CN1723034A - 治疗糖尿病的组合物和方法 - Google Patents
治疗糖尿病的组合物和方法 Download PDFInfo
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- CN1723034A CN1723034A CNA028201922A CN02820192A CN1723034A CN 1723034 A CN1723034 A CN 1723034A CN A028201922 A CNA028201922 A CN A028201922A CN 02820192 A CN02820192 A CN 02820192A CN 1723034 A CN1723034 A CN 1723034A
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- pharmaceutical composition
- peptide
- ingap
- langerhans
- islets
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Abstract
本发明包括定量给养摄取法和与蛋白质(INGAP)和INGAP肽相关联的胰岛再生的配方。本发明所公开的配方显示出作为药物组合物具有可接受的稳定性。此外,此配方可以使功能性胰岛再生。
Description
发明背景
I型糖尿病是一种进行性自身免疫反应引起的能够选择性破坏产生胰岛素的β细胞的疾病,I型糖尿病患者的胰岛细胞会丧失。II型糖尿病是所谓的成人疾病,但在肥胖的年轻人群中发生的比例也在增大,II型糖尿病患者体内的β细胞减少多达正常水平的60%。胰岛中功能性β细胞的数量对于糖尿病的开始、发展、以及带来的后果具有至关重要的意义。在I型糖尿病患者体内,β细胞数量下降到低于正常水平的2%。即使是对胰岛素有严重的排斥作用的II型糖尿病也只会在β细胞的数量没有得到充分的补充增加的情况下发生。因此,无论哪一种类型的糖尿病都是归因于β细胞不能适应性的生长和由此而引起的胰岛素分泌的缺乏。因此,激发前体细胞生成胰岛和β细胞,即“胰岛再生”,的能力对于改善糖尿病症状来说将是一种新颖而颇具吸引力的途径。
通过一系列的实验,制得了一种称之为“Ilotropin”的胰腺提取物。实验表明,此化合物激发已经存在的前体细胞使β细胞再生,而这种前体细胞与胰腺导管系统有关。根据以下假设,即胰腺导管细胞的转化从而引起胰岛的再生是由内部的生长因子、基因和蛋白质产物所决定的,开展了对ilotropin中活性成分的寻找及鉴定。也正是这一研究主线导致了一种新基因以及与其相关的蛋白质(INGAP)的发现,而这种蛋白质又与胰岛的再生相关。
INGAP肽(INGAP104-118),包含在含有175个氨基酸INGAP内的15个氨基酸序列-被证明能够激发大颊鼠类胰腺导管细胞的增殖。INGAP肽是美国专利5,834,590的序列标识号2的103至117氨基酸,该专利引入本文以供参考。
发明概述
本发明涉及定量给养摄取法和INGAP肽的配方。本发明公开的配方具有作为药物试剂应具有的可接受的稳定性和应用于人类临床试验的适当的安全性。如下制备的INGAP肽进一步显示能够使维持正常反馈控制的功能性胰岛细胞再生。
因此,本发明的目的之一在于提供一种药学上可接受的和稳定的INGAP肽组合物,该组合物参与Langerhans胰岛的再生过程。
本发明的另一目的是提供治疗哺乳动物糖尿病的方法。
本发明的又一个目的是提供治疗哺乳动物体内生理血糖调节异常的方法。
本发明的再一个目的是提供增加哺乳动物体内的胰腺β细胞或Langerhans胰岛的数目的方法。
本发明的再一个目的是提供治疗接受胰岛细胞移植的哺乳动物的方法。
本发明的再一个目的是提供诱导胰腺前体细胞分化的方法。
所有引用的相关文献都引入本发明的相应部分以供参考。任何资料的引用都不可理解为是对其作为本发明的现有技术的认可。
图表说明
图1显示INGAP肽处理过的ARIP细胞(大鼠胰腺导管细胞),显示细胞数量随INGAP的增加而增加。
图2显示在对正常的叙利亚大颊鼠施用INGAP后胰岛细胞数量的增加。
图3显示在由链脲霉素诱导引起糖尿病的C57BL/J6鼠体内施用INGAP肽或生理盐水后血糖的时间变化曲线。
图4显示将由链脲霉素诱导而引起糖尿病的C57BL/J6鼠用INGAP肽处理后其胰腺中胰岛素和胰高血糖素的正常分布。
图5显示INGAP肽诱发C57BL/J6鼠的胰腺导管壁中的细胞的PDX-1的表达。
图6显示用链脲霉素处理过的C57BL/J6鼠与依次用链脲霉素和INGAP处理过的小鼠之间的胰岛组织对比。
图7显示用INGAP肽处理31天后的正常鼠的胰岛素免疫反应性组织区域的胰岛素增加百分数。
图8显示用INGAP肽处理34天后的正常狗的胰岛素免疫反应性组织区域的胰岛素增加百分数。
发明详述
术语表
以下是本发明所使用的术语定义的列表:
