CN1112019A - 制备一种十肽冻干品的新方法 - Google Patents
制备一种十肽冻干品的新方法 Download PDFInfo
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- CN1112019A CN1112019A CN94101378A CN94101378A CN1112019A CN 1112019 A CN1112019 A CN 1112019A CN 94101378 A CN94101378 A CN 94101378A CN 94101378 A CN94101378 A CN 94101378A CN 1112019 A CN1112019 A CN 1112019A
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- Prior art keywords
- lyophilized product
- cetrorelix
- treatment
- solution
- mannitol
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Abstract
本发明提供了一种新的低压冻干品和制备方法
及该低压冻干品用于治疗女性不育症和保护性腺的
药物的用途。
Description
cetrorelix是用作乙酸盐的带末端酰胺基团的十肽。欧洲专利申请299402中介绍了合成方法和某些药理作用。
可能按0.1-20mg剂量经皮下注射此活性物质。该十肽的水溶液不稳定，在最终容器中不能进行高压消毒。按所述条件进行惯常消毒，该十肽有分解的趋势。为了获得可注射的溶液，因此需研制低压冻干品。
然而，将被低压冻干的溶液中活性物质的量是如此之低以至于在活性物质浓度低时，在无助剂物质的溶液干后，只有疏松的绒毛状物在安瓿瓶的壁上形成，用蒸汽流对此小瓶上的绒毛状物进进转移以消毒。因此，必须使用形成稳定饼状物的增量剂。在浓度高时，可以不用此助剂物质。下述助剂物质可用作增量剂：已糖醇类，尤其是甘露糖醇、葡萄糖醇、山梨糖醇，如D-山梨糖醇、半乳糖醇、altritol如D-和L-altritol、艾杜糖醇（如D-和L-艾杜糖醇），其旋光性形式（D-和L-形式）及相应的外消旋体。特别使用甘露糖醇，如D-甘露糖醇、L-甘露糖醇、DL-甘露糖醇、山梨糖醇和/或半乳糖醇，其中，优选D-甘露糖醇。使用的已糖醇也可是已糖醇类混合物，即如甘露糖醇和山梨糖醇和/或半乳糖醇的混合物。由于半乳糖醇在水中的溶解度较如甘露糖醇低，所以按重量计，半乳糖醇在水中的含量将不超过如3%。此外，甘露糖醇和山梨醇如可按任何比例进行混合。
除已糖醇外，也可加入其他惯常药用助剂物质，如氨基酸，例如丙氨酸、甘氨酸、赖氨酸、苯丙氨酸、天冬氨酸、谷氨酸、亮氨酸、乳糖、聚乙烯吡咯烷酮、葡萄糖、果糖、白蛋白和当量增量剂、也可用脲和氯化纳作增量剂。按重量计，用于冻干的溶液中，每份重cetrorelix时，此类增量物质的总量如为0-16.9份，例如0.1-7份。在所说最终低压冻干品中，这类助剂物质的总量可达16.9份（以每份重已糖醇为基准计）。详细讲这类助剂物质的量取决于存在的已糖醇的量，且按每份重cetrorelix计，在最终低压冻干品中，已糖醇和其他这类助剂物质的量可到这样程度，即不超过17份。如在低压冻干品中，仅存在0.1份重已糖醇，其他助剂物质可达16.9份重；在如存在8.5份已糖醇时，按cetrorelixl份重为基准计，其他助剂物质的量加可达8.5份重。
然而，在研制低压冻干品时发现此活性物质在制备期间的行为变化很大且是不可预计的。头几批产品可得到好的结果，但在无菌过滤期间立刻出了困难，而且几批产品不合乎要求。
据下述公知技术报导，寡肽，尤其带未端酰胺官能团的寡肽有形成凝胶的趋势：POwell,M.F.;Pharmaceutical Research,1258-1263(8)1991;Dathe,M:Int.J:Peptide Protein Res。344-349(36)1990;Szejtli,J.;Pharmaceutical Technology International 16-22,1991。在无菌过滤期间，从过滤速度上可清楚地看到这一点，的确常凭器官感觉可检查出这种溶液的粘度有所增加。而且凝胶层仍在无菌过滤器上，于是不再可能制备含有完全按所定义的活性物质含量的药物。
下表1列出了头11批产品的各种结果。
活性物质的含量在100%-36%间波动。
表1：乙酸cetrorelix
批 剂量 活性物质含量
1 100ug 100
2 500ug 100
3 500ug 90
4 500ug 36
5 500ug 100
6 500ug 85
7 1mg 80
8 1mg 100
9 2mg 100
10 2mg 80
11 2mg 100
