CN1187369C - 制备肽盐的方法,肽盐应用及包括肽盐的药物制剂 - Google Patents
制备肽盐的方法,肽盐应用及包括肽盐的药物制剂 Download PDFInfo
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- CN1187369C CN1187369C CNB018142192A CN01814219A CN1187369C CN 1187369 C CN1187369 C CN 1187369C CN B018142192 A CNB018142192 A CN B018142192A CN 01814219 A CN01814219 A CN 01814219A CN 1187369 C CN1187369 C CN 1187369C
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Abstract
本发明涉及含肽盐药用制剂，其制备及其应用。本发明尤其涉及含LHRH激动剂或拮抗剂的略溶性盐，诸如用于对哺乳动物肠胃外给用长效药物双羟萘酸西曲瑞克的药物制剂。
Description
本发明涉及一种用于制备肽盐的新方法，尤其不良溶性的肽盐，及其在制造药物方面的应用。此外，本发明还涉及含有至少一种按照本发明制备的肽盐的药物制剂，并涉及其制备。
在国际专利申请No.PCT/EP94/03904中描述了通过使酸盐的水溶液与碱性肽的乙酸溶液反应，沉淀出肽的不良溶性酸加成盐，由此制备不良溶性肽的方法。例如，描述了制备LHRH(促黄体生成激素释放激素)拮抗剂双羟萘酸西曲瑞克(cetrorelix embonate)的过程。
本发明涉及一种用于制备肽盐的新方法，其特征在于在适宜稀释剂存在下，使碱性肽的酸加成盐(起始肽盐)(1)与一种混合床的离子交换剂或酸、碱离子交换剂的混合物反应，形成游离碱性肽，随后分离出该离子交换剂，然后使此游离碱性肽与一种无机或有机酸反应，生成肽的所需酸加成盐(最后肽盐)(2)，并随后除去该稀释剂。
这里，甚至在较大整体结构内的亚结构意义上，术语“碱性肽”指的是含有碱性氨基酸诸如精氨酸、吡啶基丙氨酸或赖氨酸的多(氨基酸)，或肽的N末端或就是至少一个碱性基团。
优选的肽是LHRH拮抗剂antide、A-75998、加尼瑞克(ganirelix)、NaI-Glu拮抗剂、西曲瑞克、替维瑞克(teverelix)(Antarelix)和按照该US 5,942,493和DE19911771.3的拮抗剂，其所包括内容在此均引以参考。另外的肽是阿巴瑞克(abarelix)、azaline B、地肽瑞克(detirelix)、雷莫瑞克(ramorelix)(Stoeckemann and Sandow，J.Cancer Res.Clin.Oncol.1993，119，457)和RS-68439。所述这些肽的结构均可在Behre等人著“GnRH拮抗剂：综述”(Proceedings of the 2ndWorld Conference on Ovulation Induction(第二届世界排卵诱发会议论文集)，The Parthenon Publishing Group Ltd.)；Kutscher等人的文章(Angew.Chem.(实用化学)1997，109，2240)中找到。
所用这些作为原材料的肽的酸加成盐优选是易溶性盐，诸如醋酸盐、盐酸盐、硫酸盐。
按照本新方法，这种起始肽盐是完全或部分溶于稀释剂或是被悬浮其中。然后添加稀释剂。溶剂和稀释剂可以是相同或不同的。可能的溶剂和稀释剂是例如：水、乙醇、甲醇、丙醇、异丙醇、丁醇、丙酮、二甲基酮、甲乙酮、二甲基乙酰胺、二甲基甲酰胺、N-甲基吡咯烷酮、乙腈、戊烷、己烷、庚烷和其混合物。乙醇、异丙醇或丙酮是优选的。1-60％的含水量，优选5-50％的含水量，也同样是优选的。
将该混合床离子交换剂，即酸性离子交换剂和碱性离子交换剂的混合物，加入至起始肽盐的溶液或悬浮液中。一种可能离子交换剂例如是Amberlite。
离子交换剂用量取决于每种肽的碱性基团数。此用量通过添加至达到某恒定pH的方法确定。例如，1克的西曲瑞克需要10克的Amberlite MB-3。
在制备该碱过程中，根据所用活性化合物盐，调节该碱溶液的pH值至7.5-13，尤其在含有呈碱性反应的氨基酸的肽盐情况下，在LHRH拮抗剂的盐(如可作为例如醋酸盐存在的西曲瑞克，D-63153，阿巴瑞克，加尼瑞克、雷莫瑞克)的情况下更是如此。
为避免肽的分解，温度不应超过25-30℃。制备此游离碱的反应时间通常进行在几分钟内，例如，用醋酸西曲瑞克起始时为20分钟。也可以更长，例如用双羟萘酸西曲瑞克开始时反应时间约1小时。pH值达到恒定之后，应终止反应，因为由于溶液碱度可能会形成例如分解产物。
然后，由反应混合物除去离子交换剂。可以采用筛分、滤出、离心或柱过滤的方法进行除去。
游离肽碱的溶液不稳定，会变清亮或混浊，应尽可能快地使之与酸反应，形成所需酸加成盐。可以固态物质或溶液或悬浮液的形式加入酸。可按完全相同方法，使该游离肽碱溶液变为酸。
