CN104582728A - 脂质体制剂 - Google Patents
脂质体制剂 Download PDFInfo
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- CN104582728A CN104582728A CN201380044348.4A CN201380044348A CN104582728A CN 104582728 A CN104582728 A CN 104582728A CN 201380044348 A CN201380044348 A CN 201380044348A CN 104582728 A CN104582728 A CN 104582728A
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Abstract
本发明涉及药物制剂,其包括抗血管生成化合物和递送剂,所述抗血管生成化合物是比如选自例如抑制VEGF的作用的血管内皮生长因子粘合剂的雷珠单抗的单克隆抗体或其片段,所述递送剂选自药学上可接受的脂质体。制剂用于治疗动物和人的各种血管生成不适和疾病,并且优选地治疗选自老年性黄斑变性、糖尿病黄斑性水肿和角膜新血管形成的眼科不适。
Description
相关申请的交叉引用
本申请要求分别于2012年8月21日、2013年3月15日和2013年8月5日提交的美国临时专利申请61/691,455、61/791,693和61/862,300的优先权,全部以其整体通过参考并入本文。
技术领域
本发明涉及药物制剂,其包括通常通过玻璃体内注射施用至眼睛的眼科药物和允许所述玻璃体内药物局部施用至眼睛的脂质体递送剂。本发明也涉及抗血管生成(angiogenic)化合物,比如单克隆抗体或其片段选自,例如,雷珠单抗,其是抑制VEGF作用的血管内皮生长因子粘合剂,和/或多激酶VEGFR和PDGFR抑制剂,例如,舒尼替尼,和选自药学上可接受的脂质体的递送剂。制剂用于治疗动物和人的各种血管生成不适和疾病,并且优选地治疗选自老年性黄斑变性、糖尿病黄斑性水肿和角膜新血管形成的眼科不适。
背景技术
眼科疾病治疗通常要求局部施用或玻璃体内注射具体的药物至眼睛,这取决于具体的疾病或病况和施用途径就具体的药物和疾病的效力。在眼睛的某些疾病或病况中,仅能通过玻璃体内注射施用药物才能实现有效的治疗。有许多眼睛的疾病和病况通过玻璃体内注射有效治疗。同时,这些注射可造成和/或与严重的副作用相关,包括眼睛感染(眼内炎)、眼睛炎症、视网膜脱落和眼压的增加。因为这些副作用或风险,局部治疗眼睛已经是施用药物以治疗眼睛病况的优选途径和圣杯(Holy Grail),因为在几乎所有的情况下,局部施用药物未能有效治疗某些眼睛病况,尤其存在于眼睛后部的那些病况。因此需要开发有效治疗所述病况并且不需要玻璃体内注射的制剂。本发明人认为,他们已经发现了这种媒介。美国专利号6,884,879公开了各种抗VEGF抗体。该专利具体描述和请求保护被批准并且以商标名售卖的单克隆抗体雷珠单抗(ranibizumab)。其中公开的抗体描述为能够预防、逆转和/或减轻各种疾病的症状并且描述为能够抑制VEGF诱导的内皮细胞的增殖和能够抑制VEGF诱导的血管生成。被批准通过每月一次以0.5mg(0.05mL)的剂量强度玻璃体内注射用于新生血管性(湿性)老年性黄斑变性(AMD),并且虽然效果较差,但是批准的治疗可以是在每月一次持续至少四月的初始方案之后以每三个月一次注射施用。在美国批准使用0.5mg(0.05mL)以每月一次的玻璃体内方案用于视网膜静脉阻塞(RVO)之后的黄斑性水肿。另外,在欧洲和美国以可注射的制剂批准用于糖尿病黄斑性水肿。
舒尼替尼(sunitinib)(SU-11248,Sutent)由FDA于2006年1月批准作为治疗转移性肾细胞癌症和胃肠道基质肿瘤的单药疗法。舒尼替尼抑制至少八种受体蛋白质-酪氨酸激酶,包括血管内皮生长因子受体1-3(VEGFR1-VEGFR3),血小板衍生生长因子受体(PDGFRα和PDGFRβ)。该化合物通过减少经VEGFR1、VEGFR2和PDGFRβ的信号传导而抑制血管生成。PDGFRβ出现在围绕毛细管内皮细胞的周细胞中1(Roskoski,2007,附带的PDF文档)。有证据显示,在治疗一些VEGF相关的疾病中时,与抗PDGF的组合使用优于雷珠单抗单药疗法。
有许多与玻璃体内注射抗VEGF抗体和其他眼科药物相关的副作用或潜在的副作用,包括患者不适。玻璃体内注射程序要求具有普通无菌条例的专用清洁室,复苏设备必须随时可以使用。该程序的并发症包括感染眼内炎、视网膜脱落和外伤白内障。玻璃体内注射的其他可能的并发症包括眼内压改变,尤其眼内压上升。与注射相关的眼内压上升,其可就在注射任何类型的药物之后立即出现,与药物特异性相关的眼内压改变,其可在注射后的数天或甚至数月之后才检测到。见Serain.Opthamol.2009Mar-Apr;24(2):100-5。
对于通过玻璃体内注射施用的主要药物类型的此类抗VEGF抗体和其他有效的眼科药物,比如抗微生物剂、抗病毒剂、皮质类固醇和抗血管内皮生长因子试剂的新的局部治疗方案有非常急切未满足的药学需要。本发明包括所述脂质体和局部制剂中的所述药物类型中任何所述药物的组合。尽管美国专利号6,884,879大体上公开了各种可能的递送方法或包括脂质体的试剂和包括局部施用此类VEGF单克隆抗体的各种施用途径,唯一批准的雷珠单抗的形式是液体制剂的玻璃体内形式。需要有效治疗具有包括眼科不适的VEGF相关不适的人的局部雷珠单抗制剂。
本发明人已经满足了该未满足的需要并且令人吃惊地发现包括此类VEGF单克隆抗体和某些脂质体的某些脂质体制剂为具有糖尿病黄斑性水肿的患者提供有效缓解。制剂可有效局部施用至受影响的眼睛并且比局部施用玻璃体内制剂更有效。美国专利号6,958,160公开和要求保护自形成的、热力学稳定的脂质体。美国专利公开号2010/0076209公开了用于脂质体和药物递送的PEG-脂质缀合物,其通过参考并入本文。各种基于脂质的产品,包括以商标名QsomesTM(下文Qsome)售卖的这种自形成的热力学稳定的脂质体由Biozone Laboratories售卖,用于多种治疗性用途并且经包括通过局部施用的各种途径施用至皮肤。本发明人已经发现了包括雷珠单抗和这种自形成的、热力学稳定的脂质体的药学组合物和/或PEG-脂质缀合物可局部递送至与VEGF相关的眼科疾病和病况的患者需要治疗的眼睛。本发明进一步包括局部制剂,其包括如本文叙述的Qsome(自形成的热力学稳定的脂质体)和药物,其中制剂适于治疗眼后节疾病和/或前段/后节疾病组合的疾病。该要求保护的制剂适于局部施用并且尤其用于治疗通常经眼周途径或经玻璃体内施用(眼内递送)治疗的眼科疾病和病况。眼周施用包括结膜下、筋膜下、眼球后和球周施用。有一些药物已经公开为能够递通过局部施用送至后节——这些包括ESBA 105(一种抗TNF-α单链抗体)、地塞米松、奈帕芬胺、盐酸美金刚、多佐胺、溴莫尼定和倍他洛尔。相信,这些药物以Qsome制剂的局部施用将产生更有效的局部递送和更有效的后节递送。但是,优选地,本发明包括局部制剂,其包括如本文所描述的Qsome脂质体和迄今还未通过局部施用而有效递送的药物。
