CN107206070A - 降低药物制剂的粘度 - Google Patents
降低药物制剂的粘度 Download PDFInfo
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- CN107206070A CN107206070A CN201580057461.5A CN201580057461A CN107206070A CN 107206070 A CN107206070 A CN 107206070A CN 201580057461 A CN201580057461 A CN 201580057461A CN 107206070 A CN107206070 A CN 107206070A
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Abstract
本发明提供一种降低药物制剂的粘度的方法，其利用降粘浓度的选自由n‑乙酰基精氨酸、n‑乙酰基赖氨酸、n‑乙酰基脯氨酸及其混合物组成的组的赋形剂与治疗性蛋白质的组合。也提供一种稳定的药物制剂。
Description
相关申请的交叉引用
本申请要求2014年10月23日提交的美国临时申请号62/067,637的权益，所述美国临时申请以引用的方式整体并入本文。
背景
药物活性蛋白质诸如抗体常常以特别是用于胃肠外注射的液体溶液形式配制。对于需要通过皮下途径施用，例如用于自我施用的产品；递送体积大于1-2毫升的制剂不被良好耐受。在所述情况下，高度浓缩的蛋白质制剂合乎实现有限剂量体积的需要。所述施用的高剂量和小体积要求意指蛋白质治疗剂可达到超过100mg/ml或更大的浓度。高度浓缩的蛋白质制剂可对蛋白质治疗剂的可制造性和施用造成许多挑战。由一些高度浓缩的蛋白质制剂造成的一个挑战是粘度增加。高粘度制剂在制造期间，包括在堆放和装填阶段难以处理。高粘度制剂也难以吸入注射器中并注射，从而使得向患者施用有困难并且不舒适。对鉴定适用于降低高度浓缩的蛋白质制剂的粘度的化合物，开发降低所述制剂的粘度的方法，以及提供粘度降低的药物制剂的需要在药物行业中是熟知的。本发明提供此类化合物、方法和制剂。
概述
提供一种处于所选浓度下，用于降低蛋白质制剂的粘度的选自由以下组成的组的赋形剂：n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物。本文提供通过使高浓度治疗性蛋白质与降粘浓度的选自由以下组成的组的赋形剂组合来降低蛋白质制剂的粘度的方法：n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物。也提供包含治疗性蛋白质和选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂的冻干粉末，其中所述赋形剂以可有效地在用稀释剂复原后降低粘度的重量：重量浓度存在。也提供一种包含治疗性蛋白质的冻干粉末和一种含有选自由以下组成的组的赋形剂的用于复原的稀释剂：n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物。
本文提供一种降低包含浓度为至少70mg/ml的治疗性蛋白质的液体药物制剂的粘度的方法，其包括使所述治疗性蛋白质与降粘浓度的选自由以下组成的组的赋形剂组合的步骤：n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物。在一个实施方案中，使制剂的粘度降低至少5％。在另一实施方案中，使制剂的粘度降低至少10％。在另一实施方案中，使制剂的粘度降低至少20％。在另一实施方案中，使制剂的粘度降低至少30％。在另一实施方案中，使制剂的粘度降低至少40％。在另一实施方案中，使制剂的粘度降低至少50％。在另一实施方案中，使制剂的粘度降低至少60％。在另一实施方案中，使制剂的粘度降低至少70％。在另一实施方案中，使制剂的粘度降低至少80％。在一相关实施方案中，提供通过所述方法产生的药物制剂。
也提供一种包含浓度为至少70mg/ml的治疗性蛋白质和选自由以下组成的组的赋形剂的药物组合物：n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物。在一个实施方案中，赋形剂的浓度是约5mM至约700mM。在一相关实施方案中，赋形剂的浓度是约100mM至约400mM。在另一相关实施方案中，赋形剂的浓度是约200mM至约300mM。在另一相关实施方案中，赋形剂的浓度是约140mM至约170mM。也提供具有在约4.0至约8.0之间的pH值的所述药物组合物。在一相关实施方案中，pH值是约4.0至约6.0。在另一相关实施方案中，pH值是约4.8至约5.4。
也提供一种制备冻干粉末的方法，其包括使如上所述的药物制剂冻干的步骤。
本文提供一种包含治疗性蛋白质和选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂的冻干粉末，其中所述赋形剂以可有效地在用稀释剂复原后降低粘度的重量：重量浓度存在。在一个实施方案中，赋形剂以介于每mg治疗性蛋白质约100μg至每mg治疗性蛋白质约1mg之间的浓度存在。在一相关实施方案中，赋形剂以介于每mg治疗性蛋白质约200μg至约500μg之间的浓度存在。在另一相关实施方案中，赋形剂以介于每mg治疗性蛋白质约150μg至约250μg之间的浓度存在。也提供一种用于复原如上所述的冻干粉末的方法，其包括添加无菌水性稀释剂的步骤。
也提供是抗体的治疗性蛋白质。也提供其中治疗性蛋白质是抗体的如上所述的制剂或组合物。此外，本文也提供一种其中治疗性蛋白质是抗体的如上所述的冻干粉末。
附图简述
图1是显示各种赋形剂对抗体溶液的粘度的影响的柱状图。
图2是显示各种赋形剂对抗体溶液的粘度的影响的柱状图。
详细描述
