CN1498113A - 稳定性提高的无锌或低锌胰岛素制剂 - Google Patents
稳定性提高的无锌或低锌胰岛素制剂 Download PDFInfo
- Publication number
- CN1498113A CN1498113A CNA02807114XA CN02807114A CN1498113A CN 1498113 A CN1498113 A CN 1498113A CN A02807114X A CNA02807114X A CN A02807114XA CN 02807114 A CN02807114 A CN 02807114A CN 1498113 A CN1498113 A CN 1498113A
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- China
- Prior art keywords
- insulin
- pharmaceutical preparation
- described pharmaceutical
- zinc
- insulin human
- Prior art date
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 247
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- 229940125396 insulin Drugs 0.000 title claims abstract description 101
- 239000011701 zinc Substances 0.000 title claims abstract description 53
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229910052725 zinc Inorganic materials 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title abstract description 76
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- 239000004094 surface-active agent Substances 0.000 claims abstract description 22
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- 239000000872 buffer Substances 0.000 claims abstract description 6
- 229920001184 polypeptide Polymers 0.000 claims abstract description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 6
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 39
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- YAJCHEVQCOHZDC-QMMNLEPNSA-N actrapid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@H](C)CC)[C@H](C)CC)[C@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C(N)=O)C1=CNC=N1 YAJCHEVQCOHZDC-QMMNLEPNSA-N 0.000 claims description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 6
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Abstract
