CN105688191A - 促胰岛素释放肽的混悬制剂及其应用 - Google Patents
促胰岛素释放肽的混悬制剂及其应用 Download PDFInfo
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- CN105688191A CN105688191A CN201610052787.5A CN201610052787A CN105688191A CN 105688191 A CN105688191 A CN 105688191A CN 201610052787 A CN201610052787 A CN 201610052787A CN 105688191 A CN105688191 A CN 105688191A
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Abstract
描述了促胰岛素释放肽的混悬制剂(例如,胰高血糖素样肽-1(GLP-1)或艾塞那肽)。该混悬制剂包含(i)非水性的、单相载体,该载体包含一种或多种聚合物以及一种或多种溶剂,其中该载体表现出粘性流体特征,以及(ii)微粒制剂,其包含促胰岛素释放肽,其中该肽分散在该载体中。该微粒制剂进一步包括稳定组分,其包含一种或多种稳定剂例如碳水化合物、抗氧化剂、氨基酸和缓冲剂。还描述了用于投递该混悬制剂的装置以及使用方法。
Description
本申请是中国专利申请号200880012205.4(PCT/US2008/005235),申请日2008年4月22日,发明名称为“促胰岛素释放肽的混悬制剂及其应用”的分案申请。
相关申请的交叉引用
本申请要求于2007年4月23日提交的美国临时申请序列No.60/926,005以及2008年3月28日提交的美国临时申请序列No.61/072,202的权益,这些申请以其全部内容通过引用并入本文。
技术领域
本发明涉及用于药物研究和开发的有机化学、制剂化学以及肽化学。本发明的多方面提供了促胰岛素释放肽(insulinotropicpeptide)的混悬制剂以供用于哺乳动物以及用于疾病或病症的治疗。
背景技术
胰高血糖素样肽-1(GLP-1)是一种重要的激素和人胰高血糖素原分子的片段。GLP-1通过肽酶(二肽酰肽酶IV或DPP-IV)迅速被代谢。GLP-1的片段,胰高血糖素样肽-1(7-36)酰胺(胰高血糖素样促胰岛素释放肽,或GLIP)是一种胃肠肽,其加强胰岛素在生理浓度下的释放(GutniakM.,etal.,NEnglJMed.1992May14;326(20):1316-22)。GLP-1和GLP-1(7-36)酰胺是肠促胰岛素。肠促胰岛素是胃肠激素,它们会引起进食后从β细胞中释放的胰岛素的量增加。
食物摄取以及交感神经系统的刺激会刺激GLP-1在哺乳动物小肠中的分泌。此外,GLP-1会刺激胰岛素的产生和分泌、生长激素抑制素的释放、通过增加胰岛素敏感性的葡萄糖利用,并且在动物研究中,还会刺激β细胞功能和增殖。
GLP-1(7-36)酰胺和GLP-1(7-37)在2型糖尿病患者中使禁食高血糖病正常化(Nauck,M.A.,etal.,Diabet.Med.15(11):937-45(1998))。
毒蜥外泌肽-4(exendin-4)是一种肠促胰岛素模拟物(即,其模拟肠促胰岛素的生理作用),其是从希拉毒蜥(Helodermasuspectum)毒液中纯化的(Eng,J.,etal.,J.Biol.Chem.267:7402-05(1992)),并且显示出与肠促胰岛素激素GLP-1(7-36)酰胺的结构相关性。毒蜥外泌肽-4和截短的毒蜥外泌肽-(9-39)酰胺在胰岛瘤衍生的细胞上和肺膜上特异性地与GLP-1受体相互作用(R,etal.,JBiolChem.268:19650-55(1993))。毒蜥外泌肽-4与人GLP-1具有约53%的同源性(Pohl,M.,etal.,JBiolChem.273:9778-84(1998))。然而,与GLP-1不同,毒蜥外泌肽-4耐受经由DPP-IV的降解。甘氨酸取代使得耐受经由DPP-IV的降解(Young,A.A.,etal.,Diabetes48(5):1026-34(1999))。
发明概述
本发明涉及包含微粒制剂和混悬载体的混悬制剂,以及包含此类制剂的装置,制备此类制剂和装置的方法,以及其应用的方法。
在一个方面,本发明涉及包含微粒制剂的混悬制剂,该微粒制剂包含促胰岛素释放肽以及一种或多种选自以下的稳定剂:碳水化合物、抗氧化剂、氨基酸、缓冲剂、和无机化合物。该混悬制剂进一步包含非水性的、单相混悬载体,该混悬载体包含一种或多种聚合物以及一种或多种溶剂。该混悬载体表现出粘稠液体的性质,并且该微粒制剂被分散于载体中。
在一个实施方案中,该混悬制剂包含微粒制剂,该微粒制剂包含促胰岛素释放肽、二糖(例如,蔗糖)、蛋氨酸、和缓冲剂(例如,枸橼酸盐),以及非水性的、单相混悬载体,该混悬载体包含一种或多种吡咯烷酮聚合物(例如,聚乙烯吡咯烷酮)以及一种或多种溶剂(例如,乳酸月桂酯、月桂醇、苯甲酸苄酯或其混合物)。
促胰岛素释放肽的实例包括但不限于胰高血糖素样肽-1(GLP-1)、艾塞那肽及其衍生物或类似物。在本发明的一个实施方案中,该促胰岛素释放肽是GLP-1(7-36)酰胺。在本发明的另一个实施方案中,该促胰岛素释放肽是艾塞那肽。
本发明的该微粒制剂可进一步包含缓冲剂,其例如选自枸橼酸盐、组氨酸、琥珀酸盐及其混合物。
本发明的该微粒制剂可进一步包含无机化合物,其例如选自枸橼酸盐、组氨酸、琥珀酸盐及其混合物NaCl、Na2SO4、NaHCO3、KCl、KH2PO4、CaCl2、和MgCl2。
在该微粒制剂中的一种或多种稳定剂可包括,例如,选自乳糖,蔗糖,海藻糖,甘露醇,纤维二糖及其混合物的碳水化合物。
在该微粒制剂中的一种或多种稳定剂可包括,例如,选自蛋氨酸、抗坏血酸、硫代硫酸钠、乙二胺四乙酸(EDTA)、枸椽酸、半胱氨酸类(cysteins)、硫代甘油、巯基乙酸、硫代山梨糖醇(thiosorbitol)、丁基化羟基茴香醚(butylatedhydroxanisol)、丁基化羟基甲苯和没食子酸丙酯及其混合物的抗氧化剂。
在该微粒制剂中的一种或多种稳定剂可包括氨基酸。
在一个实施方案中,本发明混悬载体的溶剂选自乳酸月桂酯(lauryllactate)、月桂醇、苯甲酸苄酯及其混合物。可以配制该混悬载体的聚合物的实例是吡咯烷酮(例如,聚乙烯吡咯烷酮)。在优选的实施方案中,该聚合物是吡咯烷酮并且该溶液是苯甲酸苄酯。
该混悬制剂通常具有的总湿含量低于约10wt%,并且在优选的实施方案中低于约5wt%。
可植入的药物递药装置可用于包含或投递本发明混悬制剂。在一个实施方案中,该装置是渗透递药装置。
本发明混悬制剂可用于在有治疗需要的受试者中治疗任意数量的疾病状态或病症,例如II型糖尿病。在一个实施方案中,可植入的药物递药装置在约1个月至约1年时间内以基本上均匀的速率投递本发明混悬制剂。该装置可以例如在适宜的位置植入到皮下。
本发明还包括制备本发明所述混悬制剂、微粒制剂、混悬载体和装置的方法。
本发明的这些和其它实施方案对于本领域技术人员而言根据本文公开内容是容易想到的。
附图简述
图1A和1B提供促胰岛素释放肽的两个实例的序列:图1A,胰高血糖素样肽1(7-36)酰胺(GLP-1(7-36)酰胺)(SEQIDNO:1);以及图1B,合成的艾塞那肽肽(SEQIDNO:2)。
图2提供测试动物组平均体重的数据,该测试动物是由艾塞那肽从(ALZACorporation,MountainViewCA,licensedtoIntarciaTherapeutics,Inc.,HaywardCA)装置中持续投递来治疗的。在该图中,纵轴是以克表示的平均体重(体重(g)),横轴是天(天)。1组肥胖动物(封闭菱形)是对照组,每天给该组动物施用来自装置的0mcg艾塞那肽。2组动物(封闭方形)是肥胖动物,每天给该组动物施用来自装置的20mcg艾塞那肽。3组动物(封闭三角形)是精瘦动物,每天给该组动物施用20mcg艾塞那肽。
