CN1122248A - 胰岛素类似物制剂 - Google Patents
胰岛素类似物制剂 Download PDFInfo
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- CN1122248A CN1122248A CN95106568A CN95106568A CN1122248A CN 1122248 A CN1122248 A CN 1122248A CN 95106568 A CN95106568 A CN 95106568A CN 95106568 A CN95106568 A CN 95106568A CN 1122248 A CN1122248 A CN 1122248A
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- Prior art keywords
- insulin
- hexamer
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- pro
- zinc
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Images
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Abstract
本发明公开了一种人胰岛素类似物复合物和制剂。更具体地讲,本发明涉及各种非肠道用制剂,其含有:六聚物构象形式的人胰岛素类似物,锌离子和至少三分子的选自间甲苯酚、苯酚、或间甲苯酚和苯酚混合物的苯酚衍生物。此制剂起效迅速。
Description
本发明涉及人胰岛素单体类似物。更具体地讲,本发明涉及一种含有胰岛素类似物、锌和苯酚衍生物的六聚体复合物。
自从二十世纪二十年代采用胰岛素以来,对于糖尿病的治疗不断取得突飞猛进的进展。主要的进展表现在胰岛素的纯度和有效性上。而且已经开发出了各种具有不同时间-作用关系的制剂。尽管取得了如此多的进步,但是,皮下注射疗法仍然不能为患者提供方便的调节和正常化的血糖控制。如果患者一生中血糖水平经常偏离正常的血糖水平,将会导致高血糖症或低血糖症,以及长期的并发症,所述并发症包括视网膜病、神经病、肾病以及微血管病变和大血管病变。
为了避免血糖浓度过高,对糖尿病患者经常要实施多重注射疗法,借此达到每一餐都摄人胰岛素的目的。但是,此种疗法并不完美。因为,市售的最快速作用的胰岛素在注射后达到峰值的时间过于迟缓并且达到最佳控制血糖水平的时间过长。最近,在开发可以改变皮下吸收过程动力学的胰岛素制剂和胰岛素类似物制剂方面付出了巨大的努力。
由于所有市售的胰岛素药物制剂均含有自缔合形式和主要是锌-六聚物形式的胰岛素,因此据信胰岛素在由皮下注射部位向血流中吸收时的限速步骤,是自缔合胰岛素六聚物的离解过程。Brange等人,DiabetesCare 13:923-954(1990)。为了加速这种吸收过程,发展起来了单体胰岛素类似物。相比之下,这些单体胰岛素类似物较胰岛素来讲,在保持了天然人胰岛素生物活性的同时起效更快。它们在注射后能够很快被吸收,使得注射时间和胰岛素最佳峰值作用更接近于与饮食相对应的饭后葡萄糖水平波动。各种单体类似物制剂公开于Chance等人的欧洲专利公开383472和Brange等人的欧洲专利公开214826中。
然而,将胰岛素改性,使这些类似物成为单体,结果也会使在非肠道用制剂中高速产生聚合物。因为,当聚合物水平达到1%时胰岛素制品即失效(U.S.Pharmacopoeia,1990),而在减低副作用方面,尽量减小这种类型的品质降低是相当重要的。因此,最好是以某种方法配制单体类似物,使类似物自缔合形成稳定构象形式,而且还要保持它的快速吸收特性。