通常通过玻璃体内注射施用的药物包括抗微生物剂、抗病毒剂、皮质类固醇和抗血管内皮生长因子试剂。本发明包括脂质体制剂,其包括自形成的热力学稳定的脂质体和选自抗菌剂、抗病毒剂、皮质类固醇和抗血管内皮生长因子试剂的任何一种或组合的活性药物试剂,其中所述制剂适于局部递送至患者的眼睛以治疗眼科疾病或病况。双氯芬酸、加替沙星、司帕沙星乳酸、GCV、去甲金霉素、氟比洛芬、多柔比星、塞来考昔、布地奈德和顺铂已经配制成胶体药物制剂,用于经角膜或经巩膜递送。包含青霉素G、托品酰胺和乙酰唑胺的阳离子脂质体,相对于阴离子和中性脂质体已经用于提供横跨角膜的最大药物运输。见Schaeffer等,局部药物递送中的脂质体(Liposomes in topical drugdeliver),Invest.Ophthalmol.Vis Sic.1982:22(2):220-7;Nagarsenker等,用于眼部递送的托品酰胺脂质体制剂的制备和评估(Preparation and evaluation ofliposomal formulations of tropicamide for ocular delivery),Int J Pharma.1999:190(1):63-71和Hathout等,脂质体作为醋唑磺胺的眼部递送体系:体外和体内研究(Liposome as an ocular delivery system for acetazolamide:in vitro and invivo studies),AAPS PharmaSciTech.2007:8(1):1。
糖尿病视网膜病变(DR)是最常见的糖尿病的微血管并发症2(Fong,2004)并且是工龄成年人中视力减退新病例的主要原因。糖尿病黄斑性水肿(DME)是具有DR的患者中视力减退的最常见原因。DME的发病率是3%最近的诊断,每年约75,000例新的DME病例(USA)。世界范围具有糖尿病的患者的数量为2.85亿左右。DME源自一系列生物化学和细胞改变,其最终造成进行性渗漏和渗出,导致视网膜的增厚和斑点中心1disc直径的硬渗出物。DME是具有糖尿病的患者中受损视力的最主要原因之一3(Bhagat,2009)。约50%的患者在两年的随访之后经历≥2线BCVA的丧失(Meyer,2007)。
DME中,受损的血管渗漏流体进入视网膜的中心部分(斑点),其导致膨胀。斑点与敏锐的中心视力相关。凹在斑点的中心。DME可出现在具有1或2型糖尿病的患者中。美国有约2600万人的糖尿病并且每年在年龄20或更大的人中诊断190万新病例。估计每年发展多达75,000例DME的新病例。DME是大部分发达国家中工龄人群中失明的主要原因。DME的第一线疗法是激光外科手术,其密封渗漏的血管,以消除流体的渗漏并且减少视网膜中流体的量。因此,非常需要制备为这些患者提供治疗性缓解的新制剂。
发明内容
本发明是一种药物制剂,其包括抗血管生成化合物或其他眼科活性成分和脂质体。优选的抗血管生成化合物是抗VEGF抗体。药物制剂优选地作为局部制剂施用至需要其治疗的患者的眼睛。药物制剂用于治疗与VEGF相关的眼科不适,包括例如老年性黄斑变性和糖尿病黄斑性水肿。本发明也涉及适于局部施用并且在治疗角膜新生血管性疾病中有效的制剂。
优选的抗VEGF抗体选自雷珠单抗()并且可如美国专利号6,884,879中描述来制备,其通过参考并入本文。该产品作为处方玻璃体内液体制剂售卖。雷珠单抗是重组体人源化的IgG1κ同种型单克隆抗体片段。该抗体结合和抑制VEGF-A并且分子量为约48千道尔顿。该产品在包含四环素的营养培养基的大肠杆菌表达系统中产生。处方产品提供在单次使用的玻璃小瓶中,包含0.05ml的10mg/mL的雷珠单抗。其他抗VEGF抗体,比如贝伐单抗(bevacizumab)也可用于治疗某些疾病和病况,比如角膜新生血管性疾病。本文公开的局部脂质体制剂利于整个抗体(比如贝伐单抗)渗透进入具有异常新生血管的眼睛。
在本发明中有用的脂质体优选地包括美国专利号6,958,160中描述的那些脂质体,其通过参考以其整体并入本文。如其中所描述,脂质体是自闭合的胶体颗粒,其中由一个或多个脂质双层组成的膜封装一部分它们在其中悬浮的水溶液。如也在‘160专利中所叙述,并不是所有的脂质体都相同,并且事实上,脂质体可能具有包括胶体不稳定性和制造问题的问题,原因是比如升高的压力和温度以及高剪切条件的极端的条件,这些都可使脂质组分降解。与脂质体相关的其他问题大体上可包括双层尺寸和数量的不均匀分布,其可造成或加速放大(scale-up)的问题。另外,无菌条件可也产生与脂质体相关的问题。脂质体由于悬浮时的聚集也可具有胶体不稳定性。这导致融合问题并且该问题的解决方案通常是冷冻干燥,其是费用过高的步骤。‘160专利中公开的脂质体已经克服了这些问题并且已经令人吃惊地发现这些具体的脂质体当与抗VEGF抗体(比如雷珠单抗)组合时是有效的。
尤其,包括自形成的、热力学稳定脂质体和抗VEGF抗体的制剂尤其适于治疗与VEGF相关的眼科疾病和病况时局部施用。
在本制剂中有用的脂质体包括二酰基甘油-PEG化合物。这些化合物的熔点低于约40℃并且酰基链的长度大于或等于约14个碳。这些化合物的制备如‘160专利中叙述。优选的脂质PEG缀合物是PEG-12-GDM(聚乙二醇12-甘油二肉豆蔻酸酯)。通过在脂质体的外表面产生空间屏障,PEG使脂质体稳定,PEG链的分子量在约300道尔顿和5000道尔顿之间。脂质体制备使得仅仅混合脂质与水溶液是必须的。这些种类的脂质体以最低能态存在,使得脂质可在水溶液中存在,脂质体形成的再现没有问题。
当与相同的水溶液混合时,限定的脂质、脂质混合物或脂质/化合物混合物每次将形成类似的脂质体。高于临界浓度(相对于体积的约20%重量),将在水溶液中开始形成非脂质体结构。这些脂质体以它们最低的能态存在并且是热力学稳定的、自形成的脂质体。PEG-l2GDM形成非常小的小泡,从而它们可被无菌过滤。动能,比如振动或漩涡,可提供至脂质溶液和水溶液。本制剂也可使用其他脂质-PEG缀合物,如大体上或具体在6,958,160专利中描述。另外,也可使用包括美国专利公开号2010/0076209中描述的那些化合物的其他脂质PEG自形成的、热力学稳定的缀合物。下面表1描述某些PEG-12GDM特征。
表1-PEG-12 GDM特征:
分子量:1068g/mol
最佳pH:5-7
溶解度:在有机溶剂中可溶。
在本发明的雷珠单抗局部制剂中,使用基于溶液的终体积1%重量体积的PEG-l2GDM,并且局部溶液的pH为5.5并且在脂质体的适当的工作范围内。
除了抗血管生成化合物(例如抗VEGF抗体)和热力学稳定的、自形成的脂质体,制剂可进一步包括其他药学上可接受的赋形剂。优选的赋形剂选自适于局部施用至眼睛的赋形剂。这些包括表面活性剂、缓冲液试剂、pH改性剂、盐和其他此类成分。
制剂用于治疗与VEGF相关的疾病和病况和/或其他血管生成病况。因此,本发明包括此类制剂治疗老年性黄斑变性、糖尿病视网膜疾病包括糖尿病黄斑性水肿和角膜新血管形成的用途。在优选的实施方式中,本发明包括局部制剂和包括通过局部施用此类制剂至需要其治疗的患者的眼睛来治疗此类与VEGF相关的疾病和病况的方法。
附图说明
将在下列图中描述本发明。
图1显示用脂质体雷珠单抗制剂治疗的单个患者的数据,其在每天给药六滴持续两周之后的八周内具有使用光学相干断层扫描(OCT-CFT)改善的中心凹厚度测量值。在第八周时,患者显示CFT的增加,并且在第10周以2滴每天的日剂量重新开始治疗。图1显示从第12周知第14周期间再次出现的CFT的改善。