本发明涉及一种药物制剂,其含有: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;表面活性剂或几种表面活性剂的组合;任选地防腐剂或几种防腐剂的组合以及任选地等渗剂、缓冲剂或附加的辅料或它们的组合,所述药物制剂不含有任何锌或仅含少量的锌。本发明还涉及上述类型的胰岛素制品的制备。
Description
本发明涉及稳定的药物制剂,其含有选自胰岛素(例如人胰岛素、牛胰岛素或猪胰岛素)、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;表面活性剂或多种表面活性剂的组合以及任选地防腐剂或多种防腐剂的组合;以及任选地等渗剂、缓冲剂或其它赋形剂或它们的组合,所述药物制剂不含锌或含有低含量的锌。这些制剂可用于治疗糖尿病,并且特别可用于胰岛素泵、笔、注射器、吸入器中或者用于必须具有增强的物理稳定性的制剂。本发明同样涉及含有这种制剂并且能用于糖尿病的肠胃外制剂,并且涉及用于生产所述制剂和提高胰岛素制剂稳定性的方法。
在世界范围内有约1亿2千万人患糖尿病。其中,约1200万是I型糖尿病患者。对于这种患者而言,针对其内源性胰岛素缺乏而进行的胰岛素替代治疗是现今唯一可能的治疗方法。这些患者终身都依赖于胰岛素注射,通常每天要注射多次。和I型糖尿病相比,II型糖尿病中基本上不缺乏胰岛素,但在许多病例中,特别是在晚期,使用胰岛素并任选地和口服抗糖尿病药物联合进行治疗被认为是最满意的治疗形式。
在健康人体中,胰脏胰岛素的释放和血糖浓度精确对应。(比如饭后出现的)血糖水平的升高迅速地被相应的胰岛素分泌的增加所补偿。在空腹状态下,血浆胰岛素水平降低至基础值,此基础值足以保证对胰岛素敏感器官和组织的葡萄糖的连续供应并使夜间肝糖的合成保持低水平。用外源性的、主要是皮下施用的胰岛素代替内源性胰岛素分泌通常不能非常近似地达到上述血糖生理调节的质量。通常,血糖可发生向上或向下的偏差,最严重时可能危及生命。此外,血糖水平升高多年却无初发症状是严重的健康风险。在美国进行的大规模的DCCT研究(糖尿病控制和并发症临床研究组(1993)N.Engl.J.Med.329,977-986)清楚的证明:长期升高的血糖水平基本上是造成糖尿病晚期损伤的原因。糖尿病晚期损伤是微血管和大血管损伤,其在一些情况下表现为视网膜病变、肾病或神经病并可导致视力丧失、肾衰竭、截肢,而且还伴随着患心血管疾病的风险增加。由此可以得出:改进的糖尿病治疗方法的主要目的是使血糖尽可能保持在生理范围内。根据强化胰岛素治疗的概念,应该通过反复每天注射快速起效和慢速起效的胰岛素制剂达到该目的。快速起效制剂可在用餐时给药以平衡餐后血糖的增加。慢速起效的基础胰岛素应该可以(特别是在夜间)保证胰岛素的基本供给而不导致低血糖。
胰岛素是由51个氨基酸组成的多肽,所述氨基酸被分为两个氨基酸链:A链有21个氨基酸,B链有30个氨基酸。这两条链通过2个二硫键相互连接。胰岛素制剂用于治疗糖尿病已经多年。其中不仅使用了天然产生的胰岛素,而且最近还使用了胰岛素的衍生物和类似物。
胰岛素类似物是天然产生的胰岛素即人胰岛素或动物胰岛素的类似物,所述类似物通过用其它氨基酸残基代替至少一个天然的氨基酸残基和/或增加/除去至少一个氨基酸残基而和相应的天然产生的胰岛素不同(否则相同)。所增加的和/或替换的氨基酸残基也可以是非天然氨基酸残基。
胰岛素衍生物是通过化学修饰得到的天然产生的胰岛素或胰岛素类似物的衍生物。化学修饰可以是例如将一个或多个特定的化学基团加到一个或多个氨基酸上。
通常,胰岛素衍生物和胰岛素类似物的作用与人胰岛素的作用相比有些改变。
起效加速的胰岛素类似物在EP 0214826,EP 0375437和EP 0678522中述及。EP 0124826尤其涉及B27和B28的替换。EP 0678522描述了B29位可以是各种氨基酸优选脯氨酸但不是谷氨酸的胰岛素类似物。EP 0375437包括B28位是赖氨酸或精氨酸的胰岛素类似物,其还可以任选地在B3和/或A21位被修饰。
在EP 0419504中公开了被保护以不受化学修饰的胰岛素类似物,其中B3位的天冬氨酸和至少另一个在A5、A15、A18或A21位的氨基酸被修饰。
在WO 92/00321中描述了至少一个B1-B6处的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持久的作用。
