CN1662252A - 稳定性提高的酸性胰岛素制剂 - Google Patents
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Abstract
本发明涉及包含选自胰岛素、胰岛素代谢物、胰岛素类似物、胰岛素衍生物或它们的组合的多肽并且还包含一种表面活性剂或几种表面活性剂的组合、任选地一种防腐剂或几种防腐剂的组合以及任选地等张调节剂、缓冲剂或其它辅剂或它们的组合的药物制剂。根据本发明,所述的药物制剂具有酸性pH值。
Description
本发明涉及包含选自胰岛素、胰岛素代谢物、胰岛素类似物、胰岛素衍生物或它们的组合的多肽;一种表面活性剂或者两种或多种表面活性剂的组合;任选地一种防腐剂或者两种或多种防腐剂的组合;以及任选地等张调节剂、缓冲剂或其它赋形剂或它们的组合的药物制剂,该药物制剂具有酸性范围内的pH。这些制剂可用于治疗糖尿病,并且特别适于必须对热和/或物理机械应力具有高度稳定性的制剂。本发明还涉及含有所述制剂并且可用于糖尿病的胃肠外制剂,还涉及制备该制剂和提高胰岛素制剂稳定性的方法。
在世界范围内,约有1亿2千万人患有糖尿病。其中,约1200万人是I型糖尿病,对于他们而言,替代缺乏的内分泌胰岛素分泌是目前唯一可能的疗法。患者终生依赖于胰岛素注射,通常每天进行多次注射。与I型糖尿病不同,在II型糖尿病中基本上不存在胰岛素不足,但在许多病例中,尤其是在晚期,用胰岛素任选与口服抗糖尿病药组合进行治疗被认为是最有利的治疗方式。
在健康人中,胰腺释放胰岛素与血糖浓度严格相关。血糖水平升高、如餐后出现的血糖水平升高迅速被相应的胰岛素分泌增加所补偿。在空腹状态,血浆胰岛素水平降低至基础值,该值足够保证向胰岛素敏感性器官和组织持续提供葡萄糖并使夜间的肝葡萄糖产生保持在低水平。用外源性、主要是皮下施用胰岛素代替内源性胰岛素分泌通常不能近似地达到上述的血糖生理调节质量。通常,会发生血糖升高或降低的偏差,该偏差的最严重形式可危及生命。另外,然而,血糖水平增加数年而没有最初症状是相当严重的健康危险。美国大规模的DCCT研究(糖尿病控制和并发症试验研究组(1993)N.Engl.J.Med.329,977-986)清楚地证明血糖水平慢性升高是发生糖尿病晚期损伤(late damage)的主要原因。糖尿病晚期损伤是微血管和大血管损伤,其在一定条件下表现为视网膜病变、肾病或神经病并导致视力损失、肾衰竭和四肢损伤,此外还伴有增加的发生心血管疾病的危险。鉴于此,糖尿病的改进疗法主要旨在使血糖尽可能接近生理范围。根据强化胰岛素治疗概念,这应该通过每天多次注射快-和慢-作用胰岛素制剂来实现。快作用制剂在进餐时给予以便使血糖的餐后增加变平。慢作用基础胰岛素应确保胰岛素的基础供给,特别是在夜间,且不导致低血糖。
胰岛素是一种51个氨基酸的多肽,其被分为2条氨基酸链:具有21个氨基酸的A链和具有30个氨基酸的B链。这两条链通过2个二硫键桥相互连接。胰岛素制剂已经被用于治疗糖尿病多年。不仅使用天然存在的胰岛素,而且最近还使用胰岛素衍生物和类似物。
胰岛素类似物是天然存在的胰岛素、即人胰岛素或动物胰岛素的类似物,其与相应的、否则完全相同的天然存在的胰岛素的不同之处在于用其它氨基酸取代至少一个天然存在的氨基酸残基和/或加入/除去至少一个氨基酸残基。在这种情况下氨基酸也可以是非天然存在的氨基酸。
胰岛素衍生物是通过化学修饰获得的天然存在的胰岛素或胰岛素类似物的衍生物。该化学修饰可包括例如在一个或多个氨基酸上加入一个或多个特定的化学基团。通常,与人胰岛素相比,胰岛素衍生物和胰岛素类似物的作用具有一定的改进。
作用起效被加速的胰岛素类似物在EP 0 214 826、EP 0 375 437和EP 0678 522中有描述。EP 0 124 826尤其涉及B27和B28的取代。EP 0 678 522描述了在B29位上具有各种氨基酸、优选脯氨酸而非谷氨酸的胰岛素类似物。EP 0 375 437包括在B28位上具有赖氨酸或精氨酸的胰岛素类似物,其可任选地在B3和/或A21上被额外修饰。
在EP 0 419 504中,公开了被保护低抗化学修饰的胰岛素类似物,其中B3位的天冬氨酸和A5、A15、A18或A21位的至少一个其它氨基酸被修饰。
通常,与人胰岛素相比,胰岛素衍生物和胰岛素类似物的作用具有一定的改进。
在WO 92/00321中,描述了其中B1-B6位的至少一个氨基酸被赖氨酸或精氨酸代替的胰岛素类似物。根据WO 92/00321,这种类型的胰岛素具有延长的作用。EP-A 0 368 187中所述的胰岛素类似物也具有延迟的作用。
