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 PDF

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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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T·R·阿莱斯
R·D·摩瑟尔
C·M·罗洛夫
杨冰
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Intarcia Therapeutics Inc
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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

促胰岛素释放肽的混悬制剂及其应用
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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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7258869B1 (en) * 1999-02-08 2007-08-21 Alza Corporation Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicle
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
EP2280020B1 (en) 1999-06-29 2016-02-17 MannKind Corporation Pharmaceutical formulations comprising a peptide complexed with a diketopiperazine
EP1494732B1 (en) 2002-03-20 2008-01-30 MannKind Corporation Inhalation apparatus
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
US20050266087A1 (en) * 2004-05-25 2005-12-01 Gunjan Junnarkar Formulations having increased stability during transition from hydrophobic vehicle to hydrophilic medium
DK1786784T3 (da) 2004-08-20 2011-02-14 Mannkind Corp Katalyse af diketopiperazinsyntese
PL2322180T3 (pl) 2004-08-23 2015-10-30 Mannkind Corp Sole diketopiperazyny do dostarczania leków
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
WO2006083761A2 (en) 2005-02-03 2006-08-10 Alza Corporation Solvent/polymer solutions as suspension vehicles
CN104324366B (zh) 2005-09-14 2016-10-05 曼金德公司 以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法
MX360812B (es) 2006-02-22 2018-11-16 Mannkind Corp Un método para mejorar las propiedades farmacéuticas de micropartículas que contienen dicetopiperazina y un agente activo.
MX2008014870A (es) 2006-05-30 2009-02-12 Intarcia Therapeutics Inc Modulador de flujo para sistema de suministro osmotico con canal interno de dos piezas.
ES2422864T3 (es) 2006-08-09 2013-09-16 Intarcia Therapeutics, Inc Sistemas de liberación osmótica y unidades de pistón
WO2008133908A2 (en) * 2007-04-23 2008-11-06 Intarcia Therapeutics, Inc. Suspension formulations of insulinotropic peptides and uses thereof
US8785396B2 (en) * 2007-10-24 2014-07-22 Mannkind Corporation Method and composition for treating migraines
EP2229407B1 (de) 2008-01-09 2016-11-16 Sanofi-Aventis Deutschland GmbH Neue insulinderivate mit extrem verzögertem zeit- / wirkungsprofil
EP2240155B1 (en) 2008-02-13 2012-06-06 Intarcia Therapeutics, Inc Devices, formulations, and methods for delivery of multiple beneficial agents
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
DE202009018480U1 (de) 2008-06-13 2012-01-26 Mannkind Corp. Trockenpulverinhalator und System zur Medikamentenabgabe
MX2010014240A (es) 2008-06-20 2011-03-25 Mankind Corp Un metodo y aparato interactivo para perfilar en tiempo real esfuerzos de inhalacion.
TWI532497B (zh) 2008-08-11 2016-05-11 曼凱公司 超快起作用胰島素之用途
SG10201703039SA (en) 2008-09-04 2017-05-30 Amylin Pharmaceuticals Llc Sustained release formulations using non-aqueous carriers
US20100092566A1 (en) * 2008-10-15 2010-04-15 Alessi Thomas R Highly concentrated drug particles, formulations, suspensions and uses thereof
AU2014268265B2 (en) * 2008-10-15 2016-11-03 Intarcia Therapeutics, Inc. Highly concentrated drug particles, formulations, suspensions and uses thereof
CR20170369A (es) 2008-10-17 2017-11-01 Sanofi Aventis Deutschland COMBINACIÓN DE UNA INSULINA Y UN AGONISTA DE GLP-1 (Divisional 2011-0188)
US20100183876A1 (en) * 2008-12-23 2010-07-22 Hell Andre Process for the Preparation of a Peptide Powder Form
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
US8538707B2 (en) 2009-03-11 2013-09-17 Mannkind Corporation Apparatus, system and method for measuring resistance of an inhaler
KR101875969B1 (ko) 2009-06-12 2018-07-06 맨카인드 코포레이션 한정된 비표면적을 갖는 디케토피페라진 마이크로입자
CA2980198C (en) * 2009-07-06 2019-04-30 Sanofi-Aventis Deutschland Gmbh Insulin preparations containing methionine
EP2461818B1 (en) 2009-08-03 2018-10-17 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
AU2014280920B2 (en) * 2009-09-28 2016-05-12 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
WO2011037623A1 (en) * 2009-09-28 2011-03-31 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
CA2778698A1 (en) 2009-11-03 2011-05-12 Mannkind Corporation An apparatus and method for simulating inhalation efforts
EP3345593B1 (de) * 2009-11-13 2023-09-06 Sanofi-Aventis Deutschland GmbH Pharmazeutische zusammensetzung umfassend despro36exendin-4(1-39)-lys6-nh2 und methionin
EP3417871B1 (de) * 2009-11-13 2020-12-23 Sanofi-Aventis Deutschland GmbH Pharmazeutische zusammensetzung umfassend einen glp-1-agonisten, ein insulin und methionin
US8721620B2 (en) 2009-12-24 2014-05-13 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
CN102274182B (zh) * 2010-06-13 2013-04-03 上海现代药物制剂工程研究中心有限公司 一种含有艾塞那肽的多囊脂质体及其制备方法和应用
RU2571331C1 (ru) 2010-06-21 2015-12-20 Маннкайнд Корпорейшн Системы и способы доставки сухих порошковых лекарств
US20120046225A1 (en) 2010-07-19 2012-02-23 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
KR101823320B1 (ko) 2010-08-30 2018-01-31 사노피-아벤티스 도이칠란트 게엠베하 제２형 진성 당뇨병 치료용 약제를 제조하기 위한 ａｖｅ００１０의 용도
US9402807B2 (en) 2010-12-23 2016-08-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10639272B2 (en) 2010-12-23 2020-05-05 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US9284367B2 (en) 2010-12-23 2016-03-15 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8980822B2 (en) 2010-12-23 2015-03-17 Rani Therapeutics, Llc Therapeutic agent preparations comprising pramlintide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8809269B2 (en) 2010-12-23 2014-08-19 Rani Therapeutics, Llc Therapeutic agent preparations comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9402806B2 (en) 2010-12-23 2016-08-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9415004B2 (en) 2010-12-23 2016-08-16 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8734429B2 (en) 2010-12-23 2014-05-27 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US8846040B2 (en) 2010-12-23 2014-09-30 Rani Therapeutics, Llc Therapeutic agent preparations comprising etanercept for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9629799B2 (en) 2010-12-23 2017-04-25 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8809271B2 (en) 2010-12-23 2014-08-19 Rani Therapeutics, Llc Therapeutic agent preparations comprising liraglutide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8969293B2 (en) 2010-12-23 2015-03-03 Rani Therapeutics, Llc Therapeutic agent preparations comprising exenatide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9259386B2 (en) 2010-12-23 2016-02-16 Rani Therapeutics, Llc Therapeutic preparation comprising somatostatin or somatostatin analogoue for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9861683B2 (en) 2010-12-23 2018-01-09 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9283179B2 (en) 2010-12-23 2016-03-15 Rani Therapeutics, Llc GnRH preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
JP2014502985A (ja) * 2011-01-19 2014-02-06 ノヴォ ノルディスク アー／エス Ｇｌｐ−１粒子および組成物
CN103298457A (zh) * 2011-01-19 2013-09-11 诺沃—诺迪斯克有限公司 Glp-1组合物
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
EP3225235B1 (en) * 2011-03-10 2020-12-16 Xeris Pharmaceuticals, Inc. Stable peptide formulations for parenteral injection
WO2012122535A2 (en) * 2011-03-10 2012-09-13 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
BR122020008875B8 (pt) 2011-04-01 2022-12-06 Mannkind Corp Embalagem de bolha e método de fabricação de uma embalagem de bolhas
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
WO2013030160A1 (en) 2011-08-29 2013-03-07 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
AR087744A1 (es) 2011-09-01 2014-04-16 Sanofi Aventis Deutschland Composicion farmaceutica para uso en el tratamiento de una enfermedad neurodegenerativa
CA2852536A1 (en) 2011-10-24 2013-05-02 Mannkind Corporation Methods and compositions for treating pain
PL2773331T3 (pl) 2011-10-31 2016-08-31 Xeris Pharmaceuticals Inc Preparaty do leczenia cukrzycy
US9125805B2 (en) 2012-06-27 2015-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
KR102264177B1 (ko) 2012-07-12 2021-06-11 맨카인드 코포레이션 건조 분말 약물 전달 시스템 및 방법
UA116217C2 (uk) 2012-10-09 2018-02-26 Санофі Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону
US10159644B2 (en) 2012-10-26 2018-12-25 Mannkind Corporation Inhalable vaccine compositions and methods
WO2014096149A1 (en) 2012-12-21 2014-06-26 Sanofi Exendin-4 Derivatives
TWI641381B (zh) 2013-02-04 2018-11-21 法商賽諾菲公司 胰島素類似物及／或胰島素衍生物之穩定化醫藥調配物
US9018162B2 (en) 2013-02-06 2015-04-28 Xeris Pharmaceuticals, Inc. Methods for rapidly treating severe hypoglycemia
BR112015023168B1 (pt) 2013-03-15 2021-08-10 Mannkind Corporation Composição de 3,6-bis(n-fumaril-4-aminobutil)-2,5-dicetopiperazina cristalina, método de produção de partículas de 3,6-bis(n-fumaril-4-aminobutil)-2,5-dicetopiperazina e uso de uma composição de dicetopiperazina cristalina
CN114848614A (zh) 2013-07-18 2022-08-05 曼金德公司 热稳定性干粉药物组合物和方法
EP3030294B1 (en) 2013-08-05 2020-10-07 MannKind Corporation Insufflation apparatus
EP3080154B1 (en) 2013-12-13 2018-02-07 Sanofi Dual glp-1/gip receptor agonists
WO2015086733A1 (en) 2013-12-13 2015-06-18 Sanofi Dual glp-1/glucagon receptor agonists
WO2015086730A1 (en) 2013-12-13 2015-06-18 Sanofi Non-acylated exendin-4 peptide analogues
TW201609795A (zh) 2013-12-13 2016-03-16 賽諾菲公司 作為雙重ｇｌｐ－１／ｇｉｐ受體促效劑的艾塞那肽－４（ｅｘｅｎｄｉｎ－４）胜肽類似物
WO2015104311A1 (en) 2014-01-09 2015-07-16 Sanofi Stabilized glycerol free pharmaceutical formulations of insulin analogues and/or insulin derivatives
JP6735674B2 (ja) 2014-01-09 2020-08-05 サノフイＳａｎｏｆｉ インスリンアスパルトの安定化された医薬製剤
JP6641280B2 (ja) 2014-01-09 2020-02-05 サノフイＳａｎｏｆｉ インスリンアナログおよび／またはインスリン誘導体の安定化された医薬製剤
US10307464B2 (en) 2014-03-28 2019-06-04 Mannkind Corporation Use of ultrarapid acting insulin
TW201625668A (zh) 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
TW201625669A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
TW201625670A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
JP6982495B2 (ja) 2014-08-06 2021-12-17 ゼリス ファーマシューティカルズ インコーポレイテッド ペーストの皮内および／または皮下注射のためのシリンジ、キット、および方法
WO2016037128A1 (en) * 2014-09-04 2016-03-10 Nano Precision Medical, Inc. Polymeric stabilizing formulations
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
ES2949095T3 (es) 2014-12-12 2023-09-25 Sanofi Aventis Deutschland Formulación de relación fija de insulina glargina/lixisenatida
TWI748945B (zh) 2015-03-13 2021-12-11 德商賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患治療
TW201705975A (zh) 2015-03-18 2017-02-16 賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患之治療
RS62368B1 (sr) 2015-05-22 2021-10-29 Univ Leland Stanford Junior Lečenje postbarijatrijske hipoglikemije eksendinom(9-39)
CN113598842A (zh) 2015-06-03 2021-11-05 因塔西亚制药公司 植入物放置和移除系统
US9649364B2 (en) 2015-09-25 2017-05-16 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
AR105319A1 (es) 2015-06-05 2017-09-27 Sanofi Sa Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico
WO2016201248A1 (en) * 2015-06-10 2016-12-15 Xeris Pharmaceuticals, Inc. Use of low dose glucagon
TW201706291A (zh) 2015-07-10 2017-02-16 賽諾菲公司 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物
US11590205B2 (en) 2015-09-25 2023-02-28 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents
US10653753B2 (en) 2016-03-04 2020-05-19 Eiger Biopharmaceuticals, Inc. Treatment of hyperinsulinemic hypoglycemia with exendin-4 derivatives
EP3458084B1 (en) 2016-05-16 2020-04-01 Intarcia Therapeutics, Inc Glucagon-receptor selective polypeptides and methods of use thereof
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
EP3528836A1 (en) 2016-10-20 2019-08-28 Peptron, Inc. Methods of delivering a neuroprotective polypeptide to the central nervous system
AU2017361539B2 (en) 2016-11-21 2023-06-29 Eiger Biopharmaceuticals, Inc. Buffered formulations of exendin (9-39)
EP3565580B1 (en) 2017-01-03 2024-03-06 i2o Therapeutics, Inc. Continuous administration of exenatide and co-adminstration of acetaminophen, ethinylestradiol or levonorgestrel
JP7242060B2 (ja) * 2017-04-10 2023-03-20 武漢格睿特科技有限公司 代謝系疾病の治療に用いられるポリペプチドおよびその組成物
JP7299166B2 (ja) 2017-06-02 2023-06-27 ゼリス ファーマシューティカルズ インコーポレイテッド 沈殿抵抗性低分子薬物製剤
KR20200044016A (ko) 2017-08-24 2020-04-28 노보 노르디스크 에이/에스 Glp-1 조성물 및 그 용도
USD933219S1 (en) 2018-07-13 2021-10-12 Intarcia Therapeutics, Inc. Implant removal tool and assembly