降低高浓度治疗性蛋白质制剂的粘度为药物行业所关注。发现赋形剂n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物会降低所述制剂的粘度。本发明提供处于所选浓度下，用于降低蛋白质制剂的粘度的赋形剂。本文提供用于通过使治疗性蛋白质与降粘浓度的选自由以下组成的组的赋形剂组合来降低蛋白质制剂的粘度的方法：n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物。也提供包含治疗性蛋白质和选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂的冻干粉末，其中所述赋形剂以可有效地在用稀释剂复原后降低粘度的重量：重量浓度存在。
除非另外为上下文所需，否则单数术语将包括复数，并且复数术语将包括单数。通常，与本文所述的细胞和组织培养、分子生物学、免疫学、微生物学、遗传学、以及蛋白质和核酸化学和杂交关联使用的命名法以及本文所述的细胞和组织培养、分子生物学、免疫学、微生物学、遗传学、以及蛋白质和核酸化学和杂交的技术是本领域中熟知并通常使用的那些。除非另外指示，否则本发明的方法和技术通常根据本领域中熟知以及如本说明书整篇引用和讨论的各种一般性和更特定参考文献中所述的常规方法来执行。参见例如Sambrook等，Molecular Cloning：A Laboratory Manual，第3版，Cold Spring Harbor LaboratoryPress，Cold Spring Harbor，N.Y.(2001)和Ausubel等，Current Protocols in MolecularBiology，Greene Publishing Associates(1992)，以及Harlow和Lane Antibodies：ALaboratory Manual Cold Spring Harbor Laboratory Press，Cold Spring Harbor，N.Y.(1990)。根据制造商说明书，如本领域中通常所实现或如本文所述来执行酶促反应和纯化技术。与本文所述的分析化学、合成有机化学以及医学和药物化学关联使用的术语以及本文所述的分析化学、合成有机化学以及医学和药物化学的实验室程序和技术是本领域中熟知并通常使用的那些。标准技术可用于化学合成、化学分析、药物制备、配制和递送以及治疗患者。
所标识的所有专利和其它出版物都出于描述和公开例如所述出版物中所述的可能与所述内容关联使用的方法的目的而以引用的方式整体明确并入本文。
两性离子被表征为具有导致化合物的净电荷是零的单独正电荷和负电荷。大多数氨基酸在生理pH下是两性离子。如本文所公开，发现含有两性离子，特别是n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物的药物制剂通常比含有多元醇的制剂具有更低粘度，同时具有更大或类似稳定性。
N-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸和n-乙酰基脯氨酸是天然存在的氨基酸的经修饰形式。N-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸和n-乙酰基脯氨酸包括d型氨基酸与l型氨基酸两者，诸如n-乙酰基-l精氨酸、n-乙酰基-d精氨酸、n-乙酰基-l赖氨酸、n-乙酰基-d赖氨酸、n-乙酰基-l组氨酸、n-乙酰基-d组氨酸、n-乙酰基-l脯氨酸和n-乙酰基-d脯氨酸。
术语“多肽”和“蛋白质”在本文中可互换使用。被预期用于本发明的稳定的药物制剂中的示例性多肽包括抗体、肽体、免疫球蛋白样蛋白质、非抗体蛋白质和非免疫球蛋白样蛋白质。天然存在的蛋白质的类似物被预期包括在本发明制剂中，所述类似物包括具有经修饰糖基化的多肽、不具有糖基化(未糖基化)的多肽。如本文所用，“类似物”是指相对于亲本序列具有***、缺失或取代，同时仍然大致上维持亲本序列的如使用为本领域技术人员所知的生物测定所测定的生物活性的氨基酸序列。本发明制剂也可包括已被化学修饰例如以连接水溶性聚合物(例如聚乙二醇化)、放射性核素或其它诊断部分或靶向部分或治疗部分的天然存在的多肽或类似多肽的衍生物。
可根据本发明配制抗体。如本文所用，术语“抗体”包括完全装配抗体、单克隆抗体(包括人抗体、人源化抗体或嵌合抗体)、多克隆抗体、多特异性抗体(例如双特异性抗体)、大抗体(maxibody)、BiTe、DART和包含前述各物的互补决定区(CDR)，可结合抗原的抗体片段(例如Fab′、F′(ab)2、Fv、单链抗体、微型双功能抗体)，只要它们展现所需生物活性即可。
肽体，即包含抗体Fc结构域连接于至少一种抗原结合肽的分子，一般地描述于PCT公布WO 00/24782中。作为免疫球蛋白超家族的成员的免疫球蛋白样蛋白质含有一个或多个免疫球蛋白样结构域，其在结构中类似于抗体可变区的各部分进行折叠。
包括结合以下中的一种或多种的那些蛋白质的蛋白质将适用于本发明的组合物和方法中。这些包括CD蛋白，包括但不限于CD3、CD4、CD8、CD19、CD20、CD22、CD30和CD34；包括干扰受体结合的那些。HER受体家族蛋白，包括HER2、HER3、HER4和EGF受体。细胞粘着分子，例如LFA-I、MoI、pl50、95、VLA-4、ICAM-I、VCAM和αv/β3整合素(integrin)。生长因子，包括但不限于血管内皮生长因子(“VEGF”)、生长激素、甲状腺刺激激素、卵泡刺激激素、促黄体生成激素、生长激素释放因子、甲状旁腺激素、苗勒管抑制物质(mullerian-inhibitingsubstance)、人巨噬细胞炎症性蛋白质(MIP-I-α)、红血球生成素(erythropoietin，EPO)、神经生长因子诸如NGF-β、血小板源性生长因子(PDGF)、纤维母细胞生长因子包括例如aFGF和bFGF、表皮生长因子(EGF)、转化生长因子(TGF)尤其包括TGF-α和TGF-β(包括TGF-β1、TGF-β2、TGF-β3、TGF-β4或TGF-β5)、***-I和***-II(IGF-I和IGF-II)、去(l-3)-IGF-I(脑IGF-I)和骨诱导性因子。