市场上用于替代胰岛素的天然存在的胰岛素的胰岛素制剂在胰岛素的来源(例如牛、猪、人胰岛素)以及组成上不同,因此对作用的性质(作用的起效和作用的持续时间)可能有影响。通过组合各种胰岛素制剂,可以获得非常不同的作用性质并且可以建立尽可能接近生理的血糖值。现今,重组DNA技术使得制备这种改进的胰岛素成为可能。这些改进的胰岛素包括具有延长的作用持续时间的甘精胰岛素(Gly(A21)-Arg(B31)-Arg(B32)-人胰岛素)。甘精胰岛素以酸性、澄明的溶液形式注射使用并且由于其在皮下组织的生理pH范围内的溶解性质而沉淀成为稳定的六聚体缔合物。甘精胰岛素每天注射一次并且与其它长效胰岛素相比具有血清曲线平稳以及与其相关的夜间低血糖的危险减少的显著特征(Schubert-Zsilavecz等,2:125-130(2001))。
与上述制剂不同,可产生延长的作用持续时间的甘精胰岛素的特定制剂的特点在于其为具有酸性pH的澄明溶液。然而,尤其是在酸性pH下,胰岛素稳定性降低且对热和物理机械应力发生凝聚的趋势增加,这可以使其变成混浊和沉淀形式(微粒形成)(Brange等,J.Ph.Sci86:517-525(1997))。
与溶液接触的疏水表面也可增加凝聚趋势(Sluzky等,Proc.Natl.Acad.Sci.88:9377-9381(1991))。可被视为是疏水性的表面有制剂的玻璃容器、密封盖的塞子材料或溶液与上层空气的边界面。此外,在通过常规的硅化胰岛素注射器施用每天的胰岛素剂量时,非常细小的硅油滴可用作额外的疏水性凝聚核并加速该过程。
WO 01/43762描述了包含多肽和甘油的水性、胃肠外药物制剂,其中通过纯化除去甘油的去稳定成分实现了制剂的稳定化。WO 00/23098描述了用于肺部施用的、用聚山梨酯20或泊洛沙姆188稳定的胰岛素制剂,但没有描述在酸性溶液中抗凝聚核的稳定作用。
国际专利申请PCT/EP02/02625(未公布)描述了通过添加表面活性剂而在室温和体温以及机械应力下稳定性提高的无锌和低锌胰岛素制剂,但没有描述酸性胰岛素制剂抗疏水性凝聚核的稳定作用。
因此,本发明所基于的目的是发现含有表面活性剂的酸可溶性胰岛素的制剂,其对温度或物理机械应力造成的应力具有高度的长期稳定性并且耐受疏水性凝聚核的高应力。
现已令人惊奇地发现:加入表面活性剂可极大地增加酸性胰岛素制剂的稳定性并因此甚至可制备确保在温度应力下对疏水性凝聚核具有优良稳定性达数月的制剂。
所述的药物制剂含有60-6000nmol/ml、优选240-3000nmol/ml的胰岛素、胰岛素代谢物、胰岛素类似物或胰岛素衍生物。
可使用的表面活性剂尤其是非离子表面活性剂。具体而言,优选药学上常规的表面活性剂,如,例如:多元醇如甘油、山梨醇等的部分和脂肪酸酯和醚(Span、Tween,特别是Tween20和Tween80、Myrj、Brij)、Cremophor或泊洛沙姆。药物组合物中存在的表面活性剂浓度为5-200μg/ml,优选5-120μg/ml,且特别优选20-75μg/ml。
该制剂还可含有防腐剂(例如苯酚、甲酚、对羟基苯甲酸酯)、等张调节剂(例如甘露醇、山梨醇、乳糖、右旋糖、海藻糖、氯化钠、甘油)、缓冲物质、盐、酸和碱,以及其它赋形剂。这些物质在每种情况下均可以单个存在或备选地以混合物形式存在。
通常,在药物制剂中,甘油、右旋糖、乳糖、山梨醇和甘露醇的浓度为100-250mM,NaCl的浓度为不超过150mM。缓冲物质如例如磷酸盐、乙酸盐、柠檬酸盐、精氨酸、N-甘氨酰甘氨酸或TRIS(即2-氨基-2-羟甲基-1,3-丙二醇)缓冲剂和相应的盐的浓度为5-250mM,优选10-100mM。其它赋形剂尤其可以是盐或精氨酸。
因此,本发明涉及包含选自胰岛素、胰岛素类似物、胰岛素衍生物、活性胰岛素代谢物或它们的组合的多肽;一种表面活性剂或者两种或多种表面活性剂的组合;任选地一种防腐剂或者两种或多种防腐剂的组合;以及任选地等张调节剂、缓冲物质和/或其它赋形剂或它们的组合的药物制剂,该药物制剂为澄明的溶液剂,其具有酸性范围(pH1-6.8)内的pH,优选pH3.5-6.8,非常特别优选3.5-4.5。
所述药物制剂优选的是其中:表面活性剂选自多元醇如甘油和山梨醇的部分和脂肪酸酯和醚、多羟基化合物;甘油和山梨醇的部分和脂肪酸酯和醚选自Span、Tween、Myrj、Brij、Cremophor;多元醇选自聚丙二醇、聚乙二醇、泊洛沙姆、普流罗尼、四聚醇胺(Tetronics);防腐剂选自苯酚、甲酚、对羟基苯甲酸酯;等张调节剂选自甘露醇、山梨醇、氯化钠、甘油;赋形剂选自缓冲物质、酸、碱;胰岛素类似物选自Gly(A21)-Arg(B31)-Arg(B32)-人胰岛素、Lys(B3)-Glu(B29)-人胰岛素、LysB28ProB29人胰岛素、B28 