US20210244658A1 (en) * 2018-08-24 2021-08-12 North Carolina State University Microneedle-array patches with glucose-responsive matrix for closed-loop insulin delivery
WO2020127950A1 (en) 2018-12-21 2020-06-25 Novo Nordisk A/S Process of spray drying of glp-1 peptide
AU2020219125A1 (en) 2019-02-05 2021-08-12 Lindy Biosciences, Inc. Isolated cell culture components and methods for isolating the same from liquid cell culture medium
AU2020270985A1 (en) * 2019-04-11 2021-12-09 Pfizer Ireland Pharmaceuticals Formulation for oral delivery of proteins, peptides and small molecules with poor permeability
JP7132441B2 (ja) 2020-02-18 2022-09-06 ノヴォ ノルディスク アー／エス Ｇｌｐ－１組成物およびその使用
CN115493919B (zh) * 2022-11-21 2023-04-07 保定佳瑞源生物芯片有限公司 一种c肽和胰岛素检测试剂盒的校准品稀释液

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040229814A1 (en) * 2002-08-28 2004-11-18 James Dillon Methods and compositions for protecting against cataract development associated with vitrectomies
US20050059612A1 (en) * 2003-09-16 2005-03-17 Benedikt Sas Bicyclic carbohydrates as antiviral bioactives for the treatment of infections caused by the alphaherpesvirinae HSV-1 and HSV-2
TW200634060A (en) * 2005-02-03 2006-10-01 Alza Corp Solvent/polymer solutions as suspension vehicles

Family Cites Families (662)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR640907A (fr) 1927-06-25 1928-07-24 Limitateur de débit automatique
US2168437A (en) 1935-04-10 1939-08-08 Kenneth O Buercklin Injection device
US2110208A (en) 1937-02-12 1938-03-08 U S Standard Products Company Antigen preparations
US3025991A (en) 1960-05-23 1962-03-20 Carron Products Co Bottle stopper
NL280825A (zh) 1962-07-11
GB1049104A (en) 1963-05-11 1966-11-23 Prodotti Antibiotici Spa Pharmaceutical compositions for oral or parenteral administration comprising tetracycline antibiotics
US3122162A (en) 1963-06-20 1964-02-25 Asa D Sands Flow control device
BE744162A (fr) 1969-01-16 1970-06-15 Fuji Photo Film Co Ltd Procede d'encapsulage
US3632768A (en) 1969-10-02 1972-01-04 Upjohn Co Therapeutic composition and method for treating infections with actinospectacin
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
DE2010115A1 (de) 1970-03-04 1971-09-16 Farbenfabriken Bayer Ag, 5090 Leverkusen Verfahren zur Herstellung von Mikrogranulaten
US3625214A (en) 1970-05-18 1971-12-07 Alza Corp Drug-delivery device
US3995631A (en) 1971-01-13 1976-12-07 Alza Corporation Osmotic dispenser with means for dispensing active agent responsive to osmotic gradient
US3732865A (en) 1971-01-13 1973-05-15 Alza Corp Osmotic dispenser
US4034756A (en) 1971-01-13 1977-07-12 Alza Corporation Osmotically driven fluid dispenser
US4211771A (en) 1971-06-01 1980-07-08 Robins Ronald K Treatment of human viral diseases with 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
JPS523342B2 (zh) 1972-01-26 1977-01-27
BE795516A (fr) 1972-02-17 1973-08-16 Ciba Geigy Preparations de peptides huileuses et injectables et procede pour leur preparation
US3797492A (en) 1972-12-27 1974-03-19 Alza Corp Device for dispensing product with directional guidance member
US3995632A (en) 1973-05-04 1976-12-07 Alza Corporation Osmotic dispenser
GB1413186A (en) 1973-06-27 1975-11-12 Toyo Jozo Kk Process for encapsulation of medicaments
DE2528516A1 (de) 1974-07-05 1976-01-22 Sandoz Ag Neue galenische zubereitung
JPS523653A (en) 1975-06-27 1977-01-12 Fuji Photo Film Co Ltd Process for producing fine polymer particles
US3987790A (en) 1975-10-01 1976-10-26 Alza Corporation Osmotically driven fluid dispenser
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4078060A (en) 1976-05-10 1978-03-07 Richardson-Merrell Inc. Method of inducing an estrogenic response
US4203439A (en) 1976-11-22 1980-05-20 Alza Corporation Osmotic system with volume amplifier for increasing amount of agent delivered therefrom
US4111202A (en) 1976-11-22 1978-09-05 Alza Corporation Osmotic system for the controlled and delivery of agent over time
US4111201A (en) 1976-11-22 1978-09-05 Alza Corporation Osmotic system for delivering selected beneficial agents having varying degrees of solubility
US4111203A (en) 1976-11-22 1978-09-05 Alza Corporation Osmotic system with means for improving delivery kinetics of system
USD258837S (en) 1977-10-17 1981-04-07 Gambro Dialysatoren Gmbh And Co. Kg Dialyzer cartridge
US4243030A (en) 1978-08-18 1981-01-06 Massachusetts Institute Of Technology Implantable programmed microinfusion apparatus
US4305927A (en) 1979-02-05 1981-12-15 Alza Corporation Method for the management of intraocular pressure
US4373527B1 (en) 1979-04-27 1995-06-27 Univ Johns Hopkins Implantable programmable medication infusion system
US4310516A (en) 1980-02-01 1982-01-12 Block Drug Company Inc. Cosmetic and pharmaceutical vehicle thickened with solid emulsifier
US4384975A (en) 1980-06-13 1983-05-24 Sandoz, Inc. Process for preparation of microspheres
AU546785B2 (en) 1980-07-23 1985-09-19 Commonwealth Of Australia, The Open-loop controlled infusion of diabetics
US4350271A (en) 1980-08-22 1982-09-21 Alza Corporation Water absorbing fluid dispenser
US4389330A (en) 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
US4376118A (en) 1980-10-06 1983-03-08 Miles Laboratories, Inc. Stable nonaqueous solution of tetracycline salt
PH19942A (en) 1980-11-18 1986-08-14 Sintex Inc Microencapsulation of water soluble polypeptides
US4340054A (en) 1980-12-29 1982-07-20 Alza Corporation Dispenser for delivering fluids and solids
US4455145A (en) 1981-07-10 1984-06-19 Alza Corporation Dispensing device with internal drive
AU561343B2 (en) 1981-10-19 1987-05-07 Genentech Inc. Human immune interferon by recombinant dna
EP0079143A3 (en) 1981-10-20 1984-11-21 Adnovum Ag Pseudoplastic gel transfer
EP0080879B1 (en) 1981-11-28 1986-10-01 Sunstar Kabushiki Kaisha Pharmaceutical composition containing interferon in stable state
US5004689A (en) 1982-02-22 1991-04-02 Biogen, Massachusetts DNA sequences, recombinant DNA molecules and processes for producing human gamma interferon-like polypeptides in high yields
US4439196A (en) 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4455143A (en) 1982-03-22 1984-06-19 Alza Corporation Osmotic device for dispensing two different medications
US6936694B1 (en) 1982-05-06 2005-08-30 Intermune, Inc. Manufacture and expression of large structural genes
DE3220116A1 (de) 1982-05-28 1983-12-01 Dr. Karl Thomae Gmbh, 7950 Biberach Mikrobiologisch hergestellte (alpha)- und ss-interferone, dna-sequenzen, die fuer diese interferone codieren, mikroorganismen, die diese genetische information enthalten, und verfahren zu ihrer herstellung
US4530840A (en) 1982-07-29 1985-07-23 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US4753651A (en) 1982-08-30 1988-06-28 Alza Corporation Self-driven pump
US4966843A (en) 1982-11-01 1990-10-30 Cetus Corporation Expression of interferon genes in Chinese hamster ovary cells
US4552561A (en) 1982-12-23 1985-11-12 Alza Corporation Body mounted pump housing and pump assembly employing the same
US4673405A (en) 1983-03-04 1987-06-16 Alza Corporation Osmotic system with instant drug availability
US4639244A (en) 1983-05-03 1987-01-27 Nabil I. Rizk Implantable electrophoretic pump for ionic drugs and associated methods
US4783337A (en) 1983-05-11 1988-11-08 Alza Corporation Osmotic system comprising plurality of members for dispensing drug
US4765989A (en) 1983-05-11 1988-08-23 Alza Corporation Osmotic device for administering certain drugs
DE3320583A1 (de) 1983-06-08 1984-12-13 Dr. Karl Thomae Gmbh, 7950 Biberach Neue galenische zubereitungsformen von oralen antidiabetika und verfahren zu ihrer herstellung
JPS6058915A (ja) 1983-09-12 1985-04-05 Fujisawa Pharmaceut Co Ltd 薬物含有脂質小胞体製剤
US4594108A (en) 1983-09-19 1986-06-10 The Dow Chemical Company Highly pseudoplastic polymer solutions
US5385738A (en) 1983-10-14 1995-01-31 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release injection
US5639639A (en) 1983-11-02 1997-06-17 Genzyme Corporation Recombinant heterodimeric human fertility hormones, and methods, cells, vectors and DNA for the production thereof
US4840896A (en) 1983-11-02 1989-06-20 Integrated Genetics, Inc. Heteropolymeric protein
US4923805A (en) 1983-11-02 1990-05-08 Integrated Genetics, Inc. Fsh
MX9203641A (es) 1983-12-16 1992-07-01 Genentech Inc Interferones gamma recombinantes que poseen estabilidad mejorada y metodos biotecnologicos para su obtencion.
US4855238A (en) 1983-12-16 1989-08-08 Genentech, Inc. Recombinant gamma interferons having enhanced stability and methods therefor
US4851228A (en) 1984-06-20 1989-07-25 Merck & Co., Inc. Multiparticulate controlled porosity osmotic
US5231176A (en) 1984-08-27 1993-07-27 Genentech, Inc. Distinct family DNA encoding of human leukocyte interferons
US5120832A (en) 1984-08-27 1992-06-09 Genentech, Inc. Distinct family of human leukocyte interferons
US4927687A (en) 1984-10-01 1990-05-22 Biotek, Inc. Sustained release transdermal drug delivery composition
US5411951A (en) 1984-10-04 1995-05-02 Monsanto Company Prolonged release of biologically active somatotropin
IE58110B1 (en) 1984-10-30 1993-07-14 Elan Corp Plc Controlled release powder and process for its preparation
FI90990C (fi) 1984-12-18 1994-04-25 Boehringer Ingelheim Int Rekombinantti-DNA-molekyyli, transformoitu isäntäorganismi ja menetelmä interferonin valmistamiseksi
US4655462A (en) 1985-01-07 1987-04-07 Peter J. Balsells Canted coiled spring and seal
JPS61189230A (ja) 1985-02-19 1986-08-22 Nippon Kayaku Co Ltd エトポシド製剤
US4609374A (en) 1985-04-22 1986-09-02 Alza Corporation Osmotic device comprising means for governing initial time of agent release therefrom
US4885166A (en) 1985-06-11 1989-12-05 Ciba-Geigy Corporation Hybrid interferons
US4845196A (en) 1985-06-24 1989-07-04 G. D. Searle & Co. Modified interferon gammas
US4847079A (en) 1985-07-29 1989-07-11 Schering Corporation Biologically stable interferon compositions comprising thimerosal
IE59361B1 (en) 1986-01-24 1994-02-09 Akzo Nv Pharmaceutical preparation for obtaining a highly viscous hydrogel or suspension
DE3607835A1 (de) 1986-03-10 1987-09-24 Boehringer Ingelheim Int Hybridinterferone, deren verwendung als arzneimittel und als zwischenprodukte zur herstellung von antikoerpern und deren verwendung sowie verfahren zu ihrer herstellung
US4865845A (en) 1986-03-21 1989-09-12 Alza Corporation Release rate adjustment of osmotic or diffusional delivery devices
US4737437A (en) 1986-03-27 1988-04-12 East Shore Chemical Co. Light sensitive diazo compound, composition and method of making the composition
US5120712A (en) 1986-05-05 1992-06-09 The General Hospital Corporation Insulinotropic hormone
US7138486B2 (en) 1986-05-05 2006-11-21 The General Hospital Corporation Insulinotropic hormone derivatives and uses thereof
US6849708B1 (en) 1986-05-05 2005-02-01 The General Hospital Corporation Insulinotropic hormone and uses thereof
US5118666A (en) 1986-05-05 1992-06-02 The General Hospital Corporation Insulinotropic hormone
US5614492A (en) 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
US4755180A (en) 1986-06-16 1988-07-05 Alza Corporation Dosage form comprising solubility regulating member
DE3636123A1 (de) 1986-10-23 1988-05-05 Rentschler Arzneimittel Arzneizubereitungen zur oralen verabreichung, die als einzeldosis 10 bis 240 mg dihydropyridin enthalten
ZA878295B (en) 1986-11-06 1988-05-03 Amarillo Cell Culture Co. Inc. Treatment of immuno-resistant disease
CA1320905C (en) 1986-11-06 1993-08-03 Joseph M. Cummins Treatment of immuno-resistant disease
DE3642096A1 (de) 1986-12-10 1988-06-16 Boehringer Ingelheim Int Pferde-(gamma)-interferon
US5371089A (en) 1987-02-26 1994-12-06 Senetek, Plc Method and composition for ameliorating the adverse effects of aging
US5278151A (en) 1987-04-02 1994-01-11 Ocular Research Of Boston, Inc. Dry eye treatment solution
JPH0720866B2 (ja) 1987-05-15 1995-03-08 三生製薬株式会社 エペリゾン又はトルペリゾン或いはそれらの塩類含有経皮適用製剤
US4940465A (en) 1987-05-27 1990-07-10 Felix Theeuwes Dispenser comprising displaceable matrix with solid state properties
US4892778A (en) 1987-05-27 1990-01-09 Alza Corporation Juxtaposed laminated arrangement
US4874388A (en) 1987-06-25 1989-10-17 Alza Corporation Multi-layer delivery system
US5938654A (en) 1987-06-25 1999-08-17 Alza Corporation Osmotic device for delayed delivery of agent
US5023088A (en) 1987-06-25 1991-06-11 Alza Corporation Multi-unit delivery system
US4915949A (en) 1987-07-13 1990-04-10 Alza Corporation Dispenser with movable matrix comprising a plurality of tiny pills
US4897268A (en) 1987-08-03 1990-01-30 Southern Research Institute Drug delivery system and method of making the same
ATE86484T1 (de) 1987-08-08 1993-03-15 Akzo Nv Kontrazeptives implantat.