胰岛素和胰岛素相关蛋白质，包括但不限于胰岛素、胰岛素A链、胰岛素B链、胰岛素原和***结合蛋白。凝结和凝结相关蛋白质，尤其诸如因子VIII、组织因子、范威尔邦德(von Willebrands)因子、蛋白质C、α-1-抗胰蛋白酶、纤维蛋白溶酶原活化因子诸如尿激酶和组织纤维蛋白溶酶原活化因子(“t-PA”)、邦巴辛(bombazine)、凝血酶和血小板生成素；(vii)其它血液和血清蛋白质，包括但不限于白蛋白、IgE和血型抗原。集落刺激因子及其受体，尤其包括以下：M-CSF、GM-CSF和G-CSF，及其受体诸如CSF-1受体(c-fms)。受体和受体相关蛋白质，包括例如flk2/flt3受体、肥胖(OB)受体、LDL受体、生长激素受体、血小板生成素受体(“TPO-R”、“c-mpl”)、升糖素受体、白介素受体、干扰素受体、T细胞受体、干细胞因子受体诸如c-Kit、和本文所列的其它受体。受体配体，包括例如OX40L，即OX40受体的配体。神经营养因子，包括但不限于骨源性神经营养因子(BDNF)和神经营养素-3、神经营养素-4、神经营养素-5或神经营养素-6(NT-3、NT-4、NT-5或NT-6)。松弛素(Relaxin)A链、松弛素B链和松弛素原；干扰素和干扰素受体，包括例如干扰素-α、干扰素-β和干扰素-γ，以及它们的受体。白介素和白介素受体，包括但不限于IL-I至IL-33和IL-I至IL-33受体，诸如IL-8受体以及其它。病毒抗原，包括但不限于AIDS包膜病毒抗原。脂蛋白、降血钙素、升糖素、心房利钠因子、肺表面活性剂、肿瘤坏死因子-α和肿瘤坏死因子-β、脑啡肽酶(enkephalinase)、RANTES(受活化调控，通常由T细胞表达和分泌)、小鼠***相关肽、DNA酶、抑制素(inhibin)和活化素(activin)。整合素、蛋白质A或蛋白质D、类风湿因子、免疫毒素、骨形态发生蛋白质(BMP)、超氧化物歧化酶、表面膜蛋白、衰变加速因子(DAF)、AIDS包膜、转运蛋白、归巢受体、地址素(addressin)、调控蛋白、免疫粘附素、抗体。肌抑素(Myostatin)、TALL蛋白包括TALL-I、淀粉状蛋白包括但不限于淀粉状蛋白-β蛋白、胸腺基质淋巴细胞生成素(“TSLP”)、RANK配体(“OPGL”)、c-kit、TNF受体包括1型TNF受体、TRAIL-R2、促血管生成素(angiopoietin)以及任何前述各物的生物活性片段或类似物或变体。
示例性蛋白质和抗体包括(阿替普酶(Alteplase))；阿里库单抗(alirocumab)(指定为H1H316P的抗PCSK9单克隆抗体，参见U.S.P.N.8.062,640)；(达贝泊汀-α(Darbepoetin-alfa))，(依伯汀α(Epoetin alfa)或红血球生成素(erythropoietin))；(干扰素β-Ia)；(托西莫单抗(Tositumomab))；(干扰素-β)；博克珠单抗(bococizumab)(指定为L1L3的抗PCSK9单克隆抗体，参见U.S.P.N.8,080,243)；(阿来珠单抗(Alemtuzumab))；(依伯汀δ)；(硼替佐米(bortezomib))；MLN0002(抗α4β7 mAb)；MLN1202(抗CCR2趋化因子(chemokine)受体mAb)；(依那西普(etanercept))；(依伯汀α)；(西妥昔单抗(Cetuximab))；依伏库单抗(evolocumab)(指定为21B12的抗PCSK9单克隆抗体，参见U.S.P.N.8,030,467)；(促生长激素(Somatropin))；(曲妥珠单抗(Trastuzumab))；(注射用促生长激素[rDNA来源])；(阿达木单抗(Adalimumab))；(干扰素Alfacon-1)；(奈西利肽(nesiritide))；(阿那白滞素(Anakinra))，(沙格司亭(Sargamostim))；(依帕珠单抗(Epratuzumab))；BenlystaTM(贝利木单抗(Belimumab))；(替奈替普酶(Tenecteplase))；(甲氧基聚乙二醇-依伯汀β)；(奥佐米星吉妥单抗(Gemtuzumabozogamicin))(依法珠单抗(efalizumab))；(聚乙二醇赛妥珠单抗(certolizumab pegol))；SolirisTM(依库珠单抗(Eculizumab))；培克珠单抗(Pexelizumab)(C5补体抗体)；MEDI-524(雷珠单抗(Ranibizumab))；依决洛单抗(Edrecolomab) (乐地单抗(lerdelimumab))；TheraCim hR3(尼妥珠单抗(Nimotuzumab))；奥密塔克(Omnitarg)(帕妥珠单抗(Pertuzumab)、2C4)；(IDM-I)；(B43.13)；(维利珠单抗(visilizumab))；莫坦辛坎妥珠单抗(Cantuzumab mertansine)(huC242-DMl)；(依伯汀β)；(奥普瑞白介素(Oprelvekin))；(聚乙二醇化非格司亭(Pegylated filgastrim)、聚乙二醇化G-CSF、聚乙二醇化hu-Met-G-CSF)；(非格司亭(Filgrastim))；Orthoclone(莫罗莫那-CD3(Muromonab-CD3))，(依伯汀α)；(英夫利昔单抗(Infliximab))，(阿昔单抗(Abciximab))，(抗IL6受体mAb)，(贝伐单抗(Bevacizumab))，HuMax-CD4(扎木单抗(zanolimumab))，(利妥昔单抗(Rituximab))；(埃罗替尼(Erlotinib))；Roferon--(干扰素α-2a)；(巴利昔单抗(Basiliximab))；StelaraTM(优特克单抗(Ustekinumab))；(罗美昔布(lumiracoxib))；(帕利珠单抗(Palivizumab))；14687-CHO(抗IL15抗体，参见U.S.P.N.7.153,507)，(那他珠单抗(Natalizumab))；(MDX-1303、抗炭疽杆菌保护性抗原mAb)；ABthraxTM；(帕尼单抗(Panitumumab))；(奥马珠单抗(Omalizumab))，ETI211(抗MRSA