图3提供了测试动物的组平均血糖浓度,该测试动物是由艾塞那肽从装置中持续投递来治疗的。在该图中,纵轴是以mg/dL(血糖(mg/dL))表示的平均血糖(血糖(mg/dL)),横轴是天(天),其中每天具有三个相关血糖值(A、B、C)。天-1A是禁食血糖值,天8A是禁食血糖值。1组肥胖动物(封闭菱形)是对照组,每天给该组动物施用0mcg艾塞那肽。2组动物(封闭方形)是肥胖动物,每天给该组动物施用来自装置的20mcg艾塞那肽。3组动物(封闭三角形)是精瘦动物,每天给该组动物施用来自装置的20mcg艾塞那肽。
图4提供了测试动物的组平均HbA1c值,该测试动物是由艾塞那肽从装置中持续投递来治疗的。在该图中,纵轴是平均百分HbA1c(HbA1c(%)),横轴是天(天)。1组肥胖动物(封闭菱形)是对照组,每天给该组动物施用0mcg艾塞那肽。2组动物(封闭方形)是肥胖动物,每天给该组动物施用20mcg艾塞那肽。3组动物(封闭三角形)是精瘦动物,每天给该组动物施用来自装置的20mcg艾塞那肽。
发明详述
本说明书引述的所有专利、出版物和专利申请通过引用并入本文,如同每个单个的专利、出版物和专利申请特别地和单独地说明以其全部内容为所有目的通过引用并入本文。
1.0.0定义
应理解,本文所用术语仅是为了描述特定实施方案的目的,并且不是要对其限制。如本说明书和所附权利要求所使用的,单数形式“一”、“一个”和“该”包括复数指代,除非上下文明显另有它指。因此,例如,提及“溶剂”包括两种或多种此类溶剂的组合,提及“肽”包括包括一种或多种肽、肽混合物等。
除非另有定义,本文所用的所有技术和科学术语具有与本发明相关的本领域技术人员通常理解的相同含义。尽管与本文所述那些相似或者等同的其它方法和材料可用于实施本发明,在本文描述了优选的材料和方法。
在描述和主张本发明时,以下术语将与以下定义相一致地使用。
术语"肽"、"多肽"和"蛋白质"可在本文互换使用,并且通常是指包含两个或多个氨基酸(例如,最常见的为L-氨基酸,但是还包括例如D-氨基酸、修饰的氨基酸、氨基酸类似物和/或氨基酸模拟物)的链的分子。肽还可包括修饰该氨基酸链的其它基团,例如通过翻译后修饰添加的官能团。翻译后修饰的实例包括但不限于乙酰化、烷基化(包括甲基化)、生物素化、谷氨酰基化、甘氨酰基化、糖基化、异戊二烯化、脂化(lipoylation)、磷酸泛酰巯基乙胺化(phosphopantetheinylation)、磷酸化、硒化、C-末端酰胺化。术语肽还包括包含氨基末端和/或羧基末端修饰的肽。末端氨基基团的修饰包括但不限于脱氨基、N-低级烷基、N-二-低级烷基、和N-酰基修饰。末端羧基的修饰包括但不限于酰胺、低级烷基酰胺、二烷基酰胺和低级烷基酯修饰(例如,其中低级烷基是C1-C4烷基)。
在肽链一个末端的末端氨基酸通常具有游离基团(即,氨基末端)。在该链的另一末端的末端氨基酸通常具有游离羧基(即,羧基末端)。通常,形成肽的该氨基酸是以这样的次序编号的,即从氨基末端开始,并在该肽的羧基末端方向增加。
本文使用的短语"氨基酸残基"是指通过酰胺键或酰胺键模拟物并入到肽中的氨基酸。
术语"促胰岛素的"如本文使用的是指化合物例如肽刺激或影响胰岛素(例如,促胰岛素激素)的生成和/或活化的能力。此类化合物通常刺激胰岛素在受试者中的分泌或生物合成。
短语"促胰岛素释放肽"如本文使用的包括但不限于胰高血糖素样肽1(GLP-1)及其衍生物和类似物,和艾塞那肽及其衍生物和类似物。
术语"载体"如本文使用的是指用于携载化合物的载体。本发明的载体通常包含例如聚合物和溶剂的组分。本发明混悬载体通常包含用于制备多肽微粒的混悬制剂溶剂和聚合物。
短语"相分离"如本文使用的是指在该混悬载体中多相(例如,液相或凝胶相)的形成,例如当该混悬载体接触水性环境时。在本发明的一些实施方案中,配制该混悬载体使得在与具有至少约10%水的水性环境接触时显现相分离。
短语"单相"如本文使用的是指固体、半固体或液体均相系统,其始终是物理和化学均匀的。
术语"分散"如本文使用的是指将化合物例如肽溶解、分散、混悬或分配在混悬载体中。
短语"化学稳定"如本文使用的是指通过化学方式例如脱酰胺作用(通常通过水解)、聚集作用或氧化作用,形成一种在一定时间内生成的降解产物为可接受的百分数的制剂。
短语"物理稳定"如本文使用的是指形成一种聚集物(例如,二聚体和其它更高分子量的产物)为可接受的百分数的制剂。此外,物理稳定制剂不会改变其物理状态,例如从液体变为固体,或者从无定形形式为结晶形式。
术语"粘度"如本文使用的通常是指由剪切应力比剪切速率的比率确定的值(参见,例如,Considine,D.M.&Considine,G.D.,EncyclopediaofChemistry,4thEdition,VanNostrand,Reinhold,NY,1984),其基本如下:
F/A=μ*V/L(方程1)
其中F/A=剪切应力(每单位面积的力),
μ=比率常数(粘度),和
V/L=每层厚度的流速(剪切速率)。
根据这种关系,剪切应力比剪切速率的比定义为粘度。剪切应力和剪切速率的测定通常是使用平行板流变测定法在所选条件(例如,约37℃的温度)下进行测定的。测定粘度的其它方法包括使用粘度计,例如Cannon-Fenske粘度计、Ubbelohde粘度计以用于Cannon-Fenske不透明溶液,或者Ostwald粘度计测定运动粘度。通常,本发明混悬载体具有足以防止混悬在其中的微粒制剂在贮藏期间沉降的粘度,并用于投递例如在可植入的药物递药装置中的方法。
术语"非水性的"如本文使用的是指总湿含量例如混悬制剂的总湿含量通常低于或等于约10wt%,优选低于或等于约5wt%,并且更优选低于约4wt%。
术语"受试者"如本文使用的是指脊索动物亚门的任何成员,非限制性的包括人和其它灵长类,包括非人灵长类例如猕猴、黑猩猩和其它猿以及猴类;畜牧动物例如牛、羊、猪、山羊和马;家养哺乳动物例如狗和猫;试验动物包括啮齿类例如小鼠、家兔和豚鼠;鸟类,包括家养、野生和猎鸟例如鸡、火鸡和其它鹑鸡鸟类、鸭、鹅等。该术语不表示特定年龄。因此,成年和新生个体均被涵盖。
术语"药物"、"治疗药"和"有益药"可互换使用以指投递给受试者的任何治疗活性物质以产生需要的有益作用。在本发明的一个实施方案中,该药物是促胰岛素释放肽,例如GLP-1、艾塞那肽及其衍生物或类似物。本发明的该装置和方法非常适用于投递多肽以及小分子及其组合。
术语"渗透递药装置"如本文使用的通常是指用于投递一种或多种有益药(例如,促胰岛素释放肽)给受试者的装置,其中该装置包括例如具有内腔的贮库(例如由钛合金制成),该内腔含有混悬制剂(例如,包含促胰岛素释放肽)和渗透剂制剂。位于该内腔中的活塞组件使该混悬制剂与该渗透剂成分分离。位于该贮库第一末端的半透膜,邻近该渗透剂制剂,和位于该贮库第二末端的流量调节器(其定义为一个递送孔,该混悬制剂通过该孔从该装置中出来)邻近该混悬制剂。通常,该渗透递药装置被植入到受试者中,例如皮下(例如,在上臂的内侧、外侧或背侧;或者在腹部区域)。
2.0.0本发明一般概况
在详细描述本发明之前,应当理解,本发明不限于药物递送的特定类型、药物递药装置的特定类型、肽的特定来源、特定溶剂、特定聚合物等,此类特定情形的使用可根据本说明书的教导选择。还应理解为,本文使用的术语仅是为了描述本说明书的特定实施方案的目的,并非用于限制。
在一个方面,本发明涉及一种混悬制剂,其包含微粒制剂和混悬载体。该微粒制剂包括但不限于促胰岛素释放肽和一种或多种稳定剂。该一种或多种稳定剂通常选自碳水化合物、抗氧化剂、氨基酸和缓冲剂。该混悬载体通常是非水性的、单相混悬载体,该混悬载体包含一种或多种聚合物以及一种或多种溶剂。该混悬载体表现出粘性流体性质。该微粒制剂均匀地分散在该载体中。