图2显示用脂质体雷珠单抗制剂治疗的相同的临床患者在每天给药六滴持续两周之后的八周期间内具有改善的视敏度测量值(ETDRS BCVA)。在第八周,患者显示VA的降低,并且在第10周以每天2滴的日剂量重新开始治疗。图1显示从第12周至第14周期间再次出现的VA的改善。
图3显示多层脂质体和单层脂质体的显微镜图片。
图4显示用雷珠单抗的脂质体制剂治疗的患者随着时间推移的中心凹厚度的OCT结果。
图5显示随着时间的推移患者的对侧眼睛中心凹厚度的OCT结果。
图6显示三个患者中随着时间的推移研究眼睛的BCVA结果。
图7显示随着时间的推移对侧眼睛的BCVA结果。
发明详述
本发明涉及药物制剂和其用途,其中优选的制剂包括抗VEGF抗体和自形成的、热力学稳定的脂质体。本发明也涉及局部制剂,其包括抗VEGF抗体和自形成的、热力学稳定的脂质体。本发明进一步包括治疗与VEGF相关的疾病或病况的方法,其包括向需要其治疗的患者施用包括抗VEGF抗体和自形成的、热力学稳定的脂质体的制剂。在优选的实施方式中,与VEGF相关的疾病或病况选自糖尿病视网膜病变(DR)。
尽管结合各种活性成分的递送已经“大体上”描述了脂质体,但是现有技术未公开或教导自形成的、热力学稳定的脂质体结合抗VEGF抗体的组合。该制剂的脂质体尤其适于递送抗VEGF抗体至需要治疗与VEGF相关疾病或病况和尤其眼科疾病或病况的患者。本发明的脂质体制剂尤其适于局部施用至需要例如治疗糖尿病黄斑性水肿或老年性黄斑变性或角膜新血管形成的患者的眼睛。本发明的脂质体具有期望的基础特性,使得它们尤其适于这些局部制剂。脂质体悬液在制剂的温度下是热力学稳定的。组成脂质体的脂质的组分具有数个基本特性。脂质具有允许形成脂质体的包装参数(packing parameter)。脂质包括,作为头基团的一部分,聚乙二醇(PEG)或具有类似特性的聚合物,其空间上使脂质体在悬液中稳定。另外,脂质体的熔解温度使得它们当与水或水溶液混合时为液体形式。
如在6,610,322专利中描述,当在水溶液中形成脂质体悬液时需要很少或不需要添加能量。在本发明中,优选的方法涉及在存在包含活性成分——抗VEGF抗体的水溶液的情况下形成脂质体悬液。因此优选地与活性成分产生自组装(self-assembly)而不是在将活性成分添加至悬液之前。脂质分子分散并且自组装成自然低能态。脂质体形成大的或小的单层小泡(SUV)或多层小泡(MLV)(见图3)并且如在Biozone实验室网站对QusomesTM的描述。
优选地,PEG链的分子量在约300道尔顿和5000道尔顿之间。适当的脂质的例子包括PEG-12CDO(甘油二油酸酯)和PEG-12GDM(甘油二肉豆蔻酸酯)。PEG-12GDM在25℃下是流体并且具有分别为.853和.889的Pa和Pv的包装参数。这些脂质的每一个在20℃、37℃和60℃下形成自发脂质体。Pa范围可在0.84和0.88之间并且Pv在约0.88和0.93之间。优选地,适当的化合物形成脂质体而不是例如胶束。另外,脂质组分的相变温度应在约0℃和100℃之间——脂质组分的熔解温度使得当组分与水溶液混合时为液体形式。而且,组分的弯曲弹性模数应使得脂质组分可在水性环境中形式脂质体,而不需要任何或任何明显的能量输入。动能可施加至溶液。优选的弯曲弹性模数是在约0kt和15kt之间。弯曲弹性模数主要由骨架确定,并且甘油是本发明优选的骨架,尽管就弯曲弹性模数和适当的功能而言也可使用任何等价的骨架。终溶液中,按重量计脂质的相对百分数范围可从大于0至约20wt%(w/w)。该范围可在约1%和15wt%之间或在约1%和10%之间或在约1%和5%wt/wt之间或大于0%和4%wt/wt之间。
其他分子和PEG链大于12的脂质的混合物也可用于本发明,前提是它们形成脂质体。例如,PEG-45GDS(甘油二硬脂酸酯)和胆固醇的混合物形成脂质体。如在‘322专利中描述,本领域普通技术人员可改变包括PEG链长度和组分的参数,以制备热力学稳定的、自由形成的脂质体并且这些当与抗VEGF抗体结合时包括在本发明的范围内。当在脂质体形成之前,添加至脂质时胆固醇的量最多达约10%w/w。
除了‘322专利中描述的脂质,本发明也可使用其他脂质。美国专利公开号2010/0076209描述了某些PEG-LIPID缀合物,其形成适于药物递送具体描述的活性成分的脂质体。在该参考文献中没有教导或提及递送抗VEGF抗体。尤其,如‘209公开中描述的二酰基甘油-聚乙二醇化合物可在本发明的制剂中结合抗VEGF抗体来使用。脂质化合物的一般结构显示在‘209公开中并且包括具有式(R2)(R1)甘油-X-PEG-R1和/或R1-PEG-X-甘油(R2)(R1)的化合物,其中R1优选地是-OH或-OCH3;R2和R3是脂肪酸,包括但不限于月桂酸酯、油酸酯、豆蔻酸酯、棕榈酸酯、硬脂酸酯和亚油酸酯;和X表示脂质和PEG之间的单个连接体或重复的连接体或两个或更多个连接体的组合。R2和R3可以相同或不同。如果R2在甘油的C1位,那么R3可位于C2或C3处。一般结构包括所有的外旋体和结构异构体和/或其功能等价物。
R1也可选自例如-NH2、-COOH、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2OH、-COCH=CH2、-OCH2CH2NH2、-OSO2CH3、-OCH2C6H6、-OCH2COCH2CH2COONC4H4O2、-CH2CH2=CH2和-OC6H6。而且Rl可以是帮助将治疗性或靶向试剂连接至脂质体表面的官能团。这些可包括氨基烷基酯、马来酰亚胺、缩水甘油醚、马来酰亚胺丙酸酯、氨基甲酸甲酯、甲苯磺酰基腙盐、叠氮化合物、炔丙基-胺、炔丙基醇、NHS酯、酰肼、琥珀酰亚胺基酯、琥珀酰亚胺基酒石酸酯、琥珀酰亚胺基琥珀酸酯和甲苯磺酸盐。本发明包括具有在脂质体组分中的抗VEGF抗体的脂质体制剂并且可进一步包括任何其他治疗性化合物,包括经R1官能团共价键合或连接至脂质体的抗VEGF抗体。在该情况下,本发明包括或是具有非共价键合的活性成分和共价键合的活性成分的组合制剂或制剂,其中所述活性成分可以相同或不同。
用于或适合于该类型脂质体制剂的连接体包括在‘209公开中描述的那些,并且其通过参考并入本文。其中的表1描述或列举了这种适当的连接体并且其包括氨基、琥珀酰氨基、乙酰氨基、2-氨基戊酰氨基(aminopentanamido)、2(2’)-R’-氨基乙酰基等。在每种情况下,脂质在20和37℃下形成自发脂质体,如‘209公开的表4所显示。本发明因此包括描述为PEG-12-N1-GDO、PEG-23-N2-GDO、PEG-18-N3-GDO、PEG-23-N4-GDO、PEG-8-S1-GDO、PEG-18-S2-GDO、PEG-12-S3-GDO、PEG-18-Acl-GDO、PEG-12-Ac2-GDO、PEG-12-N1-GDM、PEG-12-N1-GDLO、PEG-12-S3-GDM、PeG-12-S3-GDLO、PEG-12-Ac2-GDM、PEG-12-Ac2-GDLO、PEG-23-N1-GDL、PEG-12kNl-GDP、PEG-23-Ac2-GDL和PEG-12-Ac2-GDP的那些脂质。GDLO意思是甘油二亚油酸酯和GDP意思是甘油二棕榈酸酯。每种化合物在25℃下是是流体并且包装参数Pa范围从.830至.869和Pv范围从0.872至0.924。