加入某些金属离子,首选锌,通过使胰岛素缔合并形成六聚物,典型的是Zn(II)-T6构象、可以增强化学稳定性。另外,苯酚类物质也已表现出可以与胰岛素六聚物特异性结合并且可以诱导变构的构象变化,借此可以将B-链中8个N-末端氨基酸由扩展构象转变成α-螺旋形。Derewenda等人,Nature,338:594-596(1989)。此结合了苯酚类的构象形式以Zn(II)-R形式公知。
已证实在锌存在下胰岛素易于缔合形成确定的、稳定的Zn-六聚物结构。但与这些已被证实无误的实验结果完全相反,用单体胰岛素类似物进行的早期研究发现,锌与胰岛素类似物之间的任何缔合作用不同于所观察到的锌与胰岛素之间的缔合作用。B.H.Frank,Text and Slidecopies of Lecture given at the Conference on Insulin″Self-Association and Conformational Studies on Human Proinsulin andInsulin Analogs".University of York,(1989,8,29-9,1)。另外,用胰岛素能够形成高度稳定的Zn-六聚物,但用单体的类似物没有观察到这种结果。文献同上。Brems等人,在Protein Engineering,5:6,527-533(1992)中表明,单体LysB28ProB29-hI与人胰岛素相比更不易于发生二聚作用和自缔合成较高分子量形式。Brems等人进一步得出结论,AspB28ProB29-hI、AlaB28ProB29-hI和LysB28ProB29-hI几乎不会发生或者不会发生Zn-诱导的缔合作用,而ProB29胰岛素、LysB28胰岛素、AspB28胰岛素和AlaB28胰岛素表现出Zn-诱导的缔合作用,但比Zn-胰岛素要弱。后来,本发明发明人未公开的试验结果表明,可以观察到与锌的缔合作用;但是,这种类似物与锌之间的缔合作用不同于与胰岛素的缔合作用。用这些类似物时所观察到的缔合作用,将会产生大量大分子量物质并且不同于大多数情况下的、已明确定义的Zn-胰岛素六聚物。因此,很显然,单体胰岛素类以物不会以类似于胰岛素的方式形成Zn-(II)-T6构象。
纵观已公开的文献可以惊奇地发现,本发明获得了单体胰岛素类似物的确定的、稳定的锌-苯酚六聚物复合物,此六聚物复合物完全不同于相同条件下用胰岛素形成的复合物。胰岛素与锌和苯酚形成的复合物为Zn-(II)-T6构象、本发明的六聚物复合物与此构象不同。而且很明显,胰岛素类似物六聚物复合物与胰岛素相比更易离解,此易离解的特性导致了所需的作用迅速的特性。
Brange等人在Current Opinion in Structural Biology 1:934-940(1991)中公开了各种快速作用的稳定型胰岛素单体并且指出,产生快速作用的胰岛素的明显途径是防止二聚物和六聚物的生成。同样,Brange等人在Diabetes Care 13:923-954(1990)中还指出,当胰岛素是以六聚物的形式用药时,除了它的较慢地自由扩散外,在皮下组织扩散转移期间和/或在通过毛细血管膜期间,此六聚物一定会比单体立体位阻大。另外,当经皮下注射时,Zn-(II)-R6构象不会直接离解,而是必须通过Zn-(II)-T6构象转化。这些构象变化和由此的离解会延误作用的开始。因此,本领域的技术人员在完成本发明时会相信,通过形成确定的六聚物复合物从化学上稳定单体胰岛素和锌的努力是不会成功的,或者说,如果成功,将会是以牺牲所希望的起效迅速为代价。
本发明制剂是一种锌-苯酚类物质诱导的可迅速吸收的六聚物复合物。所述六聚物复合物的吸收速率至少是所述胰岛素的两倍。而且,当将所述六聚物复合物配制成制剂时,其与胰岛素相比较,在防止化学品质降低方面是同样稳定的。因而,令人惊奇的是,本发明是将单体胰岛素类似物转变成确定的、稳定的锌-苯酚类物质六聚物复合物。值得注意的是,当被配制成制剂时,此六聚物复合物保持了单体胰岛素类似物所特有的作用快速的特性。因此,本发明提供了一种稳定的并且作用快速的胰岛素类似物六聚物复合物的非肠道用制剂。