在本发明的一个实施方案中,该促胰岛素释放肽是胰高血糖素样肽-1(GLP-1)、GLP-1的衍生物(例如,GLP-l(7-36)酰胺)或者GLP-1的类似物。
在本发明的另一个实施方案中,促胰岛素释放肽是艾塞那肽、艾塞那肽的衍生物或艾塞那肽的类似物。
本发明的该微粒制剂通常包括一种或多种下列稳定剂:一种或多种碳水化合物(例如,二糖,例如乳糖、蔗糖、海藻糖、纤维二糖及其混合物);一种或多种抗氧化剂(例如,蛋氨酸、抗坏血酸、硫代硫酸钠、乙二胺四乙酸(EDTA)、枸椽酸、丁基化羟基甲苯及其混合物);以及一种或多种缓冲剂(例如,枸橼酸盐、组氨酸、琥珀酸盐及其混合物)。在优选的实施方案中,该微粒制剂包含促胰岛素释放肽、蔗糖、蛋氨酸和枸橼酸盐缓冲剂。促胰岛素释放肽比蔗糖+蛋氨酸的比率通常为约1/20、约1/10、约1/5、约1/2、约5/1、约10/1或约20/1,优选为约1/5至5/1,更优选为约1/3至3/1。该微粒制剂优选是通过喷雾干燥制备的微粒制剂并且具有低的湿含量,该湿含量优选低于或等于约10wt%,更优选低于或等于约5wt%。在另一实施方案中,该微粒制剂可以是冷冻干燥的。
本发明混悬载体包含一种或多种溶剂和一种或多种聚合物。优选的,该溶剂选自乳酸月桂酯、月桂醇、苯甲酸苄酯及其混合物。更优选的该溶剂是乳酸月桂酯或苯甲酸苄酯。优选的,该聚合物是吡咯烷酮。在一些实施方案中,该聚合物是聚乙烯吡咯烷酮(例如,聚乙烯吡咯烷酮K-17,其通过具有7,900-10,800的近似平均分子量范围)。在本发明的一个实施方案中,该溶剂基本上由苯甲酸苄酯和聚乙烯吡咯烷酮组成。
该混悬制剂通常具有低的总湿含量,其例如低于或等于约10wt%,在优选的实施方案中,低于或等于约5wt%。
在另一方面,本发明涉及包含本发明混悬制剂的可植入的药物递药装置。在优选的实施方案中,该药物递药装置是渗透递药装置。
本发明进一步包括制备本发明混悬制剂以及装载有本发明混悬制剂的渗透递药装置的方法。在一个实施方案中,本发明包括制备渗透递药装置的方法,该方法包括将混悬制剂装载到该渗透递药装置的贮库中。
在另一方面,本发明涉及在有此治疗需要的受试者中治疗糖尿病(例如,2型糖尿病或妊娠糖尿病)的方法,该方法包括以基本上均匀的速率从渗透递药装置中投递本发明混悬制剂。通常,该混悬制剂投递约1个月至约1年的时间,优选约3个月至约1年。该方法可进一步包括将渗透递药装置皮下植入到受试者中,该渗透递药装置装载有本发明混悬制剂。
在进一步的方面,本发明涉及刺激胰岛素分泌、抑制胰高血糖素分泌、减慢胃排空、治疗糖尿病相关障碍、治疗高血糖病、治疗肥胖症、控制食欲、减轻体重、和调节胃肠蠕动的方法。
2.1.0制剂和组合物
2.1.1微粒制剂
在一个方面,本发明提供了一种药物组合物,其包含促胰岛素释放肽例如GLP-1或艾塞那肽的混悬制剂。该混悬制剂包含非水性的、单相载体,该载体包括至少一种聚合物和至少一种溶剂。该载体优选呈现出粘性流体特征。该肽组分包括在微粒制剂中的促胰岛素释放肽,所述微粒制剂分散于该载体中。通常,该微粒制剂包括一种稳定组分,其包括选自碳水化合物,抗氧化剂,氨基酸、缓冲剂、和无机化合物中的多种稳定剂组分中的一种。
用于实施本发明的促胰岛素释放肽包括但不限于GLP-1和艾塞那肽。
Bell,G.I.,etal.,(Nature302:716-718(1983))发现胰高血糖素原(Lund,etal.,Proc.Natl.Acad.Sci.U.S.A.79:345-349(1982);Patzelt,etal.,Nature,282:260-266(1979))含有三个分离的、高度同源的肽区域,它们被命名为胰高血糖素、胰高血糖素样肽1(GLP-1)和胰高血糖素样肽2(GLP-2)。Lopez,etal.,(Proc.Natl.Acad.Sci.U.S.A.80:5485-5489(1983))证实GLP-1的肽序列是37个氨基酸的序列,而GLP-2的肽序列是34个氨基酸的序列。
大鼠胰高血糖素前原(preproglucagon)结构研究显示相似模式的溶蛋白性裂解,导致形成胰高血糖素、GLP-1和GLP-2(Heinrich,G.,etal.,Endocrinol.,115:2176-2181(1984))。发现GLP-1的人、大鼠、牛和仓鼠序列是相同的(Ghiglione,M.,etal.,Diabetologia,27:599-600(1984))。
胰高血糖素前原的裂解首先产生GLP-1(1-37),它是一种具有弱的促胰岛素活性的37个氨基酸的肽。然后氨基酸残基6和7之间的肽键的裂解产生一种生物学活性的GLP-1,称之为GLP-1(7-37)(根据规定,该GLP-1(7-37)的氨基酸末端指定为编号7,而羧基末端编号为37)。在哺乳动物中产生的GLP-1(7-37)的大约80%是在L-细胞中除去末端甘氨酸残基之后而在C-末端被酰胺化,产生GLP-1(7-36)酰胺。游离酸GLP-1(7-37)和酰胺GLP-1(7-36)酰胺的生物学作用和代谢更新基本上是相同的。GLP-1(7-36)酰胺的序列提供于图1A中。
GLP-1(包括该肽的三种形式,GLP-1(1-37)、GLP-1(7-37)和GLP-1(7-36)酰胺,以及GLP-1的类似物)已显示刺激胰岛素分泌(即,它是促胰岛素的),这会诱发细胞的葡萄糖摄取并导致降低血清葡萄糖水平(参见,例如,Mojsov,S.,Int.J.PeptideProteinResearch,40:333-343(1992))。另一种GLP-1类似物是利拉糖肽(liraglutide),它是一种长效DPP-4-耐受的GLP-1受体拮抗剂。利拉糖肽与GLP-1(7-37)具有97%的同一性。利拉糖肽还称为NN-2211和[Arg34,Lys26]-(N-ε-(γ-Glu(N-α-十六酰基))-GLP-1(7-37)(参见,例如,美国专利No.6,969,702)。
本领域已知有多种促胰岛素作用的GLP-1衍生物和类似物(参见,例如,美国专利No.5,118,666;5,120,712;5,512,549;5,545,618;5,574,008;5,574,008;5,614,492;5,958,909;6,191,102;6,268,343;6,329,336;6,451,974;6,458,924;6,514,500;6,593,295;6,703,359;6,706,689;6,720,407;6,821,949;6,849,708;6,849,714;6,887,470;6,887,849;6,903,186;7,022,674;7,041,646;7,084,243;7,101,843;7,138,486;7,141,547;7,144,863;和7,199,217)。因此,为了易于在本文的讨论,具有促胰岛素活性的GLP-1衍生物和类似物的家族统称为GLP-1。
抑胃肽(GIP)也是一种促胰岛素释放肽(Efendic,S.,etal.,HormMetabRes.36:742-6(2004))。GIP是一种十二指肠和空肠粘膜分泌的针对吸收脂肪和碳水化合物响应以刺激胰腺分泌胰岛素的激素。GIP也称为葡萄糖依赖性促胰岛素多肽。GIP是一种42-氨基酸胃肠调节肽,其在葡萄糖存在下刺激胰岛素从胰脏β细胞中分泌(Tseng,C.,etal.,PNAS90:1992-1996(1993))。
毒蜥外泌肽是从毒蜥(Gila-monster)的毒液中分离的肽。毒蜥外泌肽-4存在于希拉毒蜥的毒液中(Eng,J.,etal.,J.Biol.Chem.,265:20259-62(1990);Eng.,J.,etal.,J.Biol.Chem.,267:7402-05(1992);美国专利No.5,424,286)。该毒蜥外泌肽与胰高血糖素样肽家族的若干成员具有一些序列相似性,最高同源性为GLP-1(7-36)酰胺的53%(Goke,etal.,J.Biol.Chem.,268:19650-55(1993))。