本发明进一步包括符合本文叙述的物理要求的已知的脂质并且其,例如,在25℃下是液体并且在20℃和37℃下自形成,并且具有功能上等同的或等价的包装参数以及当与水溶液结合时少量或不用能量输入而形成热力学稳定的脂质体。
用于本制剂的抗VEGF抗体包括任何已知的抗VEGF抗体。这些抗体包括整个抗体或抗体片段,前提是它们具有必要的抗VEGF生物特性。在优选的实施方式中,抗体是具有必要的抗VEGF生物和药理学特性的抗体片段。美国专利号6,884,879公开了用于本发明的抗VEGF抗体。这种抗体包括具有包括对VEGF强的结合亲和力的特性的人源化的抗VEGF抗体和抗VEGF抗体变体;抑制VEGF的能力促进内皮细胞的增殖并且抑制VEGF的能力诱导血管生成。对于体外抑制VEGF诱导的内皮细胞增殖,优选的结合亲和力(Kd)不大于约5×10-9M并且ED50值不大于约5nM。抗体包括在A673体内肿瘤模型中以5mgs/kg的抗体剂量抑制至少约50%肿瘤生长的那些。最优选的抗体以商标名(雷珠单抗)售卖并且作为玻璃体内制剂批准用于治疗老年性黄斑变性和各种形式的黄斑性水肿。术语“抗VEGF抗体”包括整个抗体以及抗体片段。可用抗VEGF抗体治疗的疾病的范围包括与血管生成或病理学血管生成病况相关的那些疾病或病况。这些包括癌症以及眼内新生血管综合症,比如增生性视网膜病或老年性黄斑变性(AMD)、风湿性关节炎和牛皮癣。尽管优选的施用途径是局部治疗眼睛和优选的疾病形式是糖尿病黄斑性水肿,本文叙述的制剂也可用于其他递送方式(即,可注射的、静脉内输注)和治疗一连串与VEGF相关的疾病和病况。
抗VEGF抗体包括由分离的编码亲本抗VEGF抗体的人源化变体的核酸产生的那些,该亲本抗体包括非人可变区,其中所述人源化的变体结合人VEGF并且具有那些重链互补决定区氨基酸序列,如6,884,879专利中描述和要求保护的,其通过参考并入本文。抗VEGF抗体包括可使用具有编码这种CDR氨基酸序列的核酸的载体和包含这种载体的分离的宿主细胞产生的那些。可培养宿主细胞,以产生这些序列并且可从这些宿主细胞培养物中回收人源化的抗VEGF抗体。上述分离的核酸可进一步编码具有轻链互补决定区(CDR)的人源化的变体,那些序列如在‘879专利中叙述。这种人源化的变体可包括具有如‘879专利中SEQ ID NO:7显示的序列的重链可变区和具有如SEQ IDNO:8显示的序列的轻链可变区。这种人源化的变体也可包括如’879专利中显示的SEQ ID NO:116的重链可变区序列和SEQ ID NO:115的轻链可变区序列。
美国专利号7,060,269也通过参考并入本文。该专利要求保护和公开了雷珠单抗。‘269专利的权利要求1要求保护抑制受试者中VEGF诱导的血管生成的方法,其包括向所述受试者施用有效量的以不大于约1x 10-8的Kd值结合人VEGF的人源化的抗VEGF抗体,所述人源化的抗VEGF抗体包括SEQ IDNO:116的重链可变区序列和SEQ ID NO:115的轻链可变区序列。雷珠单抗是设计用于眼内使用的重组体人源化的IgG 1κ同种型单克隆抗体片段。该单克隆抗体结合和抑制人血管内皮生长因子A(VEGF-A)。雷珠单抗的分子量为约48,000道尔顿并且在包含四环素的营养培养基的大肠杆菌表达系统中产生。该产品以商标名商业上可获得的并且在单次使用的玻璃小瓶中提供为无防腐剂、无菌溶液,其可递送0.05mL的10mg/mL雷珠单抗水溶液,以及10mM组氨酸HCl、10%α,α海藻糖脱水物、0.01%聚山梨醇酯20并且pH为5.5。
雷珠单抗由Chen等描述在1999年出版的科学期刊《分子生物学(JMB)期刊》中,题目为“选择和分析优化的抗VEGF抗体:与抗原复合物的亲和性-成熟的Fab的晶体结构(Selection and Analysis of an Optimized Anti-VEGFantibody:Crystal Strucutre of an Affinity-matured Fab in complex with Antigen)”5(Chen等,JMB,293:865-881(1999)。在该文章中,雷珠单抗的重链和轻链序列命名为YO317,并且显示在其中的图1中。除了该描述,该文章也提供了有关该抗体片段与VEGF的结合亲和力的数据(其870页上的表6)。已知雷珠单抗结合和抑制VEGF-A的生物活性,所述VEGF-A造成眼睛血管生成模型中新血管形成和渗漏。雷珠单抗结合和抑制VEGF-A并且防止VEGF-A与内皮细胞的表面上的VEGF受体相互作用,并因此减少新血管形成(血管生成)、血管渗漏和内皮细胞增殖。施用药学上有效量的雷珠单抗抑制VEGF诱导的血管生成。术语抗VEGF抗体包括全长抗体和抗体片段,比如Fab、Fab’、F(ab)2和Fv,前提是所述片段通过结合人VEGF显示期望的药理学活性。雷珠单抗与VEGF的的结合亲和力(Kd)不大于约1×10-8M,即约1.4×10-10(见Chen等,870页)。‘269专利的图10A和10B提供雷珠单抗的轻链可变区和重链可变区的序列(如Chen等显示的Fab Y0317)。这些序列与‘269专利的SEQ ID NO:115和SEQ ID NO:116相同。
除了在上述文章和专利中描述的雷珠单抗和其他抗VEGF抑制剂或药物,另外的抗VEGF或抗血管生成药物也可用于本制剂中。尽管本发明人已经公开了在治疗涉及向具有健康的角膜或微小新血管形成的角膜但是具有一些其他眼睛病况(例如老年性黄斑变性或糖尿病黄斑性水肿)的患者的眼睛局部施用的疾病和病况的脂质体制剂中抗体片段是优选的抗VEGF抗体,但是包括整个抗VEGF抗体和自形成的、热力学稳定的脂质体的制剂也用于治疗角膜新血管形成和这些其他眼睛疾病(在具有两种疾病的患者),前提是角膜新血管形成允许或加速大的整个抗体和其制剂进入。完整的或整个抗VEGF抗体的例子由Genentech以商标名(贝伐单抗)售卖。该抗体是重组人源化的IgG1抗体,其抑制VEGF的生物活性。其包含人框架区和结合VEGF的鼠抗体的互补决定区,并且分子量为约149kD。该抗体在包含庆大霉素的营养培养基的哺乳类细胞(中国仓鼠卵巢细胞)表达系统中产生。美国专利号6,054,297(通过参考以其整体并入本文)要求保护和公开了贝伐单抗或制造贝伐单抗的方法(见其中权利要求1、6、7、8、9、10、12、29和30)。
如在批准的产品包装插入物中描述,贝伐单抗是重组体人源化的单克隆IgGl抗体,其在体外和体内试验系统中结合和抑制人血管内皮生长因子的生物活性。该抗体包含结合VEGF的鼠抗体的人框架区6(见L.G.Presta等(1997)Cancer Res)57:4593-99)。贝伐单抗的分子量是约149千道尔顿。该文章公开了人源化的F(ab)抗体片段,“F(ab)l-12”的可变区的相互作用。贝伐单抗具有源自鼠抗体的序列的非人CDR以及在轻链(VL)46位和重链(VH)49、69、71、73、78和94的可变区中与F(ab)-12对应位置显示的替换相同的框架替换,如Presta等的图1中显示。Presta等具有关于贝伐单抗的分子特征和结合特征的信息。
