冠状动脉疾病的可能疗法处于I期试验中。mavrilimumab是被设计用于治疗类风湿性关节炎的人单克隆抗体。由Cambridge Antibody Technology以CAM-3001发现的mavrilimumab正在由MedImmune开发。
MEDI-546和MEDI-570是目前处于由AstraZeneca针对治疗狼疮而进行的I期和II期试验中的单克隆抗体。MEDI-546在II期研究中通过常规静脉内输注300-1,000mg来给药。MEDI-551是另一种由AstraZeneca开发的用于多种适应症的单克隆抗体且目前也通过静脉内输注来给药。NN8209是由Novo Nordisk A/S(“Novo Nordisk”)开发的用于阻断C5aR受体的单克隆抗体且已完成针对治疗类风湿性关节炎的II期给药研究。NN8210是另一种正在由Novo Nordisk开发的抗C5aR单克隆抗体且目前处于I期试验中。IPH2201(NN8765)是由NovoNordisk正在开发的用于对患有炎性病症和自身免疫性疾病的患者进行治疗的靶向于NKG2A的人源化单克隆抗体。NN8765最近完成了I期试验。
olokizumab是强效靶向于细胞因子IL-6的人源化单克隆抗体。IL-6参与几种自身免疫性和炎性通路。olokizumab已完成针对治疗类风湿性关节炎的II期试验。otelixizumab(也已知为TRX4)是正在被开发用于治疗1型糖尿病、类风湿性关节炎和其它自身免疫性疾病的单克隆抗体。ozoralizumab是已完成II期试验的人源化单克隆抗体。
Pfizer目前进行针对单克隆抗体PD-360324和PF-04236921用于治疗狼疮的I期试验。利妥昔单抗生物类似物PF-05280586已由Pfizer开发且处于针对类风湿性关节炎的I期/II期试验中。
rontalizumab是正在由Genentech开发的人源化单克隆抗体。其最近完成了针对治疗狼疮的II期试验。SAR113244(抗CXCR5)是由Sanofi开发的处于I期试验中的单克隆抗体。sifalimumab(抗IFN-α单克隆抗体)是处于针对治疗狼疮的II期试验中的单克隆抗体。
高分子量低粘度液体制剂可包含处于针对治疗各种血液疾病的早期临床开发中的单克隆抗体中的一种。例如,贝利木单抗最近已完成针对血管炎患者的I期试验。处于针对血液疾病的早期试验中的其它单克隆抗体包括来自Boehringer IngelheimGmbH(“Boehringer Ingelheim”)的BI-655075、来自Eli Lily的膜铁转运蛋白单克隆抗体和铁调素单克隆抗体及来自Selexys Pharmaceuticals,Corp.(“Selexys”)的SelG1。
处于针对治疗各种癌症和相关病症的早期开发中的一种或多种单克隆抗体可包含在低粘度高分子量液体制剂中。United Therapeutics,Corporation具有两种处于I期试验中的单克隆抗体即8H9单克隆抗体和ch14.18单克隆抗体。来自AbbVie的单克隆抗体ABT-806、enavatuzumab和volociximab处于早期开发中。Actinium Pharmaceuticals,Inc.针对单克隆抗体Actimab-A(M195mAb)、抗CD45mAb和Iomab-B已进行早期试验。SeattleGenetics,Inc.(“Seattle Genetics”)具有处于针对癌症和相关病症的早期试验中的几种单克隆抗体,包括抗CD22ADC(RG7593;pinatuzumab vedotin)、抗CD79b ADC(RG7596)、抗STEAP1ADC(RG7450)、来自Agensys,Inc.(“Agensys”)的ASG-5ME和ASG-22ME、抗体-药物缀合物RG7458和vorsetuzumab mafodotin。来自Genentech的早期癌症治疗剂可包含在低粘度制剂中,包括ALT-836、抗体-药物缀合物RG7600和DEDN6526A、抗CD22 ADC(RG7593)、抗EGFL7mAb(RG7414)、抗HER3/EGFR DAF mAb(RG7597)、抗PD-L1mAb(RG7446)、DFRF4539A、MINT1526A。Bristol-Myers Squibb正在开发针对癌症治疗剂的早期单克隆抗体,包括被鉴定为抗CXCR4的那些单克隆抗体、抗PD-L1、IL-21(BMS-982470)、lirilumab和urelumab(抗CD137)。作为癌症治疗剂处于早期试验中的其它单克隆抗体包括来自Apeiron BiologicsAG的APN301(hu14.18-IL2)、来自AVEO Pharmaceuticals,Inc.(“AVEO”)的AV-203、来自AlphaVax的AVX701和AVX901、来自Baxter International,Inc.(“Baxter”)的BAX-69、来自Bayer HealthCare AG的BAY 79-4620和BAY 20-10112、来自Novartis AG的BHQ880、来自AREVA Med的212-Pb-TCMCtrastuzumab、来自AbGenomics International Inc.的AbGn-7和来自Abiogen Pharma S.p.A的ABIO-0501(TALL-104)。
可与使粘度降低的水溶性染料一起配制的其它抗体治疗剂包括alzumab、GA101、daratumumab、siltuximab、ALX-0061、ALX-0962、ALX-0761、bimagumab(BYM338)、CT-011(pidilizumab)、actoxumab/bezlotoxumab(MK-3515A)、MK-3475(pembrolizumab)、dalotuzumab(MK-0646)、icrucumab(IMC-18F1、LY3012212)、AMG 139(MEDI2070)、SAR339658、dupilumab(REGN668)、SAR156597、SAR256212、SAR279356、SAR3419、SAR153192(REGN421,enoticumab)、SAR307746(nesvacumab)、SAR650984、SAR566658、SAR391786、SAR228810、SAR252067、SGN-CD19A、SGN-CD33A、SGN-LIV1A、ASG 15ME、抗LINGO、BIIB037、ALXN1007、teprotumumab、concizumab、anrukinzumab(IMA-638)、ponezumab(PF-04360365)、PF-03446962、PF-06252616、etrolizumab(RG7413)、quilizumab、兰尼单抗(ranibizumab)、lampalizumab、onclacumab、gentenerumab、crenezumab(RG7412)、IMC-RON8(narnatumab)、tremelimumab、vantictumab、eemcizumab、ozanezumab、mapatumumab、tralokinumab、XmAb5871、XmAb7195、cixutumumab(LY3012217)、LY2541546(blosozumab)、olaratumab(LY3012207)、MEDI4893、MEDI573、MEDI0639、MEDI3617、MEDI4736、MEDI6469、MEDI0680、MEDI5872、PF-05236812(AAB-003)、PF-05082566、BI 1034020、RG7116、RG7356、RG7155、RG7212、RG7599、RG7636、RG7221、RG7652(MPSK3169A)、RG7686、HuMaxTFADC、MOR103、BT061、MOR208、OMP59R5(抗notch 2/3)、VAY736、MOR202、BAY94-9343、LJM716、OMP52M51、GSK933776、GSK249320、GSK1070806、NN8828、CEP-37250/KHK2804AGS-16M8F、AGS-16C3F、LY3016859、LY2495655、LY2875358和LY2812176。