Asp-人胰岛素、其中B28位的脯氨酸已被Asp、Lys、Leu、Val或Ala取代和其中B29位的Lys可被Pro取代的人胰岛素、AlaB26-人胰岛素、des(B28-B30)-人胰岛素、des(B27)-人胰岛素或des(B30)-人胰岛素;胰岛素衍生物选自B29-N-肉豆蔻酰基-des(B30)人胰岛素、B29-N-棕榈酰基-des(B30)人胰岛素、B29-N-肉豆蔻酰基人胰岛素、B29-N-棕榈酰基人胰岛素、B28-N-肉豆蔻酰基LysB28ProB29人胰岛素、B28-N-棕榈酰基-LysB28ProB29人胰岛素、B30-N-肉豆蔻酰基-ThrB29LysB30人胰岛素、B30-N-棕榈酰基-ThrB29LysB30人胰岛素、B29-N-(N-棕榈酰基-γ-谷氨酰基)-des(B30)人胰岛素、B29-N-(N-石胆酰基(lithocholyl)-γ-谷氨酰基)-des(B30)人胰岛素、B29-N-(ω-羧基十七烷酰基)-des(B30)人胰岛素和B29-N-(ω-羧基十七烷酰基)人胰岛素。
本发明的另一个主题是以上所述的药物制剂,其中胰岛素、胰岛素类似物、活性胰岛素代谢物和/或胰岛素衍生物以60-6000nmol/ml、优选以240-3000nmol/ml的浓度(这相当于约1.4-35mg/ml或40-500单位/ml的浓度)存在;其中表面活性剂以5-200μg/ml、优选以5-120μg/ml、且特别优选以20-75μg/ml的浓度存在。
本发明的另一个主题是以上提及的药物制剂,其中甘油和/或甘露醇以100-250mM的浓度存在,和/或NaCl优选以不超过150mM的浓度存在。
本发明的另一个主题是以上提及的药物制剂,其中缓冲物质以5-250mM的浓度存在。
本发明的另一个主题是还含有添加剂如例如延迟释放胰岛素的盐的药用胰岛素制剂。其中包括所述的延迟释放胰岛素与上述制剂的混合物。
本发明的另一个主题是制备所述药物制剂的方法。另外,本发明的另一个主题是所述制剂在治疗糖尿病中的用途。
本发明的另一个主题是在制备胰岛素、胰岛素类似物或胰岛素衍生物或它们的制剂过程中作为稳定剂使用或添加表面活性剂。
下面通过一些实施例阐述本申请,这些实施例绝非旨在限制本发明。
实施例
以下实施例旨在更详细地阐明本发明的概念,而非旨在限制本发明。
对比研究:制备含有胰岛素类似物甘精胰岛素(Gly(A21),Arg(B31),Arg(B32)-人胰岛素)的不同制剂。为此,将甘精胰岛素混悬在一部分注射用水中,在pH3-4下溶解,加入其它组分,用盐酸/NaOH将pH调至4.0+/-0.2,并将混合物定容至终体积。在以下所述的每个实验中甘精胰岛素的浓度均为3.6378mg/ml(相当于100单位/ml)。用同样方法制备第二种制剂,但另外还加入特定量的表面活性剂。将溶液装入10ml玻璃容器(小瓶)中并装上压盖(crimp cap)。现在将这些容器暴露于模拟的使用或物理机械应力条件下:
1.使用试验:将容器分装入具有翻盖的箱中并在28天的研究期间于+25℃和控制的室内湿度以及避光条件下贮存。为了模拟被患者使用,每天一次用常规胰岛素注射器取出约5IU溶液并弃去。在工作周开始和结束时,该步骤进行两次以模拟周末的使用。在每次取药前,对容器中溶液的浊度和/或微粒形成进行目视评价。
2.振摇试验:将容器放置在具有翻盖的箱中,该箱位于具有培养箱和恒温箱的实验室摇动器上,并在25℃下以90次运动/分钟平行于水平运动方向振摇10天。在既定时间后,用实验室浊度光度计(浊度计)以福尔马肼(formaldazine)浊度单位(福尔马肼浊度单位=FNU)测定样品的浊度值。浊度值相当于入射光在样品中的混悬微粒上的散射强度。
实施例1:使用聚山梨酯20(Tween20)对甘精胰岛素在使用期间的稳定作用
a)将溶液通过0.2μm和0.1μm滤器组合进行无菌过滤。然后将其倒入10ml注射小瓶中并用具有嵌入式密封片的压盖密封。
b)用同样方法制备对比溶液,但首先将适宜量的表面活性剂(10-30ppm聚山梨酯20)混悬在注射用水中。
将样品在+5℃、25℃和37℃下贮存固定的时间。
然后在每种情况下用10个样品进行使用试验。结果如下表所示。
于5℃下贮存3个月
若干天后有微粒形成的小瓶数 | ||||
供试样品 | 7天 | 14天 | 21天 | 28天 |
甘精胰岛素 | 7 | 10 | 10 | 10 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 1 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
于5℃下贮存6个月
若干天后有微粒形成的小瓶数 | ||||
供试样品 | 7天 | 14天 | 21天 | 28天 |
甘精胰岛素 | 1 | 10 | 10 | 10 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 0 | 0 | 0 | 1 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 1 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 1 | 0 |