毒蜥外泌肽-4作用于胰岛素分泌β-TC1细胞上的GLP-1受体,所述细胞是分散的来自豚鼠胰腺的腺泡细胞和来自胃的膜壁细胞。该毒蜥外泌肽-4肽在分离的胃中还刺激生长激素抑制素释放,并抑制胃泌素释放(Goke,etal.,J.Biol.Chem.268:19650-55(1993);Schepp,etal.,Eur.J.Pharmacol.,69:183-91(1994);Eissele,etal.,LifeSci.,55:629-34(1994))。根据它们的促胰岛素活性,已经提出了毒蜥外泌肽-3和毒蜥外泌肽-4治疗糖尿病和预防高血糖病的应用(美国专利No.5,424,286)。
证明有促胰岛素作用的若干毒蜥外泌肽-4衍生物和类似物(包括,例如,毒蜥外泌肽-4激动剂)是本领域已知的(参见,例如,美国专利No.5,424,286;6,268,343;6,329,336;6,506,724;6,514,500;6,528,486;6,593,295;6,703,359;6,706,689;6,767,887;6,821,949;6,849,714;6,858,576;6,872,700;6,887,470;6,887,849;6,924,264;6,956,026;6,989,366;7,022,674;7,041,646;7,115,569;7,138,375;7,141,547;7,153,825;和7,157,555)。艾塞那肽是一种合成的肽,其与毒蜥外泌肽-4一样具有相同的39个氨基酸序列。艾塞那肽是一种肽肠促胰岛素模拟物,其显示出类似于哺乳动物肠促胰岛素激素胰高血糖素样肽1(GLP-1)的葡萄糖调节活性。肠促胰岛素激素是当葡萄糖水平正常或者特别是当它们升高时引起胰岛素释放量增加的激素。肠促胰岛素激素影响由胰岛素分泌限定的其它活性,例如它们可降低胰高血糖素生成并延迟胃排空。此外,肠促胰岛素激素可改善胰岛素敏感度并且可能增加胰岛细胞再生。
为了易于在本文讨论,具有促胰岛素活性的毒蜥外泌肽-4肽的家族包括合成形式(例如,艾塞那肽)、衍生物和类似物统称为艾塞那肽。
在一个方面,本发明提供了促胰岛素释放肽的微粒制剂,其可用于制备混悬制剂。本发明的促胰岛素释放肽将不受合成或制备方法的限制,并且将包括从天然来源、或者通过重组(不论是从cDNA还是基因组DNA产生的)、合成、转基因、和基因活化方法合成或制备而获得的那些。在本发明优选的实施方案中,该促胰岛素释放肽是GLP-1肽或毒蜥外泌肽(如本文上文描述的),例如GLP-1(7-36)酰胺或艾塞那肽。本发明还包括两种或多种促胰岛素释放肽例如GLP-1(7-36)酰胺和GIP的组合。
本发明微粒制剂在投递温度下优选化学和物理稳定达至少1个月,优选至少3个月,更优选至少6个月,更优选至少12个月。该投递温度通常是正常人体温,例如约37℃,或者稍高,例如约40℃。此外,本发明微粒制剂在贮存温度下优选化学和物理稳定达至少3个月,优选至少6个月,更优选至少12个月。贮存温度的实例包括冷藏温度,例如约5℃,或者室温,例如约25℃。
如果在投递温度下约3个月后,优选约6个月后,优选约12个月后,以及在贮存温度下约6个月后,约12个月后,并且优选约24个月后,形成的肽微粒的分解产物低于约25%,优选低于约20%,更优选低于约15%,更优选低于约10%,并且更优选低于约5%,则认为微粒制剂是化学稳定的。
如果在投递温度下约3个月后,优选约6个月后,以及在贮存温度下约6个月,约12个月,形成的肽微粒的聚集物低于约10%,优选低于约5%,更优选低于约3%,更优选低于1%,则认为微粒制剂是物理稳定的。
为了保护蛋白质稳定性,通常使促胰岛素释放肽溶液保存在冷冻条件下,以及冷冻干燥或喷雾干燥成固体状态。Tg(玻璃转变温度)可能是实现稳定的肽组合物要考虑的一个因素。虽然不愿受任何特定理论的束缚,使肽、多肽或蛋白质稳定的高Tg无定形固体的形成理论已被应用于制药工业。通常,如果无定形固体具有更高的Tg,例如100℃,肽产物在室温或者甚至在40℃下保存将不具有迁移率,因为该贮存温度低于Tg。使用分子信息计算显示,如果玻璃转变温度高于50℃的贮存温度,则分子迁移率为0。分子无迁移率与无不稳定性问题有关。Tg还取决于在产物形成中的湿度水平。通常,湿度越大,则该组合物的Tg越低。
相应地,在本发明的一些方面,具有较高Tg的赋形剂可包括在该蛋白制剂中以改善稳定性,例如蔗糖(Tg=75℃)和海藻糖(Tg=110℃)。优选地,使用例如喷雾干燥、冷冻干燥法、脱水、冷冻干燥、研磨、制粒、超声液滴形成、结晶、沉淀或本领域可得的用于从组分混合物形成微粒的其它技术的方法,可以使微粒制剂形成微粒。该微粒优选在形状和大小上基本上均匀。
一种典型的喷雾干燥法可包括,例如,装载含有肽例如促胰岛素释放肽(例如,GLP-1(7-36)酰胺或艾塞那肽)的喷雾溶液,并使赋形剂稳定进入样品室中。该样品室通常维持在需要的温度,例如冷藏温度至室温。冷藏通常有助于蛋白质的稳定。将溶液、乳液或混悬液引入到喷雾干燥器中,在此处将液体雾化成液滴。可以通过使用旋转雾化器、压力喷嘴、气动喷嘴或声波喷嘴形成液滴。立即引入液滴雾气与干燥室中的干燥空气接触。干燥空气除去液滴的溶剂,并携带该微粒进入收集室。在喷雾干燥中,影响产率的因素包括但不限于微粒上的局部电荷(这会促使微粒附着在喷雾干燥器上)以及微粒的空气动力学(这会使它难以收集微粒)。通常,喷雾干燥方法的产率部分取决于该微粒制剂。
在本发明的一个实施方案中,该微粒大小为它们可通过可植入的药物递药装置投递。均匀形状和大小的微粒通常有助于提供从此递药装置中的连续和均匀的释放速率;然而,也可以使用具有非正态粒度分布的微粒制剂。例如,在具有投递孔的典型的可植入渗透递药装置中,微粒的大小低于约30%,优选低于约20%,更优选低于约10%的投递孔直径。在与渗透投递系统使用的微粒制剂的实施方案中,其中该植入剂的投递孔直径范围为例如约0.1至约0.5mm,微粒大小可优选低于约50微米,更优选低于约10微米,更优选范围为约3至约7微米。在一个实施方案中,该孔为约0.25mm(250μm),而该微粒大小为约3-5μm。
在优选的实施方案中,当该微粒掺入到混悬载体中时,它们在投递温度下在低于约3个月中不会沉降。一般来说,在粘性混悬载体中较小微粒比之于较大微粒具有更低的沉降速率。相应地,微米-至纳米-大小的微粒通常是需要的。在本发明用于可植入渗透递药装置中的该微粒制剂的一个实施方案中,其中植入剂的投递孔直径范围为例如约0.1至约0.5mm,微粒大小可优选低于约50微米,更优选低于约10微米,更优选范围为约3至约7微米。
在一个实施方案中,本发明微粒制剂包含一种或多种如上文所述的促胰岛素释放肽,一种或多种稳定剂,以及任选的缓冲剂。该稳定剂例如可以是碳水化合物、抗氧化剂、氨基酸、缓冲剂或无机化合物。稳定剂和缓冲剂在该微粒制剂中的量可以根据稳定剂和缓冲剂的活性以及制剂所需要的性质试验性地确定。通常,碳水化合物在该制剂中的量是通过聚集反应影响确定的。通常,该碳水化合物水平不应太高,以便避免在水存在下由于未结合促胰岛素释放肽的过量碳水化合物而促进晶体生长。通常,抗氧化剂在该制剂中的量是通过氧化反应影响确定的,而在喷雾干燥期间氨基酸在该制剂中的量是通过氧化反应影响和/或微粒可形成性确定的。通常,缓冲剂在该制剂中的量是通过预处理影响、稳定性影响和喷雾干燥期间微粒可形成性确定的。稳定剂可能是需要的,以便在操作过程例如当所有赋形剂均溶解时的溶液制备和喷雾干燥中使促胰岛素释放肽稳定。