可与使粘度降低的水溶性染料一起配制的其它早期单克隆抗体包括来自AstraZeneca和MedImmune的benralizumab、MEDI-8968、anifrolumab、MEDI7183、sifalimumab、MEDI-575、tralokinumab;来自Biogen Idec/Eisai Co.LTD(“Eisai”)/BioArctic Neuroscience AB的BAN2401;来自Biogen的CDP7657(一种抗CD40L一价聚乙二醇化抗体Fab片段)、STX-100(一种抗avB6单克隆抗体)、BIIB059、抗TWEAK(BIIB023)和BIIB022;来自Janssen和Amgen的fulranumab;来自BioInvent International/Genentech的BI-204/RG7418;来自Biotest Pharmaceuticals Corporation的BT-062(indatuximabravtansine);来自Boehringer Ingelheim/Xencor的XmAb;来自Bristol-Myers Squibb的抗IP10;来自BZL Biologics LLC的J 591Lu-177;来自Celldex Therapeutics的CDX-011(glembatumumab vedotin)、CDX-0401;来自Crucell的foravirumab;来自Daiichi SankyoCompany Limited的tigatuzumab;来自Eisai的MORAb-004、MORAb-009(amatuximab);来自Eli Lilly的LY2382770;来自EMD Serono Inc.的DI17E6;来自Emergent BioSolutions,Inc.的zanolimumab;来自FibroGen,Inc.的FG-3019;来自Fresenius SE&Co.KGaA的catumaxomab;来自Genentech的pateclizumab、rontalizumab;来自Genzyme和Sanofi的fresolimumab;来自Gilead的GS-6624(simtuzumab);来自Janssen的CNTO-328、bapineuzumab(AAB-001)、carlumab、CNTO-136;来自KaloBios Pharmaceuticals,Inc.的KB003;来自Kyowa的ASKP1240;来自Labrys Biologics Inc.的RN-307;来自Life SciencePharmaceuticals的ecromeximab;来自Eli Lilly的LY2495655、LY2928057、LY3015014、LY2951742;来自MassBiologics的MBL-HCV1;来自MENTRIK Biotech,LLC的AME-133v;来自Merck KGaA的abituzumab;来自Merrimack Pharmaceuticals,Inc.的MM-121;来自Novartis AG的MCS110、QAX576、QBX258、QGE031;来自Novartis AG和XOMA Corporation(“XOMA”)的HCD122;来自Novo Nordisk的NN8555;来自Peregrine Pharmaceuticals,Inc.的bavituximab、cotara;来自Progenics Pharmaceuticals,Inc.的PSMA-ADC;来自QuestPharmatech,Inc.的oregovomab;来自Regeneron的fasinumab(REGN475)、REGN1033、SAR231893、REGN846;来自Roche的RG7160、CIM331、RG7745;来自TaiMed Biologics Inc.的ibalizumab(TMB-355);来自Theraclone Sciences的TCN-032;来自TRACONPharmaceuticals,Inc.的TRC105;来自United Biomedical Inc.的UB-421;来自ViventiaBio,Inc.的VB4-845;来自AbbVie的ABT-110;来自Ablynx的caplacizumab、ozoralizumab;来自CytoDyn,Inc.的PRO 140;来自Medarex,Inc.的GS-CDA1、MDX-1388;来自Amgen的AMG827、AMG 888;来自TG Therapeutics Inc.的ublituximab;来自Tolera Therapeutics,Inc.的TOL101;来自ImmunoGen Inc.的huN901-DM1(lorvotuzumab mertansine);来自Immunomedics,Inc.的epratuzumab Y-90/veltuzumab组合(IMMU-102);来自Agenix,Limited的抗纤维蛋白单克隆抗体/3B6/22Tc-99m;来自Alder Biopharmaceuticals,Inc.的ALD403;来自Pfizer的RN6G/PF-04382923;来自CG Therapeutics,Inc.的CG201;来自KaloBios Pharmaceuticals/Sanofi的KB001-A;来自Kyowa.的KRN-23;来自Immunomedics,Inc.的Y-90hPAM 4;来自Morphosys AG和OncoMed Pharmaceuticals,Inc.的Tarextumab;来自Morphosys AG和Novartis AG的LFG316;来自Morphosys AG和Jannsen的CNTO3157、CNTO6785;来自Roche和Chugai的RG6013;来自Merrimack Pharmaceuticals,Inc.(“Merrimack”)的MM-111;来自GlaxoSmithKline的GSK2862277;来自Amgen的AMG 282、AMG172、G 595、AMG 745、AMG 761;来自Biocon的BVX-20;来自Celltrion的CT-P19、CT-P24、CT-P25、CT-P26、CT-P27、CT-P4;来自GlaxoSmithKline的GSK284933、GSK2398852、GSK2618960、GSK1223249、GSK933776A;来自Morphosys AG和Bayer AG的anetumab ravtansine;来自Morphosys AG和Boehringer Ingelheim的BI-836845;来自Morphosys AG和Novartis AG的NOV-7、NOV-8;来自Merrimack的MM-302、MM-310、MM-141、MM-131、MM-151;来自Roche和Seattle Genetics的RG7882;来自Roche/Genentech的RG7841;来自Pfizer的PF-06410293、PF-06438179、PF-06439535、PF-04605412、PF-05280586;来自Roche的RG7716、RG7936、gentenerumab、RG7444;来自Astrazeneca的MEDI-547、MEDI-565、MEDI1814、MEDI4920、MEDI8897、MEDI-4212、MEDI-5117、MEDI-7814;来自Bristol-Myers Squibb的ulocuplumab、PCSK9 adnectin;来自FivePrime Therapeutics,Inc.的FPA009、FPA145;来自Gilead的GS-5745;来自Kyowa Hakko Kirin的BIW-8962、KHK4083、KHK6640;来自Merck KGaA的MM-141;来自Regeneron的REGN1154、REGN1193、REGN1400、REGN1500、REGN1908-1909、REGN2009、REGN2176-3、REGN728;来自Sanofi的SAR307746;来自Seattle Genetics的SGN-CD70A;来自Ablynx的ALX-0141、ALX-0171;来自Immunomedics,Inc.的milatuzumab-DOX、milatuzumab、TF2;来自Millennium的MLN0264;来自AbbVie的ABT-981;来自AbGenomics InternationalInc.的AbGn-168H;来自AVEO的ficlatuzumab;来自BioInvent International的BI-505;来自Celldex Therapeutics的CDX-1127、CDX-301;来自Cellerant Therapeutics Inc.的CLT-008;来自Circadian的VGX-100;来自Daiichi Sankyo Company Limited的U3-1565;来自Dekkun Corp.的DKN-01;来自Eli Lilly的flanvotumab(TYRP1蛋白)、IL-1β抗体、IMC-CS4;来自Eli Lilly和ImClone,LLC的VEGFR3单克隆抗体、IMC-TR1(LY3022859);来自Elusys Therapeutics Inc.的Anthim;来自Galaxy Biotech LLC的HuL2G7;来自ImmunoGenInc.