CN102151271A - 四氢叶酸的天然立体异构体在制备药物制剂中的用途 - Google Patents
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Abstract
本发明涉及四氢叶酸的天然立体异构体在制备用于调节同型半胱氨酸水平,尤其是促进同型半胱氨酸再甲基化的药物制剂中的用途。其临床应用范围包括同型半胱氨酸水平的所有异常情况,尤其是预防和治疗心血管疾病,及预防神经管营养缺乏症。本发明还涉及这样的药物制剂,尤其是在缺乏亚甲基四氢叶酸还原酶的情况下,如存在热不稳定性的亚甲基四氢叶酸还原酶时,四氢叶酸与药学上相容的活性物质和辅剂一同用于调节同型半胱氨酸的水平。
Description
本申请是申请号为98102983.3、申请日为1998年6月12日、发明名称为“四氢叶酸的天然立体异构体在制备药物制剂中的用途”的中国专利申请的分案申请。
技术领域
本发明涉及四氢叶酸的天然立体异构体在制备用于调节同型半胱氨酸水平,尤其是促进半胱氨酸再甲基化的药物制剂中的用途。其临床应用范围包括同型半胱氨酸水平的所有异常情况,尤其是预防和治疗心血管疾病,及预防神经管营养缺乏症。
本申请文件中的“四氢叶酸的天然立体异构体”代表5-甲酰-(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸或(6S)-四氢叶酸,或其药学上相容的盐。
背景技术
作为药物,四氢叶酸迄今主要以5-甲酰-5,6,7,8-四氢叶酸(甲酰四氢叶酸)或5-甲基-5,6,7,8-四氢叶酸的钙盐形式用于治疗巨成红细胞叶酸缺乏性贫血;作为癌症治疗中增进叶酸拮抗剂(尤其是氨基喋呤和氨甲喋呤)相容性的解毒剂(抗叶酸救助剂);用于增强氟化嘧啶的疗效;用于治疗牛皮癣和类风湿性关节炎等自身免疫疾病;用于增进某些抗寄生虫药-如三甲氧苄二氨嘧啶-磺胺甲恶唑-的相容性以及用于降低化疗中双去氮杂(dideaza)-四氢叶酸的毒性。
同型半胱氨酸是由蛋氨酸去甲基化形成的一种含有硫醇的氨基酸。在体液中,同型半胱氨酸以二硫化物(同型胱氨酸)、混合二硫化物和环氧产物(同型半胱氨酸硫代内酯)等氧化态存在。
高同型半胱氨酸血症是一种可以有各种先天的或后天的原因引起的临床疾病。这种疾病导致同型半胱氨酸在血液和尿液中的浓度增加。
高同型半胱氨酸血症的最常见类型是由缺乏胱硫酮β-合成酶导致的,此酶存在于同型半胱氨酸经胱硫醚转化成半胱氨酸的B6依赖性的反硫化路径中。另一类型是由于缺乏5,10-亚甲基四氢叶酸还原酶导致的,此酶为同型半胱氨酸转化成蛋氨酸的B12-依赖性转化提供底物5-甲基-(6S)-四氢 叶酸。肾功能紊乱也会导致高同型半胱氨酸血症。在所有这些情况中,“高同型半胱氨酸血症”一词表示血液中同型半胱氨酸浓度暂时或持久的增加,并有时伴以同型半胱氨酸尿液分泌的增加。
高同型半胱氨酸血症导致一系列疾病,表现为严重的血管、眼、神经系统和骨骼系统的疾病。
各种临床研究已表明血清中同型半胱氨酸水平的增加与发生心血管疾病之间有明确关联。同型半胱氨酸血症被认为是心血管疾病中一项独立的危险因素。在K.L.Resch(ed.),Risikofaktor Homocystein Daten-Fakten-Strategien[Homocysteine Risk Factor-Data-Facts-Strategies],Gesellschaft fur Medizinische Information ISBN 3-9804536-0-X.中可以看到这方面综合的信息,关于高同型半胱氨酸血症与动脉硬化的相互关系可参考L.J.Fortin et al,临床生物化学,Vol.28(2),1995,pages 155-162。在J.L.Mills et al,Supplement Publication to the Ceres Forum on June 14,1995,1996pages 756S-760S记载了高同型半胱氨酸血症和神经管营养缺乏症。
四氢叶酸的天然立体异构体在制备用于调节同型半胱氨酸水平的药物制剂中的用途迄今既未被提出,也未见记载。
现已发现含有四氢叶酸天然立体异构体的药物制剂在调节四氢叶酸水平,尤其在促进同型半胱氨酸的再甲基化方面的用途。
四氢叶酸的天然立体异构体指5-甲酰-(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、10-甲酰-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸或(6S)-四氢叶酸的化合物,或其药学上相容的盐。一般在叶酸代谢中其还原型能相互转化,所以制剂中习惯使用还原型叶酸。然而,由于5-甲基-(6S)-四氢叶酸作为甲基供体直接参与由同型半胱氨酸生成蛋氨酸的甲基转移反应,所以优选5-甲基-(6S)-四氢叶酸和其药学上相容的盐。尤其是在缺乏亚甲基四氢叶酸还原酶时使用这种叶酸,缺乏这一酶意味着如功能受限或活性降低等疾病。在此应将热不稳定性亚甲基四氢叶酸还原酶的存在作为最常见的一种亚甲基四氢叶酸还原酶缺乏症提出。在这种情况下,四氢叶酸的转化是有限的,从而其只能有限地参与甲基化反应。