如之前叙述,除了雷珠单抗和贝伐单抗,本发明也可使用其他已知的抗VEGF抗体或抗血管生成药物。如在引用的专利文献中描述以相同方式制备本发明的抗VEGF抗体。一般而言,分离的编码抗体的核酸、载体(其包括可操作地连接至由载体转化的宿主细胞的控制序列的核酸)、具有所述载体的宿主细胞都共同用于在培养所述细胞和收集和纯化抗体之后产生感兴趣抗体的方法。任何适当的药学赋形剂可添加至抗体并且抗体也可根据需要冻干。“抗VEGF抗体”包括各种形式并且可以是具有完整人Fc区的全长或抗体片段,例如Fab、Fab’或F(ab’)2。适于和本文公开的脂质组合以形成脂质体制剂的其他抗血管生成药物包括派加他尼(pegaptanib)或依那西普(etanercept)(TNF抑制剂)。在后者的情况下,该制剂可用于治疗各种自身免疫性疾病或病况。依那西普以商标名售卖,其用于治疗风湿性关节炎、幼年风湿性关节炎和银屑病关节炎、斑块牛皮癣和强直性脊柱炎。其他适当的药物包括舒尼替尼(一种VEGF和PDGF受体蛋白质激酶和血管生成抑制剂(以名售卖的2-羟吲哚)并且其在美国专利号6,573,293中描述并且要求保护,其通过参考并入本文))或FOVISTATM(之前称为EI0030,一种血小板衍生生长因子B(PDGF-B)的调节剂(1.5mgs/.5mgs雷珠单抗))。组合中使用的其他适当的药物包括干扰素-α-2a或西罗莫司脂化物(temsirolimus)或其他mTOR抑制剂,比如雷帕霉素。可用于组合的用于眼睛疾病的药物类型也包括蛋白酶体抑制剂、自噬抑制剂、类维生素A、溶酶体抑制剂、热休克应答激活剂、Hsp90伴侣蛋白抑制剂、蛋白质运输抑制剂、糖苷酶抑制剂、酪氨酸激酶抑制剂和组蛋白脱乙酰酶抑制剂。这些药物可在脂质体制剂中单独使用或可用于与抗VEGF化合物或抗体的组合制剂或可用于连续组合和优选地用于局部制剂。当结合FOVISTATM(0.03-3.0mgs/眼睛,与0.5mg雷珠单抗或其他抗VEGF化合物结合)(和/或具有PDGF抑制活性的其他药物)和雷珠单抗时,优选的适应症是治疗老年性黄斑变性。阿柏西普(aflibercept)(2.0mgs/0.05mL)(EyleaTM)也可单独或结合雷珠单抗或其他活性成分用于脂质体制剂。本发明进一步包括如本文叙述的局部脂质体制剂,包括FOVISTA和阿柏西普和/或任何其他抗血管生成药物,前提是至少一种活性成分掺混/结合本发明热力学稳定的、自形成的脂质体。FOVISTA(一种针对PDGF-B的适配体)也在美国专利公开号2012/0100136中描述并且称为“拮抗物(Antagonist)A”,其通过参考以其整体并入本文。拮抗物A的合成描述在‘136公开的实施例4中(也见其中的图7)。当至少一种试剂与本文所述的形成热力学稳定的、自形成的脂质体的脂质配制时,其中描述的每个个体VEGF拮抗物和PDGF拮抗物也包括在本发明的范围内。通过玻璃体内注射施用时,具有本文叙述的任何一种或任何组合的活性成分的局部制剂优于该药物或其组合。另外,对于眼睛疾病,局部施用至眼睛优于全身性口服施用。作为脂质体制剂或脂质体制剂和/或任何其他组合的制剂,本发明使用的组合物包括(a)(PDGF抑制剂)ARC-127、拮抗物A、拮抗物B、拮抗物C、拮抗物D、1B3抗体、CDP860、IMC-3G3、伊马替尼、162.62抗体、163.31抗体、169.14抗体、169.31抗体、αR1抗体、2A1E2抗体、M4TS.11抗体、M4TS.22抗体、A10、布雷非德菌素A、舒尼替尼、Hyb 120.1.2.1.2抗体、Hyb121.6.1.1.1抗体、Hyb 127.5.7.3.1抗体、Hyb 127.8.2.2.2抗体、Hyb 1.6.1抗体、Hyb 1.11.1抗体、Hyb 1.17.1抗体、Hyb 1.18.1抗体、Hyb 1.19.1抗体、Hyb 1.23.1抗体、Hyb 1.24抗体、Hyb 1.25抗体、Hyb 1.29抗体、Hyb 1.33抗体、Hyb 1.38抗体、Hyb 1.39抗体、Hyb 1.40抗体、Hyb 1.45抗体、Hyb 1.46抗体、Hyb 1.48抗体、Hyb 1.49抗体、Hyb 1.51抗体、Hyb 6.4.1抗体、F3抗体、人源化的F3抗体、Cl抗体、人源化的C1抗体、6.4抗体、抗mPGDF-C山羊IgG抗体、C3.1抗体、5-甲基-7-二乙基氨基-s-三唑并(l,5-a)吡啶、干扰素、鱼精蛋白、PDGFR-B 1单克隆抗体、PDGFR-B2单克隆抗体、6D11单克隆抗体、S is 1单克隆抗体、PR7212单克隆抗体、PR292单克隆抗体、HYB9610单克隆抗体、HYB 9611单克隆抗体、HYB 9612单克隆抗体、HYB 9613单克隆抗体、4-(2-(N-(2-甲酰胺基-吲哚)氨乙基)-苯磺酸盐、4-(2-(N-(-2-甲磺酰吲哚)氨乙基)-磺酰脲类、CGP 53716、人抗体gl62、吡唑并[3,4-g]喹喔啉、6-[2-(甲基氨甲酰基)苯基硫基]-3-E-2-(吡啶-2-基)乙烯基]-吲唑、1-{2-[5-(2-甲氧基-乙氧基)-苯并咪唑-1-基]-喹啉-8-基}-哌啶-4-基胺、4-{4-[N-(4-硝基苯基)氨甲酰基]-1-哌嗪基}-6,7-二甲氧基喹唑啉、4-氨基-5-氟-3-(6-(4-甲基-哌嗪-l-基)-lH-苯并咪唑-2-基)1H-喹啉-2-酮、(4-叔丁基苯基){4-[(6,7-二甲氧基-4-喹啉基)氧基]苯基}甲烷酮、5-甲基-N-[4-(三氟甲基)苯基]-4-异唑(izoxazole)甲酰胺、反式-4-[(6,7-二甲氧基喹喔啉-2-基)氨基]环己醇、(Z)-3-[(2,4-二甲基-5-(2-氧-l,2-二氢吲哚-3-基茚甲基)-1H-吡咯-3-基)-丙酸、5-(5-氟-2-氧-1,2-二氢吲哚-3-基茚甲基)-2,4-二甲基-1H-吡咯-3-羧酸、l-(4-氯苯胺基)-4-(4-吡啶基甲基)二氮杂萘、N-{4-(3-氨基-lH-吲唑-4-基)苯基-N”-(2-氟-5-甲基苯基)尿素、l,2-二甲基-7-(2-噻吩)咪唑[5,4-g]喹喔啉、1,2-二甲基-6-苯基-咪唑并[5,4-g]喹喔啉、l,2-二甲基-6-(2-噻吩)咪唑并[5,4-g]喹喔啉、AG1295、AG1296、3-芳基喹啉、4-吡啶基-2-芳基嘧啶、索拉非尼、MLN518、PKC412、ΑΜΝ107、苏拉明、新霉素或其药学上可接受的盐和(b)(VEFG抑制剂)雷珠单抗、贝伐单抗、阿柏西普、KH902VEGF受体-Fe融合蛋白质、2C3抗体、ORA102、派加他尼、贝伐西尼(bevasiranib)、平端贝伐西尼、SIRNA-027、前胡素、前胡醇、鬼臼苦素、没药固酮、PLG101、类花生酸LXA4、PTK787、帕唑帕尼、阿西替尼、CDDO-Me、CDDO-Imm、紫草素、β羟基异戊酰紫草素、神经节苷脂GM3、DC101抗体、Mab 25抗体、Mab73抗体、4A5抗体、4E10抗体、5F12抗体、VA01抗体、BL2抗体、BECG-相关的蛋白质、sFLT0l、sFLT02、肽B3、TG100801、索拉非尼、G6-31抗体或抑制与VEGF相关血管生成的其他化合物。除了抗体,适于治疗眼科疾病或病况(包括眼睛前部的疾病,比如角膜疾病或由于外科切口需要的愈合、创伤或溃疡)的其他基于蛋白质的活性成分包括例如人生长激素或其他已知的激素肽或其变体。