的IMGB853、IMGN529;来自Janssen的CNTO-5、CNTO-5825;来自Kaketsuken的KD-247;来自KaloBios Pharmaceuticals的KB004;来自MacroGenics,Inc.的MGA271、MGAH22;来自MorphoSys AG/Xencor的XmAb5574;来自Neogenix Oncology,Inc.的ensituximab(NPC-1C);来自Novartis AG和XOMA的LFA102;来自Novartis AG的ATI355;来自Santarus Inc.的SAN-300;来自Selexys的SelG1;来自Targa Therapeutics,Corp.的HuM195/rGel;来自TevaPharmaceuticals,Industries Ltd.(“Teva”)和Vaccinex Inc.的VX15;来自TheracloneSciences的TCN-202;来自Xencor的XmAb2513、XmAb5872;来自XOMA和美国国立过敏与感染性疾病研究所的XOMA 3AB;来自MabVax Therapeutics的神经母细胞瘤抗体疫苗;来自CytoDyn,Inc.的cytolin;来自Emergent BioSolutions Inc.的thravixa;来自CytovanceBiologics的FB 301;来自Janssen和Sanofi的狂犬病单克隆抗体;来自Janssen且由美国国立卫生研究院部分资助的流感单克隆抗体;来自Mapp Biopharmaceutical,Inc.的MB-003和ZMapp;和来自Defyrus Inc.的ZMAb。
其它蛋白质治疗剂
蛋白质可为酶、融合蛋白、隐形或聚乙二醇化蛋白质、疫苗或其它生物活性蛋白质(或蛋白质混合物)。本文使用的术语“酶”是指催化靶标分子生化转化成所需产物的蛋白质或其功能性片段。
作为药物的酶具有至少两个重要的特征即i)通常以高亲和力和特异性结合且作用于其靶标,和ii)催化并转化多种靶标分子成所需产物。在一些实施方案中,蛋白质可如本文所定义的那样为聚乙二醇化的。
本文使用的术语“融合蛋白”是指由对两种单独蛋白质进行编码的两种不同基因产生的蛋白质。融合蛋白通常通过本领域技术人员已知的重组DNA技术来产生。两种蛋白质(或蛋白质片段)共价融合在一起并展现出两种母体蛋白的性质。
有多种上市的融合蛋白。
(Etanercept)是由Amgen上市的竞争性抑制TNF的融合蛋白。
即抗血友病因子(重组)Fc融合蛋白是由重组DNA产生的抗血友病因子,适用于在患有甲型血友病(先天性凝血因子VIII缺乏)的成人和儿童中控制和预防出血发作、围手术期管理、旨在防止或减少出血发作频率的常规预防。
(aflibercept)是由与人IgG1的Fc部分融合的人VEGF受体1和2细胞外结构域部分构成的配制成用于玻璃体内给药的等渗溶液的重组融合蛋白。(aflibercept)是由与人IgG1的Fc部分融合的人VEGF受体1和2细胞外结构域部分构成的配制成用于玻璃体内给药的等渗溶液的重组融合蛋白。aflibercept是蛋白质分子量为97千道尔顿(kDa)的二聚体糖蛋白且包含糖基化,构成总分子量的另外15%,导致总分子量为115kDa。aflibercept在重组中华仓鼠卵巢(CHO)细胞中产生,由Regeneron上市。
ALPROLIXTM即凝血因子IX(重组)Fc融合蛋白是由重组DNA产生的凝血因子IX浓缩物,适用于在患有乙型血友病的成人和儿童中控制和预防出血发作、围手术期管理、旨在防止或减少出血发作频率的常规预防。
pegloticase是由Savient Pharmaceuticals,Inc.开发的用于治疗重度难治性慢性痛风的药物且是第一种被批准用于该适应症的药物。pegloticase是分子量为约497kDa的聚乙二醇化重组猪样尿酸酶。pegloticase目前通过静脉内输注8mg/kg来给药。高分子量低粘度液体制剂可包含pegloticase,优选浓度为约300mg/mL至约800mg/mL。
阿替普酶(alteplase)是通过重组DNA技术来产生的组织纤溶酶原活化剂。其是包含527个氨基酸的经纯化的糖蛋白并使用得自人黑色素瘤细胞系的天然人组织型纤溶酶原活化物的互补DNA(cDNA)来合成。阿替普酶在中风症状后立即经由静脉内输注约100mg来给药。在一些实施方案中提供含有阿替普酶的低粘度制剂,优选浓度为约100mg/mL。
glucarpidase是被FDA批准用于在对肾功能受损的癌症患者进行治疗期间治疗甲氨蝶呤水平升高(定义为至少1μmol/L)的药物。glucarpidase以约50IU/kg的单一剂量静脉内给药。在一些实施方案中提供含有glucarpidase的低粘度制剂。
alglucosidaseα是治疗蓬佩病(II型糖原贮积病)(一种罕见的溶酶体贮积病)的酶代替疗法孤儿药物。其具有约106kDa的分子量且目前通过静脉内输注约20mg/kg来给药。在一些实施方案中提供alglucosidaseα的低粘度药物制剂,优选浓度为约100mg/mL至约2,000mg/mL。
pegdamase bovine是用于酶代替疗法的经修饰的酶,其用于治疗与腺苷脱氨酶缺乏相关的重度联合免疫缺陷病(SCID)。pegdamasebovine是分子量为5,000Da的多股单甲氧基聚乙二醇(PEG)与已由牛肠得到的腺苷脱氨酶共价接附的缀合物。
α-半乳糖苷酶是催化糖脂即神经酰胺三己糖苷(GL-3)水解成半乳糖和神经酰胺二己糖苷的溶酶体酶。法布里病是罕见的遗传性溶酶体贮积病,其特征在于低于正常酶活性的α-半乳糖苷酶和由此产生的GL-3积累。半乳糖苷酶α是由人细胞系产生的人α-半乳糖苷酶A。半乳糖苷酶β是在CHO细胞系中表达的重组人α半乳糖苷酶。以0.2mg/kg的剂量每隔一周通过静脉内输注来给药以治疗法布里病并在说明书外用于治疗戈谢病。以1.0mg/kg体重的剂量每隔一周通过静脉内输注来给药。也可使用其它溶酶体酶。例如,所述蛋白质可为在US 2012/0148556中所述的溶酶体酶。
拉布立酶(rasburicase)是适用于在患有恶性白血病、淋巴瘤和实体瘤的正在接受预期会导致肿瘤溶胞和随后血浆尿酸升高的抗癌疗法的儿童和成人患者中对血浆尿酸水平进行初始控制的重组尿酸氧化酶。以0.2mg/kg的剂量通过每天静脉内输注来给药。
伊米苷酶(imiglucerase)是人β葡糖脑苷脂酶的重组类似物。初始剂量为2.5U/kg体重每周3次至60U/kg每2周1次。通过静脉内输注来给药。
abraxane即与紫杉醇缀合的白蛋白被批准用于转移性乳腺癌、非小细胞肺癌和晚期胰腺癌。
taligluceraseα是适用于1型戈谢病长期酶代替疗法的对水解性溶酶体葡糖脑苷脂具有特异性的酶。推荐剂量为以60U/kg体重每2周一次经由静脉内输注来给药。
laronidase是人α-L-艾杜糖醛酸酶的由CHO细胞系产生的多态性变体。的推荐剂量方案是以0.58mg/kg每周一次通过静脉内输注来给药。
elosulfaseα是BioMarin Pharmaceuticals Inc(“BioMarin”)的由CHO细胞系产生的人N-乙酰基半乳糖胺-6-硫酸酯酶。其在2014年2月14日被FDA批准用于治疗IVA型粘多糖贮积症。其以2mg/kg的剂量每周经由静脉内输注来给药。
可与使粘度降低的水溶性染料一起配制的其它生物制品包括asparaginaseerwinia chrysanthemiincobotulinumtoxin A(阿法依泊汀)、(阿法依泊汀)、(阿法达贝泊汀)、(阿巴西普(abatacept))、(干扰素β-1b)、(加硫酶);(艾杜硫酸酯酶);(α-葡萄糖苷酶);(velaglucerase)、abobotulinumtoxin A来自Baxter的BAX-326、辛凝血素α;来自GlaxoSmithKline的syncria;来自Eli Lilly的liprotamase;来自Auxilium和BioSpecifics Technologies Corp.的xiaflex(溶组织梭菌胶原酶);来自SwedishOrphan Biovitrum AB的阿那白滞素;来自Bristol-Myers Squibb的美曲普汀;来自Biogen的avonex、plegridy(BIIB017);来自Novo Nordisk的NN1841、NN7008;来自Kyowa的KRN321(阿法达贝泊汀)、AMG531(romiplostim)、KRN125(pegfilgrastim)、KW-0761(mogamulizumab);来自Inspiration Biopharmaceuticals的IB1001;来自CanyonPharmaceuticals Group的iprivask。
开发中的蛋白质治疗剂
Versartis,Inc.的VRS-317是使用XTEN半衰期延长技术的重组人生长激素(hGH)融合蛋白。其旨在降低患有hGH缺乏的患者所需要的hGH注射的频率。VRS-317已完成II期研究,对其效力与每天注射的非衍生化hGH进行了比较,具有阳性结果。计划进行III期研究。