本发明提供了一种人胰岛素类似物复合物,其包括:六分子人胰岛素类似物,二分子锌离子和至少三分子的选自间甲苯酚、苯酚、或间甲苯酚和苯酚混合物的苯酚衍生物;以使得类似物复合物是六聚物。本发明还提供了含有此六聚物复合物的非肠道用制剂。
图1是用图解表示LysB28ProB29-hI和人胰岛素的作用情况。曲线表示平均葡萄糖输注响应速率。此图表明了本发明的优越性。
图2是用图解表示LysB28ProB29-人胰岛素的稳定性。曲线表示的是通过测定其聚合物形成而得到的六聚物缔合形式的胰岛素类似物相对于单体LysB28ProB29-人胰岛素和胰岛素的稳定性。此图表明了本发明的优越性。
图3是用图解表示六聚物复合物形式的LysB28ProB29-人胰岛素的离解作用。曲线代表通过在488nm在90度角静态光散射监测到的配制成制剂的胰岛素(○);配制成六聚物复合物的LysB28ProB29-hI(△);未配制成制剂的胰岛素(□)以及单体LysB28ProB29-hI(*)的体外离解作用。经配制的样品中含有0.5molZn/mol蛋白质,1.25mg/ml间甲苯酚和1.09mg/ml苯酚,7mM磷酸钠和16mg/ml甘油。未经配制的样品和单体样品中不含有其它赋形剂。此图表明了本发明的优越性。
综上所述,本发明提供了一种六聚物形式的单体人胰岛素类似物复合物。本文所用术语“单体胰岛素类似物”或“人胰岛素类似物”是指人胰岛素,其中:
第B28位上Pro被Asp、Lys、Leu、Val或Ala取代;而且第B29位上Lys是赖氨酸或者是被脯氨酸取代;
脱(B28-B30);或
脱(B27)。单体胰岛素类似物公开于Chance等人的欧洲专利公开383472和Brange等人的欧洲专利公开214826中,而上述专利并人本文中作为参考文献。单体胰岛素类似物与胰岛素相比不易发生二聚合或自缔合。
本领域的技术人员会发现本发明存在着一些其它变化,这些变化在本领域是完全可以接受的,这些变化包括:B10位上的组氨酸残基被天冬氨酸替代;B1位上的苯丙氨酸残基被天冬氨酸替代;B30位上的苏氨酸残基被丙氨酸替代;B9位上的丝氨酸被天冬氨酸替代;Bl位上氨基酸的缺失;或者B1位和B2位上的氨基酸一起缺失;以及B30位上苏氨酸缺失。
本文中所用所有氨基酸的缩写均是在37C.F.R.§1.822(b)(2)中确立的美国专利和商标局接受的氨基酸缩写。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)。
本文所用术语“治疗”是指为了防治疾病和症状或异常而对患者进行的处置和护理,包括施用本发明化合物以预防病症或并发症出现,或者减轻病症或并发症,或者消除疾病和症状或异常。
术语“等渗剂”是指生理上耐受的并且能使制剂获得适宜的渗透压以阻止水通过细胞膜净流的试剂。为此目的,通常是以公知的浓度使用例如甘油等化合物。
术语“苯酚衍生物”或“苯酚类物质”是指间甲苯酚、苯酚或间甲苯酚和苯酚的混合物。优选苯酚类物质是间甲苯酚。
术语“生理上耐受的缓冲剂”是本领域公知的。生理上耐受的缓冲剂优选是磷酸盐缓冲剂,如磷酸钠。其它生理上耐受的缓冲剂包括TRIS、乙酸钠或柠檬酸钠。缓冲剂的选择和浓度是本领域公知的常识。
本发明胰岛素类似物与锌离子和苯酚衍生物复合形成稳定的六聚物构象。为形成稳定的并且能够迅速离解和发生作用的复合物,锌和苯酚衍生物都是关键的。此六聚物复合物的组成是:每个人胰岛素类似物的六聚物中有两个锌离子和至少三个选自间甲苯酚、苯酚、或间甲苯酚和苯酚混合物的苯酚衍生物分子。
将可溶性单体类似物转化成六聚物复合物,其方法是:将单体类似物溶于pH约为7.5的含有苯酚衍生物的稀释剂中并加入锌。所加入的锌优选是盐的形式,锌盐的典型实例包括乙酸锌、溴化锌、氯化锌、氟化锌、碘化锌和硫酸锌。本领域的技术人员会发现有许多其它的锌盐也可以用于本发明的方法中。优选使用乙酸锌或氯化锌,这是因为这些盐对于商业上可以接受的方法来讲不会加入新的化学离子。