市售的用于胰岛素替代治疗的天然胰岛素的胰岛素制剂在胰岛素来源(例如牛、猪、人胰岛素)以及组成方面存在差异,因此作用模式(起效和作用持续时间)可能受到影响。通过对各种胰岛素制剂进行组合,可得到截然不同的作用模式,并且可以得到尽可能接近生理状况的血糖值。目前,已上市的具有改良的动力学的胰岛素不仅有所提到的天然产生的胰岛素而且还有胰岛素衍生物或类似物的制剂。现今的重组DNA技术使得这种改良胰岛素的制备成为可能。这些胰岛素包括起效迅速的“单体胰岛素类似物”如胰岛素Lispro、胰岛素Aspart和HMR1964(Lys(B3),Glu(B29)人胰岛素),还包括作用时间持久的胰岛素Glargin。
除作用持续时间外,制剂的稳定性对患者也是非常重要的。特别是对于暴露于特定机械压力或较高温度下的制剂,需要具有增强的长期物理稳定性的稳定化胰岛素制剂。这些制剂包括例如给药系统如笔、吸入系统,无针注射系统或胰岛素泵中的胰岛素。胰岛素泵或者被佩戴在患者身上或者被植入到患者体内。在这两种情况下,所述制剂都暴露于体热或运动中,并且暴露于泵的输送运动并因此受到非常高的热机械压力。由于胰岛素笔(一次性的和可反复使用的笔)也通常被佩戴在身体上,所以也会产生同样的情况。以往的制剂在这些条件下仅具有有限的稳定性。
胰岛素可以以药用浓度、以稳定的含锌六聚物的形式存在与中性溶液中,所述六聚物由3个相同的二聚体单元组成(Brange等人,Diabetes Care13:923-954(1990))。通过修饰氨基酸序列可以减少胰岛素的聚集。这样,胰岛素类似物Lispro例如可以主要以单体的形式存在,从而可以被吸收得更快且作用时间更短(HPT Ammon and C.Werning;Antidiabetika[Antidiabetics];第二版;Wiss.Verl.-Ges.Stuttgart;2000;p.94.f)。然而,特别是这些以单体或二聚体形式存在的迅速起效的胰岛素类似物当处于热或机械压力下时,表现出稳定性降低且更易聚集。这使得在其中可观察到混浊和不溶的聚集物沉淀(Bakaysa等人,美国专利5474978号)。这些高分子量的转化产物(二聚体、三聚体、多聚体)和聚集物不仅可降低所施用的胰岛素的剂量而且也可以在病人中引起刺激或免疫反应。而且,这种不溶性聚集物可以影响和堵塞泵的套管和配管。由于锌可以增强胰岛素的稳定性,所以无锌或低锌的胰岛素和胰岛素类似物的制剂特别容易不稳定。特别地,因为不溶性聚集物的形成是通过单体胰岛素进行的,所以起效迅速的单体胰岛素类似物更易迅速聚集而且物理稳定性差。为了保证胰岛素制剂的质量,必须避免聚集物的形成。
有各种方法可用于稳定胰岛素制剂。因此,在国际专利申请WO98/56406中已经描述了用TRIS或精氨酸缓冲液进行稳定的制剂。美国专利5866538描述了含有浓度为5至100mM的甘油和氯化钠并且其稳定性应该增强的胰岛素制剂。美国专利5948751描述了通过加入甘露醇或类似的糖获得的物理稳定性增强的胰岛素制剂。将过量的锌加入到含锌的胰岛素溶液中同样也能增强稳定性(J.Brange等人,Diabetic Medicine,3:532-536,1986)。pH和各种赋形剂对胰岛素制剂的稳定性的影响也已被详细描述(J.Brange&L.Langkjaer,Acta Pharm.Nordica 4:149-158)。
对于增长的需求(提高在室温或体温下、在机械压力下保存的能力)或者对于特别容易受物理压力影响的“单体”胰岛素类似物或起效迅速的胰岛素,这些稳定化方法常常是不够的。而且,所有商品化的胰岛素制剂都含有为稳定所述制剂而加入的锌。因此,Bakaysa等人在美国专利5474978中描述了胰岛素复合物的稳定化制剂,所述复合物由6个胰岛素类似物单体、2个锌原子和至少3个分子的酚防腐剂组成。这些制剂还可以额外地含有生理上可接受的缓冲剂和防腐剂。但是,如果想制备不含锌或低锌的胰岛素制剂,所提及的稳定化方法对于可出售的制剂是不够的。例如,由于缺乏物理稳定性,开发不含锌的胰岛素Lispro制剂是不可能的(Bakaysa等,Protein Science(1996),5:2521-2531)。具有足够稳定性特别是物理稳定性的低锌或无锌的胰岛素制剂在现有技术中还没有被述及。
因此,本发明的目的是:发现胰岛素和其衍生物与类似物的无锌制剂,所述制剂特别地具有较高的稳定性。