弧菌溶血素是由革兰氏阴性海洋微生物Vibrio proteolyticus分泌的蛋白质水解酶。该内切蛋白酶对蛋白质的疏水区具有特异性亲和力且能够在邻近疏水性氨基酸处裂解蛋白质。弧菌溶血素目前正在由Biomarin研究用于烧伤的清理和/或治疗。弧菌溶血素制剂参见专利WO 02/092014。
PEG-PAL(聚乙二醇化重组苯丙氨酸解氨酶或“PAL”)是用于治疗苯丙酮酸尿症(PKU)(一种由于缺乏苯丙氨酸羟化酶(PAH)而引起的遗传性代谢病)的研究性酶代替疗法。PEG-PAL正在被开发作为用于血液苯丙氨酸(Phe)水平没有被所充分控制的患者的潜在疗法。PEG-PAL现在处于针对治疗对没有充分响应的患者的2期临床开发中。
可与使粘度降低的水溶性染料一起配制的其它蛋白质治疗剂包括Alprolix/rFIXFc、Eloctate/rFVIIIFc、BMN-190;BMN-250;Lamazyme;Galazyme;ZA-011;Sebelipaseα;SBC-103;和HGT-1110。此外,含XTEN半衰期延长技术的融合蛋白可与使粘度降低的水溶性染料一起配制,包括但不限于VRS-317GH-XTEN;凝血因子VIIa、凝血因子VIII、凝血因子IX;PF05280602、VRS-859;艾塞那肽-XTEN;AMX-256;GLP2-2G/XTEN;和AMX-179叶酸-XTEN-DM1。
可与使粘度降低的水溶性染料一起配制的其它后期蛋白质治疗剂包括来自CureMark LLC的CM-AT;来自Novo Nordisk的NN7999、NN7088、利拉鲁肽(Liraglutide)(NN8022)、NN9211、索马鲁肽(Semaglutide)(NN9535);来自Amgen的AMG 386、非格司亭(Filgrastim);来自CSL Behring的CSL-654、凝血因子VIII;来自Novartis AG的LA-EP2006(聚乙二醇化非格司亭生物类似物);来自CEL-SCI Corporation的Multikine(白细胞介素);来自Eli Lilly的LY2605541、特立帕肽(Teriparatide)(重组PTH 1-34);来自NuronBiotech,Inc.的NU-100;来自Sigma-Tau Pharmaceuticals,Inc.的Calaspargase Pegol;来自Polaris Pharmaceuticals,Inc.的ADI-PEG-20;来自BioMarin的BMN-110、BMN-702;来自Molmed S.p.A.的NGR-TNF;来自Pharming Group/Santarus Inc.的重组人C1酯酶抑制剂;来自LG Life Sciences LTD的生长激素生物类似物;来自NPS Pharmaceuticals,Inc.的Natpara;来自Asahi Kasei Corporation的ART123;来自Baxter的BAX-111;来自Inspiration Biopharmaceuticals的OBI-1;来自Octapharma AG的Wilate;来自AgennixAG的Talactoferrinα;来自Lundbeck的去氨普酶(Desmoteplase);来自Shire的Cinryze;来自Roche和Exelixis,Inc.的RG7421;来自Novartis AG的米哚妥林(Midostaurin)(PKC412);来自Bayer AG的Damoctocogαpegol、BAY 86-6150、BAY 94-9027;来自Bristol-Myers Squibb的聚乙二醇化干扰素λ-1a、Nulojix(Belatacept);来自Merck KGaA的Pergoveris、绒促卵泡素α(MK-8962);来自Biogen的重组凝血因子IX Fc融合蛋白(rFIXFc;BIIB029)和重组凝血因子VIII Fc融合蛋白(rFVIIIFc;BIIB031);和来自AstraZeneca的Myalept。
可与使粘度降低的水溶性染料一起配制的其它早期蛋白质生物制品包括来自Hemispherx BioPharma,Inc.的Alferon LDO;来自Stemline Therapeutics,Inc.的SL-401;来自Protalix Biotherapeutics,Inc.的PRX-102;来自Kaketsuken/Teijin PharmaLimited的KTP-001;来自Bayer AG的Vericiguat;来自BioMarin的BMN-111;来自Janssen的ACC-001(PF-05236806);来自Eli Lilly的LY2510924、LY2944876;来自Novo Nordisk的NN9924;来自Exsulin的INGAP肽;来自Abbvie的ABT-122;来自AstraZeneca的AZD9412;来自Biogen的NEUBLASTIN(BG00010);来自Celgene Corporation的Luspatercept(ACE-536)、Sotatercept(ACE-011);来自GlaxoSmithKline的PRAME免疫治疗剂;来自Merck KGaA的Plovamer acetate(PI-2301);来自Shire的PREMIPLEX(607);来自BioMarin的BMN-701;来自Eisai的Ontak;来自Halozyme,Inc.的rHuPH20/胰岛素;来自PhaseBioPharmaceuticals,Inc.的PB-1023;来自Alvine Pharmaceuticals Inc.和Abbvie的ALV-003;来自Novo Nordisk的NN8717;来自Proteon Therapeutics Inc.的PRT-201;来自Halozyme,Inc.的PEGPH20;来自Astellas Pharma Inc.的 alefacept;来自Regeneron的F-627;来自Allergan,Inc.的AGN-214868(senrebotase);来自Baxter的BAX-817;来自Portola Pharmaceuticals,Inc.的PRT4445;来自Ventria Bioscience的VEN100;来自Tamir Biotechnology Inc.的Onconase/ranpirnase;来自Medtronic,Inc.的干扰素α-2b融合蛋白;来自Synageva BioPharma的sebelipaseα;来自IRX Therapeutics,Inc的IRX-2;来自GlaxoSmithKline的GSK2586881;来自Seikagaku Corporation的SI-6603;来自Alexion的ALXN1101、asfotaseα;来自Shire的SHP611、SHP609(Elaprase,idursulfase);来自Pfizer的PF-04856884、PF-05280602;来自Acceleron Pharma的ACE-031、Dalantercept;来自Altor BioScience Corp.的ALT-801;来自BioAxone Biosciences,Inc.的BA-210;来自GlaxoSmithKline的WT1免疫治疗剂;来自Sanofi的GZ402666;来自Merck KGaA的MSB0010445、Atacicept;来自Bayer AG的Leukine(沙格司亭(sargramostim));来自Baxter的KUR-211;来自CardioVascular BioTherapeutics Inc.的纤维母细胞生长因子-1;来自Hanmi Pharmaceuticals Co.,LTD/Spectrum Pharmaceuticals的SPI-2012;来自MerckKGaA的FGF-18(sprifermin);来自Merck的MK-1293;来自HanAll Biopharma的干扰素-α-2b;来自Cytheris SA的CYT107;来自Revance Therapeutics,Inc.的RT001;来自AztraZeneca的MEDI6012;来自Biogen的E2609;来自BioMarin的BMN-190、BMN-270;来自Acceleron Pharma的ACE-661;来自Amgen的AMG 876;来自GlaxoSmithKline的GSK3052230;来自Roche的RG7813;来自Sanofi的SAR342434、Lantus;来自Allozyne Inc.的AZ01;来自Ambrx,Inc.的ARX424;来自FivePrime Therapeutics,Inc.的FP-1040、FP-1039;来自MerckKGaA的ATX-MS-1467;来自Amunix Operating Inc.