可以包括在该微粒制剂中的碳水化合物的实例包括但不限于单糖(例如,果糖、麦芽糖、半乳糖、葡萄糖、D-甘露糖和山梨糖)、二糖(例如,乳糖、蔗糖、海藻糖和纤维二糖)、多糖(例如,棉子糖、松三糖(melezitose)、糊精-麦芽糖复合剂(maltodextrins)、右旋糖酐和淀粉)、以及糖醇(非环状多元醇;例如,甘露醇、木糖醇、麦芽糖醇、拉克替醇、木糖醇山梨醇、吡喃糖基山梨醇和肌醇(myoinsitol))。优选的碳水化合物包括非还原糖,例如蔗糖、海藻糖和棉子糖。
可包括在该微粒制剂中的抗氧化剂的实例包括但不限于蛋氨酸、抗坏血酸、硫代硫酸钠、过氧化氢酶、铂、乙二胺四乙酸(EDTA)、枸椽酸、半胱氨酸类、硫代甘油、巯基乙酸、硫代山梨糖醇、丁基化羟基茴香醚、丁基化羟基甲苯和没食子酸丙酯。
可包括在该微粒制剂中的氨基酸的实例包括但不限于精氨酸、蛋氨酸、甘氨酸、组氨酸、丙氨酸、L-亮氨酸、谷氨酸、异-亮氨酸、L-苏氨酸、2-苯胺、缬氨酸、正缬氨酸、胡桃糖(praline)、苯丙氨酸、色氨酸(trytophan)、丝氨酸、天冬酰胺、半胱氨酸、酪氨酸、赖氨酸和正亮氨酸。优选的氨基酸包括容易氧化的那些,例如,半胱氨酸、蛋氨酸和色氨酸。
可包括在该微粒制剂中的缓冲剂的实例包括但不限于枸橼酸盐、组氨酸、琥珀酸盐、磷酸盐、马来酸盐、tris、乙酸盐、碳水化合物和gly-gly。优选的缓冲剂包括枸橼酸盐、组氨酸、琥珀酸盐和tris。
可包括在该微粒制剂中的无机化合物的实例包括但不限于NaCl、Na2SO4、NaHCO3、KCl、KH2PO4、CaCl2和MgCl2。
此外,该微粒制剂可包括其它赋形剂,例如表面活性剂、填充剂和盐。表面活性剂的实例包括但不限于聚山梨酯20、聚山梨酯80、(BASFCorporation,MountOlive,NJ)F68和十二烷基硫酸钠(SDS)。填充剂的实例包括但不限于甘露醇和甘氨酸。盐的实例包括但不限于氯化钠、氯化钙和氯化镁。
包括在该微粒制剂中的所有组分通常是用于哺乳动物特别是人的药物可接受的。
以下表1提供了包含艾塞那肽的微粒的微粒制剂组成范围的实例。
表1
在一个实施方案中,该艾塞那肽微粒制剂包含艾塞那肽肽、蔗糖(碳水化合物)、蛋氨酸(抗氧化剂)和枸橼酸钠/枸椽酸(枸椽缓冲剂)。
以下表2提供了包含GLP-1的微粒的微粒制剂组成范围的实例。
表2
在该微粒制剂的组分的重量百分数范围内,一些优选的组分比率如下:促胰岛素释放肽(例如,艾塞那肽或GLP-1)比抗氧化剂(例如,蛋氨酸)-1/10、1/5、1/2.5、1/1、2.5/1、5/1、10/1,优选为约1/5至5/1,更优选为约1/3至3/1(这些同样的组分比适用于促胰岛素释放肽比氨基酸的比);促胰岛素释放肽(例如,艾塞那肽或GLP-1)比碳水化合物(例如,蔗糖)-1/10、1/5、1/2.5、1/1、2.5/1、5/1、10/1,优选为约1/5至5/1,更优选为约1/3至3/1;和/或促胰岛素释放肽(例如,艾塞那肽或GLP-1)比抗氧化剂+碳水化合物(例如,蛋氨酸+蔗糖)-1/20,1/10,1/5,1/2,5/1,10/1,20/1,优选为约1/5至5/1,更优选为约1/3至3/1(这些同样的组分比适用于促胰岛素释放肽比氨基酸+碳水化合物的比)。本发明还包括与所有这些比率相应的范围,例如约1/20至约20/1,约1/10至约10/1,约1/5至约5/1等等,以及例如约1/5至约3/1等等。
总之,促胰岛素释放肽配制在呈固体状态的干燥粉末中,其保持了蛋白质或肽的最大的化学和生物学稳定性。该微粒制剂提供了在高温下的长期贮藏稳定性,并且因此使得在延长的时间段给受试者投递稳定的和生物学有效的肽。
例如,通过使用喷雾干燥或冷冻干燥方法制备该微粒制剂,干燥微粒粉末的粒度分布可以得到良好的控制(0.1微米-20微米)。优化形成干燥粉末的过程参数,以制备具有需要的粒度分布、密度和表面积的微粒。
所选择的在该微粒制剂中的赋形剂和缓冲剂,可提供例如以下功能:干燥粉末密度改善;保护肽化学稳定性;保持肽的物理稳定性(例如,高玻璃转变温度,并避免相到相的转变);通过使用填充剂在混悬液中产生均质分散;疏水性和/或亲水性的改善以利用在所选溶液中的干粉溶解度;以及加工过程中的pH操作和维持产物中的pH(对于溶解度和稳定性而言)。
本发明的该微粒制剂参照艾塞那肽和GLP-1(7-36)酰胺作为示例性的促胰岛素释放肽示例性地说明于下文(参见实施例1和实施例2)。这些实施例不是用来限制。
2.1.2载体和混悬制剂
在本发明的一个方面,该混悬载体提供了稳定的环境,其中促胰岛素释放肽微粒制剂分散在该环境中。该微粒制剂在该混悬载体中是化学和物理稳定的(如上文所述)。该混悬载体通常包含一种或多种聚合物以及一种或多种溶剂,所述溶剂形成一种足够粘度的溶液,以使该包含促胰岛素释放肽的微粒均匀地悬浮。
混悬载体的粘度通常足以防止微粒制剂在保存以及在以投递方法例如在可植入药物递药装置中使用期间沉降。该混悬载体是可生物降解的,即该混悬载体在一定期间针对生物环境而分解或破坏。可通过一种或多种物理或化学降解过程例如酶作用、氧化、还原、水解(例如蛋白质水解)、置换(例如,离子交换),或者通过增溶、乳化、胶束形成的溶解而发生该混悬载体的分解。混悬载体分解之后,混悬载体的组分被吸收或者被患者的身体和周围组织分散。
聚合物溶解于其中的溶剂可影响该混悬制剂的性质,例如在保存期间该促胰岛素释放肽微粒制剂的行为。可以选择溶剂与聚合物组合,以便所得的混悬载体在与水性环境接触时出现相分离。在本发明的一些实施方案中,可以选择溶剂与聚合物组合,以便所得的混悬载体在与具有低于约10%的水的水性环境接触时出现相分离。
该溶剂可以是与水不能混溶的可接受的溶剂。可以选择该溶剂以便使该聚合物以高浓度溶解在该溶剂中,例如聚合物浓度大于约30%。然而,通常促胰岛素释放肽基本上不溶解在该溶剂中。用于实施本发明的溶剂的实例包括但不限于月桂醇,苯甲酸苄酯,苯甲醇,乳酸月桂酯,癸醇(又称为癸基醇),乳酸异辛酯(ethylhexyllactate),以及长链(C8至C24)脂肪醇、酯或其混合物。用于混悬载体的溶剂可以是"干燥的",即它具有低的湿含量。用于配制该混悬载体的优选溶剂包括乳酸月桂酯、月桂醇、苯甲酸苄酯及其组合。
用于配制本发明混悬载体的制剂的聚合物的实例包括但不限于聚酯(例如,聚乳酸或聚乳酸聚乙醇酸),吡咯烷酮(例如,分子量范围为约2,000至约1,000,000的聚乙烯吡咯烷酮(PVP)),不饱和醇的酯或醚(例如,乙酸乙烯酯),聚氧乙烯聚氧丙烯嵌段共聚物或其混合物。在一个实施方案中,该聚合物是分子量为2,000至1,000,000的PVP。在优选的实施方案中,该聚合物是聚乙烯吡咯烷酮K-17(通常具有约7,900-10,800的平均分子量)。聚乙烯吡咯烷酮通过其K-值来表征(例如,K-17),该K-值是粘度指数。用于该混悬载体的聚合物可包括一种或多种不同的聚合物,或者可包括不同级别的单一聚合物。用于该混悬载体的聚合物还可以是干燥的或者具有低的湿含量。
一般来说,本发明的混悬载体可以在组合物中基于所需要的特征性能而改变。在一个实施方案中,该混悬载体可包含约40%至约80%(w/w)聚合物和约20%至约60%(w/w)溶剂。混悬载体的优选实施方案包括聚合物和溶剂以以下比率组合形成的载体:约25%溶剂和约75%聚合物;约50%溶剂和约50%聚合物;约75%溶剂和约25%聚合物。
该混悬载体可表现出牛顿行为。该混悬载体通常配制成提供一定的粘度,该粘度保持了微粒制剂的均匀分散达预定时间。这有助于制备适合提供促胰岛素释放肽以需要的速度受控投递的混悬制剂。该混悬载体的粘度可根据需要的应用、微粒制剂的大小和种类、以及微粒制剂在该混悬载体中的加入而改变。该混悬载体的粘度可通过改变所用溶剂或聚合物的种类和相对量而改变。
该混悬载体可具有约100泊至约1,000,000泊,优选约1,000泊至约100,000泊的粘度范围。可以使用平行板流变仪以10-4/秒的剪切速率在37℃下测定粘度。在一些实施方案中,该混悬载体的粘度范围为约5,000泊至约50,000泊。在优选的实施方案中,在33℃下的粘度范围为约12,000至约18,000泊。