US4915954A (en) 1987-09-03 1990-04-10 Alza Corporation Dosage form for delivering a drug at two different rates
US5756450A (en) 1987-09-15 1998-05-26 Novartis Corporation Water soluble monoesters as solubilisers for pharmacologically active compounds and pharmaceutical excipients and novel cyclosporin galenic forms
US4886668A (en) 1987-09-24 1989-12-12 Merck & Co., Inc. Multiparticulate controlled porosity osmotic pump
GB8723846D0 (en) 1987-10-10 1987-11-11 Danbiosyst Ltd Bioadhesive microsphere drug delivery system
WO1989003678A1 (en) 1987-10-30 1989-05-05 Stolle Research & Development Corporation Low residual solvent microspheres and microencapsulation process
US4917895A (en) 1987-11-02 1990-04-17 Alza Corporation Transdermal drug delivery device
US4907788A (en) 1988-04-25 1990-03-13 Peter J. Balsells Dual concentric canted-coil spring apparatus
US4974821A (en) 1988-04-25 1990-12-04 Peter J. Balsells Canted-coil spring with major axis radial loading
US5079388A (en) 1989-12-01 1992-01-07 Peter J. Balsells Gasket for sealing electromagnetic waves
US4964204A (en) 1988-04-25 1990-10-23 Peter J. Balsells Method for making a garter-type axially-resilient coil spring
DE68909295T2 (de) 1988-04-25 1994-05-11 Peter J Balsells In sich geschlossene ringförmige Schraubenfeder mit äusserem, rückwärtigem Neigungswinkel.
US5160122A (en) 1990-03-20 1992-11-03 Peter J. Balsells Coil spring with an elastomer having a hollow coil cross section
US4876781A (en) 1988-04-25 1989-10-31 Peter J. Balsells Method of making a garter-type axially resilient coiled spring
US5117066A (en) 1988-04-25 1992-05-26 Peter J. Balsells Retaining and locking electromagnetic gasket
US4915366A (en) 1988-04-25 1990-04-10 Peter J. Balsells Outside back angle canted coil spring
US4826144A (en) 1988-04-25 1989-05-02 Peter J. Balsells Inside back angle canted coil spring
US4961253A (en) 1988-04-25 1990-10-09 Peter J. Balsells Manufacturing method for canted-coil spring with turn angle and seal
US4934666A (en) 1988-04-25 1990-06-19 Peter J. Balsells Coiled spring electromagnetic shielding gasket
US5108078A (en) 1988-04-25 1992-04-28 Peter J. Balsells Canted-coil spring loaded while in a cavity
US5203849A (en) 1990-03-20 1993-04-20 Balsells Peter J Canted coil spring in length filled with an elastomer
US4830344A (en) 1988-04-25 1989-05-16 Peter J. Balsells Canted-coil spring with turn angle and seal
US4893795A (en) 1988-08-15 1990-01-16 Peter J. Balsells Radially loaded canted coiled spring with turn angle
US5072070A (en) 1989-12-01 1991-12-10 Peter J. Balsells Device for sealing electromagnetic waves
US5006346A (en) 1988-04-28 1991-04-09 Alza Corporation Delivery system
US4931285A (en) 1988-04-28 1990-06-05 Alza Corporation Aqueous based pharmaceutical coating composition for dosage forms
US5024842A (en) 1988-04-28 1991-06-18 Alza Corporation Annealed coats
US5160743A (en) 1988-04-28 1992-11-03 Alza Corporation Annealed composition for pharmaceutically acceptable drug
JP2827287B2 (ja) 1988-07-05 1998-11-25 武田薬品工業株式会社 水溶性薬物含有徐放型マイクロカプセル
JP2794022B2 (ja) 1988-11-11 1998-09-03 三生製薬株式会社 ブナゾシン或いはその塩類含有経皮適用製剤
US5059423A (en) 1988-12-13 1991-10-22 Alza Corporation Delivery system comprising biocompatible beneficial agent formulation
US5110596A (en) 1988-12-13 1992-05-05 Alza Corporation Delivery system comprising means for delivering agent to livestock
US5728088A (en) 1988-12-13 1998-03-17 Alza Corporation Osmotic system for delivery of fluid-sensitive somatotropins to bovine animals
US5034229A (en) 1988-12-13 1991-07-23 Alza Corporation Dispenser for increasing feed conversion of hog
US5057318A (en) 1988-12-13 1991-10-15 Alza Corporation Delivery system for beneficial agent over a broad range of rates
US4969884A (en) 1988-12-28 1990-11-13 Alza Corporation Osmotically driven syringe
US5234424A (en) 1988-12-28 1993-08-10 Alza Corporation Osmotically driven syringe
US4976966A (en) 1988-12-29 1990-12-11 Alza Corporation Delayed release osmotically driven fluid dispenser
IL92344A0 (en) 1989-01-04 1990-07-26 Gist Brocades Nv Microencapsulation of bioactive substances in biocompatible polymers,microcapsules obtained and pharmaceutical preparation comprising said microcapsules
US5288479A (en) 1989-01-17 1994-02-22 Sterling Drug, Inc. Extrudable elastic oral pharmaceutical gel compositions and metered dose dispensers containing them and method of making and method of use thereof
US5705363A (en) 1989-03-02 1998-01-06 The Women's Research Institute Recombinant production of human interferon τ polypeptides and nucleic acids
US5906816A (en) 1995-03-16 1999-05-25 University Of Florida Method for treatment of autoimmune diseases
US5219572A (en) 1989-03-17 1993-06-15 Pitman-Moore, Inc. Controlled release delivery device for macromolecular proteins
US5019400A (en) 1989-05-01 1991-05-28 Enzytech, Inc. Very low temperature casting of controlled release microspheres
EP0432232B1 (en) 1989-05-01 1994-01-05 Alkermes Controlled Therapeutics, Inc. Process for producing small particles of biologically active molecules
EP0471036B2 (en) 1989-05-04 2004-06-23 Southern Research Institute Encapsulation process
US5133974A (en) 1989-05-05 1992-07-28 Kv Pharmaceutical Company Extended release pharmaceutical formulations
US5126142A (en) 1989-07-18 1992-06-30 Alza Corporation Dispenser comprising ionophore
US5439688A (en) 1989-07-28 1995-08-08 Debio Recherche Pharmaceutique S.A. Process for preparing a pharmaceutical composition
US5225205A (en) 1989-07-28 1993-07-06 Debiopharm S.A. Pharmaceutical composition in the form of microparticles
EP0489843A4 (en) 1989-08-28 1992-08-12 Pharmaceutical Delivery Systems, Inc. Bioerodible polymers useful for the controlled release of therapeutic agents
US5112614A (en) 1989-09-14 1992-05-12 Alza Corporation Implantable delivery dispenser
US5290558A (en) 1989-09-21 1994-03-01 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
SE465950B (sv) 1989-10-23 1991-11-25 Medinvent Sa Kombination av ett aggregat partikelformat, kristallint eller frystorkat laekemedel med en pseudoplastisk gel foer beredning av ett injicerbart preparat samt foerfarande foer dess framstaellning
US5707644A (en) 1989-11-04 1998-01-13 Danbiosyst Uk Limited Small particle compositions for intranasal drug delivery
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
JPH0659302B2 (ja) 1989-11-13 1994-08-10 ベクトン・ディッキンソン・フランス・ソシエテ・アノニム ボトル
JPH03236317A (ja) 1989-12-06 1991-10-22 Sansei Seiyaku Kk ドパミン誘導体含有経皮用製剤
US5030216A (en) 1989-12-15 1991-07-09 Alza Corporation Osmotically driven syringe
US5733572A (en) 1989-12-22 1998-03-31 Imarx Pharmaceutical Corp. Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
USD326718S (en) 1989-12-26 1992-06-02 Minnesota Mining And Manufacturing Co. Blood sensor cassette
US5545618A (en) 1990-01-24 1996-08-13 Buckley; Douglas I. GLP-1 analogs useful for diabetes treatment
US5223266A (en) 1990-01-24 1993-06-29 Alza Corporation Long-term delivery device with early startup
US5213809A (en) 1990-01-24 1993-05-25 Alza Corporation Delivery system comprising means for controlling internal pressure
US5126147A (en) 1990-02-08 1992-06-30 Biosearch, Inc. Sustained release dosage form
US5478564A (en) 1990-02-22 1995-12-26 Teva Pharmaceutical Industries, Ltd. Preparation of microparticles for controlled release of water-soluble substances
US5122128A (en) 1990-03-15 1992-06-16 Alza Corporation Orifice insert for a ruminal bolus
US5120306A (en) 1990-03-21 1992-06-09 Gosselin Leon F Direct delivery of anti-inflammatories to the proximal small bowel
US5213810A (en) 1990-03-30 1993-05-25 American Cyanamid Company Stable compositions for parenteral administration and method of making same
US5207752A (en) 1990-03-30 1993-05-04 Alza Corporation Iontophoretic drug delivery system with two-stage delivery profile
US5324280A (en) 1990-04-02 1994-06-28 Alza Corporation Osmotic dosage system for delivering a formulation comprising liquid carrier and drug
US5091188A (en) 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5290271A (en) 1990-05-14 1994-03-01 Jernberg Gary R Surgical implant and method for controlled release of chemotherapeutic agents
JPH0441153A (ja) 1990-06-07 1992-02-12 Daikin Ind Ltd ビルトインモータの冷却装置
US5374620A (en) 1990-06-07 1994-12-20 Genentech, Inc. Growth-promoting composition and its use
US5234692A (en) 1990-07-11 1993-08-10 Alza Corporation Delivery device with a protective sleeve
US5180591A (en) 1990-07-11 1993-01-19 Alza Corporation Delivery device with a protective sleeve
US5234693A (en) 1990-07-11 1993-08-10 Alza Corporation Delivery device with a protective sleeve
US5234695A (en) 1990-07-24 1993-08-10 Eastman Kodak Company Water dispersible vitamin E composition
US5300302A (en) 1990-10-04 1994-04-05 Nestec S.A. Pharmaceutical composition in gel form in a dispensing package
US5529914A (en) 1990-10-15 1996-06-25 The Board Of Regents The Univeristy Of Texas System Gels for encapsulation of biological materials
US5151093A (en) 1990-10-29 1992-09-29 Alza Corporation Osmotically driven syringe with programmable agent delivery
US5122377A (en) 1990-11-19 1992-06-16 A.H. Robins, Company, Incorporated Oral delivery system for veterinary drugs
IT1243390B (it) 1990-11-22 1994-06-10 Vectorpharma Int Composizioni farmaceutiche in forma di particelle atte al rilascio controllato di sostanze farmacologicamente attive e procedimento per la loro preparazione.
US5161806A (en) 1990-12-17 1992-11-10 Peter J. Balsells Spring-loaded, hollow, elliptical ring seal
GB9027422D0 (en) 1990-12-18 1991-02-06 Scras Osmotically driven infusion device
WO1992011843A1 (en) 1991-01-09 1992-07-23 Alza Corporation Bioerodible devices and compositions for diffusional release of agents
NL9100160A (nl) 1991-01-30 1992-08-17 Texas Instruments Holland Injector.