“药学上可接受的盐”是指本发明中的化合物上的任何酸性基团(如,羧基)形成的阳离子盐或者任何碱性基团(如,氨基、烷胺基、二烷胺基、吗啡啉基和其它类似的基团)形成的阴离子盐。由于INGAP肽是两性的,因此两种盐都是可能的,也都是可以接受的。在本领域已知许多此类的盐。优选的阳离子盐包括但不限于碱金属离子盐(如,钠和钾),碱土金属离子盐(如,镁和钙)和有机盐,如铵盐。优选的阴离子盐包括卤化物、磺酸盐、羧酸盐、磷酸盐和其它类似的盐。在该种盐中清楚考虑的是提供光学活性中心的加成盐,因为加入之前是没有光学活性中心的。例如,手性的酒石酸盐可以用本发明的化合物来制备,且本定义包括了这种手性盐。所考虑的盐要在施用给患病的动物、哺乳动物或人的量内无毒性。比较适当的添加的盐有盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、乙酸盐、三氟乙酸盐、硝酸盐、柠檬酸盐、延胡索酸盐、甲酸盐、硬脂酸盐、琥珀酸盐、马来酸盐、丙二酸盐、己二酸盐、戊二酸盐、乳酸盐、丙酸盐、丁酸盐、酒石酸盐、甲磺酸盐、三氟甲磺酸盐、对甲苯磺酸盐、十二烷基磺酸盐、环己烷基氨基磺酸盐和其它类似的盐,但又不局限于这些盐。
“可生物水解的酯”是指本发明的酯化合物,其中这些酯应基本上不妨碍、优选完全不妨碍化合物的生物活性,或者选择很容易在患者体内转化生成活性化合物的酯。在本领域中已知有许多这样的酯,如Johnston和Mobashery在1988年11月8日公开的美国专利4,783,443中所述。这样的酯包括低级烷基酯、低级酰基的烷基酯(如,乙酸甲酯、乙酸乙酯、氨基甲酸甲酯、异戊酸甲酯和异戊酸乙酯)、内酯(如,2-苯并[c]呋喃酮基和硫代酞基酯)、低级烷氧羧酸烷基酯(如,碳酸二甲酯、碳酸二乙酯、异丙基乙基碳酸酯)、烷氧基烷酯、胆碱酯和酰胺基烷酯(如,乙酰胺基甲酯)。
本发明中使用的“治疗”至少是指使用本发明的化合物能够减轻生理葡萄糖失调带来的疾病,其适合对象优选哺乳动物,更优选人类。因此,术语“治疗”包括:预防实验对象因生理血糖异常而引起的紊乱,特别是当实验对象十分倾向于患此病,但还诊断不出患有此病时;抑制因生理血糖异常而引起的紊乱;和/或减轻或逆转实验对象因生理血糖异常而引起的的紊乱。目前,本发明的方法主要在于预防实验对象因生理血糖异常而引起的紊乱。应当理解,这里所说的“预防”并不要求患病的状态完全治愈(Webster第九版大学生字典),这里所指的预防是指熟练的技术人员鉴别易于因生理血糖异常而引起的紊乱的人群的能力,因此,可以在因生理血糖异常而引起紊乱之前,很好地应用本发明中的化合物来起到预防的作用。本发明所指的“预防”并不意味着可以完全避免疾病的发生。因生理血糖异常而引起紊乱(I型和II型糖尿病)的人群主要是那些通过家庭病史能看其具有易患糖尿病基因的人群。其它风险因素包括如肥胖症和饮食不当。
制造与稳定性
INGAP肽是一种由包含在175个天然氨基酸INGAP中的104至118这15个氨基酸组成的氨基酸序列。可以用本领域熟悉的多种不同的方法来合成INGAP肽,尽管优选地是通过利用9-氟甲酸甲酯(Fmoc)进行的固相合成法来合成。INGAP肽的优选形式为呈药学上可接受的盐的形式、优选乙酸盐形式的INGAP肽。肽盐的制备在本领域是熟知的。利用9-氟甲酸甲酯(moc)的合成法在美国专利4,108,846中已有描述。Fmoc利用哌啶使甲氧羰基断掉,用三氟乙酸将肽从树脂上切断。由此工艺制得的INGAP粗品可以通过制备性高效色谱柱来纯化。
INGAP肽的氨基酸序如下:
NH2-Ile-Gly-Leu-His-Asp-Pro-Ser-His-Gly-Thr-Leu-Pro-Asn-Gly-Ser-COOH(SEQ ID NO:3)
INGAP肽的分子式为C64H100N20O22,分子量为1501.6±1道尔顿,在1%浓度的乙酸中旋光度为-103.2°。
INGAP肽的结构可以通过分析由INGAP肽分子进行水解得到的组成氨基酸而得到确认。根据分子结构,可以定量表示出各种存在的氨基酸的正确摩尔比,肽的分子量可以用电子喷雾质谱仪来确认,并且应该与计算的、理论质量相一致(1501.6±1个质量单位)。
为了确认所合成的分子是否具有生物活性,可以通过生物测定来确认活性。生物测定用的是一种从ATCC(Manassas,VA)获得的大鼠胰腺导管细胞□ARIP细胞。将测试细胞以每孔10,000个细胞装在有96个孔的培养板中,在含有10%的牛胎血清的DMEM培养液中培养24小时。24个小时之后,替换成没有血清的DMEM培养液。然后用不同剂量(0,10-3和10-5克/毫升)的INGAP肽来处理相同的孔。21个小时之后,用Roche Molecular Biochemicals公司的BrDU细胞增殖ELISA试剂盒中的溴脱氧尿苷(BrdU)标记溶液加入培养液后,再培养3小时。24个小时之后,将细胞在60℃下干燥60分钟,将其固定和变性。根据试剂盒使用说明,将这些细胞放到BrdU抗体中处理90分钟,反应15分钟。带有BrdU标记的细胞可以用Wallac Victor 1420型多标记记数器进行计算。将结果与在相同培养板中进行的细胞增殖的标准曲线相对照,开始时细胞密度为每孔100至20,000细胞。正如图1所示,生物测定结果表明:与对照组相比,使用0.1微克/毫升的INGAP肽处理过的细胞增殖约1.6倍。
INGAP肽的稳定性