该混悬载体在与水性环境接触时可表现出相分离;然而,通常该混悬载体随温度的函数基本上表现出无相分离。例如,在约0℃至约70℃的的温度范围内以及在温度循环下例如从4℃至37℃至4℃的循环,该混悬载体通常表现出无相分离。
可以在干燥条件下例如在干燥箱中将聚合物与溶剂合并来制备该混悬载体。该聚合物和溶剂可以在高温例如约40℃至约70℃下合并,再使其液化并形成单相。可以在真空下将各组分混合以除去干燥组分中产生的空气泡。可以使用常规混合器例如双螺旋桨叶或类似混合器设定约40rpm的速度将各组分合并。然而,也可以使用较高速度混合各组分。一旦得到各组分的液体溶液,可以使该混悬载体冷却至室温。差示扫描量热法(DSC)可以用于验证该混悬载体是单相。此外,可以处理该载体的各组分(例如,溶剂和/或聚合物),以基本上减少或基本上除去过氧化物(例如,通过用蛋氨酸处理;参见,例如,美国专利申请公开No.2007-0027105)。
将包含促胰岛素释放肽的微粒制剂加至该混悬载体中以形成混悬制剂。可通过将该微粒制剂分散在该混悬载体中来制备该混悬制剂。可以将该混悬载体加热并将该微粒制剂在干燥条件下加至该混悬载体中。可以在真空下在高温例如约40℃至约70℃下将各组分混合。可以以足够的速度例如约40rpm至约120rpm并以足量的时间例如约15分钟混合各组分,得到该微粒制剂在该混悬载体中的均匀分散体。该混合器可以是双螺旋桨叶或其它适宜的混合器。可将所得混合物从该混合器中移出,密封在干燥容器中以防止水污染该混悬制剂,并在进一步使用之前,例如载入到可植入的药物递药装置、单位剂量容器、或多剂量容器使之冷却至室温。
该混悬制剂通常具有低于约10wt%,优选低于约5wt%并且更优选低于约4wt%的总湿含量。
本发明混悬制剂参照艾塞那肽和GLP-1(7-36)酰胺作为示例性的促胰岛素释放肽示例性地说明于下文(参见实施例3和实施例4)。这些实施例不是用来限制。
总之,该混悬载体的各组分提供了了生物相容性。该混悬载体的各组分提供了适宜于的化学-物理性质以形成稳定的例如干粉微粒制剂的混悬剂。这些性质包括但不限于下列:该混悬剂的粘度;载体的纯度;载体的残留水份;载体的密度;与干粉的相容性;与可植入装置的相容性;聚合物的分子量;载体的稳定性;以及载体的疏水性和亲水性。这些性质可以被利用和控制,例如,通过改变载体组成以及操作用于该混悬载体中的各组分的比率。
3.0.0混悬制剂的投递
本文描述的混悬制剂可用于可植入的药物递药装置,以在延长的时间例如数周、数月、或多至约1年内提供化合物的持续投递。这种可植入的药物递药装置通常能够以需要的流速在需要的时间内投递化合物。该混悬制剂通过常规技术被装载到该可植入的药物递药装置中。
该混悬制剂可使用渗透、机械、电机、或化学驱动药物递药装置而被投递。促胰岛素释放肽是以给需要治疗的受试者促胰岛素释放肽治疗有效的流速投递的。
该促胰岛素释放肽可以在多于约1周至约1年或更长,优选约1月至约1年或更长,更优选约3月至约1年或更长的时间范围内投递。该可植入的药物递药装置可包括具有至少一个孔的贮库,通过该孔投递促胰岛素释放肽。该混悬制剂可以贮存在该贮库中。在一个实施方案中,该可植入的药物递药装置是渗透递药装置,其中药物的投递是渗透驱动的。一些渗透递药装置以及它们的组件已有描述,例如递药装置或类似装置(参见,例如,美国专利No.5,609,885;5,728,396;5,985,305;5,997,527;6,113,938;6,132,420;6,156,331;6,217,906;6,261,584;6,270,787;6,287,295;6,375,978;6,395,292;6,508,808;6,544,252;6,635,268;6,682,522;6,923,800;6,939,556;6,976,981;6,997,922;7,014,636;7,207,982;7,112,335;7,163,688;美国专利公开No.2005-0175701,2007-0281024,和2008-0091176)。
递药装置通常由圆柱状贮库组成,该贮库含有渗透动力源(engine)、活塞和药物制剂。该贮库在一端由控制速率的水可渗透的膜封端,而另一端由扩散调节器封端,药物制剂通过该扩散调节器从药物贮库中释放。该活塞将药物制剂与渗透动力源分离,并利用密封以防止渗透动力源隔室中的水进入该药物贮库。该扩散调节器被设计成与药物制剂连接,以防止体液通过该孔进入药物贮库。
装置以基于渗透原理的预定速率释放治疗剂。细胞外液进入装置,即通过半透膜直接进入盐动力源,该盐动力源扩散以缓慢和平稳投递速率驱动该活塞。活塞的运动迫使该药物制剂通过孔或射出口以预定的剪切速率释放。在本发明的一个实施方案中,装置的贮库装载了本发明混悬制剂,其包含例如GLP-1(7-36)酰胺或艾塞那肽,其中该装置能够给受试者在延长的时间内(例如,约3、约6或约12个月)以预定的治疗有效的投递速率投递该混悬制剂。
可植入的装置例如装置提供了以下有益药物制剂施用的益处:有益药物的药物代谢动力学的真0级释放;长期释放时间(例如,多至约12个月);和有益药的可靠投递和给药。
其它可植入的药物递药装置可用于实施本发明,并且可包括调节器类型的可植入泵,该泵提供了化合物的恒定流速、可调流速或者可程序控制流速,例如从Codman&Shurtleff,Inc.(Raynham,MA)、Medtronic,Inc.(Minneapolis,MN)以及TricumedMedinzintechnikGmbH(德国)得到的那些。
可植入装置例如装置为本发明混悬制剂的施用提供了以下益处:促胰岛素释放肽药物的药物代谢动力学的真0级释放;长期释放时间(例如,多至约12个月);和促胰岛素释放肽的可靠投递和给药。
用于本发明递药装置的有益药的量是投递治疗有效量的药物以达到需要的治疗结果所必需的量。事实上,这会根据例如以下的变量而改变:特定的药物、投递位置、病症的严重度、和需要的治疗效果。通常,对于渗透递药装置,包含有益药制剂的有益药隔室的容积为约100μl至约1000μl,更优选为约120μl至约500μl,更优选为约150μl至约200μl。
通常,该渗透递药装置被植入到受试者中,例如皮下。该装置可被插入到一个或两个手臂上(例如,在上臂的内侧、外侧或背部)或者被插入到腹部。在腹部的优选位置是在腹部皮肤下、在肋下和腰线上扩展区域。为了提供多个位置以用于在腹部插入一个或多个渗透递药装置,可以将腹壁划分为以下4个象限:右上象限在右侧肋以下扩展5-8厘米并且到中线右侧5-8厘米,右下象限在腰线以上扩展5-8厘米并且到中线右侧约5-8厘米,左上象限在左侧肋以下扩展5-8厘米并且到中线左侧5-8厘米,以及左下象限在腰线以上扩展5-8厘米并且到中线左侧约5-8厘米。这样在一个或多个时期为植入一个或多个装置提供了多种有用的位置。
该混悬制剂也可以从药物递药装置中投递,该药物递药装置是不可植入的或者被植入,例如,外部泵如蠕动泵以用于医院环境下的皮下投递。
本发明混悬制剂也可用于输液泵,例如(DURECTCorporation,CupertinoCA)渗透泵,它是用于连续对试验动物给药(例如,小鼠和大鼠)的微型输液泵。
本发明混悬制剂还可以以注射剂的形式使用,以提供生物学有效的促胰岛素释放肽的高浓度推注剂量。
在本发明的一个实施方案中,例如,具有短半衰期的GLP-1衍生物和类似物(例如,GLP-1(7-36)酰胺或艾塞那肽)在从可植入装置中注射到人以后的连续投递将是特别有益的。此外,使用可植入装置例如装置以投递促胰岛素释放肽会降低与注射相关的副作用,并且增加给药的便利性,产生增加的治疗顺应性。药物从一个植入剂中投递的持续时间可以为数周或者长达1年。