US5443459A (en) 1991-01-30 1995-08-22 Alza Corporation Osmotic device for delayed delivery of agent
US5861166A (en) 1991-03-12 1999-01-19 Alza Corporation Delivery device providing beneficial agent stability
EP0720478A1 (en) 1991-05-07 1996-07-10 Dynagen, Inc. A controlled, sustained release delivery system for smoking cessation
US5113938A (en) 1991-05-07 1992-05-19 Clayton Charley H Whipstock
US5137727A (en) 1991-06-12 1992-08-11 Alza Corporation Delivery device providing beneficial agent stability
EP0520119A1 (de) 1991-06-17 1992-12-30 Spirig Ag Pharmazeutische Präparate Neue orale Diclofenaczubereitung
US5252338A (en) 1991-06-27 1993-10-12 Alza Corporation Therapy delayed
US5190765A (en) 1991-06-27 1993-03-02 Alza Corporation Therapy delayed
HU222501B1 (hu) 1991-06-28 2003-07-28 Endorecherche Inc. MPA-t vagy MGA-t tartalmazó nyújtott hatóanyag-felszabadulású gyógyászati készítmény és eljárás előállítására
DE4122217C2 (de) 1991-07-04 1997-02-13 Merz & Co Gmbh & Co Verfahren zur Herstellung mechanisch stabiler, gut zerfallender Komprimate aus kleinen wirkstoffhaltigen Formkörpern
US5288214A (en) 1991-09-30 1994-02-22 Toshio Fukuda Micropump
YU87892A (sh) 1991-10-01 1995-12-04 Eli Lilly And Company Lilly Corporate Center Injektibilne formulacije produženog otpuštanja i postupci za njihovo dobijanje i primenu
DE69229881T2 (de) 1991-10-04 1999-12-09 Yoshitomi Pharmaceutical Tablette mit verzögerter freisetzung
JPH07500264A (ja) 1991-10-10 1995-01-12 アルザ・コーポレーション 疎水性壁材料による浸透圧薬物投与デバイス
US5288502A (en) 1991-10-16 1994-02-22 The University Of Texas System Preparation and uses of multi-phase microspheres
US5318780A (en) 1991-10-30 1994-06-07 Mediventures Inc. Medical uses of in situ formed gels
US5236707A (en) 1991-11-08 1993-08-17 Dallas Biotherapeutics, Inc. Stabilization of human interferon
AU3136293A (en) 1991-11-15 1993-06-15 Isp Investments Inc. Pharmaceutical tablet with pvp having an enhanced drug dissolution rate
DE4137649C2 (de) 1991-11-15 1997-11-20 Gerhard Dingler Bauelement
US5200195A (en) 1991-12-06 1993-04-06 Alza Corporation Process for improving dosage form delivery kinetics
US5580578A (en) 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5223265A (en) 1992-01-10 1993-06-29 Alza Corporation Osmotic device with delayed activation of drug delivery
US5658593A (en) 1992-01-16 1997-08-19 Coletica Injectable compositions containing collagen microcapsules
US5676942A (en) 1992-02-10 1997-10-14 Interferon Sciences, Inc. Composition containing human alpha interferon species proteins and method for use thereof
US5308348A (en) 1992-02-18 1994-05-03 Alza Corporation Delivery devices with pulsatile effect
US5209746A (en) 1992-02-18 1993-05-11 Alza Corporation Osmotically driven delivery devices with pulsatile effect
US5456679A (en) 1992-02-18 1995-10-10 Alza Corporation Delivery devices with pulsatile effect
US5573934A (en) 1992-04-20 1996-11-12 Board Of Regents, The University Of Texas System Gels for encapsulation of biological materials
WO1993017075A1 (en) 1992-02-28 1993-09-02 Collagen Corporation High concentration homogenized collagen compositions
US5221278A (en) 1992-03-12 1993-06-22 Alza Corporation Osmotically driven delivery device with expandable orifice for pulsatile delivery effect
US5656297A (en) 1992-03-12 1997-08-12 Alkermes Controlled Therapeutics, Incorporated Modulated release from biocompatible polymers
WO1993019739A1 (en) 1992-03-30 1993-10-14 Alza Corporation Viscous suspensions of controlled-release drug particles
EP0633907A1 (en) 1992-03-30 1995-01-18 Alza Corporation Additives for bioerodible polymers to regulate degradation
US6197346B1 (en) 1992-04-24 2001-03-06 Brown Universtiy Research Foundation Bioadhesive microspheres and their use as drug delivery and imaging systems
FR2690622B1 (fr) 1992-04-29 1995-01-20 Chronotec Système de pompe à perfusion ambulatoire programmable.
US5314685A (en) 1992-05-11 1994-05-24 Agouron Pharmaceuticals, Inc. Anhydrous formulations for administering lipophilic agents
US5711968A (en) 1994-07-25 1998-01-27 Alkermes Controlled Therapeutics, Inc. Composition and method for the controlled release of metal cation-stabilized interferon
JP2651320B2 (ja) 1992-07-16 1997-09-10 田辺製薬株式会社 徐放性マイクロスフェア製剤の製造方法
US5413672A (en) 1992-07-22 1995-05-09 Ngk Insulators, Ltd. Method of etching sendust and method of pattern-etching sendust and chromium films
US5512293A (en) 1992-07-23 1996-04-30 Alza Corporation Oral sustained release drug delivery device
US5609885A (en) 1992-09-15 1997-03-11 Alza Corporation Osmotic membrane and delivery device
GB9223146D0 (en) 1992-11-05 1992-12-16 Scherer Corp R P Vented capsule
DE69224386T2 (de) 1992-11-06 1998-06-18 Texas Instruments Inc Vorrichtung zum subkutanen Einführen einer Nadel
EP0669128B1 (en) 1992-11-17 2000-01-05 Yoshitomi Pharmaceutical Industries, Ltd. Sustained-release microsphere containing antipsychotic and process for producing the same
US5260069A (en) 1992-11-27 1993-11-09 Anda Sr Pharmaceuticals Inc. Pulsatile particles drug delivery system
SE9203594D0 (sv) 1992-11-30 1992-11-30 Christer Nystroem Laekemedel i dispersa system
PT674506E (pt) 1992-12-02 2001-01-31 Alkermes Inc Microsferas contendo hormona de crescimento com libertacao controlada
TW333456B (en) 1992-12-07 1998-06-11 Takeda Pharm Ind Co Ltd A pharmaceutical composition of sustained-release preparation the invention relates to a pharmaceutical composition of sustained-release preparation which comprises a physiologically active peptide.
DK0686045T3 (da) 1993-02-23 2001-03-05 Genentech Inc Stabilisering af med organisk opløsningsmiddel behandlede polypeptider med et hjælpestof
US5368588A (en) 1993-02-26 1994-11-29 Bettinger; David S. Parenteral fluid medication reservoir pump
US5981719A (en) 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
AU6410494A (en) 1993-03-17 1994-10-11 Alza Corporation Device for the transdermal administration of alprazolam
US5514110A (en) 1993-03-22 1996-05-07 Teh; Eutiquio L. Automatic flow control device
HU225496B1 (en) 1993-04-07 2007-01-29 Scios Inc Pharmaceutical compositions of prolonged delivery, containing peptides
US6284727B1 (en) 1993-04-07 2001-09-04 Scios, Inc. Prolonged delivery of peptides
TW404844B (en) 1993-04-08 2000-09-11 Oxford Biosciences Ltd Needleless syringe
NZ247516A (en) 1993-04-28 1995-02-24 Bernard Charles Sherman Water dispersible pharmaceutical compositions comprising drug dissolved in solvent system comprising at least one alcohol and at least one surfactant
US5424286A (en) 1993-05-24 1995-06-13 Eng; John Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same
US5639477A (en) 1993-06-23 1997-06-17 Alza Corporation Ruminal drug delivery device
DE69401945T3 (de) 1993-06-25 2004-09-02 Alza Corp., Palo Alto Einarbeitung eines poly-n-vinylamids in ein transdermales system
US5498255A (en) 1993-08-17 1996-03-12 Alza Corporation Osmotic device for protracted pulsatile delivery of agent
US5385887A (en) 1993-09-10 1995-01-31 Genetics Institute, Inc. Formulations for delivery of osteogenic proteins
JP2700141B2 (ja) 1993-09-17 1998-01-19 富士化学工業株式会社 リン酸水素カルシウム及びその製法並びにそれを用いた賦形剤
JP3792252B2 (ja) 1993-09-29 2006-07-05 アルザ・コーポレーション オキシブチニンのためのモノグリセリド／乳酸エステル透過促進剤
US6913767B1 (en) 1993-10-25 2005-07-05 Genentech, Inc. Compositions for microencapsulation of antigens for use as vaccines
JP3645906B2 (ja) 1993-11-19 2005-05-11 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ マイクロカプセル封入された３−ピペリジニル−置換１，２−ベンズイソオキサゾール類及び１，２−ベンズイソチアゾール類
ATE212830T1 (de) 1993-11-19 2002-02-15 Alkermes Inc Herstellung biologisch abbaubarer, einen biologisch aktiven stoff enthaltender, mikropartikel
US5650173A (en) 1993-11-19 1997-07-22 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent
JPH07196479A (ja) 1994-01-04 1995-08-01 Unitika Ltd マイクロカプセルの製造法
USD358644S (en) 1994-01-18 1995-05-23 Bio Medic Data Systems, Inc. Transponder implanter
US6241734B1 (en) 1998-08-14 2001-06-05 Kyphon, Inc. Systems and methods for placing materials into bone
US5540665A (en) 1994-01-31 1996-07-30 Alza Corporation Gas driven dispensing device and gas generating engine therefor
ATE224704T1 (de) 1994-02-04 2002-10-15 Lipocore Holding Ab Doppelschicht-zusammensetzungen aus digalactosyldiacylglycerol enthaltendem galactolipid
US5697975A (en) 1994-02-09 1997-12-16 The University Of Iowa Research Foundation Human cerebral cortex neural prosthetic for tinnitus
US5458888A (en) 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
WO1995024212A1 (en) 1994-03-07 1995-09-14 Imperial College Of Science, Technology & Medicine The use of interferon subtypes in the preparation of medicaments to treat viral infections
ZA953078B (en) 1994-04-28 1996-01-05 Alza Corp Effective therapy for epilepsies
DK0768867T3 (da) 1994-06-13 2002-10-28 Alza Corp Doseringsform til indgivelse af lægemiddel i væskeformig formulering
NL9401150A (nl) 1994-07-12 1996-02-01 Nederland Ptt Werkwijze voor het aan een ontvangzijde aanbieden van een van een zendzijde afkomstig eerste aantal videosignalen, alsmede systeem, alsmede zender, alsmede netwerk, en alsmede ontvanger.