于25℃下贮存3个月
若干天后有微粒形成的小瓶数 | ||||
供试样品 | 7天 | 14天 | 21天 | 28天 |
甘精胰岛素 | 9 | 10 | 10 | 10 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 2 | 2 | 2 | 2 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 0 | 1 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
于25℃下贮存6个月
若干天后有微粒形成的小瓶数 | ||||
供试样品 | 7天 | 14天 | 21天 | 28天 |
甘精胰岛素 | 10 | 10 | 10 | 10 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 0 | 0 | 0 | 1 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 1 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
于37℃下贮存1个月
若干天后有微粒形成的小瓶数 | ||||
供试样品 | 7天 | 14天 | 21天 | 28天 |
甘精胰岛素 | 0 | 10 | 10 | 10 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 0 | 3 | 3 | 5 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
于37℃下贮存3个月
若干天后有微粒形成的小瓶数 | ||||
供试样品 | 7天 | 14天 | 21天 | 28天 |
甘精胰岛素 | 5 | 9 | 10 | 10 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 1 | 1 | 1 | 1 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
于37℃下贮存6个月
若干天后有微粒形成的小瓶数 | ||||
供试样品 | 7天 | 14天 | 21天 | 28天 |
甘精胰岛素 | 10 | 10 | 10 | 10 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 1 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 1 | 1 | 1 | 1 |
不添加聚山梨酯20,甚至在使用7天后溶液中就有微粒形成。通过添加聚山梨酯20,在使用期间微粒形成可以被显著地抑制。
甚至在升高的温度下贮存3个月聚山梨酯20仍具有稳定作用。
与贮存1个月后的数据相比,未检测到由于聚山梨酯在溶液的酸性介质中可能水解所导致的稳定作用下降。
实施例2:在物理机械应力负荷下使用聚山梨酯20对甘精胰岛素的稳定作用
a)将溶液通过0.2μm和0.1μm滤器组合进行无菌过滤。然后将其倒入10ml注射小瓶中并用具有嵌入式密封片的压盖密封。
b)用同样方法制备对比溶液,但首先将适宜量的表面活性剂(0.010-0.030mg/ml聚山梨酯20)混悬在注射用水中。
将样品在+5℃、25℃和37℃下贮存固定的时间。然后在每种情况下用5个样品进行振摇试验。结果如下表所示,限度15 FNU相当于在日光下可分辨的浊度。
于5℃下贮存1个月
>15FNU的小瓶数 | |||||||||
供试样品 | 0天 | 0.5天 | 1天 | 2天 | 3天 | 4天 | 6天 | 8天 | 10天 |
甘精胰岛素 | 0 | 0 | 0 | 2 | 3 | 3 | 4 | 4 | 4 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 4 | 5 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
于25℃下贮存1个月
>15FNU的小瓶数 | |||||||||
供试样品 | 0天 | 0.5天 | 1天 | 2天 | 3天 | 4天 | 6天 | 8天 | 10天 |
甘精胰岛素 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 2 | 3 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 3 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
