CN1185114A - 单体胰岛素类似物制剂 - Google Patents
单体胰岛素类似物制剂 Download PDFInfo
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- CN1185114A CN1185114A CN96194052A CN96194052A CN1185114A CN 1185114 A CN1185114 A CN 1185114A CN 96194052 A CN96194052 A CN 96194052A CN 96194052 A CN96194052 A CN 96194052A CN 1185114 A CN1185114 A CN 1185114A
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- Prior art keywords
- insulin
- solution
- preparation
- analog
- crystal
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明公开了具有长效的各种非胃肠道药物制剂,该制剂含有:约20/U/ml-约500U/ml胰岛素类似物的灭菌水悬浮液,约5mg/ml-10mg/ml氯化钠,约0.2-约2.0mg/ml生理上容许的缓冲剂,约0.07mg/ml-约0.1mg/ml的锌离子和生理上容许的防腐剂,pH为约6.5-约7.8;这使得悬浮液中存在的胰岛素类似物处在溶解状态的不到5%。
Description
本发明涉及人胰岛素单体类似物。更具体地说,本发明涉及长效的各种单体类似物非胃肠道制剂。这些制剂延长了药物的作用时间。
多年来就知道可以成功地将胰岛素与锌离子共结晶,得到许多种稳定的晶体,它们的药效时间比可溶性或无定形的非晶态胰岛素长。在50年代初期,研制出一种新的牛胰岛素晶体制剂,该制剂在中性pH的乙酸盐缓冲剂中只含胰岛素和锌。Hallas-Mller等,科学(Science)-,116,394-398(1952)。这种胰岛素制剂避免了能与锌离子强烈作用形成不溶性磷酸锌衍生物的磷酸根离子。在乙酸盐缓冲剂中只含晶态胰岛素的制剂被称作Ultralente(超长效的)。用这种方式制得的晶体在本文中称作Ultralente(超长效)晶体。
近来,已研制出单体胰岛素类似物,它们保持着天然人胰岛素的生物活性,但是不容易二聚和自缔合成更高分子量的形式。自缔合的减小造成了活性发作更快。这些胰岛素类似物能够迅速吸收,使得注射时间和胰岛素的峰值药效与随用餐而伴生的饭后葡萄糖浓度偏差更为接近。
本发明提供了具有持久作用的一种单体胰岛素类似物的制剂。因为单体胰岛素类似物不像胰岛素那样聚集的缔合,所以可以形成稳定的类似物晶体这一点相当出乎意料。令人惊奇的是,本发明的制剂提供了可预测的延长的作用时间。
本发明提供了一种长效的非胃肠道药物制剂,它基本上由约20-约500U/ml胰岛素类似物的灭菌水悬浮液,约5-约10mg/ml氯化钠,约0.2-约2.0mg/ml生理上容许的缓冲剂,约0.04-约20.0mg/ml锌离子和一种生理上容许的防腐剂组成,pH约为6.5-约7.8;这使得悬浮液中存在的胰岛素类似物处于溶解状态的不到5%。
本发明还提供了一种由溶液中沉淀晶体制备的胰岛素类似物晶体,该溶液基本上由约200-约1200U/ml的胰岛素类似物、约50-约100mg/ml的氯化钠、约20-约20.0mg/ml生理上容许的缓冲剂和摩尔量过剩的锌离子组成,pH为约5.0-约6.0。
本申请中使用的所有氨基酸缩写均为美国专利与商标局所认可的缩写,如在37C.F.R.§1.822(b)(2)中列出的那些。
本文中使用的术语“胰岛素类似物”或“单体胰岛素类似物”是一种二聚或自缔合倾向小于人胰岛素的胰岛素类似物。单体胰岛素类似物是一种其中B28位的Pro被Asp、Lys、Leu、Val或Ala取代,且B29位的Lys是赖氨酸或脯氨酸;去(B28-B30);或去(B27)的人胰岛素。在Chance等的美国专利申请07/388,201(EPO公布号383 472)和Brange等的EPO申请214 826中有对单体胰岛素类似物的说明,上述文献在本申请中引用作为参考。