类似物的溶解可以借助公知的酸溶解的方法进行,即为了帮助单体类似物的溶解,可以用生理上耐受的酸优选HCl将pH降至约3.0-3.5。其它生理上耐受的酸包括乙酸、柠檬酸和磷酸。然后再用生理上耐受的碱优选氢氧化钠将pH调至约7.4-7.5。其它生理上耐受的碱包括氢氧化钾和氢氧化铵。
所述六聚物复合物可以配制成稳定的、快速作用的非肠道用制剂。制剂中胰岛素类似物的浓度约为0.5mg/ml-20mg/ml;优选约1.2mg/m1-17.5mg/ml;最优选约3.5mg/ml。通常,锌的浓度约是10μg/ml-50μg/ml。制剂中锌的最佳浓度约是14μg/ml-35μg/ml,其中每个六聚物键合两个锌离子。当制成制剂时,六聚物复合物键合有多至7个苯酚类物质。通常,当制成制剂时,六聚物键合有6个苯酚类物质。因此,优选的是向制剂中加入过量的苯酚类物质。苯酚类物质也可以用作防腐剂。这样,苯酚类物质的优选浓度约为23mM-35mM,最优选29mM。苯酚类物质优选是间甲苯酚。
制剂中可以加入等渗剂,优选是甘油。等渗剂的浓度范围是胰岛素制剂领域中公知的,优选为约16mg/ml,制剂的pH值可以用生理上耐受的缓冲剂调节,所述缓冲剂优选磷酸盐缓冲剂如磷酸钠。
在完成本发明时,出版的文献中均教导,本领域的技术人员需要消除聚集作用以达到吸收快速的目的。然而,令人惊奇地是,所述配制成制剂的六聚物类似物实现了快速起效的效果。与胰岛素不同,胰岛素类似物六聚物复合物的形成对获得血浆中胰岛素类似物峰值浓度所需时间并没有不利影响。图1说明了患者平均葡萄糖输注率与下列因素的关系:含有单体LysB28ProB29-hI的制剂(配制时没有加入锌);配制成制剂的LysB28ProB29-hI六聚物;和普通人胰岛素。制成制剂的六聚物复合物保留了单体LysB28ProB29-hI的快速作用的特性。其吸收速率明显比普通人胰岛素快。这样,图1的结果表明:第一、六聚物LysB28ProB29-hI和单体LysB28ProB29-hI具有相似的吸收速率;第二、六聚物和单体的LysB28ProB29-hI两者的吸收速率均比胰岛素快。
含有六聚物形式的胰岛素类似物复合物制剂是稳定的。在对比试验中,经过六周的试验,单体LysB28ProB29-hI表现出最高的品质降低的速度,其中每周增加1.63%的聚合物形式;未制成制剂的人胰岛素的聚合物形成速率较慢,为每周0.61%。但是,当制成制剂时,对于胰岛素,高分子量的聚合物形成速率会降至每周0.095%。配制成制剂的六聚物复合物形式的LysB28ProB29-hI表现出降低了的较高分子量聚合物的形成速率,为每周0.11%,该速率与配制成制剂的胰岛素所示的速率差不多。这些试验的例证见实施例1,而说明见图2。
本发明胰岛素类似物可以通过各种不同的已知的合成肽的方法制备,包括经典法(溶液法)、固相法、半合成法以及现代的重组DNA法。例如Chance等人在欧洲专利公开383472和Brange等人在欧洲专利公开214826中所描述的各种单体类似物的制备方法。
下列实施例和制备例仅用于进一步说明本发明以及胰岛素类似物的制备方法。本发明的范围不能解释为仅由下列实施例构成。
制备例1
蛋白质贮液的制备
根据所进行的试验,在有或没有1.25mg/ml间甲苯酚、1.09mg/ml苯酚和16mg/ml甘油存在的情况下,于7mM磷酸钠中制备胰岛素和LysB28ProB29-hI的未制成制剂的样品3.5mg/ml。除了加入19.7μg/ml锌以外,用相同的方法制备六聚物复合物形式的LysB28ProB29-hI样品。所有样品经过酸处理,使pH为3.0,此时向制剂中加入锌,然后调节pH至7.4。在加入苯酚类物质之前,用AVIV型14DS双光束分光光度计经UV吸收光谱测定蛋白质浓度。如Frank,B.H.,Pekar,A.H.和Veros,A.J.(1972)DiaBETES,21(增刊2),486-491所述计算蛋白质浓度。
实施例1
化学稳定性