通过渗透递药装置例如装置投递的本发明混悬制剂的一些优点和益处包括但不限于下面的。增加的治疗顺应性可产生更好的效果,并且此增加的顺应性可使用可植入的渗透递药装置来实现。可以改善治疗效果,原因是可植入的渗透装置例如装置可以每天24小时提供连续和连贯的药物(例如,GLP-1或艾塞那肽)投递,以提供白天和夜间更好的血糖水平控制。此外,据认为肠促胰岛素和肠促胰岛素模拟物可以保护胰腺中的β细胞并减缓2型糖尿病的发展。因此,肠促胰岛素或肠促胰岛素模拟物从装置中24小时连续和连贯的药物投递可提供对β细胞的更大的保护作用,并且可提供疾病发展的逆转。与例如用相对于每天主餐需要定时的推注治疗相比,促胰岛素释放肽(例如,GLP-1或艾塞那肽)从装置中的连续投递还使受治疗的受试者完全灵活计划配餐,并因此增加了生活质量。而且,与其它缓释制剂和贮库注射剂不同,当使用装置给药时,例如,如果对于特定受试者出现安全问题,则可通过除去该装置来立即中止给药。
除了证明有促胰岛素作用的GLP-1衍生物和类似物外,GLP-1的其它衍生物(例如,GLP-1(9-36)酰胺)显示出通过与胰岛素分泌无关的机制降低血糖(Deacon,C.F.,etal.,Am.J.Physiol.Endocrinol.Metab.282:E873-E879(2002))。此外,已显示GLP-1(9-36)酰胺不依赖胃排空和胰岛素分泌降低餐后高血糖(Meier,J.J.,etal.,Am.J.Physiol.Endocrinol.Metab.290.Ε1118-El123(2006))。相应地,在另一方面,本发明包括将此类GLP-1衍生物配制在微粒中,将该微粒混悬在载体中,以及给受试者投递这些混悬制剂,以基本上如上文针对证明有促胰岛素作用的GLP-1衍生物和类似物所述的降低血糖和/或降低餐后高血糖。此外,GIP(3-42)似乎是一种弱的GIP受体拮抗剂,其不产生胰岛素相关的糖代谢调节。此类GIP衍生物也可以根据本文提供的指导而被配制(单一地,或者与其它肽组合)。
本发明还包括制备本发明制剂,包括上文所述的微粒制剂、混悬载体和混悬制剂的方法。
4.0.0混悬制剂应用
本文描述的混悬制剂提供了糖尿病受试者胰岛素治疗的有希望的备选方案。2型糖尿病或2型糖尿病(亦称为非胰岛素依赖性糖尿病(NIDDM)或成年型糖尿病)是一种代谢障碍,其主要特征在于胰岛素耐受、相对胰岛素缺乏和高血糖病。本发明包含促胰岛素释放肽的混悬制剂可用于刺激胰岛素分泌、抑制胰高血糖素分泌、减慢胃排空、和可能增强周缘组织例如肌肉和脂肪中的胰岛素敏感度。
本发明混悬制剂可用于治疗糖尿病(例如,糖尿病和妊娠糖尿病),和糖尿病相关障碍(例如,糖尿病性心肌病、胰岛素耐受、糖尿病性神经病变、糖尿病性肾病变、糖尿病性视网膜病、白内障、高血糖病、高胆固醇血症、高血压、高胰岛素血症、高脂血症、动脉粥样硬化、和组织缺血特别是心肌缺血),以及高血糖病(例如,与用增加高血糖病风险的医药治疗相关的,包括β-阻滞剂、噻嗪类利尿剂、皮质激素、烟酸、喷他脒、蛋白酶抑制剂、L-门冬酰胺酶、和一些抗精神病药物),减少食物摄取(例如,治疗肥胖症、控制食欲或减轻体重),中风,降血脂,急性冠状动脉综合征,冬眠心肌,调节胃肠蠕动,和增加尿流量。
此外,本发明混悬制剂可能是用制剂治疗受试者的食欲的潜在调节剂。
在一个实施方案中,混悬制剂是使用上文所述渗透递药装置来施用的。投递本发明包含促胰岛素释放肽的混悬制剂的目标速率的实例包括但不限于:包含有GLP-1(例如,GLP-1(7-36)酰胺)的微粒制剂的混悬制剂,约20μg/天至约900μg/天,优选为约100μg/天至约600μg/天,例如约480μg/天;以及包含有艾塞那肽的微粒制剂的混悬制剂,约5μg/天至约320μg/天,优选为约5μg/天至约160μg/天,例如约10μg/天至约20μg/天。该混悬制剂从渗透递药装置出来的剪切速率确定为,促胰岛素释放肽的目标的每天目标投递速率是通过基本上连续地、均匀地从渗透递药装置投递该混悬制剂而适当地实现的。出口剪切速率的实例包括但不限于约1至约1x10-7倒数秒,优选约4x10-2至约6x10-4倒数秒,更优选5x10-3至1x10-3倒数秒。
用本发明混悬制剂治疗的受试者还可以从与其它药物(例如,磺酰脲类、氯茴苯酸类(例如,瑞格列奈和那格列奈)、二甲双胍和这些药物的组合)、α葡萄糖苷酶抑制剂、糊精(以及合成类似物例如普兰林肽)、二肽基肽酶IV(DPP-IV)抑制剂(例如,西格列汀(sitagliptin)和维格列汀(vildagliptin))、以及长/短效胰岛素的共同治疗中获益。
当本发明混悬制剂包含可通过二肽基肽酶-IV分解的GLP-1变异体时,口服二肽基肽酶-IV(DPP-IV或DPP-4)抑制剂经口应用以防止GLP-1分解可能是特别有用的(参见,例如,美国专利No.7,205,409)。
实施例5提供的数据证实,使用装置投递包含艾塞那肽的制剂会导致治疗动物的葡萄糖水平降低和体重减轻。
在阅读以下说明书和权利要求后,其它目的对于本领域技术人员而言会是显而易见的。
试验
阐明以下实施例是为以给本领域技术人员提供如何制备和使用本发明装置、方法和配方的完整讨论和说明,而不是限制发明人所考虑的本发明范围。已经作出努力以确保相对于所用数字的准确性(例如,量、温度等),但是一些试验误差和偏差是应当考虑的。除非另有说明,份是重量份,分子量是重均分子量,温度是摄氏度,压力为大气压或接近大气压。
根据本发明制备的组合物符合医药产品所要求的含量和纯度的技术要求。
实施例1
艾塞那肽微粒制剂
本实施例描述了制备艾塞那肽微粒制剂。
A.制剂1。
将艾塞那肽(0.25g)溶解于pH6.04的50mM枸橼酸钠缓冲液中。将该溶液用含有枸橼酸钠缓冲剂、蔗糖和蛋氨酸的制剂溶液透析。然后将配制的溶液使用Buchi290喷雾干燥,该Buchi290配有0.7mm喷嘴,出口温度为75℃,雾化压力100Psi,固含量2%,流速2.8mL/min。该干粉含有21.5%的含4.7%残留水份的艾塞那肽,和0.228g/ml密度。
B.制剂2和3。
艾塞那肽的两种其它制剂基本上通过上面所述方法制备。以下表3总结了制剂1、2和3的各组分的重量百分数(wt%)。
表3
*为此微粒制剂形成枸橼酸钠/枸椽酸的枸橼酸盐缓冲剂。
实施例2
GLP-1干粉
本实施例描述了制备GLP-1(7-36)酰胺微粒制剂。将GLP-1(7-36)酰胺(1.5g)溶解于pH4的5mM枸橼酸钠缓冲溶液中。将该溶液用含有枸橼酸钠缓冲剂和蛋氨酸的制剂溶液透析。然后将配制的溶液使用Buchi290喷雾干燥,该Buchi290配有0.7mm喷嘴,出口温度为70℃,雾化压力100Psi,固含量1.5%,流速5mL/min。该干粉含有90%的GLP-1(7-36)酰胺。
实施例3
艾塞那肽混悬制剂
本实施例描述了制备包含混悬载体和艾塞那肽微粒制剂的混悬制剂。
A.20wt%艾塞那肽微粒的混悬制剂。
艾塞那肽微粒制剂是通过喷雾-干燥产生的,含有20wt%艾塞那肽、32wt%蔗糖、16wt%蛋氨酸和32wt%枸橼酸盐缓冲剂。
通过将聚合物聚乙烯吡咯烷酮以约50/50重量比溶解于溶剂苯甲酸苄酯中形成混悬载体。当在33℃下测定时,该载体粘度为约12,000至18,000泊。将含有肽艾塞那肽的微粒分散在该载体中,微粒浓度为10%重量。
B.微粒制剂1、2和3的混悬制剂。
在干燥气氛和减压下,通过将聚合物聚乙烯吡咯烷酮K-17(通常具有大约7,900-10,800的平均分子量范围)以约50/50重量比溶解于加热至约65℃的溶剂苯甲酸苄酯中形成混悬载体。当在33℃下测定时,该载体粘度为约12,000至18,000泊。将实施例1描述的微粒制剂1-3分散在该载体中,浓度(重量百分数)显示于表4。
表4
实施例4
GLP-1(7-36)酰胺制剂
