CN1486181A - 过氧化脂质降低剂组合物 - Google Patents

过氧化脂质降低剂组合物 Download PDF

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CN1486181A
CN1486181A CNA018218024A CN01821802A CN1486181A CN 1486181 A CN1486181 A CN 1486181A CN A018218024 A CNA018218024 A CN A018218024A CN 01821802 A CN01821802 A CN 01821802A CN 1486181 A CN1486181 A CN 1486181A
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大泽常起
高木郁夫
清水一平
近藤达仁
中山正人
鸟住保博
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Abstract

本发明提供一种优良的血液中过氧化脂质降低剂。具体地说,提供一种血液中过氧化脂质降低剂组合物,其含有普伐他汀以及选自牛磺酸、泛硫乙胺和烟酸肌醇酯中的1种以上物质。根据本发明,能够提供一种可以降低血液中过氧化脂质浓度的优良的预防或治疗剂,其中,该血液中的过氧化脂质具有血管内皮细胞障碍、血小板凝聚亢进、泡沫细胞形成等作用。

Description

过氧化脂质降低剂组合物
技术领域
本发明涉及一种血液中过氧化脂质降低剂组合物,其含有普伐他汀以及选自牛磺酸、泛硫乙胺和烟酸肌醇酯中的1种以上物质。
背景技术
过氧化脂质在血液中浓度增加时,具有引起动脉硬化的血管内皮细胞障碍、血小板凝聚亢进、泡沫细胞形成等作用,因此,过氧化脂质降低剂是有用的药物。
普伐他汀是在生物体内通过抑制HMG-CoA还原酶从而具有降低血液中总胆固醇量的作用的药物,但是还不知道其具有降低血液中过氧化脂质的作用。
另一方面,已知牛磺酸和泛硫乙胺具有降低血液中过氧化脂质的作用,尽管这种作用较弱(文献:含硫氨基酸,Vol.7 No.1 1984p.201-205以及Geriatr.Med.,Vol.19 No.3 1981 p.415-422)。
另外,对于烟酸肌醇酯,还不知道降低血液中过氧化脂质的作用。
发明公开
本发明涉及一种血液中过氧化脂质降低剂组合物,其含有普伐他汀以及选自牛磺酸、泛硫乙胺和烟酸肌醇酯中的1种以上物质。
本发明人对降低血液中过氧化脂质的组合物进行了悉心研究,结果发现通过并用普伐他汀以及牛磺酸、泛硫乙胺或烟酸肌醇酯,能够显著降低血液中过氧化脂质,从而完成了本发明。
普伐他汀(化学名:(+)-(3R,5R)-3,5-二羟基-7-[(1S,2S,6S,8S,8aR)-6-羟基-2-甲基-8-[(S)-2-甲基丁酰氧基]-1,2,6,7,8,8a-六氢-1-萘基]庚酮)是下式表示的化合物及其盐(特别是钠盐),其制备方法在特开昭57-2240号等中有记载,由于有市售品,因而能够容易得到。
Figure A0182180200041
血液中的过氧化脂质是存在于血液中的过氧化脂质,例如包括过氧化LDL(低密度脂蛋白)等。
血液中过氧化脂质降低剂的“降低”是指临床上有意义地降低。
本发明的血液中过氧化脂质降低剂组合物在固体制剂的场合,含有的普伐他汀的重量%通常为0.01-5%,优选0.05-0.03%,另外,牛磺酸的重量%通常为0.3-50%,优选1-25%,而且,泛硫乙胺的重量%通常为1.3-50%,优选2.7-20%,另外,烟酸肌醇酯的重量%通常为0.05-50%,优选0.5-25%。
本发明的血液中过氧化脂质降低剂组合物在液体制剂的场合,含有的普伐他汀的含量通常为1-100mg/mL,优选3-7mg/mL,另外,牛磺酸的含量通常为2.5-50mg/mL,优选8-35mg/mL,而且,泛硫乙胺的含量通常为1-200mg/mL,优选5-100mg/mL,另外,烟酸肌醇酯的含量通常为1-40mg/mL,优选2-20mg/mL。
作为本发明的血液中过氧化脂质降低剂组合物的具体剂型,例如片剂、细粒剂(包括散剂)、胶囊、液体制剂等,可以适当使用适于各种剂型的添加剂或基质,根据日本药典等记载的常规方法进行制备。
上述各种剂型中,根据其剂型,也可以使用通常使用的各种添加剂。
例如,片剂的场合,可以使用乳糖、结晶纤维素等作为赋形剂,使用偏硅酸铝酸镁等作为稳定剂,使用羟丙基纤维素等作为粘合剂,使用硬脂酸镁等作为润滑剂。
细粒剂和胶囊剂的场合,可以使用乳糖、精制蔗糖等作为赋形剂,使用偏硅酸铝酸镁等作为稳定剂,使用玉米淀粉等作为吸附剂,使用羟丙基纤维素、聚山梨醇酯等作为粘合剂。
液体制剂的场合,可以使用I-山梨糖醇溶液、蜂蜜等作为甜味剂,使用d1-苹果酸等作为矫味剂,使用乙二胺四乙酸钠等作为稳定剂,使用乙醇等作为溶解助剂,使用硬脂酸聚氧乙烯硬化蓖麻油60等作为增溶剂。
上述各种剂型中,根据需要,也可以添加交联聚维酮等崩解剂,硅酸钙等吸附剂,三氧化二铁、焦糖等着色剂,苯甲酸钠等pH调节剂,香料。
发明的最佳实施方式
下面例举实施例进一步详细说明本发明,但本发明并不受这些实施例的限定。
实施例1片剂
(1)成分
表1
                            <牛磺酸>            <泛硫乙胺>          <烟酸肌醇酯>
                            4片中               4片中               4片中
                            (680mg)             (1440mg)            (1400mg)
普伐他汀钠                  20mg                20mg                20mg
牛磺酸                      500mg               -                   -
泛硫乙胺                    -                   500mg               -
烟酸肌醇酯                  -                   -                   500mg
结晶纤维素                  120mg               12mg                12mg
偏硅酸铝酸镁                144mg               -                   -
蔗糖脂肪酸酯                -                   140mg               140mg
羟丙基纤维素                96mg                48mg                96mg
硬脂酸镁                    24mg                24mg                24mg
交联聚维酮                  100mg               48mg                100mg
乳糖                        适量                适量                适量
(2)制法
按上述各成分的量,量取上述成分,按照日本药典制剂总则“片剂”一项制备片剂。
实施例2细粒剂
(1)成分
表2
                            <牛磺酸>           <泛硫乙胺>           <烟酸肌醇酯>
                            4包中              4包中                4包中