的XTEN融合蛋白;来自ClevelandBioLabs,Inc.的entolimod(CBLB502);来自Shire的HGT2310;来自Hanmi PharmaceuticalsCo.,LTD的HM10760A;来自Alexion的ALXN1102/ALXN1103;来自CSL Behring的CSL-689、CSL-627;来自Acorda Therapeutics,Inc.的神经胶质生长因子2;来自NephrxCorporation的NX001;来自Novo Nordisk的NN8640、NN1436、NN1953、NN9926、NN9927、NN9928;来自EMD Serono的NHS-IL 12;来自ZZ Biotech LLC的3K3A-APC;来自PhaseBioPharmaceuticals,Inc.的PB-1046;来自R-Tech Ueno,Ltd.的RU-101;来自Adocia的赖脯胰岛素/BC106;来自Iconic Therapeutics,Inc.的hl-con1;来自ProtalixBioTherapeutics,Inc.的PRT-105;来自Pfizer的PF-04856883、CVX-096;来自AlphaCorePharma LLC的ACP-501;来自Baxter的BAX-855;来自Celldex Therapeutics的CDX-1135;来自Promedior,Inc.的PRM-151;来自Thrombolytic Science International的TS01;来自Thrombotargets Corp.的TT-173;来自Quintessence Biosciences,Inc.的QBI-139;来自Glenmark Pharmaceuticals的Vatelizumab、GBR500、GBR600、GBR830和GBR900;和来自Cytimmune Sciences,Inc.的CYT-6091。
其它生物药物
可与使粘度降低的水溶性染料一起配制的其它生物药物包括来自Pfizer的PF-05285401、PF-05231023、RN317(PF-05335810)、PF-06263507、PF-05230907、Dekavil、PF-06342674、PF06252616、RG7598、RG7842、RG7624d、OMP54F28、GSK1995057、BAY1179470、IMC-3G3、IMC-18F1、IMC-35C、IMC-20D7S、PF-06480605、PF-06647263、PF-06650808、PF-05335810(RN317)、PD-0360324、PF-00547659;来自Merck的MK-8237;来自Biogen的BI033;来自Sanofi的GZ402665、SAR438584/REGN2222;IMC-18F1;来自ImClone LLC的Icrucumab、IMC-3G3;来自Novo Nordisk的Ryzodeg、Tresiba、Xultophy;来自Sanofi的Toujeo(U300)、LixiLan、Lyxumia(lixisenatide);来自GlaxoSmithKline的MAGE-A3免疫治疗剂;来自Merck KGaA的Tecemotide;来自Novartis AG的Sereleaxin(RLX030);红细胞生成素;聚乙二醇化非格司亭;来自Eli Lilly的LY2963016、度拉糖肽(Dulaglutide)(LY2182965);和来自Boehringer Ingelheim的甘精胰岛素。
B.药用水溶性有机染料
包含低分子量和/或高分子量蛋白质的液体蛋白质制剂的粘度通过添加一种或多种水溶性有机染料来降低。可通过添加有效量的一种或多种水溶性有机染料将药物制剂由非牛顿流体转变成牛顿流体。“水溶性有机染料”是以下有机分子,其在25℃和pH 7的情况下具有至少0.001M的摩尔溶解度且吸收一些波长的光优选电磁波谱的可见光至红外线部分同时可透射或反射其它波长的光。水溶性有机染料可为吖啶染料、蒽醌染料、二芳基甲烷染料、三芳基甲烷染料、偶氮染料、重氮染料、硝基苯基染料、亚硝基苯基染料、酞菁染料、醌染料、噻唑染料、呫吨染料或其组合。有机染料可为盐或两性离子。
虽然通常任何水溶性有机染料都可降低蛋白质制剂的粘度,但是在一些实施方案中,有机染料在电磁波谱的可见光至红外线部分所具有的摩尔吸光系数大于500M-1cm-1,大于1,000M-1cm-1,大于10,000M-1cm-1,大于20,000M-1cm-1或大于50,000M-1cm-1。
有机染料可具有式I的稠环结构,其中X为碳原子或杂原子,任选具有一个或多个取代基;且每个A独立为具有3至50个碳原子、3至30个碳原子或6至25个碳原子的经取代或未经取代的芳基。应当理解的是,X可具有满足化合价的一个或多个氢原子或其它取代基,例如当X为碳时,X可为CH基团、CH2基团、CHR基团、CR基团或CR2基团,其中每个R独立为具有任何数目碳原子的任何有机基团。
在一些实施方案中,有机染料具有式I的结构,其中X为C、N、O或S;或其中A是经取代或未经取代的苯基或萘基或这两者。此类化合物的实例是吖啶,其中X是CH基团,且每个A为未经取代的苯基。
有机染料可为吖啶染料。有机染料可具有式II的结构:
其中每个R1独立选自氢、R2、-OH、NH2、-F、-Cl、-Br、-I、-NO2、-CN、-C(=O)R4a、-C(=NR4a)R4、-C(=O)OH、-C(=O)OR4、-OC(=O)R4、-OC(=O)OR4、-SO3H、-SO2N(R4a)2、-SO2R4、-SO2NR4aC(=O)R4、-PO3H2、-R4aC(=NR4a)N(R4a)2、-NHC(=NR4a)NH-CN、-NR4aC(=O)R4、-NR4aSO2R4、-NR4aC(=NR4a)NR4aC(=NR4a)N(R4a)2、-NR4aC(=O)N(R4a)2、-C(=O)NH2、-C(=O)N(R4a)2、-OR4、-SR4a和-N(R4a)2;
其中R2独立选自C1-12烷基、C3-12环烷基、C6-12芳基、C1-12杂芳基和C2-12杂环基,
其中每个C1-12烷基可被C3-12环烷基、C6-12芳基、C1-12杂芳基、C2-12杂环基、-OH、NH2、(=O)、(=NR4a)、-F、-Cl、-Br、-I、-NO2、-CN、-C(=O)R4a、-C(=NR4a)R4、-C(=O)OH、-C(=O)OR4、-OC(=O)R4、-OC(=O)OR4、-SO3H、-SO2N(R4a)2、-SO2R4、-SO2NR4aC(=O)R4、-PO3H2、-R4aC(=NR4a)N(R4a)2、-NHC(=NR4a)NH-CN、-NR4aC(=O)R4、-NR4aSO2R4、-NR4aC(=NR4a)NR4aC(=NR4a)N(R4a)2、-NR4aC(=O)N(R4a)2、-C(=O)NH2、-C(=O)N(R4a)2、-OR4、-SR4a或-N(R4a)2取代一次或多次;
其中每个C3-12环烷基可被C1-12烷基、C6-12芳基、C1-12杂芳基、C2-12杂环基、-OH、NH2、-F、-Cl、-Br、-I、-NO2、-CN、-C(=O)R4a、-C(=NR4a)R4、-C(=O)OH、-C(=O)OR4、-OC(=O)R4、-OC(=O)OR4、-SO3H、-SO2N(R4a)2、-SO2R4、-SO2NR4aC(=O)R4、-PO3H2、-R4aC(=NR4a)N(R4a)2、-NHC(=NR4a)NH-CN、-NR4aC(=O)R4、-NR4aSO2R4、-NR4aC(=NR4a)NR4aC(=NR4a)N(R4a)2、-NR4aC(=O)N(R4a)2、-C(=O)NH2、-C(=O)N(R4a)2、-OR4、-SR4a或-N(R4a)2取代一次或多次;
其中每个C6-12芳基可被C1-12烷基、C3-12环烷基、C1-12杂芳基、C2-12杂环基、-OH、NH2、-F、-Cl、-Br、-I、-NO2、-CN、-C(=O)R4a、-C(=NR4a)R4、-C(=O)OH、-C(=O)OR4、-OC(=O)R4、-OC(=O)OR4、-SO3H、-SO2N(R4a)2、-SO2R4、-SO2NR4aC(=O)R4、-PO3H2、-R4aC(=NR4a)N(R4a)2、-NHC(=NR4a)NH-CN、-NR4aC(=O)R4、-NR4aSO2R4、-NR4aC(=NR4a)NR4aC(=NR4a)N(R4a)2、-NR4aC(=O)N(R4a)2、-C(=O)NH2、-C(=O)N(R4a)2、-OR4、-SR4a或-N(R4a)2取代一次或多次;