药学上相容的盐应既是药理学上相容同时药剂学上也相容。这些药理 学和药剂学相容的盐可以是碱金属盐或碱土金属盐,优选钠盐、钾盐、镁盐、钙盐。
“药物制剂”这一表达方式代表经肠的(如口服、舌下含服或直肠给药)、胃肠外的或经表皮(如透皮制剂)剂型。不与活性组分反应的有机或无机物可以作为载体,如水、油、苯甲醇、聚乙二醇、甘油三酯或其它脂肪酸甘油酯、明胶、卵磷脂、环糊精、乳二糖或淀粉等糖类、硬脂酸镁、滑石或纤维素。口服用药首选片剂、糖衣丸、胶囊粉、浓缩糖浆剂或滴剂,直肠给药首选栓剂,胃肠外给药首选水溶液或油溶液,或冻干剂。
也可以使用混悬剂、乳剂或植入剂,局部用药可以用贴剂或乳膏剂。
胃肠外使用的药物制剂包括具药学活性化合物的无菌含水或无水注射液,在此优选与受体血液等渗的溶液。
这些制剂可以含有稳定剂、控制具药学活性化合物释放的添加剂、抗氧剂、缓冲剂、抑菌剂和用于制备等渗溶液的辅剂。无菌含水和无水混悬剂可以含有混悬添加剂和增稠剂。药物制剂可以分装在单剂量或多剂量容器如密封针剂瓶中,也可以作为冻干制品保存,如需要,使用时可用无菌液体如水或盐溶液配制。可以以同样方式使用无菌粉剂、颗粒剂或片剂。另外,所有的药物制剂还可以含有单独起作用或具有协同作用的活性化合物。在此应注意维生素,尤其是B族维生素,如B6和/或B12,它们在这种应用中具有协同作用。在此,VB6每天可以使用1mg~20mg,优选1mg~6mg的常规剂量,每天使用6mg~20mg为高剂量应用。VB12每天可以使用的常规剂量为0.001mg~0.5mg,优选0.001mg~0.15mg,每天使用0.15mg~0.5mg为高剂量应用。
每剂量药物制剂含有0.001mg-1000mg活性组分。在预防用药时,优选使用每剂量含有5μg-1000μg活性组分的药物制剂。在治疗用药时,优选使用每剂量含有0.1mg-200mg活性组分的药物制剂。
药物使用剂量取决于治疗方式、制剂的剂型以及病人的年龄、体重、营养状况和病情。治疗可以从低于最佳剂量的低剂量开始,逐渐增加至达到最佳效果。预防用剂量可以优选在每日5μg~1000μg之间,尤其优选每日50μg~500μg。治疗的最佳剂量为每日0.1mg~100mg,尤其优选每日0.5mg~5mg。用药方法可以是单次给药或重复剂量给药。
实施例1
含有1mg 5-甲酰-(6S)-四氢叶酸的片剂
将13.3g 5-甲酰-(6S)-四氢叶酸钙盐五水合物(相当于10g 5-甲酰-(6S)-四氢叶酸)、4kg乳糖、1.2kg淀粉、0.2kg滑石和0.1kg硬脂酸镁的混合物压制成片剂,即得每片含有5-甲酰-(6S)-四氢叶酸1mg的片剂。
可将此片剂用薄膜包衣,或粉碎装入胶囊。
实施例2
含有60mg 5-甲基-(6S)-四氢叶酸的栓剂
将5-甲基-(6S)-四氢叶酸钙盐五水合物632g(相当于5-甲基-(6S)-四氢叶酸500g)、羟丙基纤维素50g和半合成甘油酯2kg的混合物熔化制成栓剂,即得每粒含有5-甲基-(6S)-四氢叶酸500mg的栓剂。
实施例3
含有0.5mg 5-甲基-(6S)-四氢叶酸的注射液
将5-甲基-(6S)-四氢叶酸0.5g、谷胱甘肽10g、柠檬酸30g、甘露醇160g、甲基-对-羟基苯甲酸1g和氢氧化钠17.7g(或保持溶液pH7.3~7.8所需的量),溶于3升注射用水中,并灌封于针剂瓶中,即得每支含5-甲基-(6S)-四氢叶酸0.5mg的注射剂。
实施例4
含有1mg(6S)-四氢叶酸的注射用冻干剂
将(6S)-四氢叶酸钠盐1g溶于1000ml双蒸水中制得的溶液经过无菌过滤灌封于针剂瓶中并冻干,即得每支含(6S)-四氢叶酸1mg的注射剂。
四氢叶酸对氧非常敏感,因此必须严格控制在无氧状态下操作。使用如抗坏血酸的抗氧剂或许是必要的。
实施例5
含20mg 5,10-亚甲基-(6R)-四氢叶酸的注射用冻干剂
将5,10-亚甲基-(6R)-四氢叶酸钠盐的β-羟丙基环糊精包含物10g溶于2000ml双蒸水中制得的溶液,经过无菌过滤灌封于针剂瓶中,即得每支含5,10-亚甲基-(6R)-四氢叶酸20mg的注射剂。
对5,10-亚甲基-四氢叶酸采用与四氢叶酸相同的防氧化措施(实施例4)。
实施例6
含有0.4mg 5-甲酰-(6S)-四氢叶酸的片剂
将5.32g 5-甲酰-(6S)-四氢叶酸钙盐五水合物(相当于4g 5-甲酰-(6S)-四氢叶酸)、4kg乳糖、1.2kg淀粉,0.2kg滑石和0.1kg硬脂酸镁的混合物压制成片剂,即得每片含有5-甲酰-(6S)-四氢叶酸4mg的片剂。
可将此片剂用薄膜包衣,或粉碎装入胶囊。
实施例7
含有10μg 5-甲基-(6S)-四氢叶酸的注射用冻干剂
将10mg 5-甲基-(6S)-四氢叶酸钠盐溶于1000ml双蒸水中制得的溶液,在惰性气体条件下经过无菌过滤灌封于针剂瓶中并冻干,即得每支含5-甲基-(6S)-四氢叶酸10μg的注射剂。