mAb)，IL-I捕集剂(人IgGl的Fc部分和两种IL-I受体组分(I型受体和受体辅助蛋白)的细胞外结构域)，VEGF捕集剂(VEGFRl的Ig结构域融合于IgGl Fc)，(达利珠单抗(Daclizumab))；(达利珠单抗)，(替坦异贝莫单抗(Ibritumomab tiuxetan))，泽天(Zetia)(依折麦布(ezetimibe))，阿塞西普(Atacicept)(TACI-Ig)、抗α4β7 mAb(维多珠单抗(vedolizumab))；加利昔单抗(galiximab)(抗CD80单克隆抗体)，抗CD23 mAb(鲁昔单抗(lumiliximab))；BR2-Fc(huBR3/huFc融合蛋白，可溶性BAFF拮抗剂)；SimponiTM(戈利木单抗(Golimumab))；马帕木单抗(Mapatumumab)(人抗TRAIL受体-1 mAb)；奥瑞珠单抗(Ocrelizumab)(抗CD20人mAb)；HuMax-EGFR(扎鲁木单抗(zalutumumab))；M200(伏洛昔单抗(Volociximab)，抗α5β1整合素mAb)；MDX-010(易普利单抗(Ipilimumab)，抗CTLA-4 mAb)和VEGFR-I抗体(IMC-18F1)；抗BR3 mAb；抗艰难梭菌(C.difficile)毒素A和毒素B C mAbMDX-066(CDA-I)和MDX-1388；抗CD22 dsFv-PE38缀合物(CAT-3888和CAT-8015)；抗CD25mAb (HuMax-TAC)；抗TSLP抗体(参见U.S.P.N.7,982,016、U.S.P.N.8232372和美国公布申请20090186022)；抗TSLP受体抗体(参见U.S.P.N.8,101,182)；指定为A5的抗TSLP抗体(参见U.S.P.N.7,982,016)；(参见抗CD3 mAb(NI-0401))；阿德木单抗(Adecatumumab)(MT201，抗EpCAM-CD326 mAb)；MDX-060，SGN-30，SGN-35(抗CD30 mAb)；MDX-1333(IFNAR抗体)；HuMax CD38(抗CD38 mAb)；抗CD40L mAb；抗Cripto mAb；Fibrogen特发性肺纤维化I期CTGF抗体(FG-3019)；抗CTLA4 mAb；抗嗜酸性粒细胞趋化因子mAb(CAT-213)；抗FGF8 mAb；抗神经节苷脂GD2 mAb；抗硬化蛋白(sclerostin)抗体(参见U.S.P.N.8,715,663或U.S.P.N.7,592,429)。指定为Ab-5的抗硬化蛋白抗体(参见U.S.P.N.8,715,663或U.S.P.N.7,592,429)；抗神经节苷脂GM2 mAb；抗GDF-8人mAb(MYO-029)；抗GM-CSF受体mAb(CAM-3001)；抗HepC mAb(HuMax HepC)；MEDI-545，MDX-1103(抗IFNαmAb)；抗IGFIR mAb；抗IGF-IR mAb(HuMax-Inflam)；抗IL12/IL23p40 mAb(布雷奴单抗(Briakinumab))；抗IL-23p19 mAb(LY2525623)；抗IL13 mAb(CAT-354)；抗IL-17 mAb(AIN457)；抗IL2Ra mAb(HuMax-TAC)；抗IL5受体mAb；抗整合素受体mAb(MDX-Ol8、CNTO 95)；抗IPIO溃疡性结肠炎mAb(MDX-1100)；抗LLY抗体；BMS-66513；抗甘露糖受体/hCGβmAb(MDX-1307)；抗间皮素(mesothelin)dsFv-PE38缀合物(CAT-5001)；抗PDlmAb(MDX-1 106(ONO-4538))；抗PDGFRα抗体(IMC-3G3)；抗TGFβmAb(GC-1008)；抗TRAIL受体-2人mAb(HGS-ETR2)；抗TWEAK mAb；抗VEGFR/Flt-1 mAb；抗ZP3 mAb(HuMax-ZP3)；1号NVS抗体；2号NVS抗体；和包含序列SEQ ID NO：8和SEQ ID NO：6的淀粉状蛋白-β单克隆抗体(参见U.S.P.N.7,906,625)。
制剂中的示例性蛋白质浓度可在约70mg/ml至约300mg/ml，约120mg/ml至约270mg/ml，约140mg/ml至约255mg/ml，约140mg/ml至约240mg/ml，或约140mg/ml至约220mg/ml，或替代地，约190mg/ml至约210mg/ml的范围内。蛋白质的浓度将取决于药物制剂的终端用途，并且可易于由本领域技术人员确定。特别涵盖的蛋白质浓度是至少约70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、215、220、225、230、235、240、245、250、255、260、265、270、275、280、285、290、295和300mg/ml，并且包括介于之间的所有值。
如本文所用，“药物制剂”是适于向有需要的患者胃肠外施用(包括但不限于静脉内、肌肉内、皮下、气雾化、肺内、鼻内或鞘内)的药物活性药物诸如生物活性蛋白质的无菌组合物，并且仅包括由联邦药物管理局(Federal Drug Administration)或其它外国国立机关视为安全的药学上可接受的赋形剂、稀释剂和其它添加剂。药物制剂包括可直接施用的液体溶液例如水溶液，和可在施用之前通过添加稀释剂来复原成溶液的冻干粉末。从术语“药物制剂”的范围明确排除的是用于向患者表面施用的组合物、用于口服摄取的组合物和用于胃肠外馈入的组合物。