其中每个C1-12杂芳基可被C1-12烷基、C3-12环烷基、C6-12芳基、C2-12杂环基、-OH、NH2、-F、-Cl、-Br、-I、-NO2、-CN、-C(=O)R4a、-C(=NR4a)R4、-C(=O)OH、-C(=O)OR4、-OC(=O)R4、-OC(=O)OR4、-SO3H、-SO2N(R4a)2、-SO2R4、-SO2NR4aC(=O)R4、-PO3H2、-R4aC(=NR4a)N(R4a)2、-NHC(=NR4a)NH-CN、-NR4aC(=O)R4、-NR4aSO2R4、-NR4aC(=NR4a)NR4aC(=NR4a)N(R4a)2、-NR4aC(=O)N(R4a)2、-C(=O)NH2、-C(=O)N(R4a)2、-OR4、-SR4a或-N(R4a)2取代一次或多次;
其中每个C2-12杂环基可被C1-12烷基、C3-12环烷基、C6-12芳基、C1-12杂芳基、-OH、NH2、-F、-Cl、-Br、-I、-NO2、-CN、-C(=O)R4a、-C(=NR4a)R4、-C(=O)OH、-C(=O)OR4、-OC(=O)R4、-OC(=O)OR4、-SO3H、-SO2N(R4a)2、-SO2R4、-SO2NR4aC(=O)R4、-PO3H2、-R4aC(=NR4a)N(R4a)2、-NHC(=NR4a)NH-CN、-NR4aC(=O)R4、-NR4aSO2R4、-NR4aC(=NR4a)NR4aC(=NR4a)N(R4a)2、-NR4aC(=O)N(R4a)2、-C(=O)NH2、-C(=O)N(R4a)2、-OR4、-SR4a或-N(R4a)2取代一次或多次;
R4独立选自C1-12烷基、C3-12环烷基、C6-12芳基、C1-12杂芳基和C2-12杂环基,其各自可被-OH、-NH2、-F、-Cl、-Br、-I、-NO2、-CN、-C(=O)OH、-SO3H、-PO3H2或-C(=O)NH2取代一次或多次;
R4a可为R4或氢;
其中R2、R3、R4和R4a基团中的任何两个或更多个可一起形成环。
在一些实施方案中,至少一次、至少两次或至少三次出现的R1不为氢。在一些实施方案中,至少一次、至少两次、至少三次或至少四次出现的R1为胺基团诸如二甲基胺或其它二烷基胺。其它优选的R1基团包括NO2、SO3H和CO2H。
水溶性有机染料还可为蒽醌染料:
二芳基甲烷染料:
或三芳基甲烷染料:
其中R1具有上述含义。在其它实施方案中,水溶性有机染料可为下式所表示的偶氮染料:
其中R1如上文所定义,且Ra为芳基或杂芳基环。示例性环系包括:
其中X为O、S、SO2或NR2,X1可为氮原子或CR1,且R2如上文所定义。
水溶性有机染料还可为硝基苯基染料、亚硝基苯基染料、酞菁染料、醌染料、三唑染料或呫吨染料。
示例性染料包括但不限于黄色5(Yellow 5)、橙黄G(Orange G)、喹诺酮黄(Quinolone Yellow)、甜菜红(Betanin)、红色40(Red 40)、carmosin、天蓝C(Azure C)、刚果红(Congo Red)、苋菜红(amaranth)、丽春红(Ponceau S)、赤藓红(erythrosine)、专利蓝(patent blue)、亮黑BN(brilliant black BN)、酸性品红(acid fuchsine)、萘酚黄S(napthol yellow S)、喹啉黄(quinoline yellow)、靛蓝胭脂红(indigo carmine)、固绿FCF(fast green FCF)、橙色2(Orange 2)、天然红(Natural Red)、二甲苯腈蓝FF(XyleneCyanol FF)、乙酸甲酚紫(Cresyl violet acetate)、浅绿色SF淡黄色(Light Green SFYellowish)、噻唑黄G(Thiaozle Yellow G)、结晶紫(crystal violet)、尼罗蓝A(Nileblue A)和吲哚花菁绿(Cardiogreen)。
C.赋形剂
很多种可用于液体蛋白质制剂的药物赋形剂是本领域技术人员已知的。其包括一种或多种添加剂,诸如液体溶剂或共溶剂;糖或糖醇,诸如甘露醇、海藻糖、蔗糖、山梨醇、果糖、麦芽糖、乳糖或葡聚糖;表面活性剂,诸如20、60或80(聚山梨醇酯20、60或80);缓冲剂;防腐剂,诸如苯扎氯铵、苄索氯铵、叔铵盐和二乙酸氯己定;载体,诸如聚(乙二醇)(PEG);抗氧化剂,诸如抗坏血酸、焦亚硫酸钠和甲硫氨酸;螯合剂,诸如EDTA或枸橼酸;或可生物降解的聚合物,诸如水溶性聚酯;冷冻保护剂;冻干保护剂;填充剂;和稳定剂。
其它药用载体、赋形剂或稳定剂诸如在Remington:“The Science and Practiceof Pharmacy”,第20版,Alfonso R.Gennaro,Ed.,Lippincott Williams&Wilkins(2000)中描述的那些也可包含在本文所述的蛋白质制剂中,条件是其不会不利地影响制剂的所需性质。
本文所述的使粘度降低的水溶性染料可与一种或多种其它类型的使粘度降低的物质组合,例如典型的大体积极性有机化合物,诸如疏水性化合物、GRAS(美国食品药品监督管理局通常认为是安全的化合物的列表)中的多种物质和非活性注射用成分及FDA所批准的治疗剂;在由Arsia Therapeutics共同提交的标题为“LIQUID PROTEIN FORMULATIONSCONTAINING VISCOSITY-LOWERING AGENTS”的PCT申请中所述的粘度降低剂;在由ArsiaTherapeutics共同提交的标题为“LIQUID PROTEIN FORMULATIONS CONTAINING IONICLIQUIDS”的PCT申请中所述的离子性液体粘度降低剂;和在由Arsia Therapeutics共同提交的标题为“LIQUID PROTEIN FORMULATIONS CONTAINING ORGANOPHOSPHATES”的PCT申请中所述的有机磷酸酯粘度降低剂。
III.制备方法
待配制的蛋白质诸如单克隆抗体可通过任何已知的技术来产生,诸如通过如本领域已知的那样对用含有一种或多种编码所述蛋白质的核酸序列的载体转化或转染的细胞进行培养或通过合成技术(诸如重组技术和肽合成或这些技术的组合)或可从所述蛋白质的内源性来源中分离。
待配制的蛋白质的纯化可通过本领域已知的任何合适的技术来进行,诸如乙醇或硫酸铵析出、反相HPLC、硅胶或阳离子交换树脂(例如DEAE-纤维素)色谱、透析、色谱聚焦、使用蛋白A柱(例如G-75)以除去杂质的凝胶过滤、与表位标签形式结合的金属螯合柱和超滤/渗滤(非限制性实例包括离心过滤和切向流动过滤(TFF))。
以使粘度降低的浓度诸如0.010M至1.0M、优选0.050M至0.50M、最优选0.01M至0.10M引入的使粘度降低的水溶性有机染料允许使用本领域技术人员已知的常规方法将药学活性单克隆抗体的溶液纯化和/或浓缩至较高的单克隆抗体浓度,包括但不限于切向流动过滤、离心浓缩和透析。
在一些实施方案中,蛋白质的冻干制剂被提供和/或使用在浓缩的低粘度蛋白质制剂的制备和制造中。在一些实施方案中,呈粉末形式的预冻干蛋白质通过溶解在水溶液中来复溶。在该实施方案中,将液体制剂填充到特定剂量单元容器诸如小瓶或预填充的混合式注射器中,冻干,任选与冻干保护剂、防腐剂、抗氧化剂和其它典型的药用赋形剂一起,然后在无菌储存条件下储存直到临用前,此时将其用限定体积的稀释剂复溶以使液体达到所期望的浓度和粘度。
本文所述的制剂可通过本领域技术人员已知的任何合适的方法来储存。用于制备供储存的蛋白质制剂的方法的非限制性实例包括对液体蛋白质制剂进行冷冻、冻干和喷雾干燥。在一些情况下,冻干制剂在零度以下的温度诸如在约-80℃或在液氮中冷冻储存。在一些情况下,冻干或含水制剂在2-8℃储存。
可用于在注射前复溶冻干制剂的稀释剂的非限制性实例包括无菌水、注射用抑菌水(BWFI)、pH缓冲溶液(例如磷酸盐缓冲盐水)、无菌盐水溶液、林格溶液、葡萄糖溶液或盐和/或缓冲剂的水溶液。在一些情况下,将制剂喷雾干燥,然后储存。
IV.向有此需要的个体给药
通过肌内、腹膜内(即注射到体腔中)、脑脊髓内或皮下注射使用18-32号针头(任选薄壁的针头)以小于约5mL、小于约3mL、优选小于约2mL、更优选小于约1mL的体积向有此需要的人类给药蛋白质制剂,包括但不限于复溶制剂。
蛋白质诸如单克隆抗体的适当剂量(“治疗有效量”)将取决于待治疗的病症、疾病或病症的严重程度和病程、给药蛋白质是出于预防还是治疗目的、先前的疗法、患者的临床史和对蛋白质的应答、所用蛋白质的类型及主治医师的判断。蛋白质适当地以单次或多次注射来一次性给药或在一系列治疗过程中作为单一疗法或与其它药物或疗法联合。
对剂量制剂进行设计以使注射在注射部位不引起显著的刺激迹象,例如其中当使用Draize评分系统进行评价时,主要刺激指数小于3。在可选择的实施方案中,当与注射等体积的盐水溶液相比时,注射引起目视相似的刺激水平。在另一个实施方案中,当与其它方面相同但不含一种或多种使粘度降低的水溶性有机染料的以相同方式给药的制剂相比时,蛋白质的生物利用度是较高的。在另一个实施方案中,所述制剂在药学上是至少大致如通过静脉内输注来给药的约相同剂量的蛋白质那样有效的。