四氢叶酸对于氧气非常敏感,因此必须严格控制在无氧状态下操作。使用如抗坏血酸的抗氧剂或许是必要的。
实施例8
含有15mg 5-甲基-(6S)-四氢叶酸的片剂
将19.18g 5-甲基-(6S)-四氢叶酸钙盐五水合物(相当于15g 5-甲基-(6S)-四氢叶酸)、120g乳糖、21.5g玉米淀粉、7.08g乙酰纤维素、2.28g邻苯二甲酸二乙酯、0.64g硅氧烷HK-15和2g硬脂酸镁的混合物压制成片剂,即得每片含有5-甲基-(6S)-四氢叶酸15mg的片剂。
可将此片剂用薄膜包衣,或粉碎装入胶囊。
实施例9
含有15mg 5-甲基-(6S)-四氢叶酸的片剂
按与实施例8类似的方法,用玉米淀粉、乳糖、硬脂酸镁、聚乙二醇6000、聚甲基丙烯酸酯、聚山梨醇80、二甲基聚硅氧烷、氢氧化钠和滑石制成每片含有5-甲基-(6S)-四氢叶酸15mg的片剂。
实施例10
含有5-甲基-(6S)-四氢叶酸、维生素B6和B12的联合制剂
按配方制备含有如下组分的口服薄膜片剂:
0.4mg 5-甲基-(6S)-四氢叶酸
3mg 维生素B6
0.002mg 维生素B12
药学相容的辅剂
此联合制剂可以制成溶液,如胃肠外给药的溶液剂。
Claims (9)
1.四氢叶酸的天然立体异构体在制备用于调节同型半胱氨酸水平的药物制剂中的用途。
2.四氢叶酸的天然立体异构体在制备用于预防和治疗心血管疾病的药物制剂中的用途。
3.四氢叶酸的天然立体异构体在制备用于预防神经管营养缺乏症的药物制剂中的用途。
4.根据权利要求1-3所述的四氢叶酸的天然立体异构体的用途,其特征在于5-甲酰-(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、10-甲酰-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸或(6S)-四氢叶酸的化合物,或其药学上相容的盐可用作四氢叶酸。
5.根据权利要求1-3所述的四氢叶酸的天然立体异构体的用途,其特征在于5-甲基-(6S)-四氢叶酸或其药学上相容的盐可用作四氢叶酸。
6.根据权利要求1-3所述的四氢叶酸的天然立体异构体的用途,其特征在于5-甲基-(6S)-四氢叶酸或其药学上相容的盐可用作四氢叶酸,在缺乏亚甲基四氢叶酸还原酶的情况下使用。
7.根据权利要求1-3所述的四氢叶酸的天然立体异构体的用途,其特征在于5-甲基-(6S)-四氢叶酸或其药学上相容的盐可用作四氢叶酸,当存在热不稳定性的亚甲基四氢叶酸还原酶时使用。
8.一种调节同型半胱氨酸水平的药物制剂,其特征在于其含有至少一种选自5-甲酰-(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、10-甲酰-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸或(6S)-四氢叶酸的化合物,或其药学上相容的盐作为活性成分,同时含有药学上相容的活性物质和辅剂。
9.一种在存在热不稳定性亚甲基四氢叶酸还原酶时用于调节同型半胱氨酸水平的药物制剂,其特征在于其含有5-甲酰-(6S)-四氢叶酸或其药学上相容的盐作为活性成分,同时含有药学上相容的活性物质和辅剂。
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CH01456/97A CH693255A5 (de) | 1997-06-13 | 1997-06-13 | Verwendung von Tetrahydrofolaten in der natürlichenstereoisomeren Form zur Herstellung einer pharmazeutischenZubereitung geeignet zur Beeinflussung des Homocystein-Spiegels. |
CH1456/97 | 1997-06-13 |
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CN 98102983 Division CN1205206A (zh) | 1997-06-13 | 1998-06-12 | 四氢叶酸的天然立体异构体在制备药物制剂中的用途 |
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US (1) | US6011040A (zh) |
EP (2) | EP0898965B9 (zh) |
JP (1) | JPH11116482A (zh) |
CN (1) | CN102151271A (zh) |
AT (2) | ATE538793T1 (zh) |
AU (1) | AU739544B2 (zh) |
CA (1) | CA2240571C (zh) |