本领域的技术人员会认识到,可以对这种单体胰岛素类似物进行其它修饰。这些修饰是本领域中广泛采用的,包括在B1位用天冬氨酸代替苯丙氨基酸;用丙氨酸代替B30位的苏氨酸残基;用天冬氨酸代替B9位处的丝氨酸残基;只去掉B1位的或是一并去掉B2位的氨基酸,以及去掉B30位处的苏氨酸。特别优选的单体胰岛素类似物是LysB28ProB29-人胰岛素(B28是Lys;B29是Pro)和AspB28-人胰岛素(B28是Asp)。
术语“Utralente胰岛素”是指其中含有胰岛素晶体的制剂,该晶体基本上按照Hallas-Mller等,在科学(Science),116,394-398(1952)中的叙述在乙酸盐缓冲液中制得。用这种方式制得的晶体以后称作Ultralente(超长效)胰岛素晶体。
术语“胰岛素类似物晶体”是指用本文所述方法制得的胰岛素类似物晶体。
术语“U”是指胰岛素活性的标准国际单位。
本文中所用的“基本上”一词意味着大于约95%,优选大于约98%。例如,基本上晶态意味着结晶度大于95%的物质。
本文中的“治疗”一词,描述了为战胜疾病、症状或失调而对患者采取的措施和护理,它包括施用本发明化合物以防止症状或并发症的发作,减轻症状或并发症,或消除疾病、症状或失调现象。
术语“生理上容许的防腐剂”是指间甲酚、对羟基苯甲酸甲酯、间苯二酚、苯酚或本领域认可的其它防腐剂。
术语“生理上容许的缓冲剂”是本领域已知的。生理上容许的缓冲剂包括乙酸 钠或乙酸铵,或者与锌无强烈作用的其它缓冲剂。
术语“锌离子”是本领域技术人员所了解的。锌离子的来源优选为锌盐。锌盐的代表性实例包括乙酸锌、溴化锌、氯化锌、氟化锌、碘化锌和硫酸锌。熟练的技术人员会认识到,很多其它的锌盐也可以用来制备本发明的制剂。
如上面所指出的,本发明提供了胰岛素类似物晶体和长效的胰岛素类似物制剂。胰岛素类似物晶体是从溶液中沉淀晶体制得的,所述溶液中基本上由约200-约1200U/ml胰岛素类似物、约50-约100mg/ml的氯化钠、约2.0-约20.0mg/ml的生理上可接受的缓冲剂和摩尔量过剩的锌离子组成,溶液的pH为胰岛素类似物的等电点,通常pH为约5.0-约6.0。
胰岛素类似物晶体优选用自溶液中沉淀晶体法制备,该溶液中基本上由约400-约1000U/ml胰岛素类似物、约65-约75mg/ml氯化钠、5.0-约10.0mg/ml乙酸钠和约0.1-约0.5mg/ml锌离子组成,pH约为5.5-约5.9。最好是,胰岛素类似物晶体用从溶液中沉淀晶体法制备,该溶液基本上由400U/ml胰岛素类似物、约70mg/ml氯化钠、约8.0mg/ml乙酸钠和0.15mg/ml锌离子组成,pH约为5.5-约5.6。
当把pH调节到胰岛素类似物的等电点时,晶体形成。利用生理上容许的碱(如氢氧化钠)调节溶液的碱度,将pH由较酸性调节到5.0-6.0。类似地,利用生理上容许的酸(如盐酸)调节溶液的酸度,将pH由较碱性调节到5.0-6.0。
优选配制两种溶液,它们在合并时形成一种溶液,该溶液基本上由约200-约1200U/ml胰岛素类似物、约50-约100mg/ml氯化钠、约2.0-约20.0mg/ml生理上容许的缓冲剂和摩尔量过剩的锌离子组成,其pH为类似物的等电点。第一种溶液下文称为胰岛素类似物部分,它含有约300-约2000U/ml胰岛素类似物和摩尔量过剩的锌离子,其pH为酸性,约2.0-约3.0。第二种溶液下文称作缓冲剂部分,含有约130-约270mg/ml氯化钠、约5.0-约55.0mg/ml生理上容许的缓冲剂,pH为碱性,约10.5-约12.5。在合并后,溶液的pH平衡到胰岛素类似物的等电点,pH约为5.0-6.0。晶体自溶液中沉淀出来。此溶液下文称作晶体部分。
在约5.0-6.0的pH下,晶体在搅拌下于约6-72小时内沉淀。但是,完成晶体生长的准确时间取决于所选择的胰岛素类似物和所采用的条件。所形成的要求保护的晶体是轮廓分明的,形状为菱形。