在优选实施方案中,注射所述制剂以得到水平提高的治疗性蛋白质。例如,AUC值可比就其它方面相同但不含一种或多种使粘度降低的水溶性有机染料的以相同方式给药的制剂所计算的AUC值高至少10%,优选至少20%。
一种或多种使粘度降低的水溶性染料也可影响生物利用度。例如,蛋白质的百分比生物利用度可为其它方面相同但不含一种或多种使粘度降低的水溶性染料的以相同方式给药的制剂的百分比生物利用度的至少1.1倍,优选至少1.2倍。
一种或多种使粘度降低的水溶性染料也可影响药物动力学。例如,皮下或肌内注射后的CMAX可比大致等同的药学上有效的静脉内给药剂量的CMAX低至少10%,优选至少20%。
在一些实施方案中,蛋白质以比其它方面相同但不含一种或多种使粘度降低的水溶性有机染料的制剂高的剂量和低的频率来给药。
粘度较低的制剂需要较小的注射力。例如,注射力可比其它方面相同但不含一种或多种使粘度降低的水溶性有机染料的以相同方式给药的制剂所需要的注射力小至少10%,优选至少20%。在一个实施方案中,用27号针头进行注射,且注射力小于30N。在大多数情况下,制剂可使用非常小号的针头来给药,例如27至31号,通常27、29或31号。
一种或多种使粘度降低的水溶性有机染料可用于制备适于复溶以形成供皮下或肌内注射的液体药物制剂的剂量单元制剂。剂量单元可含有一种或多种蛋白质的干燥粉末;一种或多种使粘度降低的水溶性有机染料;和其它赋形剂。存在于剂量单元中的蛋白质使在药用溶剂中复溶后所得到的制剂具有约100mg至约2,000mg/1mL的蛋白质浓度(mg/mL)。此类复溶制剂可在25℃具有约1cP至约50cP的绝对粘度。
低粘度制剂可按溶液或剂量单元形式提供,其中在具有或不具有一种或多种使粘度降低的水溶性有机染料和其它赋形剂的情况下将蛋白质在一个小瓶中冻干,且将具有或不具有一种或多种使粘度降低的水溶性有机染料和其它赋形剂的溶剂提供在第二个小瓶中。在该实施方案中,在注射前即刻或在注射时向蛋白质中添加溶剂以确保均匀混合和溶解。
一种或多种使粘度降低的水溶性有机染料按以下浓度存在于制剂中,所述浓度当经由皮下、肌内或其它注射类型来给药时不引起显著的毒性迹象和/或不可逆的毒性迹象。本文使用的“显著的毒性迹象”包括中毒、嗜睡、行为改变诸如当中枢神经系统受损时发生的那些行为改变、不育、严重的心脏毒性迹象诸如心律失常、心肌病、心肌梗塞和心源性或充血性心力衰竭、肾衰竭、肝衰竭、呼吸困难及死亡。
在优选实施方案中,所述制剂当给药不超过每天两次、每天一次、每周两次、每周一次或每月一次时不引起显著的刺激。所述蛋白质制剂的给药可在注射部位不引起显著的刺激迹象,其如下测量:当使用Draize评分系统进行评价时,主要刺激指数小于3,小于2或小于1。本文使用的“显著的刺激迹象”包括在注射部位直径大于10cm、大于5cm或大于2.5cm的红斑、发红和/或肿胀、在注射部位出现坏死,在注射部位出现剥脱性皮炎及妨碍日常活动和/或需要就医或住院的严重疼痛。在一些实施方案中,当与注射等体积的盐水溶液相比时,所述蛋白质制剂的注射引起目视相似的刺激水平。
当经由皮下或肌内注射来给药时,所述蛋白质制剂与其它方面相同但不含一种或多种使粘度降低的水溶性有机染料的制剂相比可展现出提高的生物利用度。“生物利用度”是指生物活性物质诸如单克隆抗体进入循环或到达作用部位的程度和速率。皮下或肌内注射的整体生物利用度与其它方面相同但不含一种或多种使粘度降低的水溶性有机染料的制剂相比是提高的。“百分比生物利用度”是指生物活性物质的给药剂量中进入循环的分数,其相对于静脉内给药剂量来确定。测量生物利用度的一种方式是通过比较血浆浓度对时间的函数曲线的“曲线下面积”(AUC)。AUC可例如使用线性梯形规则来计算。本文使用的“AUC∞”是指零时间至血浆浓度恢复到基线水平时的时间的血浆浓度曲线下面积。本文使用的“AUC0-t”是指零时间至后来的t时间例如至达到基线的时间的血浆浓度曲线下面积。时间通常将以天进行测量,虽然当上下文明显时,也可使用小时。例如,AUC与其它方面相同但不含一种或多种使粘度降低的水溶性有机染料的以相同方式给药的制剂相比可增加超过10%、20%、30%、40%或50%。
本文使用的“tmax”是指在给药后血浆浓度达到最大值的时间。
本文使用的“Cmax”是指在给药剂量后且在给药后续剂量前的最大血浆浓度。
本文使用的“Cmin”或“C谷”是指在给药剂量后且在给药后续剂量前的最小血浆浓度。
皮下或肌内注射后的Cmax可比静脉内给药剂量的Cmax小例如至少10%,更优选至少20%。Cmax的这种减少也可使毒性降低。
药物动力学和药效学参数可使用本领域技术人员已知的措施进行跨物种近似。抗体治疗剂的药物动力学和药效学可基于具体的抗体而是显著不同的。经批准的鼠单克隆抗体在人类中显示出的半衰期为约1天,而人单克隆抗体的半衰期通常将为约25天(Waldmann等人,Int.Immunol.,2001,13:1551-1559)。抗体治疗剂的药物动力学和药效学可基于给药途径而是显著不同的。肌内或皮下注射IgG后达到最大血浆浓度的时间通常为2至8天,尽管可能出现较短或较长的时间(Wang等人,Clin.Pharm.Ther.,2008,84(5):548-558)。抗体治疗剂的药物动力学和药效学可基于制剂而是显著不同的。
低粘度蛋白质制剂与不含一种或多种使粘度降低的水溶性有机染料的那些蛋白质制剂相比可允许给药中较大的灵活性并降低给药频率。例如,通过使每次注射给药的剂量增加多倍,可在一些实施方案中将给药频率由每2周一次降低至每6周一次。
包括但不限于复溶制剂在内的蛋白质制剂可使用经加热的和/或自混合式注射器或自动注射器来给药。蛋白质制剂也可在填充注射器前在单独的温热单元中预加热。
i.经加热的注射器
经加热的注射器可为使用注射器温热装置来预加热的标准注射器。注射器温热装置通常将具有一个或多个各自能够接收含蛋白质制剂的注射器的开口和用于在使用前将注射器加热和保持在特定温度(通常在环境温度以上)的装置。其在本文中将被称为经预加热的注射器。适于经加热的注射器的温热装置包括可得自Vista Dental Products和Inter-Med的那些温热装置。温热装置能够容纳各种尺寸的注射器并加热到至多约130℃的任何温度(通常变化在1℃内)。在一些实施方案中,将注射器在加热浴中预加热,诸如保持在所需温度的水浴。
经加热的注射器可为自加热式注射器即能够将注射器中的液体制剂加热和保持在特定温度。自加热式注射器也可为其已与加热装置接附的标准医用注射器。能够与注射器接附的合适的加热装置包括可得自Watlow Electric Manufacturing Co.,St.Louis,MO的注射器加热器或注射器加热带及可得自Warner Instruments,Hamden,CT的注射器加热模块、阶段式加热器和在线预灌注加热器诸如SW-61型注射器温热器。加热器可通过中央控制器来控制,例如可得自Warner Instruments的TC-324B或TC-344B型加热器控制器。
经加热的注射器将液体蛋白质制剂保持在特定温度或变化在1℃、2℃或5℃内的特定温度。经加热的注射器可将蛋白质制剂保持在室温至高达约80℃、至高达约60℃、至最高达约50℃或至高达约45℃的任何温度,只要蛋白质制剂在该温度是足够稳定的。经加热的注射器可将蛋白质制剂保持在20℃至60℃、21℃至45℃、22℃至40℃、25℃至40℃或25℃至37℃的温度。通过在注射期间将蛋白质制剂保持在升高的温度而降低了液体制剂的粘度,增加了制剂中蛋白质的溶解度或两者兼备。
ii.自混合式注射器
注射器可为自混合式的或可具有所接附的混合器。混合器可为静态混合器或动态混合器。静态混合器的实例包括美国专利5,819,988、6,065,645、6,394,314、6,564,972和6,698,622公开的那些静态混合器。一些动态混合器的实例可包括美国专利6,443,612和6,457,609及美国专利申请公开文本US2002/0190082公开的那些动态混合器。注射器可包括多个用于对液体蛋白质制剂的组分进行混合的桶。美国专利5,819,998描述了具有用于对双组分粘性物质进行混合的两个桶和混合梢的注射器。
iii.蛋白质制剂的自动注射器和预填充注射器
液体蛋白质制剂可使用预填充针筒式自动注射器或无针注射装置来给药。自动注射器包括可手持的通常为笔状的用于抓握替换式预填充筒的筒抓握件和用于从预填充筒中皮下或肌内注射液体药物剂量的基于弹簧或类似的机构。自动注射器通常被设计为用于自我给药或由未经培训的人员进行给药。自动注射器可用于从预填充筒中分配单一剂量或多个剂量。自动注射器能够实现不同的用户设置,尤其包括注射深度、注射速度等。其它注射系统可包括美国专利8,500,681所述的那些注射系统。