JP4090072B2 (ja) 1994-07-13 2008-05-28 アルザ・コーポレーション 経皮電気的移送式作用剤投与を促進するための組成物と方法
US5633011A (en) 1994-08-04 1997-05-27 Alza Corporation Progesterone replacement therapy
US5574008A (en) 1994-08-30 1996-11-12 Eli Lilly And Company Biologically active fragments of glucagon-like insulinotropic peptide
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5595759A (en) 1994-11-10 1997-01-21 Alza Corporation Process for providing therapeutic composition
WO1996014834A1 (en) 1994-11-10 1996-05-23 University Of Kentucky Research Foundation Implantable refillable controlled release device to deliver drugs directly to an internal portion of the body
FR2731150B1 (fr) 1995-03-03 1997-04-18 Oreal Utilisation de composes amphiphiles en tant qu'agent epaississant de milieux non aqueux
US6100346A (en) 1995-03-06 2000-08-08 Ethicon, Inc. Copolymers of polyoxaamides
US5700583A (en) 1995-03-06 1997-12-23 Ethicon, Inc. Hydrogels of absorbable polyoxaesters containing amines or amido groups
US6403655B1 (en) 1995-03-06 2002-06-11 Ethicon, Inc. Method of preventing adhesions with absorbable polyoxaesters
US5464929A (en) 1995-03-06 1995-11-07 Ethicon, Inc. Absorbable polyoxaesters
US5698213A (en) 1995-03-06 1997-12-16 Ethicon, Inc. Hydrogels of absorbable polyoxaesters
US5844017A (en) 1995-03-06 1998-12-01 Ethicon, Inc. Prepolymers of absorbable polyoxaesters containing amines and/or amido groups
US5597579A (en) 1995-03-06 1997-01-28 Ethicon, Inc. Blends of absorbable polyoxaamides
US5859150A (en) 1995-03-06 1999-01-12 Ethicon, Inc. Prepolymers of absorbable polyoxaesters
US5595751A (en) 1995-03-06 1997-01-21 Ethicon, Inc. Absorbable polyoxaesters containing amines and/or amido groups
US5648088A (en) 1995-03-06 1997-07-15 Ethicon, Inc. Blends of absorbable polyoxaesters containing amines and/or amide groups
US5607687A (en) 1995-03-06 1997-03-04 Ethicon, Inc. Polymer blends containing absorbable polyoxaesters
US5962023A (en) 1995-03-06 1999-10-05 Ethicon, Inc. Hydrogels containing absorbable polyoxaamides
US6147168A (en) 1995-03-06 2000-11-14 Ethicon, Inc. Copolymers of absorbable polyoxaesters
US5618552A (en) 1995-03-06 1997-04-08 Ethicon, Inc. Absorbable polyoxaesters
US5542682A (en) 1995-03-27 1996-08-06 American Variseal Slant coil spring and seal
US5736159A (en) 1995-04-28 1998-04-07 Andrx Pharmaceuticals, Inc. Controlled release formulation for water insoluble drugs in which a passageway is formed in situ
KR100404293B1 (ko) 1995-05-02 2004-02-18 다이쇼 세이야꾸 가부시끼가이샤 경구투여용조성물
US5939286A (en) 1995-05-10 1999-08-17 University Of Florida Hybrid interferon tau/alpha polypeptides, their recombinant production, and methods using them
US5922253A (en) 1995-05-18 1999-07-13 Alkermes Controlled Therapeutics, Inc. Production scale method of forming microparticles
US5882676A (en) 1995-05-26 1999-03-16 Alza Corporation Skin permeation enhancer compositions using acyl lactylates
US5718922A (en) 1995-05-31 1998-02-17 Schepens Eye Research Institute, Inc. Intravitreal microsphere drug delivery and method of preparation
DK0831826T3 (da) 1995-06-06 2003-02-03 Hoffmann La Roche Farmaceutisk præparat, som omfatter en proteaseinhibitor og et monoglycerid
US5690952A (en) 1995-06-07 1997-11-25 Judy A. Magruder et al. Implantable system for delivery of fluid-sensitive agents to animals
US6572879B1 (en) 1995-06-07 2003-06-03 Alza Corporation Formulations for transdermal delivery of pergolide
US7833543B2 (en) 1995-06-07 2010-11-16 Durect Corporation High viscosity liquid controlled delivery system and medical or surgical device
US5747058A (en) 1995-06-07 1998-05-05 Southern Biosystems, Inc. High viscosity liquid controlled delivery system
US6129761A (en) 1995-06-07 2000-10-10 Reprogenesis, Inc. Injectable hydrogel compositions
US5876746A (en) 1995-06-07 1999-03-02 Cygnus, Inc. Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen
US5904935A (en) 1995-06-07 1999-05-18 Alza Corporation Peptide/protein suspending formulations
US5782396A (en) 1995-08-28 1998-07-21 United States Surgical Corporation Surgical stapler
US5906830A (en) 1995-09-08 1999-05-25 Cygnus, Inc. Supersaturated transdermal drug delivery systems, and methods for manufacturing the same
US5942253A (en) 1995-10-12 1999-08-24 Immunex Corporation Prolonged release of GM-CSF
GB9521125D0 (en) 1995-10-16 1995-12-20 Unilever Plc Cosmetic composition
SE505146C2 (sv) 1995-10-19 1997-06-30 Biogram Ab Partiklar för fördröjd frisättning
US5766620A (en) 1995-10-23 1998-06-16 Theratech, Inc. Buccal delivery of glucagon-like insulinotropic peptides
GB9521805D0 (en) 1995-10-25 1996-01-03 Cortecs Ltd Solubilisation methods
PT771817E (pt) 1995-10-30 2003-06-30 Oleoyl Estrone Developments S Mono-esteres de oleato de estrogenos para o tratamento da obesidade e/ou excesso de peso
US5908621A (en) 1995-11-02 1999-06-01 Schering Corporation Polyethylene glycol modified interferon therapy
PT858343E (pt) 1995-11-02 2004-07-30 Schering Corp Terapia por infusao continua de uma dose baixa de citoquina
CA2192782C (en) 1995-12-15 2008-10-14 Nobuyuki Takechi Production of microspheres
CA2192773C (en) 1995-12-15 2008-09-23 Hiroaki Okada Production of sustained-release preparation for injection
AUPN723395A0 (en) 1995-12-19 1996-01-18 Macnaught Medical Pty Limited Lubrication methods
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
EP0787569B1 (en) 1996-01-31 2002-10-02 Sumitomo Bakelite Company Limited Method of producing epoxy resin-encapsulated semiconductor device
DE69734168T2 (de) 1996-02-02 2006-01-19 Alza Corp., Mountain View Implantierbares System mit verzögerter Wirkstofffreisetzung
US6261584B1 (en) 1996-02-02 2001-07-17 Alza Corporation Sustained delivery of an active agent using an implantable system
US6156331A (en) 1996-02-02 2000-12-05 Alza Corporation Sustained delivery of an active agent using an implantable system
US6395292B2 (en) 1996-02-02 2002-05-28 Alza Corporation Sustained delivery of an active agent using an implantable system
CA2279349C (en) 1996-02-02 2007-09-25 Rhomed Incorporated Ascorbate-stabilized radiopharmaceutical method and composition
US6132420A (en) 1996-02-02 2000-10-17 Alza Corporation Osmotic delivery system and method for enhancing start-up and performance of osmotic delivery systems
US5807876A (en) 1996-04-23 1998-09-15 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
US6245349B1 (en) 1996-02-23 2001-06-12 éLAN CORPORATION PLC Drug delivery compositions suitable for intravenous injection
ES2187756T3 (es) 1996-03-01 2003-06-16 Novo Nordisk As Uso de una composicion farmaceutica que comprende un peptido supresor del apetito.
JPH09241153A (ja) 1996-03-04 1997-09-16 Q P Corp 静脈注射用脂肪乳剤
CN1084747C (zh) 1996-03-08 2002-05-15 曾尼卡有限公司 作为神经活性剂的吡咯并苯并氮杂䓬衍生物
AU728146B2 (en) 1996-03-14 2001-01-04 Immune Response Corporation, The Targeted delivery of genes encoding interferon
US5703200A (en) 1996-03-15 1997-12-30 Ethicon, Inc. Absorbable copolymers and blends of 6,6-dialkyl-1,4-dioxepan-2-one and its cyclic dimer
WO1997035563A2 (en) 1996-03-28 1997-10-02 Takeda Chemical Industries, Ltd. Sustained-release preparation and its production
US5660858A (en) 1996-04-03 1997-08-26 Research Triangle Pharmaceuticals Cyclosporin emulsions
US6204022B1 (en) 1996-04-12 2001-03-20 Pepgen Corporation And University Of Florida Low-toxicity human interferon-alpha analogs
US6074673A (en) 1996-04-22 2000-06-13 Guillen; Manuel Slow-release, self-absorbing, drug delivery system
US5976109A (en) 1996-04-30 1999-11-02 Medtronic, Inc. Apparatus for drug infusion implanted within a living body
US5792477A (en) 1996-05-07 1998-08-11 Alkermes Controlled Therapeutics, Inc. Ii Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent
TW487572B (en) 1996-05-20 2002-05-21 Janssen Pharmaceutica Nv Aqueous suspensions of 9-hydroxyrisperidone fatty acid esters
DE69725745D1 (de) 1996-06-05 2003-11-27 Ashmont Holdings Ltd Injizierbare zusammensetzungen
JP2000516912A (ja) 1996-06-05 2000-12-19 ロシュ ダイアグノスティクス ゲゼルシャフト ミット ベシュレンクテル ハフツング エキセンジン類似体、それらの製造方法およびそれらを含有する製剤
DE29610419U1 (de) 1996-06-14 1996-10-24 Filtertek Sa Schwerkraftinfusionsvorrichtung für medizinische Infusionen
GB9613858D0 (en) 1996-07-02 1996-09-04 Cortecs Ltd Hydrophobic preparations
PT909175E (pt) 1996-07-03 2003-10-31 Alza Corp Formulacoes nao aquosas de peptidos proticos
US5916582A (en) 1996-07-03 1999-06-29 Alza Corporation Aqueous formulations of peptides
US5932547A (en) 1996-07-03 1999-08-03 Alza Corporation Non-aqueous polar aprotic peptide formulations
ATE322272T1 (de) 1996-07-15 2006-04-15 Alza Corp Neue formulierungen zur transdermale verabreichung von fluoxetin
AR008789A1 (es) 1996-07-31 2000-02-23 Bayer Corp Piridinas y bifenilos substituidos
US6458337B1 (en) 1996-08-02 2002-10-01 Dibra S.P.A Diagnostic imaging contrast agent with improved in serum relaxivity
AU4063697A (en) 1996-08-08 1998-02-25 Amylin Pharmaceuticals, Inc. Methods for regulating gastrointestinal motility
AU3981097A (en) 1996-08-21 1998-03-06 Alkermes Controlled Therapeutics, Inc. Controlled release microparticles with a hydrophobic material
US6458924B2 (en) 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
US6268343B1 (en) 1996-08-30 2001-07-31 Novo Nordisk A/S Derivatives of GLP-1 analogs
US5984890A (en) 1996-09-27 1999-11-16 American Home Products Corporation Medical device for the placement of solid materials
IN184589B (zh) 1996-10-16 2000-09-09 Alza Corp
CA2264687C (en) 1996-10-24 2006-04-25 Alza Corporation Permeation enhancers for transdermal drug delivery compositions, devices, and methods
US5817129A (en) 1996-10-31 1998-10-06 Ethicon, Inc. Process and apparatus for coating surgical sutures
UA65549C2 (uk) 1996-11-05 2004-04-15 Елі Ліллі Енд Компані Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція
DE19646392A1 (de) 1996-11-11 1998-05-14 Lohmann Therapie Syst Lts Zubereitung zur Anwendung in der Mundhöhle mit einer an der Schleimhaut haftklebenden, Pharmazeutika oder Kosmetika zur dosierten Abgabe enthaltenden Schicht
US5928666A (en) 1996-11-12 1999-07-27 Cygnus Inc. Crystalline form of estradiol and pharmaceutical formulations comprising same
PT1066081E (pt) 1996-11-15 2003-12-31 Alza Corp Sistema de distribuicao osmotica e processo para melhorar o inicio e o desempenho de sistemas de distribuicao osmotica
GB9626513D0 (en) 1996-12-20 1997-02-05 Bioglan Ireland R & D Ltd A pharmaceutical composition
ATE203157T1 (de) 1996-12-20 2001-08-15 Alza Corp Injizierbare depotgelzubereitung und herstellungsverfahren
CA2277112C (en) 1997-01-07 2008-08-26 Amylin Pharmaceuticals, Inc. Use of exendins and agonists thereof for the reduction of food intake
JP2001511128A (ja) 1997-01-28 2001-08-07 ファルマシア・アンド・アップジョン・カンパニー 水不溶性ポルフィリンの脂質錯体の凍結乾燥物
US5945126A (en) 1997-02-13 1999-08-31 Oakwood Laboratories L.L.C. Continuous microsphere process
ZA981610B (en) 1997-03-24 1999-08-26 Alza Corp Self adjustable exit port.