优选向溶液中加入种晶以形成大小分布更均匀的晶态物质并加速晶化。种晶的制备是本领域已知的,可以由人胰岛素、牛胰岛素、猪胰岛素或胰岛素类似物衍生得到。
因为单体胰岛素类似物不发生自缔合,故其物理性质和特征与胰岛素不相似。例如,各种单体类似物很少或者不发生Zn诱导的缔合。这与胰岛素显著不同,后者在锌存在下几乎完全是六聚体构型。因为要形成合适的Ultralente胰岛素晶体,每个胰岛素六聚体内至少需要络合两个锌原子,所以在与制备Ultralente胰岛素使用的类似条件下能形成胰岛素类似物晶体是相当出乎意料的。
此外,本发明的晶体优选在约500-3000ppm的低含量苯酚存在下制备。因为按摩尔比发生的防腐剂的结合会引起胰岛素类似物自缔合,所以单体类似物在不存在高浓度防腐剂的条件下发生晶化是令人惊奇的。因此,晶体的形成是出乎意料的,因为单体类似物形成六聚体的倾向有限。这与胰岛素不同,后者在有锌但没有防腐剂存在下容易形成六聚体。
再者,本领域已知酚类防腐剂会损害Ultralente胰岛素结晶。因此,在酚类防腐剂存在时于本文所述条件下形成胰岛素类似物晶体是令人惊奇的。
本发明还提供了适合用皮下注射治疗糖尿病的胰岛素类似物晶体的制剂。非肠道用药的药物制剂基本上由约20-约500U/ml胰岛素类似物的灭菌水悬浮液,约5-约10mg/ml的氯化钠、0.2至约2.0mg/ml的生理上容许的缓冲剂,约0.04-约20.0mg/ml的锌离子和生理上容许的防腐剂组成,其pH约为6.5-约7.8;这就使悬浮液中存在的胰岛素类似物处在溶解状态的不到5%。优选,制剂中胰岛素类似物处于溶解状态的不到2%。
本文所述的胰岛素类似物制剂是用本领域用来制备人胰岛素超长效制剂的公认技术制备的。胰岛素类似物晶体的悬浮液用稀释溶液稀释,该稀释溶液中含有生理上容许的缓冲剂和防腐剂。制剂的pH调节到约7.3-约7.4。
本发明专利要求保护的这种胰岛素类似物制剂造成胰岛素类似物的缓慢吸收,因此如果愿意,所需的注射用药每天不超过一次。
这些制剂中含有防腐剂(如对羟基苯甲酸甲酯),锌含量为约0.04-约20.0mg/ml,pH约为7.1-约7.5。晶体中存在的氯化钠起等渗剂的作用。但是,本领域技术人员会认识到,如有必要,制剂的等渗性可以用氯化钠或工艺上已知的其它等渗调节剂(如甘油)调节。另外,普通技术人员都了解,很多其它的防腐剂都可用于本发明。在优选的实施方案中,总锌浓度对于U40制剂为0.04-约0.1mg/ml,优选为0.08mg/ml,对于U100制剂为约0.1-约0.24mg/ml,优选为0.14mg/ml。
制剂的pH可以用生理上容许的缓冲剂缓冲。生理上容许的缓冲剂包括乙酸钠或与锌无强烈作用的其它缓冲剂。
最有意义的是,通过向制剂中加入额外的锌使总锌浓度为每100单位胰岛素约0.5-约20mg,优选每100单位约0.5-约7mg,进一步延长了制剂的作用时间。额外的锌是在晶体络合与配制后加入。增加了锌的制剂中超过50%的总锌量是在可溶部分中而不是与胰岛素络合。增加了锌的制剂的pH一般为6.0-7.4。
本发明还提供了胰岛素类似物制剂,包括主要由晶态和无定形物质混合物构成的Lente(长效)类制剂,以及只含有无定形物质的SemiLente(半长效)类制剂。这些混合物提供了可预知的药效持续时间和更快的清除。另外,这些制剂比可溶性胰岛素的药效持续时间更长久。
本文所述的特殊的结晶条件只形成晶态制品。如果改变条件,则形成不同数量非晶态的无定形物质。一般来说,从缓冲剂部分去掉卤化物或者在中性pH下而不是在等电点下结晶将产生非晶态物质。优选利用这些变化的组合来制备无定形产物,以保证完全生成无定形物质。因为各种单体类似物在只生成晶态产物的最佳条件方面略有不同,本领域技术人员应该理解,其它制备无定形物质的程序或条件也是可行的。例如,加入对锌离子有强亲合力的缓冲剂将中断结晶过程。
无定形锌类似物的浓悬浮液优选用从溶液中沉淀无定形锌胰岛素类似物颗粒的方法制备,该溶液主要由约200-约1200U/ml胰岛素类似物、约2.0-约20.0mg/ml生理上容许的缓冲剂、约50.0-约100mg/ml氯化钠和摩尔量过剩的锌离子组成,pH值约为7.0-约7.5。