稳定性是通过对比不同的参数来确定的,这些参数包括但不限于样本的纯度、杂质总百分含量、杂质单独百分含量(用高效液相色谱或其它合适的定量的方法来确定)、表观和水含量等。高效液相色谱的方法可以用来确定相对于INGAP肽的各种降级产物的含量的增加。INGAP肽样品(无论是溶液还是冷冻干燥粉末)存储在各种不同的温度、潮湿或干燥状态下,以及存储在透明或避光的小瓶子中。不同的存储条件下的降解都会导致杂质的增加和INGAP肽的含量的降低。样品制备的纯度大于80%是可取的,优选大于90%,更优选大于95%,最优选大于97%。
当INGAP肽以冷冻干燥粉末保存时,在任何存储条件下都是稳定的。在这些存储条件下,INGAP肽的纯度可以得到很好的保持,降解产物低于可接受的水平。进一步存储期长达六个月时,也不会引起任何明显的INGAP肽的降解。
组合物
本发明的另一方面是组合物,该组合物包括:(a)本发明的安全而有效量的肽,(b)药学上可接受的载体。应用标准的药物配制技术,例如,Mack PublishingCompany出版的Easton,Pa.编著的《雷明顿药物科学》(Remington’sPharmaceutical Sciences)的最新版本所公开的那些技术。
“安全有效量”是指本发明中的肽的量,该量足够能显著地激发治疗效果,但又足够低以尽量减少对需要肽的对象动物、优选哺乳动物、更优选人的副作用(例如,毒性、刺激或过敏反应),使用本发明从而得到一个合理的“效果/风险比值”。显然,这里所说的“安全有效量”又随着作用对象的具体因素的不同而改变,具体因素包括如身体状况、治疗的期限、同时进行的疗法的性质、所用的剂量、应用的载体、其中肽的溶解性以及药剂的用法等。本领域熟练的技术人员会按照与本发明相一致的下列方法来确定一种“安全有效量”。可以参考以下文献:
Spilker B编,《临床研究和发展草案指南》(Guide to Clinical Studies andDeveloping Protocols),New York:Raven Press Books,Ltd.,1984,pp.7-13,54-60;
Spilker,《临床实验指南》(Guide to Clinical Trials),New York:RavenPress Books,Ltd.,1991,pp.93-101;
Craig C.和R.Stitzel,编著,《现代药物学》(Modern Pharmacology)(第二版),Little,Brown and Co.,Boston:1986,pp.127-33;
T.Speight编著,《艾弗里药物治疗:原理、药物临床实践和疗法》(Avery’sDrug Treatment:Principles and Practice of Clinical Pharmacology andTherapeutics)(第三版),Williams and Wilkins,Baltimore,1987,pp.50-56;
R.Tallarida,R.Raffa和P.McGonigle,《常用药物学原理》(Principlesin General Pharmacology),Springer-Verlag,New York:1988,pp.18-20。
本发明的肽溶解或悬浮在药学上可接受的缓冲液里面。其中溶解肽的缓冲溶液会影响肽的pH值、溶解性,从而会影响肽的生物可获得性。缓冲溶液的选择取决于肽组分、施用方法、希望得到的肽的溶解度、在生理学基础上肽的半衰期以及生理体液的pH值和缓冲能力。理想的缓冲溶液的pH值可能更接近肽的pKa值,或其取决于随肽在体内传导的生理学环境。适合的缓冲溶液包括但不限于磷酸盐、乙酸盐、碳酸盐、碳酸氢盐、氨基乙酸盐、柠檬酸盐、咪唑盐以及其它盐。尤其优选的是乙酸盐缓冲溶液。
除了主体肽以外,本发明的组合物还包含药学上可接受的载体。本发明中使用的术语“药学上可接受的”载体是指适用于动物、优选哺乳动物、更优选人的一种或多种兼容的固态或液态的填料稀释剂或胶囊包封物质。本发明中使用的术语“兼容的”是指组合物的各种组分可以与肽混合后,在通常的应用条件下不会实质性地降低化合物的药物功效的相互作用。药学上可接受的载体当然必须要有足够高的纯度和足够低的毒性,并且适合施用于动物、优选哺乳动物、更优选人类。选择药学上可接受的载体与肽联合使用基本上是由肽的施用方式决定的。如果主题肽是用来注射的,优选的药学上可接受的载体应该是经过消毒的,并且具有与血液兼容的胶状悬浮剂。
更具体地讲,用于系统给药的药学上可接受的载体包括糖、淀粉、纤维素及其衍生物、麦芽、凝胶、滑石粉、硫酸钙、植物油、合成油、多羟基化合物、褐藻酸、磷酸缓冲溶液、乳化剂、生理盐水和无热原质水。经肠胃使用的优选的载体包括丙二醇、油酸乙酯、吡咯啉酮、乙醇和芝麻油。,在经肠胃施用的组合物中,药学上优选的可接受的载体至少占整个组合物重量的90%。
本发明的组合物优选以单位剂量的形式提供。如本发明中所使用的“单位剂量形式”是指根据比较好的临床实践经验,包含适合用于动物、优选哺乳动物、更优选人类对象的单剂量的INGAP肽的本发明的组合物。这些组合物优选含有约0.1毫克至约300毫克,更优选约5毫克至约150毫克的INGAP肽。使用本发明的组合物进行治疗的频率可以更改以获得所希望的大剂量并能避免副作用。因此,治疗计划的非限制性实施例包括一天一次、一天两次、一天三次、每周一次、两周一次、每月一次,和这几种方式的组合。另一种可供选择的方法是也可以连续输液给药。