于37℃下贮存1个月
>15FNU的小瓶数 | |||||||||
供试样品 | 0天 | 0.5天 | 1天 | 2天 | 3天 | 4天 | 6天 | 8天 | 10天 |
甘精胰岛素 | 0 | 0 | 0 | 2 | 5 | 5 | 5 | 5 | 5 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.015mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.020mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
甘精胰岛素+0.030mg/ml聚山梨酯20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
不添加聚山梨酯20,甚至在剧烈的物理机械应力2天后,溶液中就可产生可见的混浊。通过添加聚山梨酯20,物理机械应力期间混浊的形成可被显著地延迟。甚至在升高的温度下进行贮存聚山梨酯20仍具有稳定作用。
未检测到由于聚山梨酯在溶液的酸性介质中可能水解所造成的稳定作用下降。
实施例3:使用聚山梨酯20(Tween20)和使用聚山梨酯80(Tween80)对甘精胰岛素在使用期间的稳定作用对比
在每种情况下打开10个小瓶,得到5ml甘精胰岛素注射用溶液并且:
a)加入0.001mg/ml聚山梨酯20
b)加入0.01mg/ml聚山梨酯20
c)加入0.001mg/ml聚山梨酯80
d)加入0.01mg/ml聚山梨酯80,
均为浓贮备液形式。
然后将样品进行使用试验。
结果如下表所示。
若干天后有微粒形成的小瓶 | ||||
供试样品 | 7天 | 14天 | 21天 | 28天 |
甘精胰岛素+0.001mg/ml聚山梨酯20 | 否 | 是 | 是,微粒不断增加 | 是,微粒不断增加 |
甘精胰岛素+0.010mg/ml聚山梨酯20 | 否 | 否 | 否 | 否 |
甘精胰岛素+0.001mg/ml聚山梨酯80 | 否 | 是 | 是,微粒不断增加 | 是,微粒不断增加 |
甘精胰岛素+0.010mg/ml聚山梨酯80 | 否 | 否 | 否 | 否 |
加入浓度为0.01mg/ml的聚山梨酯20或聚山梨酯80同样地能稳定溶液防止使用期间微粒的形成。
Claims (20)
1.一种药物制剂,其包含选自(牛、猪或人)胰岛素、胰岛素类似物、胰岛素衍生物、活性胰岛素代谢物或它们的组合的多肽;一种表面活性剂或者两种或多种表面活性剂的组合;任选地一种防腐剂或者两种或多种防腐剂的组合;以及任选地等张调节剂、缓冲剂或其它赋形剂或它们的组合,该药物制剂为具有酸性范围(pH 1-6.8)内的pH的澄明溶液。
2.权利要求1所述的药物制剂,其具有pH 3.5-6.8范围内的pH。
3.权利要求1所述的药物制剂,其具有pH 3.5-4.5范围内的pH。
4.权利要求1至3之一所述的药物制剂,其中的表面活性剂选自多元醇、甘油、山梨醇以及蔗糖的部分和脂肪酸酯和醚、多羟基化合物。
5.权利要求4所述的药物制剂,其中的多元醇、甘油和山梨醇的部分和脂肪酸酯和醚选自Span、Tween(聚山梨酯)、Myrj、Brij、Triton、Cremophor。
6.权利要求5所述的药物制剂,其中的多元醇、甘油和山梨醇的部分和脂肪酸酯和醚选自Tween20和Tween80。
7.权利要求4所述的药物制剂,其中的多羟基化合物选自聚丙二醇、聚乙二醇、泊洛沙姆、普流罗尼、四聚醇胺。
8.权利要求1至7之一所述的药物制剂,其中的防腐剂选自苯酚、甲酚、氯甲酚、苯甲醇、对羟基苯甲酸酯。
9.权利要求1至8之一所述的药物制剂,其中的等张调节剂选自甘露醇、山梨醇、乳糖、右旋糖、海藻糖、氯化钠、甘油。
10.权利要求1至9之一所述的药物制剂,其中的赋形剂选自缓冲物质如例如TRIS、磷酸盐、柠檬酸盐、乙酸盐、N-甘氨酰甘氨酸或其它物质如酸、碱、盐。
11.权利要求1至10之一所述的药物制剂,其中的胰岛素类似物选自Gly(A21),Arg(B31),Arg(B32)-人胰岛素、Lys(B3),Glu(B29)-人胰岛素、Asp(B28)-人胰岛素、Lys(B28)Pro(B29)-人胰岛素、des(B30)-人胰岛素。
12.权利要求1至10之一所述的药物制剂,其中的胰岛素衍生物选自B29-N-肉豆蔻酰基-des(B30)人胰岛素、B29-N-棕榈酰基-des(B30)人胰岛素、B29-N-肉豆蔻酰基人胰岛素、B29-N-棕榈酰基人胰岛素、B28-N-肉豆蔻酰基LysB28ProB29人胰岛素、B28-N-棕榈酰基-LysB28ProB29人胰岛素、B30-N-肉豆蔻酰基-ThrB29LysB30人胰岛素、B30-N-棕榈酰基-ThrB29LysB30人胰岛素、B29-N-(N-棕榈酰基-γ-谷氨酰基)-des(B39)人胰岛素、B29-N-(N-石胆酰基-γ-谷氨酰基)-des(B30)人胰岛素、B29-N-(ω-羧基-十七烷酰基)-des(B30)人胰岛素和B29-N-(ω-羧基-十七烷酰基)人胰岛素。