通过下述一般的步骤以任何顺序制备脂质体制剂:(1)提供包含抗VEGF抗体和/或如上述其他活性物的水溶液;(2)添加能够形成脂质体的热力学稳定的、自形成的脂质至步骤(l)的所述水溶液和(3)任选地添加药学上可接受的赋形剂。可使用制备脂质体悬液制剂的方法的任何变化,包括结合抗VEGF抗体(或VEGF抑制剂或PDGF抑制剂)和脂质和然后添加水溶液或分别添加每种成分至水溶液。基于期望的递送途径(例如局部等)制备悬液并且也基于这种途径选择另外的赋形剂。载体、稳定剂和或赋形剂包括缓冲液,比如磷酸盐、柠檬酸盐或其他无机酸;抗氧化剂,比如抗坏血酸和/或甲硫氨酸;防腐剂;低分子量多肽;蛋白质,比如明胶、血清白蛋白或免疫球蛋白;亲水性聚合物比如PVP;氨基酸;单糖或二糖或其他碳水化合物;螯合剂;糖;成盐抗衡离子、非离子表面活性剂等。脂质体制剂也可以为溶液的形式。
制剂用于治疗与VEGF相关的疾病和不适。本文所述的制剂治疗的优选的疾病或病况是眼睛疾病。如上述,本发明的优选的疾病或病况是治疗糖尿病黄斑性水肿。如上提到的,DME源自一系列生物化学和细胞事件,其最终造成进行性渗漏和渗出,导致视网膜增厚和在斑点的中心一disc直径内形成硬渗出物。激光凝固(Laser photocoagulation)是主要的治疗并且有效防止中度视力丧失的风险约505[ETDRSG.1985]。激光凝固导致改善阅读线分数但是具有相关的并发症,比如进行性扩大的伤疤、中心盲点、下降的对照灵敏度和受损的色彩视力。
脂质体制剂可广泛治疗与VEGF和/或PDGF相关的肿瘤或视网膜不适或任何其他眼科疾病或病况,这取决于具体的活性成分。抗VEGF抗体抑制由VEGF造成的一种或多种生物活性。治疗性应用涉及向需要治疗具体疾病或病况的患者施用药学上可接受的给药形式。尽管优选局部给药形式,但是适当的给药形式也可包括通过如推注的静脉内方式或通过连续注入;肌肉内、腹腔内、脑脊内、皮下、关节内、滑膜内、鞘内、口服或通过吸入施用。另外,这种抗体制剂也可通过瘤内、瘤周围、病灶内或病灶周围途径施用。适合用抗体制剂治疗的肿瘤性疾病包括各种癌,包括乳腺癌、肺癌、胃癌、食道癌、结直肠癌、肝癌、卵巢癌、男性细胞瘤(arrhenoblastomas)、宫颈癌、子宫内膜癌、子宫内膜增生、子宫内膜异位、纤维肉瘤、绒毛膜癌、头颈癌、鼻咽癌、喉癌、肝胚细胞瘤、卡波西氏肉瘤、黑素瘤、皮肤癌、血管瘤、海绵状血管瘤、血管母细胞瘤、胰腺癌和其他类型的癌症。与VEGF相关的非肿瘤性病况包括风湿性关节炎、牛皮癣、动脉粥样硬化、糖尿病和其他增生性视网膜病(包括早产儿视网膜病、晶状体后纤维组织增生、新生血管性青光眼、老年性黄斑变性、糖尿病黄斑性水肿和其他形式的黄斑性水肿)、甲状腺增生(包括格雷夫斯病(Grave’s disease))、角膜和其他组织移植、慢性炎症、肺炎症、肾综合症、先兆子痫、腹水、心包积液和胸腔积液。用优选的局部制剂治疗的优选的病况或疾病是糖尿病黄斑性水肿。剂量施用和施用频率取决于疾病的类型和严重程度以及具体的患者的病况。例如,抗VEGF抗体可以以1μg/kg至约50mg/kg或约0.1-20mg/kg的剂量范围施用至需要其治疗的患者。治疗DME的优选的剂量方案,以及就雷珠单抗的局部制剂描述在本文的实施例3中。活性成分的浓度和量可取决于具体的患者和治疗的天数而改变,并且每天或周或月提供的量也可取决于患者的应答以及视敏度和视网膜增厚二者改善的征兆而改变。
对于治疗DME或其他与VEGF相关的眼睛病况的目的,理想的治疗模态是导致快速和长期持续视力改善的模态。目前治疗DME使用的其他治疗模态包括选择性PKCβ抑制剂(鲁伯斯塔)、类固醇类(曲安奈德、醋酸氟轻松(fiuocinolone acetonide))、VEGF抑制剂(贝伐单抗、雷珠单抗和哌加他尼-注射剂)和玻璃体切除术。本脂质体制剂提供局部治疗方案,其是相对于例如目前市面上的玻璃体内制剂的显著改善。本制剂可与其他已知的用于眼睛或本文叙述的和/或如上述与VEGF相关的疾病或病况的治疗组合使用并且没有禁忌症。此类治疗方案或治疗性方法包括例如siRNA分子比如贝伐西尼和适当的递送媒介,包括本发明中使用的热力学稳定的、自形成的脂质体。
可单独或结合任何其他活性成分用于脂质体制剂的眼科类固醇类包括地塞米松、氟轻松、氯替泼诺、醋丁二氟龙、丙酮缩氟氢羟龙、去氢氢化可的松、甲羟松、曲安奈德、利美索龙和其各种盐形式。其他眼科抗炎剂(例如NSAID)也可用于脂质体制剂。取决于活性成分,可使用除了热力学稳定的自形成的脂质体之外的其他脂质体或其替代物。
下述实施例旨在进一步阐释本发明的某些实施方式并且是非限制性的:
实施例
实施例1-脂质体和雷珠单抗的溶液
获得包含0.5mg的浓度为10mg/mL(0.05mL)的雷珠单抗的小瓶。将0.015克的PEG-12甘油二肉豆蔻酸酯(PEG-12GDM)QsomesTM添加至该溶液(PEG之后的数值表示PEG链中C2H4O亚单位的数量)。使用由磷酸盐、氯化钠和polioxyl 40硬脂酸酯组成的1.45ml的缓冲液,将该脂质体悬液的体积稀释至1.5mL的终体积,以提供脂质体悬液中0.333mg/mL的雷珠单抗浓度和约1%的脂质百分数(10mg/mL)。作为防腐剂添加过硼酸钠(0.28mg/mL)。1ml的该悬液等于20滴。每滴包含约17μg的雷珠单抗。
通过结合15ml聚乙二醇40硬脂酸酯、氯化钠、偏磷酸钠和磷酸二氢钠溶液与5mL的过硼酸钠溶液制备缓冲液(V=20mL,pH 5.5)。然后,如上描述使用1.45mL的该溶液。眼科脂质体悬液制剂中每种赋形剂的浓度是0.142mg/mL(磷酸氢二钠);6.7mg/mL(偏磷酸钠);50mg/mL(polioxil 40硬脂酸酯);5.1mg/mL(氯化钠);0.333mg/mL(雷珠单抗);10mg/mL(PEG-12GDM)和2.8mg/mL(过硼酸钠)。可用HCl或NaOH调节pH并且也可使用低分子量氨基酸或有机酸。图3显示当脂质与水溶液混合时形成的至少两种脂质体()(来自Biozone实验室网站)。
实施例2-兔子角膜中的扩散腔研究
使用下述方法产生施加至兔子角膜的脂质体制剂的扩散腔数据。为了总结,在第10、20和30分钟和1、2、3、4、5、6和24小取样。数据显示在34℃下对于局部施用的脂质体雷珠单抗制剂,有大量比例的渗透进入兔子角膜的水性体液。在脂质体制剂中,在第3小时开始鉴定雷珠单抗并且在施用后24小时保持存在,相比之前对兔子非脂质体制剂报道的7和14天(数据未显示,参见Chen等,Eye London 2011Nov;25(l1):1504-11)。实验在具有水平流的玻璃Valia-Chen腔中进行。水在34℃的温度下循环。将膜放置在腔的接口之间,并且在该实施例中,兔子角膜用作该膜。用3.2mL的生理盐水溶液填充受体腔,以刺激眼睛前部分的水性体液的内容物。为供体腔提供3mL眼科制剂,其包括雷珠单抗和热力学稳定的、自形成的脂质。持续搅拌扩散腔。在不同的时间点从受体腔收集样品,取样400μL并且每次用400μL的生理盐水溶液替换。在下述时间点取样:10min、20min、30min、1hr、2hr、3hr、4hr、5hr、6hr和24hr。在早至第3小时通过HPLC检测雷珠单抗。用作HPLC标准的对照溶液。电泳也用于评估脂质体制剂穿过兔子角膜并且结果与HPLC数据一致。
实施例3-对具有DME的患者的先导临床研究