本发明的组合物可能有各种不同的形态,例如,可以口服、可以用于局部、可以作为鼻用药、或者作为注射用药。根据所希望的某种特定的施用方式,可使用多种在本领域内人们熟知的并且药学上可接受的载体。这些载体包括固态或液态的填料、稀释剂、助水溶物、表面活性剂和包封物质。不会实质性地干扰INGAP肽的活性的其它任选的药物活性材料也可以被包括。用于与INGAP肽联合的载体足以为每单位剂量提供足够的肽。在本发明的方法中实用的制备技术和组合物在以下参考文献中都有描述:1979年,Banker & Rhodes编著的《现代药物学》(ModernPharmaceutics),第九、十章;1981年,Lieberman等人编著的《药物的剂量形式:片剂》(Pharmaceutical Dosage Forms:Tablets);1976年,Ansel编著的《药物剂量形式简介》(Introduction to Pharmaceutical Dosage Forms)(第二版)。
INGAP肽的配制
在INGAP肽的各种配制中,优选的是一种用消毒水和调节肌肉的弹性所需的氯化钠配制的注射液,这种注射液制备有四种浓度:0,7.5,30和120毫克/0.5毫升/瓶。如果需要,可以用盐酸和氢氧化钠来调节PH值至所需要的水平。其它浓度可以通过用生理盐水稀释较高浓度的溶液制备。稀释并不影响INGAP肽的生物活性。
如此制备的INGAP肽当保存在5℃的黑暗或光照处时在pH值4至6的范围内是稳定的。然而,如果保存在25℃的条件下,组合物会发生部分的降解。组合物在pH值为6的条件下会比在pH值为4.5的条件下更容易发生降解反应。由上可以知道,INGAP肽保存在8℃以下和pH值低于6的条件下更稳定。
实施例1 注射用的INGAP肽溶液
120毫克的INGAP肽的溶液可以按照以下的规格进行配制。
表1
参数 | 规格 |
外观 | 无色透明的溶液 |
组成成份 | 每瓶含有90.0%至110.0%的INGAP肽 |
杂质含量 | 每种杂质:1.0%杂质总含量:3.0% |
pH值 | 4.0至5.0 |
细菌内毒素 | NMT 2.92EU/mg |
无菌状态 | 符合USP |
实施例2 对正常大颊鼠施用INGAP肽
本实验研究了INGAP肽对正常大颊鼠的胰岛生成的影响。用5毫克/千克(25毫克/平方米)INGAP肽溶液腹腔注射对象每天一次,连续进行四周,在第十天和第三十天进行β-细胞数目的评定。与用安慰剂处理过的动物相比,用INGAP肽处理过的动物表现出胰岛细胞数目的显著增加(见图2)。胰岛的再生效应可以通过更多胰岛素的生成和胰腺中胰岛数目的增加而得到证明。新形成的β-细胞生长并出现在胰腺输导管壁。这些含胰岛素的细胞是由输导管表皮细胞分化和胰岛细胞的生长产生的,并且它们的染色的外观效果与INGAP肽的剂量和作用的持续时间成正比。经过较长时间的作用,这些细胞会从输导管处发生迁移并在胰腺的软体组织中形成胰岛。连续使用10天INGAP肽后,胰岛的数量会增加30%,连续使用30天后,组织中的胰岛数量会翻一倍,这与以前在动物模型实验中应用ilotropin、rINGAP和玻璃纸包埋获得的实验结果是一致的。
实施例3 活体功效研究
连续5天以35(毫克/千克/天)量的STZ处理过的使其患糖尿病的C57BL/6J小鼠被分成两组,每组四只,其中一组用250微克INGAP肽的量,每天处理两次,而另外一组用生理盐水处理作为对照组。用INGAP肽处理过的全部四只小鼠的血糖浓度都恢复到正常,而用生理盐水处理过的四只小鼠仍然处于高血糖状态(见图3)。39天后停止使用药剂,进一步的观察结果显示,到48天停止实验时,药物作用仍有持续效果。对INHAP肽处理过的动物进行组织病理评价结果显示:正常出现胰岛以及新胰岛形成的区域,包括胰岛素和胰增血糖素的分泌细胞的补充和分布均已出现(见图4和图6)。由于胰增血糖素对预防高血糖有非常重要的作用,因此,胰增血糖素分泌细胞的出现是非常引人注目的。INGAP肽能够诱导胰岛再生的这一特点对于逆转已经受损害的低血糖负调节控制作用有很大帮助,而这一调节作用与糖尿病的过度治疗密切相关。所有用INGAP肽处理过的动物都没有发现患高血糖病,而用盐水处理的对照组的动物体内都没有观察到胰岛的生成。INGAP肽的应用会诱导导管细胞的分化,这可以通过细胞对转录因子PDX-1的表达而得到证实(见图5)。用生理盐水处理的由STZ引起糖尿病的动物的胰岛表现出严重的炎症细胞侵入,并且会坏死。而用INGAP肽处理过的动物,炎症状况明显降低,且其胰岛也很健康(见图6)。
图4显示用链脲霉素和INGAP肽依次处理过的C57BL/6J鼠的胰腺的免疫细胞化学特征。左上方的图表明胰岛仍然与部分输导管上被胰岛素抗体染色过的上皮细胞有联系,这就证明了胰岛素蛋白的正常存在和分布。左下方的图表明同样的胰岛被胰增血糖素抗体和生长激素抑制素抗体染色后,胰岛表层区的胰岛细胞蛋白仍然表现出正常分布。右上方的图显示的是与H&E染色过的输导管上新形成的胰岛。右下方的图显示的是输导管壁细胞上含胰岛素的细胞。