半长效的胰岛素类似物(Semilente-like)制剂是将无定形锌胰岛素类似物的浓悬浮液稀释成无定形制剂而制得的,该制剂中主要由约20-约500U/ml的胰岛素类似物、约5-约10mg/ml氯化钠、0.2-约2.0mg/ml生理上容许的缓冲剂、约0.07-约20.0mg/ml的锌离子以及生理上可接受的防腐剂组成,pH为约6.5-约7.8;这就使悬浮液中存在的胰岛素类似物处在溶解状态的不到5%。
长效胰岛素类似物(Lente-like)制剂是70%结晶与30%无定形物质的混合物。晶态部分是按照本文对胰岛素类似物晶体所述的方式制备的。无定形物质是按照对半长效胰岛素类似物所述的方式制备的。用常规方法将晶体部分和无定形部分混合。
本发明的胰岛素类似物可以用许多公认的合成肽方法中的任何一种来制备,包括经典的(溶液)方法、固相法、半合成法和更近的重组DNA方法。
提供以下实施例只是为了进一步说明胰岛素类似物的制备和本发明。本发明的范围不应看作只包括以下实施例。
制备例1
晶种的制备
Lente(长效)晶种的制备方法是本领域已知的,例如在JorganSchlictkrull“胰岛素晶体:IV晶核、晶种和单分散胰岛素晶体悬浮液的制备(Insulin Crystals:IV.The Preparation of Nuclie,Seedsand Monodisperse Insulin Crystal Suspensions)”斯堪的那维亚化学学报(Acta Chemica Scandinavica),11:299-302(1957)中所述。
实施例1单体类似物晶体的制备LysB28ProB29-人胰岛素部分:
向带刻度的装有磁搅棒的烧杯中加入1.034g LysB28ProB29-人胰岛素晶体(内源锌含量0.51%,苯酚浓度939ppm)。将该晶体悬浮在约30ml Milli-QTM水中。向此溶液中加入0.464ml一份10mg/ml酸性氧化锌溶液,使总锌量为4.64mg。用10%盐酸将pH调节至2.77。在溶液完全澄清后,加入Milli-QTM水使溶液的最终重量为40g。将最终的胰岛素类似物溶液(下文称用类似物部分)经过0.22μm滤器(MilliporeSterivexTM-GV过滤装置)过滤。缓冲剂部分:
向带刻度的装有磁搅棒的烧杯中加入0.565g乙酸钠和4.947g氯化钠。用大约25g Milli-QTM水将盐溶解,用10%氢氧化钠将pH调节至约11。在调节完pH之后,用Milli-QTM水将溶液的最终质量调节到30g。此溶液(下文称作缓冲溶液)经过0.22μm滤器(MilliporeSterivexTM-GV过滤装置)过滤。用0.25ml的10%NaOH将缓冲溶液调节至pH为12.01,以便在与类似物溶液合并后pH为5.6。结晶:
采用以下条件配制50ml的400U/ml晶体(下文称作晶体部分)。向结晶容器中加入29.716ml类似物部分。在搅拌下向容器中加入总计18.75ml缓冲液部分。等待60秒后,向容器中加入1.544ml人胰岛素晶种混合物(官能度=4),其数量是按1/2官能度乘以类似物的克数算出的。在环境温度下继续搅拌24小时。
实施例2具有长效的胰岛素类似物药物制剂(40U/ml)稀释溶液:
将0.6g对羟基苯甲酸甲酯溶在Milli-QTM水中使最终质量为300g,配成对羟基苯甲酸甲酯贮备液(2mg/g)。向配衡好的装有磁搅棒的烧杯中加入277.78g对羟基苯甲酸甲酯贮备液、0.444g乙酸钠和4.785ml的10mg/ml酸性氧化锌溶液。用10%氢氧化钠溶液将溶液的pH调节到5.53。加入Milli-QTM水使溶液的最终质量为500g,最后使溶液通过0.22μm的滤器(Millipore SterivexTM-GV过滤装置)。制剂:
将一份0.020ml10%的盐酸和一份0.750ml的10%氢氧化钠溶液加到稀释溶液中使pH为7.72,这使得晶体部分与稀释溶液混合后的最终pH为7.3-7.4。向一只已配衡的装有磁搅棒的容器中加入360g稀释溶液(为最终体积的90%,比重=1.000),然后加入42.40g晶体部分(为最终体积的10%,比重=1.060)。用0.010ml 10%氢氧化钠溶液将最终pH调节到7.27-7.34。
实施例3晶体及最终制剂的鉴定
用显微镜检查按本文所述制得的LysB28ProB29-人胰岛素晶体,在结晶24小时后发现主要含有大小约10μm的菱形晶体。最终的40U/mlLysB28ProB29-人胰岛素制剂用显微镜检验并用一些分析试验鉴定,以验证制备和加工的效果。显微镜检验表明制剂中存在菱形晶体。将一份1ml充分再悬浮的制剂在14000 RPM下离心30分钟。小心地取出上清液,向800μl该溶液中加入1μl 9.6M盐酸。然后将一份20μl的该混合物注入到用逆相法运行的HPLC系统上。此试验结果表明,上清液中含有0.034U/ml未结晶的LysB28ProB29-人胰岛素。为测定制剂的总药效,用3μl9.6M的盐酸将1ml重新悬浮的制剂酸化,然后用0.01M盐酸将样品稀释至5ml。将一份20μl的样品注入到按逆相法运行的HPLC系统上。实测的总药效为43.6 U/ml。制剂的纯度用逆相色谱法测定,直接注入酸化过的(用3μl 9.6M盐酸)1ml样品的20μl。根据峰值与总量比较测得纯度为98.3%。高分子量聚合物含量用尺寸排阻HPLC测定,直接注入酸化过的1ml液样的20μl。根据峰值与总量比较测得聚合物总量为0.17%。
实施例4体外溶解试验
此方法是对Graham和Pomeroy在药物与药理学杂志(J.Pharm.Pharmacol.)36,427-430(1983)中公开的方法的改进。本领域把此方法作为对生物响应的预测,它使用晶体在用不与锌结合的缓冲液充分稀释后的溶解比率作为手段,来预测晶态制剂在皮下注射到动物内之后的溶解比率。
晶态的LysB28ProB29-人胰岛素(40U/ml)制剂(表1中的LysPro)对照HumulinTM超长效胰岛素和两种40U/ml人胰岛素长效制剂进行试验。将0.2ml一份的这些悬浮液分别在环境温度和搅拌下加到装在玻璃烧杯中的20ml 0.1M pH7.5的Tris(三羟甲基氨基甲烷,Mallinckrodt,Paris,KY)缓冲液中。在0.5、3和8小时后自搅拌着的样品中取出0.2ml的液样并通过0.2μm的Acrodisc滤器。用逆相HPLC法定量测定滤液中的胰岛素量。由开始时对未过滤的酸化的液样进行的试验确定最大胰岛素含量。对于各样品,数据以对最大胰岛素含量的百分数的形式列出。
表1.体外溶解试验的时间依赖性
时间(小时)
样 品 0.5 3 8HumulinTM超长效胰岛素 17.7% 51.0% 90.4%HumulinTM长效胰岛素,1 43.0% 74.9% 98.2%HumulinTM长效胰岛素,2 45.6% 61.7% 80.1%LysPro晶体 26.0% 67.6% 95.0%
表1的结果表明,LysB28ProB29-人胰岛素晶体的溶解性质具有延长的药效持续时间。
实施例5LysB28ProB29-人胰岛素晶体的制备,对于U400晶态悬浮液LysB28ProB29-人胰岛素部分:
向带刻度的装有磁搅棒的烧杯中加入1.048g锌和少于500ppm的LysB28ProB29-人胰岛素(酚浓度检测不出)。将晶体悬浮在约30ml水中,加入0.942ml的10mg/ml酸性氧化锌溶液。用10%盐酸和10%氢氧化钠将pH调节到2.6。在溶液完全澄清后,加水使溶液的最终重量为38.95g。最终的溶液经过0.22μm滤器(Millipore SterivexTM-GV过滤装置)过滤。缓冲液部分:
向带刻度的装有磁搅棒的烧杯中加入0.565g乙酸钠和4.947g氯化钠。用大约25g水将盐溶解,用10%氢氧化钠将pH调节至约11.52。调节完pH之后,加水使溶液的最终质量为30g。最终溶液经0.22μm滤器(Millipore SterivexTM-GV过滤装置)过滤。结晶:
将LysB28ProB29-人胰岛素部分和缓冲液部分进行试验性组合(0.75ml LysB28ProB29-人胰岛素部分和0.45ml缓冲液部分),以确定为达到pH5.5-5.6的最终结晶条件所需的缓冲液部分的合适pH值。用0.28ml 10%氢氧化钠溶液将缓冲液部分调节到pH为12.13,以便在与LysB28ProB29-人胰岛素部分混合后pH为5.6。采用下列条件配制50ml400U/ml的UltraLente LysB28ProB29-人胰岛素部分(晶体部分)。向结晶容器中加入30.61g LysB28ProB29-人胰岛素部分,这是按LysB28ProB29-人胰岛素部分加上晶种等于晶体部分体积的62.5%估算出的。在搅拌下向容器中加入按晶体部分37.5%算出的18.75ml缓冲液部分。60秒之后,向晶体部分中加入按照1/2官能度乘以LysB28ProB29-人胰岛素的克数估算出的0.824ml人胰岛素晶种混合物(官能度=2)。在环境温度下继续搅拌48小时。
48小时后用显微镜(600倍放大)检验该悬浮液,发现其中包含由轮廓分明的菱形晶体、结晶不好的晶体及无定形物质构成的混合物。
实施例6LysB28ProB29-人胰岛素无定形沉淀物的制备LysB28ProB29-人胰岛素部分:
向带刻度的装有磁搅棒的烧杯中加入0.994g含锌的LysB28ProB29-人胰岛素(内源性锌0.43%,苯酚浓度2663ppm)。将该晶体悬浮在约30ml水中,向溶液中加入0.515ml的10mg/ml酸性氧化锌溶液。用0.220ml10%盐酸将pH调节至3.6。在溶液完全澄清后,加水使溶液的最终重量为40g。最终的溶液经0.22μm滤器(Millipore SterivexTM-GV过滤装置)过滤。缓冲液部分:
向带刻度的装有磁搅棒的烧杯中加入0.565g乙酸钠和4.947g氯化钠。加入约25g水将盐溶解,用10%氢氧化钠将pH调节到约12.6。调节完pH后,加水至最终质量为30g。溶液经0.22μm的滤器(MilliporeSterivexTM-GV过滤装置)过滤。无定形悬浮液:
LysB28ProB29-人胰岛素部分和缓冲液部分进行试验性组合(0.75mlLysB28ProB29-人胰岛素部分和0.45ml缓冲液部分),以确定为达到pH 7.2-7.4的最终溶液所需的缓冲液部分的合适pH值。向缓冲液部分加入额外的10%盐酸将pH调节到12.2。最终的组合溶液中含有31.25mlLysB28ProB29-人胰岛素部分和18.75ml缓冲液部分,pH为7.3。在环境温度下继续搅拌24小时。
48小时后用显微镜(600倍放大)检验该悬浮液,发现其中只含无定形物质。
实施例7晶态和无定形混合制剂
为制备一种长效制剂,将70%的实施例1的晶态LysB28ProB29-人胰岛素悬浮液与30%实施例6的无定形的LysB28ProB29-人胰岛素悬浮液混合。
Claims (12)
1.一种具有长效的非胃肠道药物制剂,它主要由约20U/ml-约500U/ml胰岛素类似物的无菌含水悬浮液,约5mg/ml-约10mg/ml氯化钠,约0.2-约2.0mg/ml生理上容许的缓冲剂,约0.04mg/ml-约20.0mg/ml的锌离子和生理上容许的防腐剂组成,pH为约6.5-约7.8;这使得悬浮液中存在的类似物处于溶解状态的不到5%。
2.权利要求1的制剂,其中的胰岛素类似物是LysB28ProB29-人胰岛素。
3.权利要求2的制剂,其中悬浮液中存在的类似物基本上是晶态物质。
4.权利要求3的非胃肠道药物制剂,其中胰岛素类似物浓度约为40U/ml,氯化钠浓度约为7mg/ml,缓冲剂为约1.6mg/ml的乙酸钠,pH约为7.0-约7.4。
5.权利要求3的非胃肠道药物制剂,其中胰岛素类似物浓度为约100U/ml,氯化钠浓度为约7mg/ml,缓冲剂为约1.6mg/ml的乙酸钠,pH为约7.0-约7.4。
6.权利要求1的制剂,其中悬浮液中存在的类似物基本上是无定形物质。
7.权利要求1的制剂,其中悬浮液中存在的类似物是约70%晶态和约30%无定形的物质。