现已令人惊讶地发现:加入表面活性剂(乳化剂)如泊洛沙姆或聚山梨酯(Tween)能够显著地增加胰岛素制剂的稳定性从而甚至可以制备具有超稳定性的无锌制剂以使之能够用于输液泵或其它给药系统。这些制剂显示出特别是在压力条件下的增强的稳定性。这可以应用于胰岛素、胰岛素类似物、胰岛素衍生物或它们的混合物。
在中性制剂中,胰岛素和锌离子形成复合物。此时,在锌的浓度足够的条件下,6个胰岛素分子和2个锌离子可以形成稳定的六聚体。为了形成该结构,锌浓度相对于胰岛素必须至少为0.4%(w/w)。这相当于在含有100 IU/ml胰岛素的制剂中锌的浓度约为13μg/ml。过量的锌(例如每个六聚体含4个锌离子)也可以显著地增强制剂对物理压力的稳定性(J.Brange等人,“通过加入Zn2+提高中性胰岛素溶液的物理稳定性”,Diabetic Med.3,532-536(1986))。与此相对,在锌浓度较低(基于胰岛素以重量计<0.4%)的制剂中,六聚体的形成减少。这导致制剂的稳定性显著降低(J.Brange和L.Langkjaer;Acta Pharm Nord,4:149-158(1992))。因此,本申请中“无锌”或“低锌”的意思是基于制剂中胰岛素的含量锌的含量以重量计小于0.4%,优选基于胰岛素含量锌的含量以重量计小于0.2%。对于通常的每毫升含100单位(0.6μmol/ml)的胰岛素制剂,这意味着例如在药物制剂中,基于100单位/ml的胰岛素浓度,Zn++离子浓度小于13μg/ml(0.2μmol/ml),优选小于6.5μg/ml。也可以通过加入可络合锌的物质例如柠檬酸或EDTA从而使锌离子的量不足以形成胰岛素/锌六聚体复合物而达到不含锌的目的。
所述药物制剂含有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。可以使用的表面活性剂尤其可以是非离子型或离子(阴离子、阳离子或两性的)型表面活性剂。特别地,优选的药学上常用的表面活性剂有例如碱金属皂、胺皂和碱土金属皂(硬脂酸盐、软脂酸盐、油酸盐、蓖麻油酸盐)、烷基硫酸盐和烷基磺酸盐(十二烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠)、天然表面活性剂(胆汁酸盐、皂角苷、阿拉伯树胶)、阳离子表面活性剂(alkoniumbromide、氯化十六烷基吡啶鎓、溴化十六烷基三甲铵),脂肪醇(十六醇、十八醇、胆固醇)、多元醇如丙三醇和山梨醇等的偏酯和脂肪酸酯(Span,Tween,Myrj,Brij),Cremophor或泊洛沙姆。所述表面活性剂在药物组合物中的浓度为0.1μg/ml至10000μg/ml,优选1μg/ml至1000μg/ml。
所述制剂还可以含有防腐剂(例如苯酚、甲酚、对羟基苯甲酸酯)、等渗剂(例如甘露醇、山梨醇、乳糖、葡萄糖、海藻糖、氯化钠、甘油)、缓冲物质、盐类、酸和碱以及其它赋形剂。这些物质在每种情况下都可以单独或者作为混合物存在。
通常,甘油、葡萄糖、乳糖、山梨醇和甘露醇在所述药物制剂中的浓度为100至250mM,NaCl浓度不超过150mM。缓冲物质如,例如磷酸盐、乙酸盐、柠檬酸盐、精氨酸、双甘氨肽或TRIS(即2-氨基-2-羟甲基-1,3-丙二醇)缓冲液和相应的盐的浓度为5至250mM,优选10至100mM。
其它的赋形剂尤其可以是盐类、精氨酸、鱼精蛋白或Surfen。
因此,本发明涉及一种药物制剂,其含有选自胰岛素、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;表面活性剂或多种表面活性剂的组合;任选地防腐剂或多种防腐剂的组合;以及任选地等渗剂、缓冲物质和/或其它赋形剂或它们的组合,所述药物制剂不含锌或含低量的锌;优选这样的药物制剂,其中的表面活性剂选自碱金属皂、胺皂、碱土金属皂、烷基硫酸盐、烷基磺酸盐、天然表面活性剂、阳离子表面活性剂、脂肪醇、多元醇如丙三醇和山梨醇的偏酯和脂肪酸酯、多元醇;其中所提及的皂类物质选自硬脂酸盐、软脂酸盐、油酸盐、蓖麻油酸盐;其中的烷基硫酸盐选自十二烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠;其中的天然表面活性剂选自胆酸盐、皂角苷、阿拉伯树胶、卵磷脂;其中的阳离子表面活性剂选自alkonium