于30℃下培养制成制剂的和未制成制剂的胰岛素和单体及六聚物LysB28ProB29-hI的制剂,引起其品质降低。制成制剂的胰岛素和六聚物LysB28ProB29-hI含有:3.5mg/ml蛋白质、16mg/ml甘油、7mM磷酸氢二钠七水合物、1.25mg/ml间甲苯酚、1.09mg/ml苯酚和0.0245mg/ml氧化锌,pH为7.3-7.4。未制成制剂的胰岛素和单体LysB28ProB29-hI含有:3.5mg/ml蛋白质、16mg/ml甘油、7mM磷酸氢二钠七水合物、1.25mg/ml间甲苯酚和1.09mg/ml苯酚,pH为7.3-7.4,间隔7天后,将样品由30℃恒温箱中取出并用筛析HPLC检测高分子量组分的形成情况。通过将20μl样品注射到Dupont Zorbax GF-250 Special(9.4×250mm)柱中进行分析,用0.4M碳酸氢铵和乙腈的混合物作流动相(流速为室温下0.5ml/min,在214nm处检测)。高分子量组分的峰值相对于单体和高分子量组分峰值总和的比率测得聚合物形成百分比。结果如图2所示。
实施例2
静态光散射试验
用静态光散射试验探测单体LysB28ProB29-hI、六聚物复合物形式的LysB28ProB29-hI以及胰岛素的体外离解特性。
如上所述制备3份制成制剂的和未制成制剂的蛋白质贮液但未制成制剂的蛋白质贮液不含有锌、甘油或防腐剂。利用这些3.5mg/ml贮液,以蛋白质浓度间隔范围为3.5mg/ml-0.2mg/ml制备胰岛素和LysB28ProB29-hI两者的系列稀释液。为了模拟皮下注射部位,用pH7.4的7mM磷酸钠缓冲液将所有稀释液的最终体积调至到10ml。在进行SLS测定之前,所有溶液均经过0.2μm Gelman可结合小蛋白的过滤器过滤。用反相HPLC测定这些样品的蛋白质浓度。
为了对制成制剂的样品进行分析,对于每组所试验的蛋白质样品都要制备不含蛋白质的溶剂的空白对照。这些空白对照含有与所试验的相应蛋白质样品相同浓度的赋形剂。为了对未制成制剂的样品进行分析,使用了一个7mM磷酸钠的空白对照,利用这些溶剂的空白对照可以确保试验数据只反映溶质的扩散情况而没有因为改变了溶剂而受到影响。
用Brookhaven Instruments 2030AT自相关分析仪和测角仪进行静态光扩散(SLS)试验。利用Lexel Model 3500氩离子激光器,设置在488nm处,以1nm针孔在90°散射角测定所有结果。用Neslab RTE-110温度浴保持温度在25℃。光电倍增管中的信号用0.1μm经过过滤的甲苯校准。
用Cantor.C.R.和Schimmel,P.R.,Biophysical Chemistry,W.H.Freeman and Company,New York.pp.838-843(1982)中所述公式计算重量-平均分子量。图3给出了光扩散试验的结果。六聚物复合物形式LysB28ProB29-hI和胰岛素的体外离解情况相差极大。结果表明,胰岛素类似物离解较快,这使得它的吸收较人胰岛素迅速。对于化学上的品质降低来说,即使两种制品均含有六聚物的缔合形式并且其制剂同样稳定,但是六聚物LysB28ProB29-hI的离解倾向还是大于胰岛素。
Claims (7)
1.一种人胰岛素类似物复合物,其包括:六分子人胰岛素类似物,二分子锌离子和至少三分子的选自间甲苯酚、苯酚、或间甲苯酚和苯酚混合物的苯酚衍生物;以使得此类似物复合物是六聚物。
2.一种含有权利要求1的人胰岛素类似物复合物的非肠道用药物制剂。
3.根据权利要求2的非肠道用药物制剂,其还含有等渗剂和生理上耐受的缓冲剂。
4.根据权利要求3的非肠道用药物制剂,其中人胰岛素类似物是LysB28ProB29-人胰岛素。
5.根据权利要求4的非肠道用药物制剂,其含有约3.5mg/mlLysB28ProB29-人胰岛素、约19.7μg/ml锌、约7mM磷酸钠、约16mg/ml甘油和约29mM间甲苯酚。