反应时间在几分钟-几小时范围。例如对于形成双羟萘酸西曲瑞克，反应时间为1.5小时。
然后对通常是清亮的该反应溶液进行无菌过滤。接着除去溶剂，得到纯肽盐。或者，在除去溶剂之前，可向该溶液中加入赋形剂(excipients)、添加剂或载体(vehicles)。可在无菌过滤之前以固体形式或在无菌过滤之后以无菌滤过溶液的形式添加赋形剂。
适宜的赋形剂为例如甘露糖醇、山梨糖醇、木糖醇、可溶性淀粉。
按照本发明，可通过添加适宜酸制备以下的盐类：醋酸盐、己二酸盐、抗坏血酸盐、藻酸盐、苯甲酸盐、苯磺酸盐、溴化物、碳酸盐、柠檬酸盐、氯化物、磷酸二丁酯、柠檬酸二氢盐、磷酸二辛酯、磷酸双十六烷基酯、富马酸盐、葡糖酸盐、葡糖醛酸盐、谷氨酸盐、碳酸氢盐、酒石酸氢盐(hydrogentartrate)、盐酸盐、柠檬酸氢盐、碘化物、乳酸盐、α-硫辛酸、苹果酸盐、马来酸盐、丙二酸盐、双羟萘酸盐(pamoate)、(双羟萘酸酯)、棕榈酸盐、磷酸盐、水杨酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、丹宁酸盐、油酸盐、磷酸辛酯。
通过以下实施例对本发明进行说明，而非由此对其限制。
实施例1
将46.47克的D-20761分成数份加至1193克的水中，对其搅拌溶解(得溶液1)。然后加入3261克96％乙醇在搅拌下对溶液1进行稀释(得溶液2)。稀释后用玻璃纤维预过滤器滤过溶液2，并将滤液与390克Amberlite MB3(由强酸性阳离子和阴离子交换剂形成的混合床离子交换剂)搅拌混合(得混合物1)。将316.8克的甘露糖醇搅拌下溶于1267克的水中(得溶液3)。搅拌15分钟后，测定混合物1的上清液的pH值，并在再搅拌5分钟后再次测定其pH值。接着，在pH值达到12.5之后用细目筛网分离该溶液与Amberlite MB3，(得溶液4)。
搅拌混合4162克溶液4与5.34克的双羟萘酸(embonic acid)。再剧烈搅拌此混合物1.5小时，然后用玻璃纤维预过滤器过滤此有些混浊的溶液。此溶液pH值为8.4(得溶液5)。所测定的pH值均是通过一种利用粘稠电解质液体的毛玻璃电极测定的。这些pH值仅是被看成为相对值，因为所测定的溶液或悬浮液含有乙醇，因此显示明显较高的数值。
在该反应装置中，无菌过滤3333克被调节至室温的溶液5，并无菌过滤528克被调节至室温的溶液3，以搅拌掺入溶液5(得溶液6)。
加热溶液6至40℃，然后真空蒸馏出乙醇/水混合物，使溶液减至1931克以下(得悬浮液1)。将此双羟萘酸西曲瑞克悬浮液1冷却至室温，并用无菌过滤后的注射用水将其搅拌稀释至3000克(得悬浮液2)。然后将调节至室温的待用悬浮液2各3.0克分装到10毫升注射管瓶中，装上冷冻干燥栓塞，并将其转移至冷冻干燥装置中。
在冷冻干燥装置中于平皿温度(plate temperature)-40℃下冷冻这些注射管瓶。干燥是通过使平皿温度从-40℃升至20℃的一种程序干燥方法完成的。用无菌过滤后的氮气注满此冷冻干燥(FD)装置，对该装置中的这些注射管瓶密封，接着盖上并滚压卷曲帽。
冷冻干燥之后，通过12kGy(最小)-15kGy的γ幅射，对这些密封注射管瓶消毒。后者是任选的。
1个140.0(7)毫克的注射管瓶装有34.07毫克的双羟萘酸西曲瑞克，相当于30毫克的西曲瑞克和106毫克的甘露糖醇。重溶时，采用2毫升注射用水。所得悬浮液可以通过i.m.(肌内)或s.c.(皮下)给药的方式用药。
生物学作用：
将按照实施例1所得的双羟萘酸西曲瑞克(2∶1)冻干物(30mg)再悬浮于2毫升注射用水中，然后可通过肠胃外给药，优选皮下(s.c.)或肌内注射(i.m.)给药。
在皮下给药情况下，双羟萘酸西曲瑞克(2∶1)可达到约30-50％的生物利用率(100％定义为通过静脉内给药醋酸西曲瑞克的生物利用率)。双羟萘酸西曲瑞克(2∶1)冻干体的特别优点是对病人仅有很小或没有“突发效应”。作用持续时间与剂量相关，在30-150毫克剂量时，为2-8周或更长。按照本发明的双羟萘酸西曲瑞克(2∶1)冻干体已经过对人临床I期试验阶段的研究。
图1说明，肌内对人给予实施例1所述双羟萘酸西曲瑞克(2∶1)冻干体60mg开始，西曲瑞克血浆浓度的进程是时间的函数(按小时计)。未能测定到突发效应(约100ng/ml(纳克/毫升))。作用持续时间在700小时以上。给药后150小时，恒定血浆水平约2ng/ml。生物利用率约40％。
按照本发明肽盐类的应用领域是例如BPH，肌瘤和子宫内膜异位症。
Claims (6)
1、制备可用于对哺乳动物进行胃肠外给药的药物制剂的方法，其特征在于在适宜稀释剂存在下，使碱性肽LHRH拮抗剂西曲瑞克的易溶酸加成盐与混合床离子交换剂或酸性、碱性离子交换剂的混合物进行反应，形成游离碱性肽，随后分离出此离子交换剂，接着使此游离碱性肽与无机或有机酸反应，形成此肽的所需难溶酸加成盐，随后加入合适的药物赋形剂、载体及/或填充剂，再除去该稀释剂。