bromide、氯化十六烷基吡啶鎓、Cetrimid;其中的脂肪醇选自十六醇、十八醇、胆固醇;其中的丙三醇和山梨醇的偏酯和脂肪酸酯和醚选自Span、Tween、Myrj、Brij、Cremophor;其中的多元醇选自聚丙二醇、聚乙二醇、泊洛沙姆、Pluronics、Tetronics;其中的防腐剂选自苯酚、甲酚、对羟基苯甲酸酯;其中的等渗剂选自甘露醇、山梨醇、氯化钠、甘油;其中的赋形剂选自缓冲物质、酸、碱;其中的胰岛素为天然胰岛素,例如人、牛或猪胰岛素;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、LysB28ProB29人胰岛素、B28Asp人胰岛素、B28位脯氨酸被Asp、Lys、Leu、Val或Ala取代且B29位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;其中的胰岛素衍生物选自B29-N-肉豆蔻酰-des(B30)人胰岛素、B29-N-棕榈酰-des(B30)人胰岛素、B29-N-肉豆蔻酰人胰岛素、B29-N-棕榈酰人胰岛素、B28-N-肉豆蔻酰LysB28ProB29人胰岛素、B28-N-棕榈酰LysB28ProB29人胰岛素、B30-N-肉豆蔻酰-ThrB29LysB30人胰岛素、B30-N-棕榈酰-ThrB29LysB30人胰岛素、B29-N-(N-棕榈酰-γ-谷氨酰基)-des(B30)人胰岛素、B29-N-(N-石胆酰-γ-谷氨酰基)-des(B30)人胰岛素、B29-N-(ω-羧基十七酰)-des(B30)人胰岛素和B29-N-(ω-羧基十七酰)人胰岛素。
本发明还涉及以上所述的药物制剂,其中所述胰岛素、胰岛素类似物、活性胰岛素代谢物和/或胰岛素衍生物的浓度为60至6000nmol/ml,优选240至3000nmol/ml(这大约相当于1.4至35mg/ml或40至500单位/ml);其中表面活性剂浓度为0.1-10000μg/ml,优选1-1000μg/ml。
本发明还涉及以上所述的药物制剂,其中甘油和/或甘露醇的浓度为100至250mM,和/或氯化物的浓度优选不超过150mM。
本发明还涉及以上所述的药物制剂,其中缓冲物质的浓度为5至250mM。
本发明还涉及药用胰岛素制剂,其还含有可延缓胰岛素释放的添加剂如,例如盐类、鱼精蛋白或Surfen。这种缓释胰岛素与所述制剂的混合物也包括在本发明中。
本发明还涉及用于制备这种药物制剂的方法。本发明同样还涉及用于治疗糖尿病的这种制剂的施用。
本发明还涉及在制备胰岛素、胰岛素类似物或胰岛素衍生物或它们的制剂的过程中使用或加入表面活性剂作为稳定剂。
在所述含有选自胰岛素、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的药物制剂中,pH为2至12,优选6至8.5,并且特别优选7至7.8。
下面通过实施例对本申请进行了描述,但这些实施例绝不是对本发明进行限制。
实施例:
比较研究:制备了各种含胰岛素类似物HMR1964(Lys(B3),Glu(B29),人胰岛素)的无锌制剂。为此,将无锌HMR1964和其它组分溶解于一份注射用水中,用盐酸/NaOH调节pH至7.3±0.2并用水定容。在下述每个实验中HMR1964的浓度都是3.5mg/ml(相当于100单位/ml)。用相同的方法制备第二种制剂,但额外地加入了特定量的表面活性剂。将溶液分装至5ml或10ml玻璃容器(小瓶)中并用钳口盖密封。然后使这些容器暴露在压力条件下:
1.旋转试验:在每种情形中,将实验组的5个容器和对照组的5个容器进行旋转试验。为此,将容器放置在旋转器上并使之在37℃以60rmp的速度至上而下地旋转(360°)。在规定时间后,将容器中制剂的浊度与浊度标准液相比或者用实验室浊度光度计(比浊计)测定其浊度,其单位是formazine比浊单位(FNU)。使实验进行至所有容器中的浊度值都超过18FNU为止。
2.振荡试验:将容器放置于孵育器中的实验室振荡器上,并在30℃下以100次/分钟的速度振荡。在规定时间后,用实验室浊度光度计(比浊计)测定样品的浊度值,浊度单位是formazine比浊单位(FNU)。
实施例1:旋转试验中通过加入锌稳定HMR1964