13.以上权利要求之一所述的药物制剂,其中胰岛素、胰岛素类似物和/或胰岛素衍生物以60-6000nmol/ml的浓度存在。
14.权利要求13所述的药物制剂,其中胰岛素、胰岛素类似物和/或胰岛素衍生物以240-3000nmol/ml的浓度存在。
15.以上权利要求之一所述的药物制剂,其中表面活性剂以5-200μg/ml的浓度存在。
16.权利要求15所述的药物制剂,其中表面活性剂以5-120μg/ml的浓度存在。
17.权利要求16所述的药物制剂,其中表面活性剂以20-75μg/ml的浓度存在。
18.权利要求10至17中一项或多项所述的药物制剂,其中甘油和/或甘露醇以100-250mM的浓度存在。
19.权利要求18所述的药物制剂,其中NaCl以不超过150mM的浓度存在。
20.以上权利要求之一所述的药物制剂,其中缓冲物质以5-250mM的浓度存在。
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CN102188367A (zh) * | 2011-01-05 | 2011-09-21 | 山东新时代药业有限公司 | 一种甘精胰岛素注射液及其制备方法 |
CN102319422A (zh) * | 2010-05-19 | 2012-01-18 | 赛诺菲-安万特 | 长效胰岛素制剂 |
CN103690958A (zh) * | 2009-07-06 | 2014-04-02 | 赛诺菲-安万特德国有限公司 | 含有甲硫氨酸的水性胰岛素制备物 |
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DE10114178A1 (de) * | 2001-03-23 | 2002-10-10 | Aventis Pharma Gmbh | Zinkfreie und zinkarme Insulinzubereitungen mit verbesserter Stabilität |
CN1160122C (zh) * | 2001-04-20 | 2004-08-04 | 清华大学 | 一种制备口服胰岛素油相制剂的方法 |
DE10227232A1 (de) * | 2002-06-18 | 2004-01-15 | Aventis Pharma Deutschland Gmbh | Saure Insulinzubereitungen mit verbesserter Stabilität |
US6960551B2 (en) * | 2002-08-23 | 2005-11-01 | Exxonmobil Research And Engineering Company | Functionalized periodic mesoporous materials, their synthesis and use |
US6906897B1 (en) * | 2003-02-28 | 2005-06-14 | Western Digital Technologies, Inc. | Disk drive including an actuator main coil and an actuator secondary coil with a lateral segment and method of operating same |
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2002
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- 2003-06-05 EP EP03732536A patent/EP1517697B1/de not_active Expired - Lifetime
- 2003-06-05 KR KR1020047020482A patent/KR101040029B1/ko active IP Right Grant
- 2003-06-05 CN CN038138107A patent/CN1662252A/zh active Pending
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- 2003-06-05 EP EP10178842.0A patent/EP2305288B1/de not_active Expired - Lifetime