US5874388A (en) 1997-04-02 1999-02-23 Dow Corning Corporation Lubricant composition for disc brake caliper pin and a disc brake asembly containing the lubricant
US6127520A (en) 1997-04-15 2000-10-03 Regents Of The University Of Michigan Compositions and methods for the inhibition of neurotransmitter uptake of synaptic vesicles
JP2001524958A (ja) 1997-04-17 2001-12-04 ジーエス ディベロップメント アクティエボラーグ 新規な液晶をベースとする生物接着性薬剤送出系
TW577759B (en) 1997-04-18 2004-03-01 Ipsen Pharma Biotech Sustained release compositions in the form of microcapsules or implants and the process for their preparation
WO1998049321A2 (en) 1997-04-28 1998-11-05 Rhone-Poulenc Rorer S.A. Adenovirus-mediated intratumoral delivery of an angiogenesis antagonist for the treatment of tumors
US20020039594A1 (en) 1997-05-13 2002-04-04 Evan C. Unger Solid porous matrices and methods of making and using the same
US6663899B2 (en) 1997-06-13 2003-12-16 Genentech, Inc. Controlled release microencapsulated NGF formulation
US6113947A (en) 1997-06-13 2000-09-05 Genentech, Inc. Controlled release microencapsulated NGF formulation
SI9700186B (sl) 1997-07-14 2006-10-31 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Nova farmacevtska oblika z nadzorovanim sproscanjem zdravilnih ucinkovin
MY125870A (en) 1997-07-25 2006-08-30 Alza Corp Osmotic delivery system flow modulator apparatus and method
MY125849A (en) 1997-07-25 2006-08-30 Alza Corp Osmotic delivery system, osmotic delivery system semipermeable body assembly, and method for controlling delivery rate of beneficial agents from osmotic delivery systems
US7157555B1 (en) 1997-08-08 2007-01-02 Amylin Pharmaceuticals, Inc. Exendin agonist compounds
GB9718986D0 (en) 1997-09-09 1997-11-12 Danbiosyst Uk Controlled release microsphere delivery system
US6172046B1 (en) 1997-09-21 2001-01-09 Schering Corporation Combination therapy for eradicating detectable HCV-RNA in patients having chronic Hepatitis C infection
US5989463A (en) 1997-09-24 1999-11-23 Alkermes Controlled Therapeutics, Inc. Methods for fabricating polymer-based controlled release devices
JPH11100353A (ja) 1997-09-29 1999-04-13 Esupo Kk 精製・脱臭液状エステルワックスとその組成物
DK1019022T4 (da) 1997-09-29 2010-11-08 Novartis Ag Perforerede mikropartikler og fremgangsmåde til anvendelse deraf
US6133429A (en) 1997-10-03 2000-10-17 Becton Dickinson And Company Chromophores useful for the preparation of novel tandem conjugates
WO1999025728A1 (en) 1997-11-14 1999-05-27 Amylin Pharmaceuticals, Inc. Novel exendin agonist compounds
AU761577C (en) 1997-12-08 2004-02-05 Genentech Inc. Human interferon-epsilon: a type I interferon
US6368612B1 (en) 1997-12-12 2002-04-09 Biohybrid Technologies Llc Devices for cloaking transplanted cells
CA2315890C (en) 1997-12-22 2009-08-11 Alza Corporation Rate controlling membranes for controlled drug delivery devices
KR100546982B1 (ko) 1997-12-29 2006-01-26 알자 코포레이션 피하 이식물 이식장치
JP4173635B2 (ja) 1997-12-29 2008-10-29 インターシア セラピューティクス，インコーポレイティド 膜プラグ保持機構を有する浸透供給装置
EP1300173B1 (en) 1997-12-29 2006-06-14 Alza Corporation Implanter device for subcutaneous implants
EP1041974B1 (en) * 1997-12-30 2006-10-11 Alza Corporation Beneficial agent delivery system with membrane plug
US20040024068A1 (en) 1998-01-23 2004-02-05 Trustees Of Tufts College Antimicrobial compounds
IT1298575B1 (it) 1998-02-06 2000-01-12 Vectorpharma Int Composizioni farmaceutiche in forma di nanoparticelle comprendenti sostanze lipidiche e sostanze antifiliche e relativo processo di
US6017545A (en) 1998-02-10 2000-01-25 Modi; Pankaj Mixed micellar delivery system and method of preparation
ATE366115T1 (de) 1998-02-13 2007-07-15 Amylin Pharmaceuticals Inc Inotropische und diuretische effekte von exendin und glp-1
US6703359B1 (en) 1998-02-13 2004-03-09 Amylin Pharmaceuticals, Inc. Inotropic and diuretic effects of exendin and GLP-1
USD408917S (en) 1998-02-26 1999-04-27 Minnesota Mining And Manufacturing Company Membrane support structure of a flow through cell for blood gas measurement
US6224577B1 (en) 1998-03-02 2001-05-01 Medrad, Inc. Syringes and plungers for use therein
US6056718A (en) 1998-03-04 2000-05-02 Minimed Inc. Medication infusion set
US6245357B1 (en) 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US6183461B1 (en) 1998-03-11 2001-02-06 Situs Corporation Method for delivering a medication
US20020136848A1 (en) 1998-03-12 2002-09-26 Fumio Yoshii Lactone-containing resin composition, molded object thereof, and film
US6029361A (en) 1998-03-25 2000-02-29 Ultratech Stepper, Inc. Air-guage nozzle probe structure for microlithographic image focusing
US6074660A (en) 1998-04-20 2000-06-13 Ethicon, Inc. Absorbable polyoxaesters containing amines and/ or amido groups
TW586944B (en) 1998-05-29 2004-05-11 Sumitomo Pharma Controlled release agent having a multi-layer structure
US8626302B2 (en) 1998-06-03 2014-01-07 Spr Therapeutics, Llc Systems and methods to place one or more leads in muscle for providing electrical stimulation to treat pain
SK19042000A3 (sk) 1998-06-12 2001-11-06 Bionebraska, Inc. Glukagónu podobný peptid-1 zlepšujúci odpoveď beta-bunkiek na glukózu u subjektov so zhoršenou toleranciou glukózy
ATE428371T1 (de) 1998-07-17 2009-05-15 Pacira Pharmaceuticals Inc Biologisch abbaubare anordnungen zur kontrollierten freigabe eingeschlossener substanzen
US7390637B2 (en) 1998-07-21 2008-06-24 Human Genome Sciences, Inc. Keratinocyte derived interferon
US6472512B1 (en) 1998-07-21 2002-10-29 Human Genome Sciences, Inc. Keratinocyte derived interferon
US6270700B1 (en) 1998-07-23 2001-08-07 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Encapsulation of water soluble peptides
US6720407B1 (en) 1998-08-28 2004-04-13 Eli Lilly And Company Method for administering insulinotropic peptides
US6551613B1 (en) 1998-09-08 2003-04-22 Alza Corporation Dosage form comprising therapeutic formulation
EP1112060B1 (en) 1998-09-09 2005-12-07 ALZA Corporation Dosage form comprising liquid formulation
US6174547B1 (en) 1999-07-14 2001-01-16 Alza Corporation Dosage form comprising liquid formulation
US6248112B1 (en) 1998-09-30 2001-06-19 C. R. Bard, Inc. Implant delivery system
US6284725B1 (en) 1998-10-08 2001-09-04 Bionebraska, Inc. Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue
AU1238500A (en) 1998-11-02 2000-05-22 Alza Corporation Controlled delivery of active agents
WO2000029206A1 (en) 1998-11-13 2000-05-25 Sensor Technologies Inc. Monodisperse preparations useful with implanted devices
US20030060425A1 (en) 1998-11-24 2003-03-27 Ahlem Clarence N. Immune modulation method using steroid compounds
CZ295890B6 (cs) 1998-12-07 2005-11-16 Societe De Conseils De Recherches Et D'application Analogy GLP-1, mající kyselinu aminoizomáselnou pozici 8 a D-arginin na pozici 36, jejich použití a farmaceutické prostředky je obsahující
ES2213404T3 (es) 1998-12-17 2004-08-16 Alza Corporation Transformacion de capsulas de gelatina rellenas de liquido en sistemas de liberacion controlada mediante multiples revestimientos.
KR100491815B1 (ko) 1998-12-23 2005-05-27 암젠 인코포레이티드 단백질의 서방성 수송을 위한 폴리올/오일 현탁액을 포함하는 제약학적 조성물 및 그것의 제조방법
US6433144B1 (en) 1999-01-12 2002-08-13 Viragen, Inc. Compositions of highly-purified natural mixtures of type I Interferon derived from leukocytes and methods
EP1140144A4 (en) 1998-12-31 2002-10-30 Viragen Inc METHODS AND COMPOSITION OF EXTREMELY PURIFIED NATURAL MIXTURES OF TYPE I INTERFERONS DERIVED FROM LEUCOCYTES
AU771132B2 (en) 1998-12-31 2004-03-11 Intarcia Therapeutics, Inc. Osmotic delivery system having space efficient piston
WO2000040273A2 (en) 1999-01-08 2000-07-13 Vical Incorporated Treatment of viral diseases using an interferon omega expressing polynucleotide
US6703225B1 (en) 1999-01-12 2004-03-09 Sumitomo Pharmaceuticals Company, Limited Interferon-α
EP1143989B1 (en) 1999-01-14 2006-12-13 Amylin Pharmaceuticals, Inc. Exendins for glucagon suppression
US7399489B2 (en) 1999-01-14 2008-07-15 Amylin Pharmaceuticals, Inc. Exendin analog formulations
PT1140145E (pt) 1999-01-14 2005-11-30 Amylin Pharmaceuticals Inc Formulacoes novas de agonistas de exendina e metodos para a sua administracao
US7919109B2 (en) 1999-02-08 2011-04-05 Intarcia Therapeutics, Inc. Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles
EP1666026B2 (en) * 1999-02-08 2015-02-25 Intarcia Therapeutics, Inc Non-aqueous single phase biocompatible viscous vehicles and methods for preparing the same
US7258869B1 (en) 1999-02-08 2007-08-21 Alza Corporation Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicle
US6451974B1 (en) 1999-03-17 2002-09-17 Novo Nordisk A/S Method of acylating peptides and novel acylating agents
US6835194B2 (en) 1999-03-18 2004-12-28 Durect Corporation Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners
WO2002043800A2 (en) 2000-11-29 2002-06-06 Durect Corporation Devices and methods for controlled delivery from a drug delivery device
US6541021B1 (en) 1999-03-18 2003-04-01 Durect Corporation Devices and methods for pain management
CA2367131C (en) 1999-04-05 2007-07-03 Solomon S. Steiner Methods for fine powder formation
GB9907658D0 (en) 1999-04-06 1999-05-26 Zeneca Ltd Chemical compounds
CO5241354A1 (es) 1999-04-19 2003-01-31 Schering Corp Terapia de combinacio para vhc
US6924264B1 (en) 1999-04-30 2005-08-02 Amylin Pharmaceuticals, Inc. Modified exendins and exendin agonists
US6291013B1 (en) 1999-05-03 2001-09-18 Southern Biosystems, Inc. Emulsion-based processes for making microparticles
TR200103188T2 (tr) 1999-05-07 2002-04-22 Pharmasol Gmbh Sıvı ve katı lipit karışımları temelli lipid parçacıklar.
US6849714B1 (en) 1999-05-17 2005-02-01 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US6514500B1 (en) 1999-10-15 2003-02-04 Conjuchem, Inc. Long lasting synthetic glucagon like peptide {GLP-!}
US6887470B1 (en) 1999-09-10 2005-05-03 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
JP4115671B2 (ja) 1999-05-17 2008-07-09 コンジュケム バイオテクノロジーズ インコーポレイテッド 長期間持続するインシュリン向性ペプチド
US6506724B1 (en) 1999-06-01 2003-01-14 Amylin Pharmaceuticals, Inc. Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus
US20030059376A1 (en) 1999-06-04 2003-03-27 Libbey Miles A. Formulations comprising dehydrated particles of pharmaceutical agents and process for preparing the same
EP1187639A1 (en) 1999-06-04 2002-03-20 Delrx Pharmaceutical Corporation Formulations comprising dehydrated particles of pharmaceutical agents and process for preparing the same
AU779277B2 (en) 1999-06-04 2005-01-13 Alza Corporation Implantable gel compositions and method of manufacture
US20010040326A1 (en) 1999-06-14 2001-11-15 Lord Corporation Resilient member with deformed element and method of forming same
US6833256B1 (en) 1999-06-22 2004-12-21 University Of Maryland Interferon tau mutants and methods for making them
US6528486B1 (en) 1999-07-12 2003-03-04 Zealand Pharma A/S Peptide agonists of GLP-1 activity
SE9903236D0 (sv) 1999-09-10 1999-09-10 Astra Ab Method to obtain microparticles
US6284283B1 (en) 1999-10-21 2001-09-04 Alkermes Controlled Therapeutics, Inc. Method of producing sub-micron particles of biologically active agents and uses thereof
US6436091B1 (en) 1999-11-16 2002-08-20 Microsolutions, Inc. Methods and implantable devices and systems for long term delivery of a pharmaceutical agent
US7022674B2 (en) 1999-12-16 2006-04-04 Eli Lilly And Company Polypeptide compositions with improved stability
WO2001043528A2 (en) 1999-12-17 2001-06-21 Durect Corporation Devices and methods in intracerebrospinal delivery of morphine-6-glucuronide
AU773354B2 (en) 1999-12-21 2004-05-20 Intarcia Therapeutics, Inc. Valve for osmotic devices
US6498193B2 (en) 1999-12-22 2002-12-24 Trustees Of Dartmouth College Treatment for complications of type 2 diabetes
US6283949B1 (en) 1999-12-27 2001-09-04 Advanced Cardiovascular Systems, Inc. Refillable implantable drug delivery pump
US6572890B2 (en) 2000-01-13 2003-06-03 Osmotica Corp. Osmotic device containing venlafaxine and an anti-psychotic agent
US6472060B1 (en) 2000-01-19 2002-10-29 Seco Tools Ab Coated body with nanocrystalline CVD coating for enhanced edge toughness and reduced friction