本实施例描述了制备包含混悬载体和GLP-1(7-36)酰胺微粒制剂的混悬制剂。GLP-1(7-36)酰胺微粒制剂是通过喷雾-干燥产生的,并且含有90wt%GLP-1、5wt%蛋氨酸和5wt%枸橼酸盐缓冲剂。
将含有聚合物聚乙烯吡咯烷酮的混悬载体以约50/50重量比溶解于溶剂苯甲酸苄酯中。当在33℃下测定时,该载体粘度为约12,000至18,000泊。将含有肽GLP-1(7-36)酰胺的微粒分散在该载体中,微粒浓度按重量计为33%。
实施例5
使用
装置连续投递艾塞那肽导致治疗动物的葡萄糖水平
降低和体重减轻
本实施例的数据证实从装置中连续和连贯的投递艾塞那肽制剂对2型糖尿病的Zucker糖尿病肥胖(ZDF)大鼠模型的葡萄糖水平和体重的作用。
ZDF大鼠模型先前已描述为2型糖尿病的精确模型,该模型基于会导致胰岛素耐受的遗传的肥胖症基因突变所引起的受损的葡萄糖耐量(参见,例如,Clark,J.,etal.,Proc.Soc.Exp.Biol.Med.173:68-75(1983);Peterson,R.G.,etal.,ILARNews32:16-19(1990);Peterson,R.G.,InFrontiersinDiabetesResearch.LessonsfromAnimalDiabetesIII,editedbyE.Shafrir,pp.456-458.London:Smith-Gordon(1990);Vrabec,J.T.,Otolaryngol.HeadNeckSurg118:304-308(1998);Sparks,J.D.,etal.,Metabolism47:1315-1324(1998))。
使用提供于表5的研究设计。
表5
组 | 治疗(mcg*/天) | ZDF大鼠类型 | 雄性数目 |
1 | 对照 | 肥胖 | 6 |
2 | 20 | 肥胖 | 6 |
3 | 20 | 精瘦 | 6 |
*微克
使治疗组大鼠(2组,肥胖;以及3组,精瘦,n=6/组)接受使用装置连续投递达7个24小时周期的20mcg/天的艾塞那肽(混悬制剂2;实施例3,表4)(其中该装置在第1天插入并在第8天除去),同时将安慰剂装置插入对照组大鼠(1组;n=6)。将该装置皮下插入到每只动物。
在治疗期间评价以下端点。临床体征/死亡率至少每天评价一次。植入之前、观察期间的每一天、以及结束时测定体重。如下测定血糖:在第1天和第8天收集禁食血样;在第1天和第8天每天3次(4-6小时间隔)取未禁食血样,在第1天和第8天取两个未禁食血样。使用OneTouch(Johnson&Johnson,NewBrunswickNJ)血糖计测定血糖。每天测定3次葡萄糖水平。使用DCA2000PlusAnalyzer(GMI,Inc.,RamseyMN)对在第1天和第8天收集的禁食血样测定定量HbA1c。在植入前(0),植后12、24、36、48、72小时和第5天及第7天获得系列血样。将这些样品离心,收集血浆,并贮存于-70℃。尸体剖检包括在观察期间的第8天进行肉眼检查。
图2提供了针对组平均体重所获得的数据(克)。在用艾塞那肽治疗的肥胖(图2;闭合正方形)和精瘦(图2;闭合三角形)大鼠中在第4天均观察到体重减轻(肥胖:第1天=329±15.2g,相比之下第4天=296.2±14.2g(p<0.01);以及精瘦:第1天=265.4±9.1g,相比之下第4天=237.6±7.8g(p<0.01))。总的说来,在第6天,肥胖治疗大鼠体重减轻10.7%,而精瘦治疗大鼠大鼠体重减轻15.1%。相反,用安慰剂装置的肥胖大鼠(图2;闭合菱形)在第6天显示体重稍微增加(1.8%)。
图3提供了针对组平均血糖浓度所获得的数据(mg/dL)。在装置插入之后1天内,与肥胖对照(图3;闭合菱形)相比,肥胖治疗大鼠(图3;闭合正方形)显示血糖水平降低明显。在第3天开始,肥胖治疗大鼠的平均葡萄糖水平为163±92mg/dL,而肥胖对照大鼠为481±47mg/dL(p<0.05)。在第3-7天,用20mcg/天的艾塞那肽治疗的肥胖大鼠血糖水平降低,其血糖水平接近于精瘦动物的,而安慰剂治疗的肥胖大鼠平均葡萄糖水平为502mg/dL。精瘦动物(图3;闭合三角形)始终为100mg/dL左右的葡萄糖水平。100mg/dL的葡萄糖水平认为是正常的。
图4提供了针对组平均血液HbA1c值所获得的数据。治疗的肥胖大鼠(图4;闭合正方形)显示HbA1c水平总体增加5.8%,而肥胖对照大鼠(图4;闭合菱形)在研究期间显示增加6.7%。尽管在此期间治疗的肥胖大鼠的平均血糖浓度降低,但在这些动物中未出现HbA1c相应的降低。此结果可能是由于该研究未足够长到在1至2个月期间HbA1c水平与平均血糖浓度成比例。
这些数据证实,连续、均匀投递艾塞那肽会导致治疗动物葡萄糖降低,并且有效影响体重。在人糖尿病的治疗中,这些结果支持了装置用于长期稳态给予肠促胰岛素模拟物例如包含艾塞那肽的混悬制剂的应用
本领域技术人员清楚,可以进行以上实施方案的各种修饰和变型而不会脱离本发明的精神和范围。这些修饰和变型落在本发明范围内。
Claims (15)
1.一种渗透递药装置,其包含
混悬制剂,其中所述混悬制剂包含:
微粒制剂,其包含促胰岛素释放肽、二糖、蛋氨酸和缓冲剂,其中(i)该促胰岛素释放肽是艾塞那肽、艾塞那肽的衍生物、或艾塞那肽的类似物,和(ii)该微粒制剂的微粒中该促胰岛素释放肽比(蛋氨酸+二糖)的重量百分比率为1/10至10/1;以及
非水性的、单相混悬载体,该混悬载体基本上由约20wt%-约60wt%苯甲酸苄酯和约80wt%-约40wt%聚乙烯吡咯烷酮构成,该混悬载体在33℃下具有的粘度为约12,000至约18,000泊;
其中该混悬载体表现出粘性流体特征,并且该微粒制剂分散在该混悬载体中,
并且该渗透递药装置提供约5μg/天至约160μg/天的该促胰岛素释放肽的真0级释放。
2.权利要求1的渗透递药装置,其中该促胰岛素释放肽是具有氨基酸序列SEQIDNO:2的合成的艾塞那肽肽。
3.权利要求1或2的渗透递药装置,其中该缓冲剂选自枸橼酸盐、组氨酸、琥珀酸盐及其混合物。
4.权利要求3的渗透递药装置,其中该缓冲剂是枸橼酸盐。
5.权利要求1-4任一项的渗透递药装置,其中该二糖选自乳糖、蔗糖、海藻糖、纤维二糖及其混合物。
6.权利要求1-5任一项的渗透递药装置,其中该微粒制剂是微粒的喷雾干燥制剂。
7.权利要求1-5任一项的渗透递药装置,其中该微粒制剂通过包括冷冻干燥的方法制备。
8.权利要求1-7任一项的渗透递药装置,其中该混悬载体为约50%溶剂和约50%聚合物。
9.权利要求1-8任一项的渗透递药装置,其中该混悬制剂具有低于或等于约10wt%的总水分含量。
10.权利要求1-8任一项的渗透递药装置,其还包括:
具有内腔的贮库,该内腔含有混悬制剂和渗透剂制剂;
位于该内腔中的活塞组件,其使该混悬制剂与该渗透剂制剂分离;
位于该贮库第一末端的半透膜,其邻近该渗透剂制剂;和
位于该贮库第二末端的流量调节器,其邻近该混悬制剂。
11.权利要求1-10任一项的渗透递药装置用于制备药物的用途,其中所述药物在有此治疗需要的受试者中治疗II型糖尿病,其中该治疗包括将所述的混悬制剂从所述渗透递药装置中以基本上均匀的速率对所述受试者投递达约1月至约1年的时间。
12.权利要求11的用途,其中所述的混悬制剂可通过除去该装置来立即中止递送。
13.权利要求1-10任一项的渗透递药装置用于制备药物的用途,其中所述药物在有此治疗需要的受试者中治疗肥胖,其中该治疗包括将所述的混悬制剂从所述渗透递药装置中以基本上均匀的速率对所述受试者投递达约1月至约1年的时间。
14.权利要求13的用途,其中所述的混悬制剂可通过除去所述装置来立即中止递送。
15.制备权利要求1-10任一项渗透递药装置的方法,该方法包括,将所述混悬制剂装载到所述渗透递药装置的贮库中。
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