8.利用从溶液中沉淀晶体制备的一种胰岛素类似物晶体,该溶液主要由约200-约1200U/ml胰岛素类似物、约50mg/ml-约100mg/ml氯化钠、约2.0-约20.0mg/ml生理上容许的缓冲剂和摩尔量过剩的锌离子组成,其pH为约5.0-约6.0。
9.利用从溶液中沉淀晶体制备的一种胰岛素类似物晶体,该溶液主要由约200-约1200U/ml胰岛素类似物、约50mg/ml-约100mg/ml氯化钠、约2.0-约20.0mg/ml生理上容许的缓冲剂、约500ppm-约3000ppm的苯酚和摩尔量过剩的锌离子,pH约为5.0-约6.0。
10.一种胰岛素类似物晶体,它通过将以下的第一种溶液和第二种溶液混合制得:第一种溶液中含有约300U/ml-约2000U/ml的胰岛素类似物,约500ppm-约3000ppm苯酚和摩尔量过剩的锌离子,pH为约2.0-约3.0;第二种溶液含有约130mg/ml-约270mg/ml氯化钠,约5.0-约55.0mg/ml生理上容许的缓冲剂,pH为约10.5-12.5;这使得混合后的溶液的pH为5.0-6.0。
11.权利要求8-10中任一项的晶体,其中胰岛素类似物是LysB28ProB29-人胰岛素。
12.一种制备LysB28ProB29-人胰岛素晶体的方法,该方法包括:将第一种溶液与第二种溶液混合;第一种溶液中含有约300U/ml-约2000U/ml胰岛素类似物、约500ppm-约3000 ppm苯酚和摩尔量过剩的锌离子,pH为约2.0-约3.0;第二种溶液含约130mg/ml-约270mg/ml氯化钠、约5.0-约55.0mg/ml生理上容许的缓冲剂,pH为约10.5-12.5;混合后溶液的pH为5.0-6.0。
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-
1996
- 1996-03-27 AR ARP960101937A patent/AR002976A1/es not_active Application Discontinuation
- 1996-03-27 YU YU18596A patent/YU18596A/sh unknown
- 1996-03-28 AU AU53812/96A patent/AU720300B2/en not_active Ceased
- 1996-03-28 HU HU9801700A patent/HUP9801700A3/hu unknown
- 1996-03-28 CZ CZ973052A patent/CZ305297A3/cs unknown
- 1996-03-28 JP JP8529728A patent/JPH11502856A/ja active Pending
- 1996-03-28 IL IL11769696A patent/IL117696A/xx not_active IP Right Cessation
- 1996-03-28 PE PE1996000217A patent/PE38797A1/es not_active Application Discontinuation
- 1996-03-28 CO CO96015449A patent/CO4700482A1/es unknown
- 1996-03-28 KR KR1019970706829A patent/KR19980703425A/ko not_active Application Discontinuation
- 1996-03-28 EP EP96302171A patent/EP0735048A1/en not_active Withdrawn
- 1996-03-28 WO PCT/US1996/004424 patent/WO1996030040A1/en not_active Application Discontinuation
- 1996-03-28 ZA ZA9602502A patent/ZA962502B/xx unknown
- 1996-03-28 NZ NZ305719A patent/NZ305719A/en unknown