US6844321B2 (en) 2000-01-31 2005-01-18 Novo Nordisk A/S Crystallization of a GLP-1 analogue
US6465425B1 (en) 2000-02-10 2002-10-15 Alkermes Controlled Therapeutics, Inc. Microencapsulation and sustained release of biologically active acid-stable or free sulfhydryl-containing proteins
US6464688B1 (en) 2000-02-15 2002-10-15 Microsolutions, Inc. Osmotic pump delivery system with flexible drug compartment
US6471688B1 (en) 2000-02-15 2002-10-29 Microsolutions, Inc. Osmotic pump drug delivery systems and methods
WO2001068112A2 (en) 2000-03-14 2001-09-20 Goeke Burkhard Effects of glucagon-like peptide-1 (7-36) on antro-pyloro-duodenal motility
US20030211974A1 (en) 2000-03-21 2003-11-13 Brodbeck Kevin J. Gel composition and methods
US8574146B2 (en) 2000-04-14 2013-11-05 Attenuex Technologies, Inc. Implant with high vapor pressure medium
ATE309822T1 (de) 2000-04-19 2005-12-15 Genentech Inc Formulierungen mit verzögerter freisetzung enthaltend wachstumshormon
WO2001080897A2 (en) 2000-04-21 2001-11-01 Vical Incorporated Compositions and methods for in vivo delivery of polynucleotide-based therapeutics
DE60134403D1 (de) 2000-05-19 2008-07-24 Amylin Pharmaceuticals Inc Behandlung des akuten koronaren syndroms mit glp-1
US6495164B1 (en) 2000-05-25 2002-12-17 Alkermes Controlled Therapeutics, Inc. I Preparation of injectable suspensions having improved injectability
DE60124710T2 (de) 2000-06-16 2007-09-13 Eli Lilly And Co., Indianapolis Analoge des glucagon ähnlichen peptid-1
US6479065B2 (en) 2000-08-10 2002-11-12 Alkermes Controlled Therapeutics, Inc. Process for the preparation of polymer-based sustained release compositions
US6824822B2 (en) 2001-08-31 2004-11-30 Alkermes Controlled Therapeutics Inc. Ii Residual solvent extraction method and microparticles produced thereby
AU2001296770A1 (en) 2000-10-06 2002-04-15 Durect Corporation Devices and methods for management of inflammation
BR0115392A (pt) 2000-11-03 2004-06-15 Biomedicines Inc Método para o tratamento de uma doença sensìvel a interferona em um animal de sangue quente, método para individualizar as dosagens de uma interferona no tratamento, método para a fabricação de um dispositivo de liberação de efeito terapêutico de longa duração de uma droga ao longo de um perìodo de tempo, e conjunto útil para a ministração de uma quantidade relativamente constante de uma droga
CA2429898C (en) 2000-11-16 2011-02-22 Durect Corporation Devices and methods for cholesterol management
DE60139430D1 (de) 2000-12-07 2009-09-10 Lilly Co Eli GLP-1 Fusionsproteine
US20020165286A1 (en) 2000-12-08 2002-11-07 Hanne Hedeman Dermal anti-inflammatory composition
EP1390061A2 (en) 2000-12-13 2004-02-25 Eli Lilly And Company Chronic treatment regimen using glucagon-like insulinotropic peptides
US7199217B2 (en) 2000-12-13 2007-04-03 Eli Lilly And Company Amidated glucagon-like peptide-1
CN1568195B (zh) 2000-12-14 2011-03-02 安米林药品公司 用于治疗代谢性疾病的肽yy及肽yy激动剂
US6899898B2 (en) 2000-12-21 2005-05-31 Nektar Therapeutics Induced phase transition method for the production of microparticles containing hydrophobic active agents
IN188924B (zh) 2001-03-01 2002-11-23 Bharat Serums & Vaccines Ltd
EP1379197A4 (en) 2001-03-23 2009-06-03 Durect Corp DISPOSAL OF MEDICINAL PRODUCTS OF DELAYED RELEASE DEVICES IMPLANTED IN MYOKARD TISSUE OR PER ICARDROOM
US6632217B2 (en) 2001-04-19 2003-10-14 Microsolutions, Inc. Implantable osmotic pump
WO2002098348A2 (en) 2001-06-01 2002-12-12 Eli Lilly And Company Glp-1 formulations with protracted time action
US6514517B2 (en) 2001-06-20 2003-02-04 Ethicon, Inc. Antimicrobial coatings for medical devices
JP4460892B2 (ja) 2001-06-21 2010-05-12 ジェネンテック インコーポレイテッド 徐放性組成物
AU2002322289A1 (en) 2001-06-22 2003-01-08 Johns Hopkins University School Of Medicine Biodegradable polymer coompositions
US7163688B2 (en) 2001-06-22 2007-01-16 Alza Corporation Osmotic implant with membrane and membrane retention means
AU2002304387A1 (en) 2001-06-22 2003-01-08 Pfizer Products Inc. Pharmaceutical compositions containing a solid dispersion of a poorly-soluble drug in a matrix and a solubility-enhancing polymer
US20030138403A1 (en) 2001-06-29 2003-07-24 Maxygen Aps Interferon formulations
KR20040019069A (ko) 2001-07-20 2004-03-04 인터뮨, 인크. 간섬유증의 치료 방법
CA2455963C (en) 2001-07-31 2017-07-04 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services Glp-1, exendin-4, peptide analogs and uses thereof
HUP0501192A3 (en) 2001-08-23 2006-06-28 Lilly Co Eli Glucagon-like peptide-1 analogs
GB0121709D0 (en) 2001-09-07 2001-10-31 Imp College Innovations Ltd Food inhibition agent
WO2003024357A2 (en) 2001-09-14 2003-03-27 Martin Francis J Microfabricated nanopore device for sustained release of therapeutic agent
US20050101942A1 (en) 2001-09-17 2005-05-12 Gillis Edward M. Device and method for accurate delivery of an active agent
BR0212985A (pt) 2001-09-24 2005-08-30 Imp College Innovations Ltd Uso de pyy ou de um agonista do mesmo na preparação de medicamentos para tratamento de distúrbios associados com excesso de peso
JP2005508943A (ja) 2001-10-05 2005-04-07 インターミューン インコーポレイテッド 多相インターフェロン送達プロフィールによる肝炎ウイルス感染症の治療法
US7041646B2 (en) * 2001-10-05 2006-05-09 Bayer Pharmaceuticals Corporation Methods of treating type 2 diabetes with peptides acting as both GLP-1 receptor agonists and glucagon receptor antagonists
CA2460676C (en) 2001-10-24 2010-03-23 Claude Jolly Implantable fluid delivery apparatuses and implantable electrode
US20040142902A1 (en) 2001-11-08 2004-07-22 Struijker- Boudier Harry A.J. Implant dosage form and use thereof for the delivery of a cholosterol lowering agent
EP1536839B1 (en) 2001-11-09 2010-09-15 Intarcia Therapeutics, Inc Combination therapy comprising omega-interferon for treating infection with hepatitis c virus or yellow fever virus
DE60239556D1 (de) 2001-11-14 2011-05-05 Durect Corp Katheterinjizierbare depotzusammensetzungen und deren verwendung
BR0206984A (pt) 2001-11-14 2004-02-03 Alza Corp Composições de depósito injetáveis e uso destas
CN100446809C (zh) 2001-11-14 2008-12-31 阿尔扎有限公司 可注射的长效组合物
IL162099A0 (en) 2001-11-21 2005-11-20 Alza Corp Osmotic delivery device having a two-way valve anddynamically self-adjusting flow channel
DE10159217A1 (de) 2001-11-27 2003-06-05 Schering Ag 17alpha-Alkyl-17ß-oxy-estratriene und Zwischenprodukte zu deren Herstellung, Verwendung der 17alpha-Alkyl-17ß-oxy-estratriene zur Herstellung von Arzneimitteln sowie pharmazeutische Präparate
US20030108608A1 (en) 2001-12-12 2003-06-12 Erik Laridon Thermoplastic articles comprising silver-containing antimicrobials and high amounts of carboxylic acid salts for increased surface-available silver
HUP0402661A3 (en) 2001-12-19 2008-04-28 Alza Corp Formulation and dosage form for the controlled delivery of therapeutic agents
EP1997829A1 (en) 2001-12-21 2008-12-03 Human Genome Sciences, Inc. Albumin fusion proteins
US8058233B2 (en) 2002-01-10 2011-11-15 Oregon Health And Science University Modification of feeding behavior using PYY and GLP-1
US7105489B2 (en) 2002-01-22 2006-09-12 Amylin Pharmaceuticals, Inc. Methods and compositions for treating polycystic ovary syndrome
NZ535008A (en) 2002-02-08 2005-09-30 Alkermes Inc Polymer-based compositions for sustained release
JP2005524657A (ja) 2002-02-27 2005-08-18 ファーメイン， エルティーディー． 治療剤及び他の物質を送達するための組成物、及び、前記組成物を作製し使用する方法
US20050260259A1 (en) 2004-04-23 2005-11-24 Bolotin Elijah M Compositions for treatment with glucagon-like peptide, and methods of making and using the same
US7635463B2 (en) 2002-02-27 2009-12-22 Pharmain Corporation Compositions for delivery of therapeutics and other materials
GB2386066A (en) 2002-02-28 2003-09-10 Norbrook Lab Ltd Long-acting parasiticidal composition with improved bioavailability comprising a salicylanilide, a further anti-parasitic compound & a polymeric species
GB0204722D0 (en) 2002-02-28 2002-04-17 Norferm Da Method
AU2003221888B2 (en) 2002-04-11 2008-11-06 Medimmune, Llc Preservation of bioactive materials by spray drying
JP4668611B2 (ja) 2002-05-31 2011-04-13 タイタン ファーマシューティカルズ インコーポレイテッド ブプレノルフィンの持続放出のための埋め込み型ポリマー製装置
MXPA04012976A (es) 2002-06-17 2005-05-16 Alza Corp Sistema de distribucion osmotica con medio de potencia de empuje de orden cero temprana que comprende un agente osmotico disperso en el vehiculo fluido.
US20040001889A1 (en) 2002-06-25 2004-01-01 Guohua Chen Short duration depot formulations
BR0312429A (pt) 2002-06-26 2005-04-19 Alza Corp Pistão de deformidade mìnima e de volume eficiente para sistemas de distribuição de drogas por osmose
US7177526B2 (en) 2002-06-28 2007-02-13 Intel Corporation System and method for improving audio during post-production of video recordings
CA2494342A1 (en) 2002-07-31 2004-02-12 Alza Corporation Injectable depot compositions and uses thereof
DK1539101T3 (da) 2002-07-31 2009-04-27 Alza Corp Injicerbare, multi-modale polymere depotsammens tninger og anvendelser deraf
US20080260838A1 (en) 2003-08-01 2008-10-23 Mannkind Corporation Glucagon-like peptide 1 (glp-1) pharmaceutical formulations
WO2004022140A1 (en) 2002-09-04 2004-03-18 Ruark Botha Device for securing a blood vessel cannula to a body
US20040121009A1 (en) 2002-10-17 2004-06-24 Alkermes Controlled Therapeutics, Inc. Method of modifying the release profile of sustained release compositions
US7164005B2 (en) 2002-10-17 2007-01-16 Alkermes, Inc. Microencapsulation and sustained release of biologically active polypeptides
AU2003283004A1 (en) 2002-10-22 2004-05-13 Waratah Pharmaceuticals, Inc. Treatment of diabetes
ATE418323T1 (de) 2002-11-06 2009-01-15 Alza Corp Depot-formulierungen mit verzögerter freisetzung
US6969702B2 (en) 2002-11-20 2005-11-29 Neuronova Ab Compounds and methods for increasing neurogenesis
US7014636B2 (en) 2002-11-21 2006-03-21 Alza Corporation Osmotic delivery device having a two-way valve and a dynamically self-adjusting flow channel
US7790681B2 (en) 2002-12-17 2010-09-07 Amylin Pharmaceuticals, Inc. Treatment of cardiac arrhythmias with GLP-1 receptor ligands
JP2006512370A (ja) 2002-12-19 2006-04-13 アルザ・コーポレーション 安定な非水性単相ゲル、および植込み型デバイスから送達するためのその配合物
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
GB0300571D0 (en) 2003-01-10 2003-02-12 Imp College Innovations Ltd Modification of feeding behaviour
JP2004238392A (ja) 2003-01-14 2004-08-26 Nipro Corp 安定化された蛋白質性製剤
US7507114B2 (en) 2003-02-18 2009-03-24 Medconx, Inc. Male medical device electrical connector with engineered friction fit
BRPI0408921A (pt) 2003-03-31 2006-03-28 Alza Corp sistema de distribuição osmótico e método para diminuir os tempos de inìcio para os sistemas de distribuição osmóticos
KR20060017749A (ko) 2003-03-31 2006-02-27 알자 코포레이션 내압 소멸 수단을 갖는 삼투성 펌프
CN1767815A (zh) 2003-03-31 2006-05-03 阿尔萨公司 非水单相载体和使用这类载体的制剂
DE202004009060U1 (de) 2003-05-16 2004-08-12 Blue Membranes Gmbh Biokompatibel beschichtete medizinische Implantate
US20040247672A1 (en) 2003-05-16 2004-12-09 Alkermes Controlled Therapeutics, Inc. Injectable sustained release compositions
ES2425221T3 (es) 2003-05-30 2013-10-14 Amylin Pharmaceuticals, Llc Nuevos métodos y composiciones para suministro por vía transmucosa potenciado de péptidos y proteínas
CA2527664A1 (en) 2003-05-30 2004-12-16 Alza Corporation Implantable elastomeric depot compositions, uses thereof and method of manufacturing
EP2292254A3 (en) 2003-06-03 2011-12-14 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8491571B2 (en) 2003-06-12 2013-07-23 Cordis Corporation Orifice device having multiple channels with varying flow rates for drug delivery
US7454765B2 (en) 2003-07-09 2008-11-18 Samsung Electronics Co., Ltd. Optical disc drive
JP2007501811A (ja) * 2003-08-08 2007-02-01 ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト 治療的な関心対象のタンパク質に対する遅延分子の選択的な化学物質接合のためのガラクトースオキシダーゼの使用。
US7205409B2 (en) 2003-09-04 2007-04-17 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US9005244B2 (en) 2003-09-30 2015-04-14 Ethicon, Inc. Tissue approximation device
BRPI0414941A (pt) 2003-09-30 2006-11-07 Alza Corp dispositivo de distribuição de agente ativo acionado osmoticamente proporcionando um perfil de liberação ascendente