(a)将无锌HMR1964(通过计算使其在最终制剂中的浓度为3.5mg/ml)溶解成为水溶液,其最终制剂中含有2.7mg/ml的间甲酚、20mg/ml的甘油和6mg/ml的氨丁三醇(tris),并用1N盐酸/1 N NaOH调节pH至7.2-7.4(室温下测量)。将溶液用水定容并用0.2μm的过滤器进行无菌过滤。然后将其装入5ml注射小瓶并用盖子密封。
(b)用相同的方法制备对照溶液,但在加水定容之前加入浓度为0.1%的氯化锌贮备液,以使最终制剂中锌的含量为15μg/ml。
在所有情况下,然后使5个样品在旋转实验中受压,并在不同时间段后测定浊度。结果显示于下表。
一定时间后浊度>18FNU的试验样品数 | ||||||
描述 | 0h | 8h | 16h | 32h | 40h | 56h |
HMR1964无添加 | 0 | 5 | - | - | - | - |
HMR1964+15μg/ml锌 | 0 | 0 | 0 | 0 | 4 | 5 |
加入锌可以显著地延缓溶液产生混浊的时间从而稳定了HMR1964制剂。不加锌的制剂在旋转试验中甚至在8小时后就出现了显著的混浊。
实施例2:旋转试验中通过加入聚山梨酯20(Tween20)稳定HMR1964
(a)将无锌HMR1964(通过计算使其在最终制剂中的浓度为3.5mg/ml)溶解成为水溶液,其最终制剂中含有3.15mg/ml的间甲酚、5mg/ml的NaCl和6mg/ml的氨丁三醇,并用1N盐酸/1N NaOH调节pH至7.2-7.4(室温下测量)。将溶液用水定容并用0.2μm的过滤器进行无菌过滤。然后将其装入5ml注射小瓶中并用盖子密封。
(b)用相同的方法制备对照溶液,但在加水定容之前加入浓度为0.1%的聚山梨酯20(Tween20)贮备液,以使其在最终制剂中的浓度为10μg/ml。
在所有情况下,然后使5个样品在旋转实验中受压,并在不同时间段后测定浊度。结果显示于下表。
一定时间后浊度>18FNU的试验样品数 | ||||||
描述 | 0h | 8h | 16h | 24h | 32h | 40h |
HMR1964无添加 | 0 | 5 | - | - | - | - |
HMR1964+10μg/mlTween20 | 0 | 0 | 0 | 0 | 5 | - |
加入聚山梨酯20非常显著地延缓了混浊的出现。
实施例3:旋转试验中通过加入泊洛沙姆稳定HMR1964
(a)将无锌HMR1964(通过计算使其在最终制剂中的浓度为3.5mg/ml)溶解成为水溶液,其最终制剂中含有4.5mg/ml的苯酚,5mg/ml的NaCl和6mg/ml的氨丁三醇,并用1N盐酸/1N NaOH调节pH至7.2-7.4(室温下测量)。将溶液用水定容并用0.2μm的过滤器进行无菌过滤。然后将其装入5ml注射小瓶并用盖子密封。
(b)用相同的方法制备对照溶液,但在加水定容之前加入浓度为0.1%的泊洛沙姆171(例如Genapol)贮备液,以使其在最终制剂中的浓度为10μg/ml。
在所有情况下,然后使5个样品在旋转实验中受压,并在不同时间段后测定浊度。结果显示于下表。
一定时间后浊度>18FNU的试验样品数 | ||||||
描述 | 0h | 8h | 16h | 24h | 32h | 40h |
HMR1964无添加 | 0 | 5 | - | - | - | - |
HMR1964+0.01mg/ml泊洛沙姆171 | 0 | 0 | 0 | 2 | 5 | - |
加入泊洛沙姆171也可以非常显著地延缓混浊的出现并可以稳定所述制剂。
实施例4:在振荡试验中通过加入聚山梨酯20或聚山梨酯80稳定HMR1964
(a)将无锌HMR1964(通过计算使其在最终制剂中的浓度为3.5mg/ml)溶解成为水溶液,其最终制剂中含有3.15mg/ml的间甲酚、5mg/ml的NaCl和6mg/ml的氨丁三醇,并用1N盐酸/1N NaOH调节pH至7.2-7.4(室温下测量)。将溶液用水定容并用0.2μm的过滤器进行无菌过滤。然后将其装入5ml注射小瓶并用盖子密封。
(b)用相同的方法制备对照溶液,但在加水定容之前加入浓度为0.1%的聚山梨酯20(Tween20)贮备液,以使其在最终制剂中的浓度为10μg/ml。
(c)用与b)相同的方法制备另一份对照溶液,但此次使用的是聚山梨酯80而不是聚山梨酯20。
将样品在30℃下于实验室振荡器中振荡(60rpm)并在特定时间后测定样品的浊度。结果显示于下表。