如本文所用的“储存期限”意指当在指定储存条件例如2-8℃下储存药物制剂时，所述药物制剂中的活性成分诸如治疗性蛋白质具有最小程度降解(例如不超过约5％至10％降解)所处的储存时期。用于评估降解的技术视药物制剂中的蛋白质的身份而变化。示例性技术包括用以检测例如聚集的尺寸排阻色谱法(SEC)-HPLC、用以检测例如蛋白质片段化的反相(RP)-HPLC、用以检测例如蛋白质的电荷变化的离子交换-HPLC、质谱测定法、荧光光谱法、圆二色性(CD)光谱法、傅里叶变换红外光谱法(Fourier transform infraredspectroscopy，FT-IR)和用以检测蛋白质构象变化的拉曼光谱法(Raman spectroscopy)。所有这些技术都可单独或组合用于评估药物制剂中的蛋白质的降解，并且确定那个制剂的储存期限。当在2-8℃下储存时，历经两年，本发明的药物制剂优选展现降解(例如片段化、聚集或展开)增加不超过约5至10％。
如本文所用，生物活性蛋白质的“稳定”制剂是相较于对照配方样品，在2-8℃下储存至少2年后，展现聚集降低和/或生物活性损失降低至少20％的制剂，或替代地，在热应激条件例如25℃持续1周至12周；40℃持续1至12周；52℃持续7-8天等下，展现聚集降低和/或生物活性损失降低的制剂。
如本文所用，“粘度”是液体的流动阻力，并且可在给定剪切速率下以厘泊(cP)或毫帕-秒(mPa-s)单位计量，其中1cP＝1mPa-s。粘度可通过使用粘度计例如BrookfieldEngineering LVT型刻度盘读数粘度计和TA instruments AR-G2来测量。粘度可使用本领域中已知的任何其它方法以及在本领域中已知的任何其它装置中来测量(例如绝对、运动或动态粘度)，同时应了解通过使用由本发明所述的重要赋形剂提供粘度降低百分比。无论用于测定粘度的方法如何，相对于对照制剂，在给定剪切速率下，赋形剂制剂的粘度降低百分比将保持近似相同。
如本文所用，含有有效“降低粘度”的量的赋形剂(或“降粘”量或浓度的所述赋形剂)的制剂意指呈它的最终施用形式(假设是溶液，或如果是粉末，那么在用预定量的稀释剂复原后)的所述制剂的粘度比适当对照制剂诸如水、缓冲剂、其它已知粘度降低剂诸如盐等对照制剂和例如本文例示的那些对照制剂的粘度小至少5％。也可能使用无赋形剂对照制剂，即使它们可能由于例如低张性而不可作为治疗性制剂进行应用。
类似地，“粘度降低”制剂是相较于对照制剂，展现粘度降低的制剂。
蛋白质治疗剂常常需要以高浓度给与，此可导致溶液的粘度增加。高度合乎需要的是提供不展现通常在所述高蛋白质浓度的情况下所见的粘度增加的高浓度制剂。
高粘度制剂在制造期间，包括在堆放和装填阶段难以处理。高粘度制剂也难以吸入注射器中并注射，从而常常使得必须使用对于患者来说可不舒适的较低规格针。向生物活性蛋白质的溶液中添加n-乙酰基-l-精氨酸使高浓度蛋白质溶液的粘度降低。
使用选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂允许较高浓度的治疗性蛋白质用于制剂中，而无如同通常在其它赋形剂的情况下所见那样巨大的粘度增加。因此，本发明提供一种用于通过以有效降低粘度的量添加选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂来稳定或降低蛋白质制剂的粘度的方法。本发明也提供包括抗体的治疗性蛋白质的粘度降低制剂，其含有有效量或浓度的选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂。也涵盖筛选一种或多种各自含有不同浓度的本文所述的赋形剂的制剂以鉴定使粘度降低的适合或最优浓度的方法。进一步提供从本发明的粘度降低溶液制剂制备冻干粉末的方法，和通过添加无菌稀释剂来复原本发明的冻干粉末的方法。
因此，本发明提供含有生物活性多肽和降粘浓度的选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂的药物制剂。相对于对照制剂，粘度降低是至少约5-90％。在一个实施方案中，粘度降低在约10-80％的范围内。在其它示例性实施方案中，粘度降低是至少5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％或85％。
本发明的制剂可任选包括药学上可接受的盐、缓冲剂、表面活性剂、其它赋形剂、载体、稀释剂和/或其它配制剂。
示例性药学上可接受的缓冲剂包括乙酸盐(例如乙酸钠)、丁二酸盐(诸如丁二酸钠)、谷氨酸、谷氨酸盐、葡萄糖酸盐、组氨酸、柠檬酸盐或其它有机酸缓冲剂。视例如缓冲剂和制剂的所需张性(例如等张、高张或低张)而定，示例性缓冲剂浓度可为约1mM至约200mM，或约10mM至约60mM。示例性pH包括约4.5至约8.0，或约4.8至约5.5，或约4至6，或约5至5.5，或约5，大于约5，大于约5.5，大于约6，或大于约6.5。
适合稀释剂、其它赋形剂、或载体和其它试剂包括但不限于抗氧化剂、着色剂、调味剂和稀释剂、乳化剂、混悬剂、溶剂、填充剂、增积剂、缓冲剂、媒介物、稀释剂和/或药物佐剂。举例来说，适合媒介物可为生理盐水溶液、柠檬酸盐缓冲盐水或人工CSF，可能补充以在用于胃肠外施用的组合物中常见的其它物质。中性缓冲盐水或与血清白蛋白混合的盐水是其它示例性媒介物。本领域技术人员将易于认识到可用于本发明中使用的组合物和剂型中的多种缓冲剂。典型缓冲剂包括但不限于药学上可接受的弱酸、弱碱或其混合物。示例性缓冲剂组分是水溶性物质，诸如磷酸、酒石酸、乳酸、丁二酸、柠檬酸、乙酸、抗坏血酸、天冬氨酸、谷氨酸或其盐。示例性盐包括处于诸如约50-200mM、或100-200mM、或约100mM、或约150mM的示例性浓度下的无机和有机酸或碱诸如金属或胺。
也可包括其它赋形剂或稳定剂，例如糖(例如蔗糖、葡萄糖、海藻糖、果糖、木糖、甘露糖、海藻糖)、多元醇(例如甘油、甘露糖醇、山梨糖醇、乙二醇、肌醇)、氨基酸或氨基酸衍生物(例如精氨酸、脯氨酸、组氨酸、赖氨酸、甘氨酸、甲硫氨酸等)或表面活性剂(例如聚山梨醇酯，包括聚山梨醇酯20或聚山梨醇酯80，或泊洛沙姆(poloxamer)，包括泊洛沙姆188，TPGS(d-α生育酚聚乙二醇1000丁二酸酯))。表面活性剂的示例性浓度可在约0.001％至约1.0％，或约0.003％至约0.5％的范围内。也可包括防腐剂，诸如苯甲醇、苯酚、间甲酚、氯丁醇或苄索氯铵，例如处于在约0.1％至约2％，或约0.5％至约1％的范围内的浓度下。