用每三小时1滴制剂按天计治疗患DME的一位患者六次/天(6×/天),持续两周。每天雷珠单抗的总剂量是6×17ug或102ug。在该两周时间之后的六周中,观察到平均中心凹厚度(CFT)的改善和视敏度的增加(见图1和图2)。在第八周出现视网膜厚度的增加和视觉敏锐性下降,并且在第10周,以每天两滴(34ug/天)重新开始治疗。在第14周OCT明显趋于改善并且观察到BCVA(见图1和2)。也使用相同的方案治疗两个另外的患者。所有三名患者的结果呈现在图4-7中并且显示CFT和VA相对于对照的改善。
实施例4-使用曲安奈德对具有DME的患者的先导临床研究
在单中心开放标签的先导研究中,合格的患DME的患者接收包括曲安西龙(TA)的局部制剂。3名DME患者(平均年龄58年,范围53-64)的总共3只眼睛涉及中心斑点和使用ETDRS测试,研究的眼睛中最佳校正视敏度(BCVA)在65和40字母之间。在十二(12)周的对照治疗期间,指导患者当他们醒着时在研究的眼睛中每两小时施用一滴包含133ug(微克)的TA(六次)。主要结果测量包括在三个月的主要试验评估指标,比如眼睛和全身性不利事件的频率和严重程度,以及中心凹厚度(CFT)从基线的变化,如随着时间的推移通过光学相干断层扫描(OCT)测量。第二结果是随着时间的推移从基线BCVA分数的改变、眼底照片(FP)上视网膜病严重程度从ETDRS基线具有>3-步发展的患者的比例、荧光素血管造影(FA)上可辨析渗漏和随着时间的推移需要黄斑性激光治疗的患者的比例。以与雷珠单抗制剂类似的方式由商业上可获得的启示原料来制备TA制剂。
曲安西龙+1%脂质体眼科悬液
终制剂是无菌的水悬液,其含量如下:
PEG-12-GDM:脂质体;二酰甘油-聚乙二醇(PEG 12),甘油二肉豆蔻酸酯(GDM)。
*TA是终产品。其是微粒化的TA(约12mm)并且不含防腐剂。
曲安西龙+1%脂质体眼科悬液的制备方案
1.将40%的终体积的蒸馏水放入烧杯中并且将其加热至70至80℃。
2.添加羟丙基甲基纤维素并且停止混合直到达到室温并且其变成透明和均质混合物。
3.将其高压灭菌并且一旦无菌使其搅拌达到室温。
4.将40%的终体积蒸馏水放入另一烧杯中。一个一个添加和混合下述试剂直到完全溶解:
a)磷酸二氢钠
b)磷酸氢二钠
c)EDTA
d)氯化钠
e)聚山梨醇酯80
5.在10%的剩余体积的水中,添加50%的苯扎氯铵并且混合直到完全溶解。一旦溶解,将该新溶液添加至上述包含磷酸盐、EDTA、氯化钠和聚山梨醇酯80的溶液。为了无菌,通过0.22μm膜过滤。
6.将羟丙基甲基纤维素的无菌溶液与包含盐和防腐剂苯扎氯铵的其他无菌溶液混合并且混合直到获得透明均质混合物。
7.将曲安西龙乙酸酯添加至具有缓冲液和苯扎氯铵的溶液并且搅拌直到完全溶解。
8.将脂质体添加至该混合物并且用磁力搅拌器搅拌15分钟以获得终悬液。
9.将悬液包装在专用滴眼管中。每个滴眼管瓶子包含1.5ml的该曲安西龙眼科悬液。
结果:包括脂质体制剂中的TA的局部制剂在具有中心涉及临床明显的DME的患者中的用途良好耐受。既没有报道眼睛不利事件也没有报道全身性不利事件。在第2个月,所有三名患者的CFT相对于基线下降。三名患者的两名的CFT下降至少100um。在第三个月,所有三名患者显示视敏度改善。一名患者获得>15个字母。
尽管已经详细描述了本发明并且参考其具体的实施方式,对于本领域普通技术人员显而易见,在不背离本发明的精神和范围的情况下,可对本发明作出各种改变和修饰。因此,例如,本领域技术人员使用常规实验认识到或能够知道本发明未明确描述的许多实施方式。此类实施方式在本发明的范围内。
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Claims (50)
1.水性制剂,其包括抗血管生成药物和由基于PEG的脂质形成的热力学稳定的、自形成的脂质体,其中所述脂质的重量百分数小于约20%wt/wt。
2.根据权利要求1所述的制剂,其中所述抗血管生成药物是选自雷珠单抗或贝伐单抗的抗VEGF抗体。
3.根据权利要求1所述的制剂,其中所述热力学稳定的、自形成的脂质体包括分子量在约300至约5,000道尔顿之间的PEG链,并且由在25℃下是流体且在20℃和37℃的水溶液中自形成的脂质形成。
4.权利要求1所述的制剂,其中所述制剂是局部制剂。
5.权利要求4所述的制剂,其中所述抗VEGF抗体是雷珠单抗。
6.权利要求5所述的制剂,其中形成所述热力学稳定的、自形成的脂质体的所述脂质选自在25℃下是流体、包括分子量在约300至约5,000道尔顿之间的PEG链并且在20℃和37℃的水溶液中自形成的脂质。
7.权利要求6所述的制剂,其中所述脂质选自PEG-12GDM或PEG-12GDO。
8.根据权利要求1的药学制剂用于在需要其的这种治疗的患者中治疗与VEGF相关的疾病或病况的用途。
9.根据权利要求8所述的用途,其中施用至所述患者的所述抗VEGF抗体的日或周剂量范围从约1μg/kg至约50mg/kg。
10.治疗与VEGF相关疾病或病况的方法,其包括向需要其治疗的患者施用药学上有效量的药物制剂,其包括抗VEGF抗体和热力学稳定的、自形成的脂质体。
11.根据权利要求10所述的方法,其中所述抗VEGF抗体选自雷珠单抗或贝伐单抗,
12.根据权利要求10所述的方法,其中形成所述热力学稳定的、自形成的脂质体的脂质在25℃下是流体并且包括分子量在约300和约5,000道尔顿之间的PEG链,并且在20℃和37℃的水溶液中自形成。
13.根据权利要求12所述的方法,其中所述制剂是局部制剂。
14.根据权利要求12所述方法,其中所述脂质选自PEG-12GDM或PEG-12GDO。
15.根据权利要求10所述的方法,其中所述与VEGF相关的疾病或病况选自肿瘤性或非肿瘤性疾病或病况。
16.根据权利要求15所述的方法,其中所述肿瘤性疾病或病况选自乳腺癌、肺癌、胃癌、食道癌、结直肠癌、肝癌、卵巢癌、男性细胞瘤、宫颈癌、子宫内膜癌、子宫内膜增生、子宫内膜异位、纤维肉瘤、绒毛膜癌、头颈癌、鼻咽癌、喉癌、肝胚细胞瘤、卡波西氏肉瘤、黑素瘤、皮肤癌、血管瘤、海绵状血管瘤、血管母细胞瘤、胰腺癌和其他类型的癌症。
17.根据权利要求15所述的方法,其中所述非肿瘤性疾病选自风湿性关节炎、牛皮癣、动脉粥样硬化、糖尿病和包括早产儿视网膜病、晶状体后纤维组织增生、新生血管性青光眼、老年性黄斑变性,糖尿病黄斑性水肿和其他形式的黄斑性水肿的其他增生性视网膜病、包括格雷夫斯病的甲状腺增生、角膜和其他组织移植、慢性炎症、肺炎症、肾综合症、先兆子痫、腹水、心包积液和胸腔积液。
18.根据权利要求17所述的方法,其中所述疾病或病况选自老年性黄斑变性、糖尿病黄斑性水肿或角膜新血管形成。
19.局部眼科制剂,其适于施用至需要其治疗的患者的眼睛,包括抗VEGF抗体和热力学稳定的、自形成的脂质体。
20.根据权利要求19所述的制剂,其中所述抗VEGF抗体选自雷珠单抗或贝伐单抗。
21.根据权利要求20所述的制剂,其中所述热力学自形成的脂质体由在25℃下是流体、包括分子量在约300和约5,000道尔顿之间的PEG链并且在20℃和37℃的水溶液中自形成的脂质形成。
22.根据权利要求23所述的制剂,其中所述脂质是PEG-12GDM或PEG-12GDO。
23.滴眼液,其包括
(a)雷珠单抗和
(b)热力学稳定的、自形成的脂质体,其由基于PEG的脂质形成并且重量百分数小于约20%wt/wt。
24.根据权利要求23所述的滴眼液,其中所述雷珠单抗以约0.01至1.0mg/mL的浓度范围存在。