6.根据权利要求1的人胰岛素类似物复合物,其中人胰岛素类似物是LysB28ProB29-人胰岛素。
7.根据权利要求1的人胰岛素类似物复合物,其中人胰岛素类似物是AspB28-人胰岛素。
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US3060093A (en) * | 1957-07-18 | 1962-10-23 | Nordisk Insulinlab | Slowly acting insulin preparation in crystalline form and method of preparation |
FI78616C (fi) * | 1982-02-05 | 1989-09-11 | Novo Industri As | Foerfarande foer framstaellning av en foer infusionsaendamaol avsedd stabiliserad insulinloesning, som har en foerhoejd zinkhalt. |
US4608634A (en) * | 1982-02-22 | 1986-08-26 | Texas Instruments Incorporated | Microcomputer with offset in store-accumulator operations |
DK347086D0 (da) * | 1986-07-21 | 1986-07-21 | Novo Industri As | Novel peptides |
PH25772A (en) * | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
DE3717370A1 (de) * | 1987-05-22 | 1988-12-01 | Hoechst Ag | Mischkristalle aus insulin und insulinderivaten, verfahren zur herstellung dieser mischkristalle, diese mischkristalle enthaltende pharmazeutische mittel und ihre verwendung zur behandlung von diabetes mellitus |
KR900701842A (ko) * | 1988-07-20 | 1990-12-04 | 헨리 브뢰늄 | 인간 인슐린 동족체와 그를 포함하는 제제 |
JPH04502465A (ja) * | 1988-12-23 | 1992-05-07 | ノボ ノルディスク アクティーゼルスカブ | ヒトインシュリン類似物質 |
PT93057B (pt) * | 1989-02-09 | 1995-12-29 | Lilly Co Eli | Processo para a preparacao de analogos da insulina |
JP2837956B2 (ja) * | 1993-06-21 | 1998-12-16 | ノボ ノルディスク アクティーゼルスカブ | Asp▲上B28▼インスリン結晶 |
US5474978A (en) * | 1994-06-16 | 1995-12-12 | Eli Lilly And Company | Insulin analog formulations |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1293916C (zh) * | 1997-06-13 | 2007-01-10 | 伊莱利利公司 | 稳定的胰岛素制剂 |
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