实施例4 对鼠的31天研究(重复剂量)
对实验鼠还进行了为期31天,每天INGAP肽的注射量为0,2,20和100(毫克/千克/天)的重复剂量毒性研究。在此研究中,分成了四个处理组和两个恢复组,每个处理组由10只雄鼠和10只雌鼠组成,每个恢复组由5只雌鼠和5只雄鼠组成。实验结束时,还收集了血样和进行了尸体剖检以便进行粗略和精微的观察。并对每组中大约半数的动物进行了临床病理学和血清水平方面的评价。对选择的器官(脑、肾上腺、心脏、肾、肝、肺、胰腺和脾)进行了称重并对相对器官重量进行了计算。胰腺中的一部分被分离并冷冻在液氮中以便评价胰岛素含量,部分胰腺组织交给相关研究人员进行独立的显微观察研究。恢复健康的实验鼠在停止进行药剂处理的28天后进行了相同的实验处理。用于进一步的研究和潜在地与药相关的异常发现的各种参数被评估以决定实验的可重复性和潜在的临床意义。
对实验鼠进行31天连续的肌肉注射INGAP肽药剂,在停止注射药剂和其后的28天后治疗的评价中,并没有产生与本药相关的副作用。随着最高剂量注射次数的增加,在雄性和雌性实验鼠的身上的注射位置观察到了炎症反应,但是以同样的剂量在恢复健康的鼠身上却不再观察到刺激反应,这表现出了炎症的可逆性。在该31天的实验研究中发现,在一只高剂量处理的雄性鼠的脾脏内发生骨髓外造血作用。在显微镜下观察没有发现发炎细胞渗透、水肿、骨疽或萎缩等迹象。非常突出的观察结果就是,在与输导管相关的组织和胰腺泡组织中小胰岛数量的增加。在连续进行31天的药剂作用后的两小时后,实验鼠体内的血清中的INGAP水平就低于限制的数值。这些动物体内观察到的含胰岛素的组织面积的增加可以衡量出药理学活性(见图7)。本实验结果表明:对CD-1鼠进行31天的药剂作用时,无副作用的水平值(NOAEL)大于100毫克/千克。
实施例5 对狗的34天研究(重复剂量)
还对小猎犬进行了为期34天的重复剂量的毒性实验,每天肌肉注射INGAP肽的量分别为0,0.5,1.5和10(毫克/千克/天)。并获得了根据免疫组织化学来定量β-细胞的胰腺组织,而这些胰腺组织分别取自34天治疗完毕时的实验鼠和治疗完毕25天后恢复健康的实验鼠的体内。胰腺β-细胞随着INGAP肽的使用量的增加而增加(见图8)。这些结果表明:在实验研究的剂量下,对正常实验犬进行INGAP肽的肌肉注射实验获得了生物学上比较重要的响应。而且,对胰腺组织区域的更深入的研究没有显示出水肿、炎性细胞侵入、骨疽或萎缩等症状。
实施例6 人的临床研究
药物的剂量通常基于药物功效和对动物的药物安全性研究。以两种剂量的INGAP肽为例,对I型或II型糖尿病患者进行治疗。这两种剂量分别为7.5毫克(对于60公斤体重的患者来讲,0.125毫克/千克,或4.625毫克/平方米)和120毫克(对于60公斤体重的患者来讲,1.6毫克/千克,或74毫克/平方米)。为了确定INGAP肽治疗的效果,对以下参数进行了评价:
1.保持总胰岛素的剂量,禁食葡萄糖水平降低大于35毫克/分升。
2.保持禁食葡萄糖水平在美国糖尿病协会(ADA)标准确定的范围之内,将胰岛素的剂量降低25%。
3.禁食C-肽的量增至1纳克/毫升,饮用SustacalBoost后的C-肽量增至2纳克/毫升。
每一位患者都随机的接受一次INGAP肽的肌肉注射。在评价药物功效和安全性数据之后,患者可以根据医生的判断进一步给患者进行INGAP肽注射。
下表中简要地概述了评估的部分列表,该评估是对接受INGAP或安慰剂治疗的患者的评估。
表2 评估表
程序 | 筛选 | 基数 | 治疗期限1至34天 | 跟踪天数35至63±2天 | ||||||||
访问日期 | 1 | 7 | 14 | 21 | 28 | 34 | 42 | 49 | 56 | 63 | ||
体检 | X | X | X | X | ||||||||
重要症状 | X | X | X | X | X | X | X | X | X | X | X | X |
临床实验检测 | X | X | X | X | X | X | X | X | ||||
INGAP肽在血浆中的PK值 | X | X | X | X | X | X | X | X |
C-肽刺激实验
C-肽刺激实验是在禁食一夜,至少10小时后的第二天早上进行的。只有禁食葡萄糖指数在80至250毫克/分升之间时才可以进行该实验。患者在实验的前一天晚上可以服用治疗糖尿病的药物,但是在实验的早上至实验完全结束期间不能再服用。确定C-肽所需要采集的血样应该分别在Boost饮用之前和饮用之后的0.5小时、2小时和4小时立即抽取。Boost通过口服摄取。如果患者禁食的C-肽水平低于1.0纳克/毫升,则认为此患者缺乏胰岛素,患者的C-肽刺激的最大值低于2.0纳克/毫升。
上述治疗的结果显示:接受INGAP肽治疗的患者表现出对糖的耐受性有所提高,禁食后葡萄糖水平有所降低,对胰岛素的需求量下降,禁食后C-肽水平有所增加,和饮用Boost后的C-肽的水平有所增加。但是,用安慰剂进行治疗的患者的状况没有显示出这样的改善。