- 1996-03-28 BR BR9607935A patent/BR9607935A/pt not_active Application Discontinuation
- 1996-03-28 CN CN96194052A patent/CN1185114A/zh active Pending
- 1996-03-28 MX MX9707428A patent/MX9707428A/es unknown
- 1996-03-28 PL PL96322626A patent/PL322626A1/xx unknown
- 1996-03-28 TR TR97/01078T patent/TR199701078T1/xx unknown
- 1996-03-28 EA EA199700285A patent/EA000970B1/ru not_active IP Right Cessation
- 1996-03-28 CA CA002216516A patent/CA2216516A1/en not_active Abandoned
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1997
- 1997-09-26 US US08/938,245 patent/US5952297A/en not_active Expired - Fee Related
- 1997-09-29 NO NO974498A patent/NO974498L/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN106794156A (zh) * | 2014-07-08 | 2017-05-31 | 美药星制药股份有限公司 | 微粒化胰岛素、微粒化胰岛素类似物及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
AR002976A1 (es) | 1998-05-27 |
IL117696A (en) | 2000-01-31 |
JPH11502856A (ja) | 1999-03-09 |
EA199700285A1 (ru) | 1998-02-26 |
ZA962502B (en) | 1997-09-29 |
EA000970B1 (ru) | 2000-08-28 |
IL117696A0 (en) | 1996-07-23 |
KR19980703425A (ko) | 1998-11-05 |
PE38797A1 (es) | 1997-10-04 |
NO974498L (no) | 1997-10-08 |
US5952297A (en) | 1999-09-14 |
HUP9801700A3 (en) | 1998-12-28 |
PL322626A1 (en) | 1998-02-02 |
YU18596A (sh) | 1998-07-10 |
CO4700482A1 (es) | 1998-12-29 |
NZ305719A (en) | 1998-09-24 |
HUP9801700A2 (hu) | 1998-11-30 |
AU720300B2 (en) | 2000-05-25 |
BR9607935A (pt) | 1998-06-02 |
AU5381296A (en) | 1996-10-16 |
WO1996030040A1 (en) | 1996-10-03 |
MX9707428A (es) | 1997-12-31 |
CZ305297A3 (cs) | 1998-02-18 |
CA2216516A1 (en) | 1996-10-03 |
EP0735048A1 (en) | 1996-10-02 |
TR199701078T1 (xx) | 1998-01-21 |
NO974498D0 (no) | 1997-09-29 |
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