振动试验,一定时间后的浊度(FNU) | |||||
加入 | 起始 | 1周 | 2周 | 3周 | 4周 |
无加入 | 0.55 | 2.04 | 4.86 | 6.12 | 10.51 |
0.01mg/ml Tween 20 | 1.75 | 2.60 | 2.44 | 2.44 | 3.80 |
0.01mg/ml Tween 80 | 2.38 | 2.98 | 2.86 | 3.01 | 4.14 |
在振动试验中,加入聚山梨酯20和聚山梨酯80都对HMR1964有稳定作用。
实施例5:振动试验中通过加入锌或泊洛沙姆(Genapol)稳定HMR1964
(a)将无锌HMR1964(通过计算使其在最终制剂中的浓度为3.5mg/ml)溶解成为水溶液,其最终制剂中含有3.3mg/ml的苯酚、5mg/ml的NaCl和6mg/ml的氨丁三醇,并用1N盐酸/1N NaOH调节pH至7.2-7.4(室温下测量)。将溶液用水定容并用0.2μm的过滤器进行无菌过滤。然后将其装入5ml注射小瓶并用盖子密封。
(b)用相同的方法制备对照溶液,但在加水定容之前加入浓度为0.1%的泊洛沙姆171(Genapol)贮备液,以使其在最终制剂中的浓度为10μg/ml。
(c)用与(a)相同的方法制备另一份对照溶液,但在加水定容之前向溶液中加入的是浓度为0.1%的氯化锌贮备液而不是泊洛沙姆贮备液,以使最终制剂中锌的浓度为15μg/ml。
振荡试验,一定时间后的浊度(FNU) | |||||
加入物 | 起始 | 1周 | 2周 | 3周 | 4周 |
无 | 0.39 | 0.70 | 4.46 | 8.74 | 14.11 |
0.01mg/ml的泊洛沙姆 | 0.36 | 0.57 | 0.52 | 1.59 | 0.89 |
0.015mg/ml的Zn | 1.02 | 0.68 | 0.70 | 0.56 | 0.86 |
加入锌和加入泊洛沙姆都能够防止振动试验中混浊的出现。
实施例6:旋转试验中通过加入泊洛沙姆稳定HMR1964
(a)将无锌HMR 1964(通过计算使其在最终制剂中的浓度为3.5mg/ml)溶解成为水溶液,其最终制剂含有3.3mg/ml的苯酚,5mg/ml的NaCl和6mg/ml的氨丁三醇,并用1N盐酸/1N NaOH调节pH至7.2-7.4(室温下测量)。将溶液用水定容并用0.2μm的过滤器进行无菌过滤。然后将其装入5ml注射小瓶并用盖子密封。
(b)用相同的方法制备对照溶液,但在加水定容之前加入浓度为0.1%的泊洛沙姆171(Genapol)贮备液,以使其在最终制剂中的含量为100μg/ml。
在所有情况下,然后使5个样品在旋转实验中受压,并在不同时间段后测定浊度。结果显示于下表。
一定时间后浊度>18FNU的试验样品数 | ||||||
描述 | 0h | 8h | 16h | 24h | 32h | 40h |
HMR1964无加入 | 0 | 5 | - | - | - | - |
HMR1964+0.10mg/ml泊洛沙姆171 | 0 | 0 | 0 | 0 | 1 | 5 |
加入100μg/ml泊洛沙姆同样可以非常显著地稳定HMR1964制剂。
Claims (24)
1.一种药物制剂,其含有选自胰岛素、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;表面活性剂或多种表面活性剂的组合;任选地防腐剂或多种防腐剂的组合;以及任选地等渗剂、缓冲剂或其它赋形剂或它们的组合,所述药物制剂不含锌或含有低含量的锌。
2.权利要求1所述的药物制剂,其中的表面活性剂选自碱金属皂;胺皂;碱土金属皂;烷基硫酸盐;烷基磺酸盐;天然表面活性剂;阳离子表面活性剂;脂肪醇;脂肪酸;多元醇、甘油、山梨醇和蔗糖的偏酯和脂肪酸酯和醚;多元醇。
3.权利要求2所述的药物制剂,其中所述的皂类物质选自硬脂酸盐、软脂酸盐、油酸盐、蓖麻油酸盐。
4.权利要求2或3所述的药物制剂,其中的硫酸盐选自十二烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠。
5. 权利要求2至4的其中一项所述的药物制剂,其中的天然表面活性剂选自胆酸盐、皂角苷、阿拉伯树胶、卵磷脂。