除特别注明外,所有的量,包括数量、百分数、分数和比例都应理解为具有“大约”的含义,数量的意义并不在于数字本身。
除特别注明外,定冠词“一个”和“所述”表示“一个或多个”。
虽然对本发明的特定实施方案进行了图示和描述,但对于本领域熟练的技术人员而言,他们在不脱离本发明的精神和范围的前提下可以进行不同的改变和修订。因此旨在在所附的权利要求书中包括属于本发明范围内的所有这些改变和修订。
序列表
<110>A.I.维尼克(Vinik,Aaron I)
L.罗森伯格(Rosenberg,Lawrence)
G.皮腾格(Pittenger,Gary)
D.泰勒-费西维克(Taylor-Fishwick,David)
M.萨勒姆(Salem,Michael)
S.莫兰德(Mohrland,Scott)
<120>治疗糖尿病的组合物和方法
<130>9016#L$
<140>Not Yet Assigned
<141>2002-09-24
<150>US 60/329,330
<151>2001-10-16
<160>3
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<213>智人(Homo sapiens)
<400>3
Ile Gly Leu His Asp Pro Ser His Gly Thr Leu Pro Asn Gly Ser
1 5 10 15
Claims (9)
1.药物组合物,所述药物组合物包括具有至少十五种连续的氨基酸的多肽,所述多肽与哺乳动物胰岛的天然再生蛋白有关,其中所述氨基酸序列为SEQ IDNO:1、SEQ ID NO:2或SEQ ID NO:3以及它们的片段,且其pH值为约4至约6。
2.如权利要求1所述的药物组合物,其中所述组合物为冷冻干燥的粉末或溶液形式。
3.如前述任一项权利要求所述的药物组合物,其中所述组合物的pH值为约4至约5。
4.如前述任一项权利要求所述的药物组合物,其中所述多肽的形式选自药学可接受的酯、盐以及它们的混合物。
5.如前述任一项权利要求所述的药物组合物,所述药物组合物包括约0.1毫克至约300毫克的所述多肽。
6.如前述任一项权利要求所述的药物组合物的使用,所述药物组合物用于制造治疗人类或其它动物所患的糖尿病的药物。
7.如前述任一项权利要求所述的药物组合物的使用,所述药物组合物用于制造再生Langerhans胰岛、胰腺β细胞或在哺乳动物中建立正常生理血糖调节的药物。
8.如前述任一项权利要求所述的药物组合物的使用,其中所述给药频率为每天一次、每天两次、每天三次、每周一次、两周一次、每月一次、连续输液或它们的组合。
9.用于如前述任一项权利要求所述的使用的试剂盒,所述试剂盒包括:
1)权利要求1的药物组合物;和
2)用法说明。
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US32933001P | 2001-10-16 | 2001-10-16 | |
US60/329,330 | 2001-10-16 |
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CN1723034A true CN1723034A (zh) | 2006-01-18 |
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CNA028201922A Pending CN1723034A (zh) | 2001-10-16 | 2002-10-15 | 治疗糖尿病的组合物和方法 |
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US (2) | US20040132644A1 (zh) |
EP (1) | EP1435995A2 (zh) |
JP (1) | JP2005506362A (zh) |
KR (1) | KR20050036865A (zh) |
CN (1) | CN1723034A (zh) |
BR (1) | BR0213291A (zh) |
CA (1) | CA2463769A1 (zh) |
CO (2) | CO5570658A2 (zh) |
CZ (1) | CZ2004479A3 (zh) |
HU (1) | HUP0401612A3 (zh) |
IL (1) | IL161073A0 (zh) |
MA (1) | MA27503A1 (zh) |
MX (1) | MXPA04003526A (zh) |
NO (1) | NO20042012L (zh) |
PE (1) | PE20030608A1 (zh) |
PL (1) | PL370069A1 (zh) |
RU (1) | RU2004114865A (zh) |
SK (1) | SK1702004A3 (zh) |
WO (1) | WO2003033808A2 (zh) |