BRPI0416094A (pt) 2003-10-31 2007-01-02 Alza Corp bomba osmótica com plugue de membrana de inicialização rápida, de auto-retenção
AU2004289218A1 (en) 2003-11-06 2005-05-26 Alza Corporation Modular imbibition rate reducer for use with implantable osmotic pump
US20050118206A1 (en) 2003-11-14 2005-06-02 Luk Andrew S. Surfactant-based gel as an injectable, sustained drug delivery vehicle
US20050106214A1 (en) 2003-11-14 2005-05-19 Guohua Chen Excipients in drug delivery vehicles
US20050281879A1 (en) 2003-11-14 2005-12-22 Guohua Chen Excipients in drug delivery vehicles
US7780973B2 (en) 2003-12-15 2010-08-24 Ethicon Endo-Surgery, Inc. Method and device for minimally invasive implantation of biomaterial
US20050216087A1 (en) 2004-01-05 2005-09-29 St. Francis Medical Technologies, Inc. Disk repair structures for positioning disk repair material
US20050175701A1 (en) 2004-02-10 2005-08-11 Alza Corporation Capillary moderator for osmotic delivery system
WO2005077072A2 (en) 2004-02-11 2005-08-25 Amylin Pharmaceuticals, Inc. Hybrid polypeptides with selectable properties
US8076288B2 (en) 2004-02-11 2011-12-13 Amylin Pharmaceuticals, Inc. Hybrid polypeptides having glucose lowering activity
US7456254B2 (en) 2004-04-15 2008-11-25 Alkermes, Inc. Polymer-based sustained release device
KR101040415B1 (ko) 2004-04-15 2011-06-09 알케르메스,인코포레이티드 중합체 기재 지속적 방출 방법
US20050266087A1 (en) 2004-05-25 2005-12-01 Gunjan Junnarkar Formulations having increased stability during transition from hydrophobic vehicle to hydrophilic medium
US20090042781A1 (en) 2004-06-28 2009-02-12 Novo Nordisk A/S Methods for Treating Diabetes
US7772182B2 (en) * 2004-08-05 2010-08-10 Alza Corporation Stable suspension formulations of erythropoietin receptor agonists
NZ553149A (en) * 2004-08-12 2010-01-29 Quest Pharmaceutical Services Use of inositol hexaphosphate or inositol hexasulphate to complex biologically active compounds for the preparation of controlled release pharmaceutical compositions
JP5244388B2 (ja) 2004-08-18 2013-07-24 ウオーターズ・テクノロジーズ・コーポレイシヨン 加圧下の流体を生成するかまたは運ぶための装置及び方法並びに該装置に用いられるシール部材
US8268791B2 (en) 2004-08-25 2012-09-18 Aegis Therapeutics, Llc. Alkylglycoside compositions for drug administration
US20080038316A1 (en) 2004-10-01 2008-02-14 Wong Vernon G Conveniently implantable sustained release drug compositions
US7442682B2 (en) * 2004-10-19 2008-10-28 Nitto Denko Corporation Transepithelial delivery of peptides with incretin hormone activities
US8394765B2 (en) 2004-11-01 2013-03-12 Amylin Pharmaceuticals Llc Methods of treating obesity with two different anti-obesity agents
CA2584806C (en) 2004-11-01 2014-06-17 Amylin Pharmaceuticals, Inc. Treatment of obesity and related disorders
US7575579B2 (en) 2004-11-18 2009-08-18 Union Surgical, Llc Drill guide tissue protector
US20060141040A1 (en) * 2004-12-23 2006-06-29 Guohua Chen Injectable non-aqueous suspension
US20060142234A1 (en) 2004-12-23 2006-06-29 Guohua Chen Injectable non-aqueous suspension
EP1841448A2 (en) * 2004-12-30 2007-10-10 Diakine Therapeutics, Inc. Pharmaceutical compositions and methods for restoring beta-cell mass and function
AU2006207447B2 (en) 2005-01-24 2012-07-19 Merck Sharp & Dohme B.V. Applicator for inserting an implant
AU2006208131A1 (en) 2005-01-25 2006-08-03 Microchips, Inc. Control of drug release by transient modification of local microenvironments
JP2008528698A (ja) * 2005-02-03 2008-07-31 インターシア セラピューティクス，インコーポレイティド 埋め込み可能なインターフェロン含有デバイス
US20060216242A1 (en) 2005-02-03 2006-09-28 Rohloff Catherine M Suspending vehicles and pharmaceutical suspensions for drug dosage forms
US20070032420A1 (en) 2005-02-09 2007-02-08 Entelos, Inc. Treating diabetes with glucagon-like peptide-1 secretagogues
US8263545B2 (en) 2005-02-11 2012-09-11 Amylin Pharmaceuticals, Inc. GIP analog and hybrid polypeptides with selectable properties
JP2008530130A (ja) 2005-02-11 2008-08-07 アミリン・ファーマシューティカルズ，インコーポレイテッド Ｇｉｐ類似体および選択可能な特性を備えるハイブリッドポリペプチド
AU2006215566A1 (en) * 2005-02-16 2006-08-24 Novo Nordisk A/S Insulinotropic agents conjugated with structurally well defined branched polymers
GB0504857D0 (en) 2005-03-09 2005-04-13 Imp College Innovations Ltd Novel compounds and their effects on feeding behaviour
US7959938B2 (en) 2005-03-15 2011-06-14 Intarcia Therapeutics, Inc. Polyoxaester suspending vehicles for use with implantable delivery systems
ES2330671T3 (es) 2005-03-31 2009-12-14 Amylin Pharmaceuticals, Inc. Amilina y agonistas de amilina para el tratamiento de enfermedades y trastornos psiquiatricos.
ATE509634T1 (de) 2005-04-08 2011-06-15 Amylin Pharmaceuticals Inc Pharmazeutische formulierungen mit incretin- peptid und aprotisch-polarem lösungsmittel
WO2006111169A1 (en) * 2005-04-21 2006-10-26 Gastrotech Pharma A/S Pharmaceutical preparations of a glp-1 molecule and an anti-emetic drug
US9233203B2 (en) 2005-05-06 2016-01-12 Medtronic Minimed, Inc. Medical needles for damping motion
DK1888031T3 (da) * 2005-06-06 2013-02-18 Camurus Ab GLP-1-analogformuleringer
US20060280795A1 (en) 2005-06-08 2006-12-14 Dexcel Pharma Technologies, Ltd. Specific time-delayed burst profile delivery system
GB2442396B (en) 2005-07-22 2011-05-11 Univ Utah Res Found Osmotically driven dispense pump and related components for use in high pressure applications
US20070027105A1 (en) 2005-07-26 2007-02-01 Alza Corporation Peroxide removal from drug delivery vehicle
EP2330124B1 (en) 2005-08-11 2015-02-25 Amylin Pharmaceuticals, LLC Hybrid polypeptides with selectable properties
FI3524261T3 (fi) 2005-08-19 2024-01-11 Amylin Pharmaceuticals Llc Exendin käytettäväksi diabeteksen hoidossa ja ruumiin painon vähentämiseksi
WO2007022518A2 (en) 2005-08-19 2007-02-22 Amylin Pharmaceuticals, Inc. New uses of glucoregulatory proteins
HUE029798T2 (en) 2005-11-04 2017-03-28 Glaxosmithkline Llc Methods of administering hypoglycemic agents
US8039432B2 (en) 2005-11-09 2011-10-18 Conjuchem, Llc Method of treatment of diabetes and/or obesity with reduced nausea side effect
AU2006329836A1 (en) 2005-12-16 2007-07-05 Amylin Pharmaceuticals, Llc Compositions and methods for treating obesity and related metabolic disorders
WO2007075534A2 (en) * 2005-12-16 2007-07-05 Nektar Therapeutics Al, Corporation Polymer conjugates of glp-1
RU2427383C2 (ru) * 2006-01-18 2011-08-27 КьюПиЭс, ЭлЭлСи Фармацевтические композиции с повышенной стабильностью
WO2007109354A2 (en) 2006-03-21 2007-09-27 Amylin Pharmaceuticals, Inc. Peptide-peptidase inhibitor conjugates and methods of using same
EP3255149A3 (en) 2006-05-02 2018-04-18 Intrexon Actobiotics NV Microbial intestinal delivery of obesity related peptides
EP2029160A2 (en) 2006-05-12 2009-03-04 Amylin Pharmaceuticals, Inc. Methods to restore glycemic control
MX2008014870A (es) 2006-05-30 2009-02-12 Intarcia Therapeutics Inc Modulador de flujo para sistema de suministro osmotico con canal interno de dos piezas.
GB0613196D0 (en) 2006-07-03 2006-08-09 Imp Innovations Ltd Novel compounds and their effects on feeding behaviour
RU2456018C2 (ru) 2006-07-11 2012-07-20 КьюПиЭс, ЭлЭлСи Фармацевтические композиции для доставки пептидов с замедленным высвобождением
WO2008019147A2 (en) 2006-08-04 2008-02-14 Amylin Pharmaceuticals, Inc. Use of exendins, exendin agonists and glp-1 receptor agonists for altering the concentration of fibrinogen
ES2422864T3 (es) 2006-08-09 2013-09-16 Intarcia Therapeutics, Inc Sistemas de liberación osmótica y unidades de pistón
JP2010505819A (ja) 2006-10-05 2010-02-25 パナセア バイオテック リミテッド デポ型注射剤組成物とその調製方法
WO2008061355A1 (en) * 2006-11-24 2008-05-29 Matregen Corp. Glp-1 depot systems, and methods of manufacture and uses thereof
TWI428346B (zh) 2006-12-13 2014-03-01 Imp Innovations Ltd 新穎化合物及其等對進食行為影響
US20090022727A1 (en) 2007-01-26 2009-01-22 Alza Corp. Injectable, nonaqueous suspension with high concentration of therapeutic agent
US8262667B1 (en) 2007-02-23 2012-09-11 Holmed Corporation Multi-diameter implant forceps
WO2008133908A2 (en) * 2007-04-23 2008-11-06 Intarcia Therapeutics, Inc. Suspension formulations of insulinotropic peptides and uses thereof
WO2008134425A1 (en) 2007-04-27 2008-11-06 Cedars-Sinai Medical Center Use of glp-1 receptor agonists for the treatment of gastrointestinal disorders
JP5718058B2 (ja) 2008-02-08 2015-05-13 キューピーエス リミテッド ライアビリティ カンパニー タンパク質又はペプチドの徐放送達用組成物
EP2240155B1 (en) 2008-02-13 2012-06-06 Intarcia Therapeutics, Inc Devices, formulations, and methods for delivery of multiple beneficial agents
US9186502B2 (en) 2008-02-14 2015-11-17 Enteromedics Inc. Treatment of excess weight by neural downregulation in combination with compositions
EP2259791A2 (en) 2008-03-05 2010-12-15 Tel HaShomer Medical Research Infrastructure and Services Ltd. Glp-1 receptor agonists and related active pharmaceutical ingredients for treatment of cancer
US20090234392A1 (en) 2008-03-13 2009-09-17 Depuy Spine, Inc. Method for inserting a spinal fixation element using implants having guide tabs
US8377881B2 (en) 2008-04-01 2013-02-19 MosaMedix B. V. Compositions and methods for reducing scar formation in wound healing
AU2009231601B2 (en) 2008-04-04 2014-02-27 Reshape Lifesciences, Inc. Methods and systems for glucose regulation
ES2552646T3 (es) 2008-05-21 2015-12-01 Amylin Pharmaceuticals, Inc. Exendinas para disminuir el colesterol y los triglicéridos
KR101683314B1 (ko) 2008-09-17 2016-12-06 키아스마 인코포레이티드 약제학적 조성물 및 연관된 투여방법
RU2510266C2 (ru) 2008-09-30 2014-03-27 Эндо Фармасьютикалз Солюшнз Инк. Имплантируемое устройство для доставки рисперидона и способы его применения
US20100092566A1 (en) 2008-10-15 2010-04-15 Alessi Thomas R Highly concentrated drug particles, formulations, suspensions and uses thereof
US20100298840A1 (en) 2009-05-22 2010-11-25 Schwartz Lyman D Phimosis Treatment Device and Method
US9358064B2 (en) 2009-08-07 2016-06-07 Ulthera, Inc. Handpiece and methods for performing subcutaneous surgery
WO2011037623A1 (en) 2009-09-28 2011-03-31 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
AR079344A1 (es) 2009-12-22 2012-01-18 Lilly Co Eli Analogo peptidico de oxintomodulina, composicion farmaceutica que lo comprende y uso para preparar un medicamento util para tratar diabetes no insulinodependiente y/u obesidad
JO2976B1 (en) 2009-12-22 2016-03-15 ايلي ليلي اند كومباني Axentomodulin polypeptide
US8263554B2 (en) 2010-06-09 2012-09-11 Amylin Pharmaceuticals, Inc. Methods of using GLP-1 receptor agonists to treat pancreatitis
USD669589S1 (en) 2010-08-31 2012-10-23 Koninklijke Philips Electronics N.V. Blood system cartridge
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
WO2013004983A1 (en) 2011-07-04 2013-01-10 Imperial Innovations Limited Novel compounds and their effects on feeding behaviour
US20130098928A1 (en) 2011-09-16 2013-04-25 Golden Aluminum, Inc. Application of designs to portion of food container
WO2013156628A1 (en) 2012-04-19 2013-10-24 Removaid As Device for removing an item implanted underneath the skin
WO2013180126A1 (ja) 2012-05-29 2013-12-05 国立大学法人高知大学 動脈可視化装置、および動脈撮像装置
US20140058425A1 (en) 2012-08-27 2014-02-27 Amir Porat Manually operated surgical devices with operative portions formed of a see-through material
US9332995B2 (en) 2012-09-25 2016-05-10 Russo Inventions, Llc Bone-harvesting tool
EP2919764A1 (en) 2012-11-19 2015-09-23 Braeburn Pharmaceuticals BVBA SPRL Implantable drug delivery compositions and methods of treatment thereof
CN113598842A (zh) 2015-06-03 2021-11-05 因塔西亚制药公司 植入物放置和移除系统

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040229814A1 (en) * 2002-08-28 2004-11-18 James Dillon Methods and compositions for protecting against cataract development associated with vitrectomies
US20050059612A1 (en) * 2003-09-16 2005-03-17 Benedikt Sas Bicyclic carbohydrates as antiviral bioactives for the treatment of infections caused by the alphaherpesvirinae HSV-1 and HSV-2
TW200634060A (en) * 2005-02-03 2006-10-01 Alza Corp Solvent/polymer solutions as suspension vehicles

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110732020A (zh) * 2019-11-25 2020-01-31 江苏豪森药业集团有限公司 稳定的含有聚乙二醇洛塞那肽的药物制剂
CN110732020B (zh) * 2019-11-25 2023-10-03 江苏豪森药业集团有限公司 稳定的含有聚乙二醇洛塞那肽的药物制剂

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