25.根据权利要求24所述的滴眼液,进一步包括药学上可接受的赋形剂和/或试剂。
26.根据权利要求25所述的滴眼液,其中所述滴眼液的pH是约4.5至约7.5。
27.根据权利要求23所述的滴眼液,其中所述脂质以约5至约25mg/mL的浓度范围存在。
28.根据权利要求27所述的滴眼液,其中所述脂质的浓度是约10mg/mL。
29.治疗具有糖尿病黄斑性水肿的患者的方法,其包括向患者受影响的眼睛局部施用药学上有效量的根据权利要求23-28的滴眼液。
30.根据权利要求29所述的方法,其中向所述患者施用的雷珠单抗的日剂量是约10μg至约125μg/天。
31.根据权利要求30所述的方法,其中所述剂量每3小时6x/天施用并且雷珠单抗的剂量是约15-20μg/剂。
32.根据权利要求31所述的方法,其中所述约15-20μg剂量的6x/天施用在两周时间内施用,并且然后基于QD或BID,根据需要其后以小于约50μg的总的日剂量施用。
33.局部制剂,其包括:
(a)VEGF抑制剂,
(b)PDGF抑制剂;和
(c)热力学稳定的、自形成的脂质体。
34.根据权利要求33所述的制剂,其中所述PDGR抑制剂(a)和所述VEGF抑制剂(b)选自(a)ARC-127、拮抗物A、拮抗物B、拮抗物C、拮抗物D、1B3抗体、CDP860、IMC-3G3、伊马替尼、162.62抗体、163.31抗体、169.14抗体、169.31抗体、αR1抗体、2A1E2抗体、M4TS.11抗体、M4TS.22抗体、A10、布雷非德菌素A、舒尼替尼、Hyb 120.1.2.1.2抗体、Hyb 121.6.1.1.1抗体、Hyb 127.5.7.3.1抗体、Hyb 127.8.2.2.2抗体、Hyb 1.6.1抗体、Hyb 1.11.1抗体、Hyb 1.17.1抗体、Hyb 1.18.1抗体、Hyb 1.19.1抗体、Hyb 1.23.1抗体、Hyb 1.24抗体、Hyb 1.25抗体、Hyb 1.29抗体、Hyb 1.33抗体、Hyb 1.38抗体、Hyb 1.39抗体、Hyb 1.40抗体、Hyb 1.45抗体、Hyb 1.46抗体、Hyb 1.48抗体、Hyb 1.49抗体、Hyb 1.51抗体、Hyb 6.4.1抗体、F3抗体、人源化的F3抗体、Cl抗体、人源化的C1抗体、6.4抗体、抗mPGDF-C山羊IgG抗体、C3.1抗体、5-甲基-7-二乙基氨基-s-三唑并(l,5-a)吡啶、干扰素、鱼精蛋白、PDGFR-B1单克隆抗体、PDGFR-B2单克隆抗体、6D11单克隆抗体、S is 1单克隆抗体、PR7212单克隆抗体、PR292单克隆抗体、HYB9610单克隆抗体、HYB 9611单克隆抗体、HYB 9612单克隆抗体、HYB 9613单克隆抗体、4-(2-(N-(2-甲酰胺基-吲哚)氨乙基)-苯磺酸盐、4-(2-(N-(-2-甲磺酰吲哚)氨乙基)-磺酰脲类、CGP53716、人抗体gl62、吡唑并[3,4-g]喹喔啉、6-[2-(甲基氨甲酰基)苯基硫基]-3-E-[2-(吡啶-2-基)乙烯基]-吲唑、1-{2-[5-(2-甲氧基-乙氧基)-苯并咪唑-1-基]-喹啉-8-基}-哌啶-4-基胺、4-{4-[N-(4-硝基苯基)氨甲酰基]-1-哌嗪基}-6,7-二甲氧基喹唑啉、4-氨基-5-氟-3-(6-(4-甲基-哌嗪-l-基)-lH-苯并咪唑-2-基)1H-喹啉-2-酮、(4-叔丁基苯基){4-[(6,7-二甲氧基-4-喹啉基)氧基]苯基}甲烷酮、5-甲基-N-[4-(三氟甲基)苯基]-4-异唑甲酰胺、反式-4-[(6,7-二甲氧基喹喔啉-2-基)氨基]环己醇、(Z)-3-[(2,4-二甲基-5-(2-氧-l,2-二氢吲哚-3-基茚甲基)-1H-吡咯-3-基)-丙酸、5-(5-氟-2-氧-1,2-二氢吲哚-3-基茚甲基)-2,4-二甲基-1H-吡咯-3-羧酸、l-(4-氯苯胺基)-4-(4-吡啶基甲基)二氮杂萘、N-{4-(3-氨基-lH-吲唑-4-基)苯基-N”-(2-氟-5-甲基苯基)尿素、l,2-二甲基-7-(2-噻吩)咪唑[5,4-g]喹喔啉、1,2-二甲基-6-苯基-咪唑并[5,4-g]喹喔啉、l,2-二甲基-6-(2-噻吩)咪唑并[5,4-g]喹喔啉、AG1295、AG1296、3-芳基喹啉、4-吡啶基-2-芳基嘧啶、索拉非尼、MLN518、PKC412、ΑΜΝ107、苏拉明、新霉素或其药学上可接受的盐和(b)雷珠单抗、贝伐单抗、阿柏西普、KH902VEGF受体-Fe融合蛋白质、2C3抗体、ORA102、派加他尼、贝伐西尼、平端贝伐西尼、SIRNA-027、前胡素、前胡醇、鬼臼苦素、没药固酮、PLG101、类花生酸LXA4、PTK787、帕唑帕尼、阿西替尼、CDDO-Me、CDDO-Imm、紫草素、β羟基异戊酰紫草素、神经节苷脂GM3、DC101抗体、Mab 25抗体、Mab73抗体、4A5抗体、4E10抗体、5F12抗体、VA01抗体、BL2抗体、BECG-相关的蛋白质、sFLT0l、sFLT02、肽B3、TG100801、索拉非尼、G6-31抗体或抑制与VEGF相关血管生成的其他化合物。
35.根据权利要求34所述的局部制剂,其中所述PDGF抑制剂选自拮抗物A或舒尼替尼和所述VEGF抑制剂选自雷珠单抗。
36.根据权利要求1所述的制剂,在结合疗法中进一步包括曲安奈德的局部或玻璃体内制剂。
37.局部制剂,其包括通常通过玻璃体内注射递送以治疗眼后节疾病或病况的药学上活性量的活性成分和由基于PEG的脂质形成的热力学稳定的、自形成的脂质体,其中所述脂质的重量百分数小于约20%wt/wt。
38.根据权利要求37所述的制剂,其中所述后节疾病或病况选自老年性黄斑变性或糖尿病视网膜病变。
39.根据权利要求37所述的制剂,其中所述活性成分选自雷珠单抗、曲安奈德或其组合。
40.根据权利要求37所述的制剂,其中雷珠单抗是所述活性成分并且与选择性PKCβ抑制剂(鲁伯斯塔)、类固醇类(曲安奈德、醋酸氟轻松)和任选地玻璃体切除术组合使用。
41.局部递送以治疗后节疾病的眼科制剂,其包括脂质体和类固醇。
42.根据权利要求41所述的制剂,其中所述脂质体是热力学稳定的自形成的脂质体。
43.根据权利要求41所述的制剂,其中所述类固醇选自曲安奈德。
44.在需要其治疗的患者中治疗后节疾病的方法,其包括施用药学上有效量的局部制剂,所述局部制剂包括脂质体和类固醇或通常通过玻璃体内注射递送的其他药物。
45.根据权利要求44所述的方法,其中所述后节疾病是糖尿病黄斑性水肿。
46.根据权利要求44所述的方法,其中所述脂质体是自形成的热力学稳定的脂质体。
47.根据权利要求44所述的方法,其中所述类固醇选自曲安奈德。
48.根据权利要求47所述的方法,其中曲安奈德以50-150ug/每滴制剂剂量范围施用并且每两个小时4-6X/天局部施用一滴至眼睛。
49.根据权利要求44所述的方法,其中所述患者显示中心凹厚度和视敏度的改善。
50.脂质体制剂,其包括自形成的热力学稳定脂质体和活性药物试剂,所述活性药物试剂选自抗菌剂、抗病毒剂、皮质类固醇和抗血管内皮生长因子试剂的任何一种或组合,其中所述制剂适于局部递送至患者的眼睛以治疗眼科疾病或病况。
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