可将经冻干的蛋白质制剂提供在预填充或单位剂量注射器中。美国专利3,682,174、4,171,698和5,569,193描述了含有两个腔室的无菌注射器,其可预填充有能够在注射前即刻混合的干燥制剂和液体。美国专利5,779,668描述了用于药物组合物的冻干、复溶和给药的注射器系统。在一些实施方案中,将蛋白质制剂以冻干形式提供在预填充或单位剂量注射器中,在给药前在注射器中复溶并通过单次皮下或肌内注射来给药。用于递送单位剂量冻干药物的自动注射器参见WO 2012/010,832。自动注射器诸如Safe Click LyoTM(由Future Injection Technologies,Ltd.,Oxford,U.K.上市)可用于给药单位剂量蛋白质制剂,其中所述制剂以冻干形式储存且在给药前即刻复溶。在一些实施方案中,将蛋白质制剂提供在用于冻干药物的单位剂量筒(有时称为Vetter筒)中。合适的筒的实例可包括美国专利5,334,162和5,454,786所述的那些筒。
V.纯化和浓缩的方法
水溶性有机染料也可用于协助蛋白质纯化和浓缩。以有效量向蛋白质中添加一种或多种水溶性有机染料和赋形剂以降低蛋白质溶液的粘度。例如,添加水溶性有机染料至浓度为约0.01M至约1.0M,优选约0.01M至约0.50M,更优选约0.01M至0.25M且最优选约0.01M至约0.10M。
然后使用选自超滤/渗滤、切向流动过滤、离心浓缩和透析的方法对含有蛋白质的水溶性有机染料溶液进行纯化或浓缩。
实施例
前述内容将通过以下非限制性实施例来进一步理解。
在25℃平衡5分钟后,所有充分混合的单克隆抗体水溶液的粘度都使用mVROC微流体粘度计(RheoSense)或DV2T锥板式粘度计(Brookfield;“C&P”)来测量(除非另有说明)。mVROC粘度计配备有“A”或“B”芯片,各自被制造有50微米通道。通常,将0.10mL蛋白质溶液在后部加载到气密性微型实验室仪器注射器(Hamilton;100μL)中,固定于芯片并以多个流速(每个芯片的最大压力的约20%、40%和60%)进行测量。例如,约50cP的样品以约10、20和30μL/min(在“A”芯片上分别为约180、350和530s-1)进行测量直到粘度稳定,通常在至少30秒后。然后由这样的至少三次测量结果来计算平均绝对粘度和标准偏差。C&P粘度计配备有CPE40或CPE52梭杆(锥角分别为0.8°和3.0°),且0.50mL样品以2至400s-1的多个剪切速率来测量。具体地,将样品以22.58、24.38、26.25、28.13、30、31.88、45、67.5、90、112.5、135、157.5、180、202.5、247、270、292.5、315、337.5、360、382、400s-1各自测量30秒,开始于实现至少10%转矩的剪切速率并继续直到仪器转矩达到100%,。然后对于在DV2T锥板式粘度计上测量的样品,外推零剪切粘度由动态粘度对剪切速率的曲线图来确定。所报道的外推零剪切粘度是至少三次测量结果的平均值和标准偏差。
实施例1:水溶性有机染料降低高分子量蛋白质的浓缩水溶液的粘度
对含有药用赋形剂(聚山梨醇酯20、磷酸盐和枸橼酸盐缓冲剂、甘露醇和NaCl)的市售生物类似物(100-400mg)进行纯化。首先使用TWEEN Medi Columns(G-Biosciences)来除去聚山梨醇酯20。随后对所得溶液进行扩展缓冲液交换成就PB样品而言的20mM磷酸钠缓冲液(PB;pH 7.0)和就水溶性染料样品而言的2mM PB(pH 7.0)并在Jumbosep离心浓缩仪(Pall Corp.)上浓缩至最终体积小于10mL。首先对缓冲液交换成2mM PB的样品进行等分。然后向每个等分试样中添加适量的水溶性有机染料的溶液(pH 7.0),从而在用水复溶后,最终赋形剂浓度是0.03-0.1M。然后将蛋白质溶液冷冻干燥。将含有蛋白质和水溶性染料(及量可忽略的缓冲盐)的干燥蛋白质饼复溶至约0.1mL的最终体积和如前所述的水溶性染料浓度。对于缓冲液交换成20mM PB的样品(PB对照样品),将所收集的蛋白质溶液冷冻干燥。将含有蛋白质和缓冲盐的干燥蛋白质饼复溶至约0.10-0.50mL的最终体积。使用额外的足以使PB的最终浓度为0.25M的PB(pH 7.0)对这些样品进行复溶。溶液中单克隆抗体的最终浓度通过Coomassie蛋白质定量测定法通过对未知浓度的样品与生物类似物的标准曲线进行比较来确定。所报道的粘度在RheoSense mVROC微流体粘度计上测量。使用相同的方案还制备了含有生物类似物和的制剂。
下表表明与磷酸盐缓冲液对照品相比,水溶性有机染料大幅降低了单克隆抗体制剂的粘度。
除非上文另有明确定义,否则本文使用的所有技术和科学术语具有与本领域技术人员通常所理解相同的含义。本领域技术人员仅使用常规实验就将认识到或将能够确定本文所述发明的具体实施方案的多种等效形式。所附权利要求书意在涵盖此类等效形式。
Claims (27)
1.用于注射的液体药物制剂,其包含
(i)至少100mg/ml的抗体;
(ii)黄色5或橙黄G;和
(iii)药用溶剂;
其中所述液体药物制剂当在适于注射的体积中时在25℃具有1cP至271cP的绝对粘度,其使用锥板式粘度计或微流体粘度计来测量;且所述液体药物制剂的绝对粘度小于包含所述抗体和所述药用溶剂但不包含所述黄色5或橙黄G的对照组合物的绝对粘度;
其中所述绝对粘度为外推零剪切粘度。
2.权利要求1的液体药物制剂,其中所述抗体的分子量为120kDa至250kDa。
3.权利要求1的液体药物制剂,其中所述抗体为单克隆抗体。
4.权利要求1的液体药物制剂,其包含150mg/ml至300mg/ml的所述抗体。
5.权利要求1的液体药物制剂,其中所述药用溶剂是水性的。
6.权利要求1的液体药物制剂,其还包含一种或多种药用赋形剂。
7.权利要求6的液体药物制剂,其中所述一种或多种药用赋形剂包括稀释剂或载体。
8.权利要求6的液体药物制剂,其中所述一种或多种药用赋形剂包括糖、糖醇、缓冲剂、天然的聚合物、合成的聚合物、表面活性剂、填充剂或其任何组合。
9.权利要求8的液体药物制剂,其中所述糖醇为山梨醇或甘露醇。
10.权利要求6的液体药物制剂,其中所述一种或多种药用赋形剂包括稳定剂。
11.权利要求10的液体药物制剂,其中所述稳定剂包括防腐剂、抗氧化剂、螯合剂、冷冻保护剂、冻干保护剂或其任何组合。
12.权利要求6的液体药物制剂,其中所述一种或多种药用赋形剂为聚山梨醇酯、泊洛沙姆188、月桂基硫酸钠或多元醇。
13.权利要求12的液体药物制剂,其中所述多元醇为聚(乙二醇)、甘油、丙二醇或聚(乙烯醇)。
14.权利要求1的液体药物制剂,其呈单位剂量小瓶、多剂量小瓶、筒或预填充注射器形式。
15.权利要求1的液体药物制剂,其中所述液体药物制剂对于人类血清为等张的。
16.权利要求1的液体药物制剂,其中当使用锥板式粘度计来测量时,所述绝对粘度以至少0.5s-1的剪切速率来测量。
17.权利要求1的液体药物制剂,其中当使用微流体粘度计来测量时,所述绝对粘度以至少1.0s-1的剪切速率来测量。
18.权利要求1-17中任一项的液体药物制剂,其中所述液体药物制剂由冻干的组合物复溶。
19.黄色5或橙黄G在制备权利要求1-17中任一项的液体药物制剂中的用途,其中所述液体药物制剂被制备成用于皮下或肌内注射。
20.权利要求19的用途,其中所述液体药物制剂被制备成用于用注射器进行皮下或肌内注射,其中所述注射器为经加热的注射器、自混合式注射器、自动注射器、预填充注射器或其组合。
21.权利要求20的用途,其中所述注射器为经加热的注射器,且所述液体药物制剂被制备成具有25℃至40℃的温度。
22.权利要求19的用途,其中当使用Draize评分系统来评价时,所述液体药物制剂被制备成引起小于3的主要刺激指数。
23.权利要求19的用途,其中所述液体药物制剂被制备成具有以下注射力,所述注射力比包含所述抗体和所述药用溶剂但不包含所述黄色5或橙黄G的对照组合物的注射力小至少10%。
24.权利要求19的用途,其中所述液体药物制剂被制备成具有以下注射力,所述注射力比包含所述抗体和所述药用溶剂但不包含所述黄色5或橙黄G的对照组合物的注射力小至少20%。
25.权利要求19的用途,其中所述液体药物制剂被制备成用于用直径为27至31号的针头进行注射,且所述液体药物制剂被制备成具有以下注射力,所述注射力用27号针头小于30N。
26.制备权利要求1-17中任一项的液体药物制剂的方法,所述方法包括组合所述抗体、所述药用溶剂和所述黄色5或橙黄G的步骤。
27.一种冻干的组合物,其包含:
(i)抗体;
(ii)黄色5或橙黄G;和
(iii)药用赋形剂;
其中所述冻干的组合物可用药用溶剂复溶为具有至少100mg/ml的所述抗体和在25℃的1cP至271cP的绝对粘度,其使用锥板式粘度计或微流体粘度计来测量,且复溶后的绝对粘度小于包含所述抗体和所述药用溶剂但不包含所述黄色5或橙黄G的对照组合物的绝对粘度,其中所述绝对粘度为外推零剪切粘度。
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