一种或多种其它药学上可接受的载体、赋形剂或稳定剂，诸如Remington′sPharmaceutical Sciences第21版，Osol，A.编(2005)中所述的那些，可包括在制剂中，前提是它们不会不利影响制剂的所需特征。
制剂中的治疗性蛋白质诸如抗体的浓度将取决于药物制剂的终端用途，并且可易于由本领域技术人员确定。
相比于是激动剂的治疗性蛋白质，是拮抗剂的治疗性蛋白质常常以更高浓度施用。包括抗体的治疗性蛋白质的特别涵盖的高浓度(不考虑化学修饰诸如聚乙二醇化的重量)是至少约70、80、90、100、110、120、130、140、150、175、180、185、190、195、200、250、300、350、400、450或500mg/ml，和/或小于约250、300、350、400、450或500mg/ml。制剂中的治疗性蛋白质诸如抗体的示例性高浓度可在至少约100mg/ml至约500mg/ml的范围内。也涵盖其它蛋白质浓度(不考虑化学修饰诸如聚乙二醇化的重量)，例如至少约1、5、10、20、30、35、40、45、50、55、60、65或70mg/ml。本发明特别涵盖以下制剂和方法：其中治疗性蛋白质的浓度导致粘度是至少6、8、10、12、14、16、18、20、25、30、35cP或更高，诸如100、125、150、175或200cP，并且包括选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂导致所述粘度降低5％或更大。举例来说，粘度是约30cP的溶液可难以用标准27规格针注射。在本文中对治疗性蛋白质的mg/ml浓度、治疗性蛋白质的重量(mg)或治疗性蛋白质的分子量(kD)的所有提及都意指治疗性蛋白质的排除任何非蛋白质修饰的蛋白质部分的相应重量。
本发明提供一种通过以下方式来降低治疗性蛋白质的液体药物制剂的粘度和/或改进其稳定性的方法：使所述治疗性蛋白质和降粘量的选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂组合。
在示例性实施方案中，治疗性蛋白质处于如上所述的高蛋白质浓度下。在一些实施方案中，相较于对照制剂，粘度降低是至少约5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％或85％。
在另一方面，本发明提供包含治疗性蛋白质和选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂的液体溶液，其中制剂相对于对照制剂展现粘度降低。在示例性实施方案中，治疗性蛋白质处于如上所述的高蛋白质浓度下。在一些实施方案中，本文所述的赋形剂以降粘(重量：体积)浓度存在。任何这些赋形剂都可以多达它们的溶解度限度的浓度使用。所述溶液可进一步以有效进一步改进稳定性，降低聚集，和/或使得制剂等张，而不显著增加粘度的量包含糖或其它多元醇诸如蔗糖或山梨糖醇，或氨基酸诸如精氨酸、脯氨酸、组氨酸、赖氨酸、甘氨酸、甲硫氨酸等。
在示例性实施方案中，选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂的浓度是至少约50mM至约300mM，或至少约100mM至约250mM，或至少约140mM至约200mM。在示例性实施方案中，赋形剂的浓度是至少约50、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、210、220、250或300mM或更大。其它示例性实施方案包括赋形剂的有效使得制剂等张，而不显著增加粘度的浓度。示例性浓度包括至少约180mM或更大的那些，在其它实施方案中，量是至少约200mM或更大。
在另一方面，本发明提供包含治疗性蛋白质和选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂的冻干蛋白质制剂，其中在用推荐量的稀释剂复原后，制剂相对于对照制剂展现粘度降低。在示例性实施方案中，治疗性蛋白质处于如上所述的高蛋白质浓度下。在一些实施方案中，赋形剂在用稀释剂复原后有效降低粘度的量(重量：重量浓度)下存在。所述制剂可进一步以有效进一步改进稳定性，降低聚集，和/或使得制剂等张，而不显著增加粘度的量包含糖或其它多元醇诸如蔗糖或山梨糖醇，或至少一种氨基酸诸如精氨酸、脯氨酸、组氨酸、赖氨酸、甘氨酸、甲硫氨酸等。
在示例性实施方案中，选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂的浓度是每mg治疗性蛋白质至少约1μg，直至每mg治疗性蛋白质约1.0mg。在一些实施方案中，赋形剂的浓度是每mg治疗性蛋白质，至少约1、10、50、100、150、200、250、300、350、400、450、500或550μg。在其它示例性实施方案中，赋形剂的浓度是每mg治疗性蛋白质多达约600、650、700、750、800、850、900、950或1000μg。
在另一实施方案中，本发明提供一种通过以任何本文所述的量或浓度使用n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物作为赋形剂来防止液体制剂中的蛋白质自我缔合的方法。也提供稳定性改进(例如聚集降低)和储存期限改进的制剂。
本发明也提供一种试剂盒，其包括本发明的液体蛋白质制剂和用于它的施用的说明书，任选具有容器、注射器和/或其它施用装置。本发明进一步提供一种试剂盒，其包括任选在容器中的本发明的冻干蛋白质制剂和用于它的复原和施用的说明书，任选具有含无菌稀释剂的小瓶，并且任选具有注射器或其它施用装置。示例性容器包括小瓶、管、瓶、单室或多室预填充注射器、或柱筒。示例性施用装置包括具有或不具有针的注射器、输注泵、射流注射器、笔式装置、经皮注射器、或其它无针注射器、或用于经鼻或经肺递送的气雾化装置。