为了避免形成凝胶，公知技术中列出了通过实验筛选出的下述添加剂：可以考虑使用的有机溶剂有如乙腈、正丁醇、叔丁醇、乙醇、异丙醇、辛醇和苄醇。也可使用盐和缓冲溶液，如乙酸盐缓冲溶液、柠檬酸盐缓冲液、氯化钠、磷酸钠、乙二胺四乙酸钠、碳酸氢钠、磷酸盐缓冲溶液、乙酸胍、脲。聚合物也可使用，如凝胶、聚乙二醇600、羟乙基淀粉、聚乙烯吡咯烷酮、聚乙烯醇。也介绍了使用氨基酸，如丙氨酸、甘氨酸、赖氨酸、苯丙氨酸、天冬氨酸、谷氨酸和亮氨酸。所用的酸有柠檬酸、辛酸、盐酸和乙酸。可使用的生理学上可接受的表面活性剂是洁尔灭、十六烷醇、胆汁酸、卵磷酯、多乙氧基醚、司盘（Spans）和普卢兰尼克R(Pluronics)。业已使用的碳水化合物和环糊精有如葡萄糖、乳糖、甘露糖醇、蔗糖、α-、β-和γ-环糊精、羟基丙基-α-和-β-环糊精、羟乙基环糊精及甲基环糊精。实验过这些助剂物质作过滤剂以防止凝胶的形成。
然而发现并未使该问题得到满意解决。用乙酸酸化只有部分获得成功。而且还存在着高的过滤损失这样的缺点。此外还惊奇地发现cetrorelix易溶于30%（V/V）的乙酸中，然后用注射用水把此溶液中的cetrorelix的最终浓度调到3%并加入甘露糖醇。虽然在公知技术中叙述过末端酰胺基团在酸性介质中易于水解，但对于cetrorelix来说，并未发现此种情况。按此法制备的溶液在过滤期间不存任何困难。发现活性物质的量总是合乎要求的。而过滤速度又能确保满意的生产程序。在现有技术Sucker第557-559页上(Fnchs和Speiser（出版者），“Pharmazentische Techozologie”第二版，(1991)Thieme-verlag,Stnttgartnew York)介绍了无菌低压冻干的一般方法。在德国专利公开说明书(Dos)3735614中也披露了低压冻干工艺。此低压冻干品用于治疗女性不育。迄今为止一直所用的一种治疗方法是用人绝经促性腺激素刺激卵泡成熟，然后用人绒〔毛〕膜促性腺激素引发排卵。这样引发的排卵在32小时后发生。以此收集的卵可用于体外受精。
用显效药进行这种治疗的缺点是在于这样一个事实，即在刺激期成熟的卵泡高达10个，卵泡成熟数的这种增加会在黄体化激素（LH）中导致激素水平峰值的出现。这些峰值会引起卵泡早期成熟，排卵时间不能准确预计。在所治疗的病例中，这种有害排卵约发生25%。由于这种不定期的排卵期不能用于收集卵，且必须在1个月以后重复整个治疗。
惯常刺激治疗的另一缺点是需要有4周长的治疗期才获得满意的抑制。在1-2%的病例中，此显效药继续呈现出过度刺激综合征，其中卵泡细胞肥大。在多囊卵巢情况下，过度刺激的危险特别大。过度刺激综合征是一种可导致死亡的严重副作用。
业已发现此种特定治疗中拮抗药cetrorelix呈现下述特点：用cetrorelix治疗5天以上即可获得完全的抑制。不会出现过度刺激综合征。此外，在第二治疗周期可使用较少HMG（卵泡刺激素），该第二治疗周期为引发排卵期。用此进行的体外受精治疗有着重要的费用优点。如当畸形管存在时，则用体外受精，进行这种治疗必须尽可能准确的测定排卵周期和排卵时间。由于用HMG/HCG（人绒促性素）刺激，常会过早发生早期排卵的LH增加或此增加不能维持足够长的时期，迄今为止做到这一点仍是十分有限的。然而为为精确确定受精时间，要想获得成功的治疗，避免这种过早成熟的增加尤为重要。这可减少患者肉体和精神上的负担且最佳利用医院后勤。为了通过使用外源促性腺激素（HMG/HCG）同时刺激卵泡成熟和在任何时候监测激素的状态，有必要尽可能完全地抑制内源激素的产生〔LH-FSH（促卵泡激素）〕以最可靠地实现上述目的。只有当获得的卵泡数目足够大（4-6），大约有同样的成熟度时才能用注射大丸剂HCG的办法来引发排卵。
对患者来说，使用拮抗药基本上是比较成功和安全的。使用根据本发明的cetrorelix低压冻干品的另一方面是可以保护男性患者的性腺。用cetrorelix低压冻干品对男性患者进行预治疗且其性腺活性得到了加强。这样，其他有害的有毒剂，如放射性治疗或用细胞抑制剂的治疗对性腺敏感组织影响的可能性就无或很小了。
制备例
用一适宜的玻璃器皿制备约1.5升注射水。在另一玻璃器皿中制备210g注射用水，加入91.17g乙酸。搅拌下，把计算量的乙酸cetrorelix（1.62-1.695g，取决于所用此批的含量）溶解在所制的30%乙酸中。把此溶液转移到装有1.5升注射用水的所说玻璃器皿中，加入82.2g甘露糖醇，使之溶解并用注射用水把此溶液配制到3039g。
工艺过程中进行的测定：
PH：2.5-3.0
密度：1.009-1.017g/cm3（20℃下）
折射率：1.227-1.340在440nm处和20℃下测得的。
于无菌条件下，用适宜的膜过滤器（孔径0.2μm）对所说溶液进行过滤消毒。把最初的100ml流出液丢弃。用过热蒸汽对过滤器消毒以防止冷冻干燥的cetrorelix溶液在贮存期间再度污染。
立即在无菌条件下把所说溶液装入无色注射瓶（DIN 2R，1类水解型）中并塞上无菌冷冻干燥塞，其一般装入量为2.0ml（2.026g）。
于注射瓶洗涤机中对2ml的注射瓶进行洗涤，热空气干燥并予以灭菌。对该洗净的冷冻干燥瓶进行高压消毒。把封闭的注射瓶转移到冷冻干燥设备中，于-40℃板温下冷冻。按板温-40℃升到40℃的干燥程序干燥。在所说冷冻干燥设备中注入无菌氮，于该设备中密封注射瓶，其所说塞用卷边盖固定，用目视法检查注射瓶密封是否合乎要求，挑选出不合乎要求的并将其毁掉。