ZA (1) | ZA200402261B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103305457A (zh) * | 2013-06-06 | 2013-09-18 | 浙江省医学科学院 | 一种体外扩增胰岛β细胞的方法 |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060009516A1 (en) * | 2002-10-24 | 2006-01-12 | Mcgill University | Use of ingap for reversing diabetes |
US8211430B2 (en) * | 2005-03-04 | 2012-07-03 | Curedm Group Holdings, Llc | Methods and pharmaceutical compositions for treating type 1 diabetes mellitus and other conditions |
US20090142338A1 (en) * | 2005-03-04 | 2009-06-04 | Curedm, Inc. | Methods and Compositions for Treating Type 1 and Type 2 Diabetes Mellitus and Related Conditions |
CA2609667C (en) * | 2005-05-25 | 2011-02-22 | Curedm, Inc. | Human proislet peptide, derivatives and analogs thereof, and methods of using same |
EP1840573A1 (en) * | 2006-03-27 | 2007-10-03 | Institut Pasteur | Secreted proteins as early markers and drug targets for autoimmunity, tumorigenesis and infections |
US8785400B2 (en) * | 2006-11-22 | 2014-07-22 | Curedm Group Holdings, Llc | Methods and compositions relating to islet cell neogenesis |
SI2193142T1 (sl) * | 2007-08-30 | 2015-05-29 | Curedm Group Holdings, Llc | Sestavek in postopek za uporabo proislet peptidov in analogov le-teh |
AU2013323462A1 (en) * | 2012-09-27 | 2015-04-23 | Claresa LEVETAN | Generation of new pancreatic beta cells |
US20160039877A1 (en) * | 2013-03-15 | 2016-02-11 | Shenzhen Hightide Biopharmaceutical, Ltd. | Compositions and methods of using islet neogenesis peptides and analogs thereof |
CN104045699A (zh) * | 2013-03-15 | 2014-09-17 | 深圳君圣泰生物技术有限公司 | 一种多肽、多肽衍生物、多肽的可药用盐及药物组合物 |
CN104045702A (zh) * | 2013-03-15 | 2014-09-17 | 深圳君圣泰生物技术有限公司 | 一种多肽、多肽衍生物、多肽的可药用盐及药物组合物 |
CN104045698B (zh) * | 2013-03-15 | 2019-04-16 | 深圳君圣泰生物技术有限公司 | 一种多肽、多肽衍生物、多肽的可药用盐及药物组合物 |
US20160039876A1 (en) * | 2014-03-28 | 2016-02-11 | Claresa Levetan | Insulin independence among patients with diabetes utilizing an optimized hamster reg3 gamma peptide |
WO2017152861A1 (en) * | 2016-03-10 | 2017-09-14 | Shenzhen Hightide Biopharmaceutical, Ltd. | Conjugates of islet neogenesis peptides and analogs, and methods thereof |