在另一方面，提供一种用于筛选赋形剂的降粘浓度的方法，其包括以下步骤：(1)评估包含第一浓度的选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂和治疗性蛋白质诸如抗体的第一溶液的粘度，(2)评估包含不同第二浓度的所述赋形剂和所述治疗性蛋白质的第二溶液的粘度，以及(3)如果所述第一溶液的粘性较小，那么确定所述第一浓度的赋形剂比所述第二浓度的赋形剂更具粘度降低性。可例如使用Aries ARG2流变仪或Brookfield RV-DVIII流变仪测定粘度。
提供用于筛选赋形剂的聚集降低性或稳定性浓度的类似方法。
可以许多方式评估稳定性，包括历经一定温度(热稳定性)和/或时期(储存期限)范围和/或在暴露于应激处理情况(例如物理振荡)之后监测构象变化。可使用多种方法测量含有不同浓度的制剂组分的制剂的稳定性。举例来说，蛋白质聚集的量可通过目视观察浊度，通过在特定波长下测量吸光度，通过尺寸排阻色谱法(其中相较于处于它的天然活性状态的蛋白质，蛋白质的聚集物将洗脱于不同部分中)、HPLC或其它色谱方法来测量。可使用测量构象变化的其它方法，包括使用例如用以测定变性温度的差示扫描量热法(DSC)，或测量蛋白质的摩尔椭圆率的圆二色性(CD)。荧光也可用于分析组合物。荧光涵盖呈光或热形式的能量的释放或吸收，以及光的极性性质的变化。荧光发射可为蛋白质所固有，或可归因于荧光报道体分子。举例来说，ANS是结合部分展开蛋白质的疏水性口袋的荧光探针。随着展开蛋白质的浓度增加，疏水性口袋的数目增加，并且随后可进行结合的ANS的浓度增加。这个ANS结合增加可通过检测蛋白质样品的荧光信号来监测。可使用用于测量稳定性的其它手段，并且为本领域技术人员所熟知。
通过参照详述本发明的示例性实施方案的以下实施例，本发明将得以更充分了解。然而，它们不应被解释为限制本发明的范围。遍及本公开的所有引用都据此以引用的方式明确并入本文。
实施例
实施例1
使用10,000MWCO折叠透析管(Thermo Fisher Scientific，Waltham，MA)，相对于含1％蔗糖的10mM谷氨酸钠(pH 5.2)透析IgG2抗体制剂(140mg/ml)(抗体A)。在各自1mL填充量下将于含1％蔗糖的10mM谷氨酸钠(pH 5.2)中的120mg/mL抗体A填充在3cc小瓶中。使用Virtis冻干器冻干小瓶。用450uL各种溶液(水-对照或200mM赋形剂溶液)复原小瓶。在复原之后，使用SOLO-VPE仪器测定抗体A浓度是190mg/mL。使用Aries ARG2流变仪在25℃下测量粘度，并且记录在下表1中。
表1：190mg/mL抗体A的赋形剂制剂，在20℃下
图1显示各种赋形剂对抗体溶液的粘度的影响。数据显示测试的赋形剂相对于水对照已使粘度降低。
实施例2
使用10,000MWCO透析管，分别相对于pH值是4.7和4.9的20mM乙酸钠透析IgG1抗体制剂(70mg/ml)(抗体B)和IgG2抗体制剂(70mg/ml)(抗体C)。使用30,000MWCO离心过滤器和Allegra X-12R离心机浓缩抗体样品。使用Agilent紫外光/可见光分光光度计测定抗体样品浓度。通过用预称重固体赋形剂外加主体浓缩溶液来制备含有赋形剂的样品。使用正位移吸移器转移粘性样品。使用Brookfield RV-DV III+可编程流变仪，在25℃下测量粘度，并且记录在下表2.1和2.2中。
表2.1：抗体B-210mg/mL
| 制剂 | 粘度(cP)，225/s，25℃ |
| 无赋形剂对照 | 26.0 |
| 200mM n-乙酰基-L精氨酸 | 14.3 |
表2.2：抗体C-140mg/mL
| 制剂 | 粘度(cP)，225/s，25℃ |
| 无赋形剂对照 | 22.7 |
| 200mM n-乙酰基-L精氨酸 | 10.0 |
对于赋形剂n-乙酰基-l精氨酸，抗体B的粘度降低是约45％，并且抗体C的粘度降低是约56％。
实施例3
使用10,000MWCO折叠透析管(Thermo Fisher Scientific，Waltham，MA)，相对于含1％蔗糖的10mM谷氨酸钠(pH 5.2)透析IgG2抗体制剂(140mg/ml)(抗体D)。在各自1mL填充量下将于含1％蔗糖的10mM谷氨酸钠(pH 5.2)中的100mg/mL抗体D填充在3cc小瓶中。使用Virtis冻干器冻干小瓶。用450uL水(对照-无赋形剂)或10mM谷氨酸盐200mMn-乙酰基-L精氨酸(pH 5.2)复原小瓶。使用SOLO-VPE仪器测定抗体D浓度。使用Aries ARG2流变仪在25℃下测量粘度，并且记录在下表3.0中。
表3.0：抗体D-175mg/mL
| 制剂 | 粘度(cP)，1000/s，25℃ |
| 无赋形剂对照 | 38.7 |
| 200mM n-乙酰基-l精氨酸 | 23.4 |
对于赋形剂n-乙酰基-l精氨酸，抗体D的粘度降低是约40％。
实施例4
使用超滤和透滤，用6个透滤体积的缓冲液A(10mM谷氨酸盐260mM n-乙酰基-l精氨酸，pH 4.6)或缓冲液B(10mM谷氨酸钠，pH 4.6)将IgG2抗体制剂(140mg/ml)(抗体E)浓缩成200mg/ml。UFDF样品的最终pH测定为5.2。使用SOLO-VPE仪器测定抗体E浓度。使用AriesARG2流变仪在20℃下测量粘度，并且记录在下表4.0中。
表4.0：抗体E-200mg/mL
对于赋形剂n-乙酰基-l精氨酸，抗体E的粘度降低是约54％。
实施例5
使用10,000MWCO折叠透析管(Thermo Fisher Scientific，Waltham，MA)，相对于含1％蔗糖的10mM谷氨酸钠(pH 5.2)透析IgG2抗体制剂(140mg/ml)(抗体A)。在各自1mL填充量下将于含1％蔗糖的10mM谷氨酸钠(pH 5.2)中的120mg/mL抗体A填充在3cc小瓶中。使用Virtis冻干器冻干小瓶。用450uL各种溶液(水-对照或200mM赋形剂溶液)复原小瓶(参见下表5)。在复原之后，使用SOLO-VPE仪器测定抗体A浓度是190mg/mL。使用AriesARG2流变仪在25℃下测量粘度，并且记录在下表5中。