将1mg白色、园形、冷冻干燥饼状cetrorelix低压冻干品装于用浅色冻冰干燥塞和黄色触关式(flip-off)卷边盖密封的2ml无色注射瓶内。
Claims (7)
1、一种带3-15个氨基酸的肽和任选的一种或几种增量剂的低压冻干品，其特征在于将1份重肽溶解在100-10，000份重乙酸中，然后将其转移到水中，把这样获得的溶液低压冻干。
2、一种根据权利要求1的低压冻干品，其特征在于所用的增量剂是甘露糖醇。
3、一种根据权利要求1的低压冻干品，其特征在于所说肽是cetrorelix。
4、根据权利要求1或2的低压冻干品用于治疗女性不育症的用途。
5、根据权利要求1或2的低压冻干品用于保护性腺的用途。
6、根据权利要求1或2的低压冻干品用于制备治疗女性不育症的药物的用途。
7、根据权利要求1或2的低压冻干品用于制备保护性腺的药物的用途。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4305225.8 | 1993-02-19 | ||
| DE4305225A DE4305225A1 (de) | 1993-02-19 | 1993-02-19 | Neues Herstellverfahren für Cetrorelix Lyophilisat |
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| CN1112019A true CN1112019A (zh) | 1995-11-22 |
| CN1109557C CN1109557C (zh) | 2003-05-28 |
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| CN100342908C (zh) * | 2000-05-18 | 2007-10-17 | 赞塔里斯有限公司 | 施用肽的药物剂型,其制备方法和应用 |
| CN102423484A (zh) * | 2011-11-23 | 2012-04-25 | 深圳翰宇药业股份有限公司 | 一种稳定的西曲瑞克药物组合物及其制备方法 |
| CN114159544A (zh) * | 2022-01-24 | 2022-03-11 | 福州华为医药技术开发有限公司 | 注射用醋酸西曲瑞克及其制备方法 |
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| EP2648755A1 (en) | 2010-12-06 | 2013-10-16 | Astron Research Limited | A stable ready-to-use cetrorelix injection |
| GB201022147D0 (en) * | 2010-12-31 | 2011-02-16 | Immune Targeting Systems Its Ltd | Formulation |
| EP3015553A1 (de) | 2014-10-30 | 2016-05-04 | Biotecon Diagnostics GmbH | Stabilisierte Reaktionsmischung |
| RU2667128C2 (ru) | 2016-12-29 | 2018-09-14 | Герман Петрович Беккер | Композиция для приготовления противоопухолевого средства и способ приготовления противоопухолевого средства на ее основе |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100342908C (zh) * | 2000-05-18 | 2007-10-17 | 赞塔里斯有限公司 | 施用肽的药物剂型,其制备方法和应用 |
| US7718599B2 (en) | 2000-05-18 | 2010-05-18 | Aeterna Zentaris Gmbh | Pharmaceutical administration form for peptides, process for its preparation, and use |
| CN102423484A (zh) * | 2011-11-23 | 2012-04-25 | 深圳翰宇药业股份有限公司 | 一种稳定的西曲瑞克药物组合物及其制备方法 |
| CN102423484B (zh) * | 2011-11-23 | 2014-01-15 | 深圳翰宇药业股份有限公司 | 一种稳定的西曲瑞克药物组合物及其制备方法 |
| CN114159544A (zh) * | 2022-01-24 | 2022-03-11 | 福州华为医药技术开发有限公司 | 注射用醋酸西曲瑞克及其制备方法 |
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