2、按照权利要求1的方法，其特征在于该酸是双羟萘酸、硬脂酸或水杨酸。
3、按照权利要求1或2的方法，其特征在于西曲瑞克与双羟萘酸的摩尔比是2∶1。
4、按照权利要求1或2的方法，其特征在于该稀释剂是通过冷冻干燥除去的。
5、按照权利要求1的方法，其特征在于所述稀释剂选自下组：水、乙醇、甲醇、丙醇、异丙醇、丁醇、丙酮、二甲基酮、甲乙酮、二甲基乙酰胺、二甲基甲酰胺、N-甲基吡咯烷酮、乙腈、戊烷、己烷、庚烷和其混合物。
6、按照权利要求1的方法，其特征在于所述赋形剂选自：甘露糖醇、山梨糖醇、木糖醇、可溶性淀粉。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10040700A DE10040700A1 (de) | 2000-08-17 | 2000-08-17 | Salze von biologisch aktiven Peptiden, ihre Herstellung und Verwendung |
| DE10040700.5 | 2000-08-17 | ||
| CA002355573A CA2355573A1 (en) | 2000-08-17 | 2001-08-22 | Method for the synthesis of peptide salts, their use and the pharmaceutical preparations, containing peptide salts |
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| Publication Number | Publication Date |
|---|---|
| CN1447817A CN1447817A (zh) | 2003-10-08 |
| CN1187369C true CN1187369C (zh) | 2005-02-02 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB018142192A Expired - Fee Related CN1187369C (zh) | 2000-08-17 | 2001-08-09 | 制备肽盐的方法,肽盐应用及包括肽盐的药物制剂 |
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| US (1) | US6780972B2 (zh) |
| EP (1) | EP1309607B1 (zh) |
| JP (1) | JP2004506647A (zh) |
| CN (1) | CN1187369C (zh) |
| AR (1) | AR030371A1 (zh) |
| AT (1) | ATE280779T1 (zh) |
| AU (2) | AU2002210439B2 (zh) |
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| BR (1) | BR0113296A (zh) |
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| DE (2) | DE10040700A1 (zh) |
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| EE (1) | EE200300065A (zh) |
| ES (1) | ES2230371T3 (zh) |
| HK (1) | HK1058366A1 (zh) |
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| PL (1) | PL204496B1 (zh) |
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| RU (1) | RU2266296C2 (zh) |
| SI (1) | SI1309607T1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6828415B2 (en) * | 1993-02-19 | 2004-12-07 | Zentaris Gmbh | Oligopeptide lyophilisate, their preparation and use |
| US7098305B2 (en) * | 2001-09-06 | 2006-08-29 | Ardana Bioscience Limited | Sustained release of microcrystalline peptide suspensions |