表5：190mg/mL抗体A的赋形剂制剂，在20℃下
| 缓冲液标识 | 赋形剂 |
| A | 200mM组氨酸 |
| B | 200mM n-乙酰基-L-组氨酸 |
| C | 200mM n-乙酰基-L精氨酸 |
| D | 对照 |
图2显示各种赋形剂对抗体溶液的粘度的影响。数据显示测试的赋形剂相对于对照已使粘度降低，并且赋形剂n-乙酰基-l精氨酸和n-乙酰基-l组氨酸相对于单独组氨酸赋形剂已使粘度降低。
Claims (25)
1. 一种降低包含浓度为至少70 mg/ml的治疗性蛋白质的液体药物制剂的粘度的方法，其包括使所述治疗性蛋白质与降粘浓度的选自由以下组成的组的赋形剂组合的步骤：n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物。
2.如权利要求1所述的方法，其中所述赋形剂是n-乙酰基精氨酸。
3.如权利要求1所述的方法，其中所述赋形剂是n-乙酰基赖氨酸。
4.如权利要求1所述的方法，其中所述赋形剂是n-乙酰基组氨酸。
5.如权利要求1所述的方法，其中所述赋形剂是n-乙酰基脯氨酸。
6.如权利要求1所述的方法，其中使所述制剂的粘度降低至少25%。
7.如权利要求1所述的方法，其中使所述制剂的粘度降低至少50%。
8.如权利要求1所述的方法，其中使所述制剂的粘度降低至少80%。
9.一种药物制剂，其通过如权利要求1-8中任一项所述的方法来产生。
10. 一种药物组合物，其包含浓度为至少70 mg/ml的治疗性蛋白质和选自由以下组成的组的赋形剂：n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物。
11.如权利要求10所述的药物组合物，其中所述赋形剂是n-乙酰基精氨酸。
12.如权利要求10所述的药物组合物，其中所述赋形剂是n-乙酰基赖氨酸。
13.如权利要求10所述的药物组合物，其中所述赋形剂是n-乙酰基组氨酸。
14.如权利要求10所述的药物组合物，其中所述赋形剂是n-乙酰基脯氨酸。
15. 如权利要求10所述的药物组合物，其中所述赋形剂的所述浓度小于约200 mM。
16.如权利要求10-15中任一项所述的药物组合物，其具有介于约4.0至约8.0之间的pH值。
17.如权利要求16所述的药物组合物，其具有约4.6至约5.4的pH值。
18.一种制备冻干粉末的方法，其包括使如权利要求10-17中任一项所述的药物组合物冻干的步骤。
19.一种冻干粉末，其包含治疗性蛋白质和选自由n-乙酰基精氨酸、n-乙酰基赖氨酸、n-乙酰基组氨酸、n-乙酰基脯氨酸及其混合物组成的组的赋形剂，其中所述赋形剂以可有效地在用稀释剂复原后降低粘度的重量:重量浓度存在。
20. 如权利要求19所述的冻干粉末，其中所述赋形剂以介于每mg治疗性蛋白质约100μg至每mg治疗性蛋白质约1 mg之间的浓度存在。
21. 如权利要求19所述的冻干粉末，其中所述赋形剂以介于每mg治疗性蛋白质约200μg至约500 μg至每mg治疗性蛋白质约1 mg之间的浓度存在。
22.一种复原如权利要求19-21中任一项所述的冻干粉末的方法，其包括添加无菌水性稀释剂的步骤。
23.如权利要求1-8、18或22中任一项所述的方法，其中所述治疗性蛋白质是抗体。
24.如权利要求9-17中任一项所述的药物制剂或药物组合物，其中所述治疗性蛋白质是抗体。
25.如权利要求19-21中任一项所述的冻干粉末，其中所述治疗性蛋白质是抗体。
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| MA48461A (fr) | 2017-04-28 | 2020-03-04 | Amgen Inc | Excipients pour réduire la viscosité de formulations d'anticorps et compositions de formulation |
| AU2018258676A1 (en) | 2017-04-28 | 2019-10-31 | Amgen Inc. | N-acetylated and non-acetylated dipeptides containing arginine to reduce the viscosity of viscous compositions of therapeutic polypeptides |
| EP3624846A1 (en) | 2017-05-16 | 2020-03-25 | Bhami's Research Laboratory, Pvt. Ltd. | High concentration protein formulations with reduced viscosity |
| JP6577683B2 (ja) * | 2017-09-22 | 2019-09-18 | 旭化成ファーマ株式会社 | 安定性に優れるテリパラチド含有液状医薬組成物 |
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| EP3628683A1 (en) * | 2018-09-28 | 2020-04-01 | Zealand Pharma A/S | Formulations of glucagon-like-peptide-2 (glp-2) analogues |
| WO2020219550A1 (en) * | 2019-04-23 | 2020-10-29 | Amgen Inc. | The use of low molecular weight polyvinylpyrrolidone (pvp) to reduce viscosity of high concentration protein formulations |
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