CH (1) | CH693255A5 (zh) |
DE (1) | DE59813465D1 (zh) |
DK (2) | DK1685840T3 (zh) |
ES (2) | ES2376472T3 (zh) |
PT (2) | PT898965E (zh) |
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- 1998-06-05 EP EP06006085A patent/EP1685840B1/de not_active Expired - Lifetime
- 1998-06-05 DK DK06006085.2T patent/DK1685840T3/da active
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- 1998-06-05 DK DK98110302T patent/DK0898965T3/da active
- 1998-06-05 AT AT98110302T patent/ATE321555T1/de active
- 1998-06-05 PT PT98110302T patent/PT898965E/pt unknown
- 1998-06-05 ES ES98110302T patent/ES2262202T3/es not_active Expired - Lifetime
- 1998-06-05 PT PT06006085T patent/PT1685840E/pt unknown
- 1998-06-05 DE DE59813465T patent/DE59813465D1/de not_active Expired - Lifetime
- 1998-06-08 TW TW087109073A patent/TW474812B/zh not_active IP Right Cessation
- 1998-06-10 JP JP10162405A patent/JPH11116482A/ja active Pending
- 1998-06-10 RU RU98111617/15A patent/RU2226099C2/ru not_active IP Right Cessation
- 1998-06-11 US US09/095,572 patent/US6011040A/en not_active Expired - Lifetime
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Also Published As
Publication number | Publication date |
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AU7007998A (en) | 1998-12-17 |
EP1685840A3 (de) | 2010-06-02 |
ATE538793T1 (de) | 2012-01-15 |
DK1685840T3 (da) | 2012-04-10 |
AU739544B2 (en) | 2001-10-18 |
JPH11116482A (ja) | 1999-04-27 |
EP0898965A3 (de) | 2000-11-15 |
DE59813465D1 (de) | 2006-05-18 |
EP0898965A2 (de) | 1999-03-03 |
ES2376472T3 (es) | 2012-03-14 |
EP0898965B9 (de) | 2006-08-09 |
TW474812B (en) | 2002-02-01 |
DK0898965T3 (da) | 2006-07-31 |
CA2240571C (en) | 2006-08-08 |
RU2226099C2 (ru) | 2004-03-27 |
ATE321555T1 (de) | 2006-04-15 |
ZA985129B (en) | 1998-12-14 |
CA2240571A1 (en) | 1998-12-13 |
EP1685840A2 (de) | 2006-08-02 |
PT898965E (pt) | 2006-08-31 |
PT1685840E (pt) | 2012-02-09 |
US6011040A (en) | 2000-01-04 |
EP1685840B1 (de) | 2011-12-28 |
CH693255A5 (de) | 2003-05-15 |
ES2262202T3 (es) | 2006-11-16 |
EP0898965B1 (de) | 2006-03-29 |
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