US20210196646A1 (en) * | 2018-08-15 | 2021-07-01 | Wake Forest University Health Sciences | Improved formulations for pancreatic islet encapsulation |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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US127624A (en) * | 1872-06-04 | Improvement in apparatus for elevating water | ||
US4658957A (en) * | 1985-01-28 | 1987-04-21 | Abbott Laboratories | Utility tray |
US6106840A (en) * | 1988-06-23 | 2000-08-22 | Anergen, Inc. | MHC conjugates useful in ameliorating autoimmunity |
US5834590A (en) * | 1995-02-22 | 1998-11-10 | Eastern Virginia Medical School Of The Medical College Of Hampton Roads | Ingap protein involved in pancreatic islet neogenesis |
ATE494374T1 (de) * | 1995-02-22 | 2011-01-15 | Eastern Virginia Med School | Ingap-protein und dessen beteiligung an der neogenese pankreatischer inselzellen |
HU224827B1 (hu) * | 1996-05-03 | 2006-02-28 | Abbott Lab | Új antiangiogén peptidek, azokat kódoló polinukleotidok, és eljárások angiogenezis gátlására |
US6090577A (en) * | 1997-05-22 | 2000-07-18 | Incyte Pharmaceuticals, Inc. | Disease associated acidic protein |
US6986994B2 (en) * | 2001-01-09 | 2006-01-17 | Gmp Endotherapeutics, Inc. | INGAP displacement assays |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103305457A (zh) * | 2013-06-06 | 2013-09-18 | 浙江省医学科学院 | 一种体外扩增胰岛β细胞的方法 |
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Publication number | Publication date |
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ZA200402261B (en) | 2004-09-28 |
CO5590933A2 (es) | 2005-12-30 |
CO5570658A2 (es) | 2005-10-31 |
MA27503A1 (fr) | 2005-09-01 |
JP2005506362A (ja) | 2005-03-03 |
WO2003033808A3 (en) | 2003-09-18 |
PE20030608A1 (es) | 2003-08-26 |
RU2004114865A (ru) | 2005-05-27 |
CZ2004479A3 (cs) | 2005-01-12 |
HUP0401612A3 (en) | 2006-04-28 |
MXPA04003526A (es) | 2004-07-22 |
NO20042012L (no) | 2004-07-16 |
IL161073A0 (en) | 2004-08-31 |
EP1435995A2 (en) | 2004-07-14 |
US20040132644A1 (en) | 2004-07-08 |
BR0213291A (pt) | 2004-10-26 |
US20080171704A1 (en) | 2008-07-17 |
SK1702004A3 (sk) | 2005-03-04 |
CA2463769A1 (en) | 2003-04-24 |
KR20050036865A (ko) | 2005-04-20 |
WO2003033808A2 (en) | 2003-04-24 |
HUP0401612A2 (hu) | 2004-12-28 |
PL370069A1 (en) | 2005-05-16 |
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