| EP1674082A1 (de) * | 2004-12-22 | 2006-06-28 | Zentaris GmbH | Verfahren zur Herstellung von sterilen Suspensionen oder Lyophilisaten schwerlöslicher basischer Peptidkomplexe, diese enthaltende pharmazeutische Formulierungen sowie ihre Verwendung als Arzneimittel |
| RU2525661C2 (ru) * | 2012-11-15 | 2014-08-20 | Федеральное государственное бюджетное учреждение "Научно-исследовательский институт вакцин и сывороток им. И.И. Мечникова" Российской академии медицинских наук (ФГБУ "НИИВС им. И.И. Мечникова" РАМН) | Способ получения высокотитражной антимикробной сыворотки для оценки антигенной активности противостафилококковых вакцин |
| CN107056894B (zh) * | 2017-05-26 | 2021-07-20 | 济南康和医药科技有限公司 | 一种片段法固相合成醋酸加尼瑞克的方法 |
| EP3590526A1 (en) * | 2018-07-05 | 2020-01-08 | Antev Limited | A lyophilization process and a teverelix-tfa lyophilizate obtained thereby |
| CN114249800B (zh) * | 2020-09-22 | 2024-07-26 | 深圳市星银医药有限公司 | 一种双羟萘酸多肽药物的制备方法 |
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| US4431635A (en) * | 1979-06-13 | 1984-02-14 | Coy David Howard | LH-RH Antagonists |
| ATE8988T1 (de) * | 1980-06-02 | 1984-09-15 | Andrew Victor Schally | Lh-rh antagonisten. |
| US4800191A (en) * | 1987-07-17 | 1989-01-24 | Schally Andrew Victor | LHRH antagonists |
| DE4305225A1 (de) * | 1993-02-19 | 1994-08-25 | Asta Medica Ag | Neues Herstellverfahren für Cetrorelix Lyophilisat |
| EP0626170A3 (en) * | 1993-05-10 | 1996-03-27 | Sandoz Ltd | Stabilization of pharmacoligically active compounds in controlled release compositions. |
| CA2178592C (en) * | 1993-12-09 | 2009-07-28 | Jurgen Engel | Long-acting injection suspensions and a process for their preparation |
| DE4342092B4 (de) * | 1993-12-09 | 2007-01-11 | Zentaris Gmbh | Langwirkende Injektionssuspension und Verfahren zur Herstellung |
| US6054432A (en) * | 1996-09-12 | 2000-04-25 | Asta Medica Aktiengesellschaft | Means for treating prostate hypertrophy and prostate cancer |
| NZ505651A (en) * | 1998-01-16 | 2003-08-29 | Takeda Chemical Industries Ltd | Sustained release composition comprising biologically active substance, hydroxynaphthoic acid and biodegradable polymer |
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