6. 权利要求2至5的其中一项所述的药物制剂,其中的阳离子表面活性剂选自alkonium halides、氯化十六烷基吡啶鎓、Cetrimid。
7.权利要求2至6的其中一项所述的药物制剂,其中的脂肪醇选自十六醇、十八醇、胆固醇。
8.权利要求2至7的其中一项所述的药物制剂,其中的多元醇、甘油和山梨醇的偏酯和脂肪酸酯以及醚选自Span、Tween(聚山梨酯)、Myrj、Brij、Triton、Cremophor。
9.权利要求2至8的其中一项所述的药物制剂,其中的多元醇选自聚丙二醇、聚乙二醇、泊洛沙姆、Pluronics、Tetronics。
10.权利要求1至9的其中一项所述的药物制剂,其中的防腐剂选自苯酚、甲酚、氯代甲苯酚、苯甲醇、对羟基苯甲酸酯。
11.权利要求1至10的其中一项所述的药物制剂,其中等渗剂选自甘露醇、山梨醇、乳糖、葡萄糖、海藻糖、氯化钠、甘油。
12.权利要求1至11的其中一项所述的药物制剂,其中的赋形剂选自缓冲物质例如TRIS、磷酸盐、柠檬酸盐、乙酸盐、双甘氨肽或其它物质如酸、碱、盐、鱼精蛋白、精氨酸、Surfen。
13.权利要求1至12的其中一项所述的药物制剂,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。
14.权利要求1至13的其中一项所述的药物制剂,其中的胰岛素衍生物选自B29-N-肉豆蔻酰-des(B30)人胰岛素、B29-N-棕榈酰-des(B30)-人胰岛素、B29-N-肉豆蔻酰人胰岛素、B29-N-棕榈酰人胰岛素、B28-N-肉豆蔻酰-LysB28ProB29人胰岛素、B28-N-棕榈酰-LysB28ProB29人胰岛素、B30-N-肉豆蔻酰-ThrB29LysB30人胰岛素、B30-N-棕榈酰-ThrB29LysB30人胰岛素、B29-N-(N-棕榈酰-γ-谷氨酰基)-des(B39)人胰岛素、B29-N-(N-石胆酰-γ-谷氨酰基)-des(B30)人胰岛素、B29-N-(ω-羧基十七酰)-des(B30)人胰岛素和B29-N-(ω-羧基十七酰)人胰岛素。
15.前述权利要求的其中一项所述的药物制剂,其中胰岛素、胰岛素类似物、胰岛素衍生物和/或胰岛素代谢物的浓度为60至6000nmol/ml。
16.权利要求15所述的药物制剂,其中胰岛素、胰岛素类似物、胰岛素衍生物和/或胰岛素代谢物的浓度为240至3000nmol/ml。
17.前述权利要求的其中一项所述的药物制剂,其中表面活性剂的浓度为0.1至10000μg/ml。
18.权利要求17所述的药物制剂,其中表面活性剂的浓度为1至1000μg/ml。
19.权利要求10至18中的一项或多项所述的药物制剂,其中甘油和/或甘露醇的浓度为100至250mM。
20.权利要求19所述的药物制剂,其中氯化物的浓度不超过150mM。
21.前述权利要求的其中一项所述的药物制剂,其中缓冲物质的浓度为5至250mM。
22.用于制备权利要求1至21中的一项或多项所述的药物制剂的方法,其中将各组分以水溶液的形式混合,然后调节至所需的pH并用水将混合物补充至最终的体积。
23.权利要求22所述的制备药物制剂的方法,其中使甲酚的最终浓度为3.15mg/ml、HMR1964的最终浓度为3.5mg/ml、氨丁三醇的最终浓度为6.0mg/ml、NaCl的最终浓度为5.0mg/ml、Tween20的最终浓度为0.1mg/ml。
24.可以按照权利要求22或23所述的方法得到的药物制剂。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101670125A (zh) * | 2008-09-12 | 2010-03-17 | 增井吉晴 | 抗菌除臭剂 |
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 |
CN105705161A (zh) * | 2013-10-25 | 2016-06-22 | 赛诺菲-安万特德国有限公司 | 赖谷胰岛素的稳定制剂 |
CN105749292A (zh) * | 2016-02-29 | 2016-07-13 | 苏州市贝克生物科技有限公司 | 促进胰岛素吸收的组合物及其制备方法 |
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