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- 2003-06-05 JP JP2004512789A patent/JP5237522B2/ja not_active Expired - Lifetime
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- 2003-06-13 PA PA20038575701A patent/PA8575701A1/es unknown
- 2003-06-13 US US10/461,740 patent/US20040048783A1/en not_active Abandoned
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2004
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2005
- 2005-01-04 NO NO20050036A patent/NO328567B1/no not_active IP Right Cessation
- 2005-03-25 US US11/089,777 patent/US7476652B2/en not_active Expired - Lifetime
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2008
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2010
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- 2010-10-15 JP JP2010232142A patent/JP2011006492A/ja active Pending
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CN101951957A (zh) * | 2008-01-04 | 2011-01-19 | 百达尔公司 | 胰岛素释放作为组织的葡萄糖水平的函数的胰岛素制剂 |
CN104873979A (zh) * | 2008-08-29 | 2015-09-02 | 健赞股份有限公司 | 控释肽制剂 |
US10117909B2 (en) | 2008-10-17 | 2018-11-06 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a GLP-1 agonist |
CN103690958A (zh) * | 2009-07-06 | 2014-04-02 | 赛诺菲-安万特德国有限公司 | 含有甲硫氨酸的水性胰岛素制备物 |
CN102319422A (zh) * | 2010-05-19 | 2012-01-18 | 赛诺菲-安万特 | 长效胰岛素制剂 |
CN104622788A (zh) * | 2010-05-19 | 2015-05-20 | 赛诺菲-安万特 | 长效胰岛素制剂 |
CN107583038A (zh) * | 2010-05-19 | 2018-01-16 | 赛诺菲-安万特 | 长效胰岛素制剂 |
CN102188367A (zh) * | 2011-01-05 | 2011-09-21 | 山东新时代药业有限公司 | 一种甘精胰岛素注射液及其制备方法 |
US10092513B2 (en) | 2013-04-03 | 2018-10-09 | Sanofi | Treatment of diabetes mellitus by long-acting formulations of insulins |
US11191722B2 (en) | 2013-04-03 | 2021-12-07 | Sanofi | Treatment of diabetes mellitus by long-acting formulations of insulins |
US10434147B2 (en) | 2015-03-13 | 2019-10-08 | Sanofi-Aventis Deutschland Gmbh | Treatment type 2 diabetes mellitus patients |
US10159713B2 (en) | 2015-03-18 | 2018-12-25 | Sanofi-Aventis Deutschland Gmbh | Treatment of type 2 diabetes mellitus patients |
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