                            (4g)               (5.2g)               (5g)
普伐他汀钠                  20mg               20mg                 20mg
牛磺酸                      500mg              -                    -
泛硫乙胺                    -                  1000mg
烟酸肌醇酯                  -                  -                    1000mg
精制蔗糖                    1400mg             1600mg               1400mg
斯特维亚菊                  -                  16mg                 16mg
(Stevia)提取物
玉米淀粉                    1200mg             1200mg               1200mg
聚山梨醇酯80                80mg               48mg                 80mg
偏硅酸铝酸镁                144mg              -                    144mg
硬脂酸镁                    24mg               24mg                 24mg
乳糖                        适量               适量                 适量
(2)制法
按上述各成分的量,量取上述成分,按照日本药典制剂总则“颗粒剂”一项制备颗粒剂。
实施例3胶囊剂
(1)成分
表3
                            <牛磺酸>           <泛硫乙胺>          <烟酸肌醇酯>
                            4胶囊中            8胶囊中             8胶囊中
普伐他汀钠                  20mg               20mg                20mg
牛磺酸                      500mg              -                   -
泛硫乙胺                    -                  500mg               -
烟酸肌醇酯                  -                  -                   500mg
玉米淀粉                    960mg              960mg               960mg
聚山梨醇酯80                80mg               48mg                80mg
偏硅酸铝酸镁                144mg              -                   144mg
硬脂酸镁                    24mg               24mg                24mg
乳糖                        适量               适量                适量
小计                        1520mg             1940mg              2000mg
胶囊                        320mg              640mg               640mg
合计                        1840mg             2580mg              2640mg
(2)制法
按上述各成分的量,量取上述成分,按照日本药典制剂总则“颗粒剂”一项制备细粒剂,然后填充至胶囊中,制得硬胶囊剂。
实施例4液体制剂
(1)成分
表4
                             <牛磺酸>             <泛硫乙胺>      <烟酸肌醇酯>
                             100mL中              100mL中         100mL中
普伐他汀钠                   20mg                 20mg            20mg
牛磺酸                       500mg                -               -
泛硫乙胺                     -                    500mg
烟酸肌醇酯                   -                    -               500mg
D-山梨糖醇溶液(70%)         4g                   6g              4g
蜂蜜                         7g                   8g              7g
d1-苹果酸                    200mg                -               200mg
乙二胺四乙酸钠               20mg                 20mg            20mg
乙醇                         2mL                  2mL             2mL
硬脂酸聚氧乙烯硬化           100mg                100mg           100mg
蓖麻油60
苯甲酸钠                     60mg                 60mg            60mg
香料                         微量                 微量            微量
蒸馏水                       适量                 适量            适量
(2)制法
按上述各成分的量,量取上述成分,按照日本药典制剂总则“液体制剂”一项制备液体制剂。
试验方法
(1)被测物质
普伐他汀使用三共株式会社的纯度99.4%的产品。
牛磺酸、泛硫乙胺和烟酸肌醇酯分别采购和使用NacalaiTesque、第一制药、白鸟制药制的产品。
(2)试验动物
作为试验动物,由Covance Research Products Inc.购入5月龄的雄性小猎犬(Beagle),经过约1个月的检疫和驯化饲养后使用。
(3)给药剂型、制剂的配制方法和制剂的保存方法
在由TORPAC公司购入的明胶胶囊(1/2盎司)中填充根据各试验动物各自的体重计算出的必要量的普伐他汀或各种配合剂。另外,普伐他汀填充后的胶囊在冷藏下保存至给药前,填充配合剂的胶囊在室温下保存至给药前。
另外,配合剂的场合,填充至相同的明胶胶囊中。
(4)给药途径和给药期间
将填充有普伐他汀或配合剂的胶囊每日1次在9:00~12:30之间强制口服给与试验动物。另外,试验动物在给药前2至3小时断食。
给药期间为11天。
(5)被测试样的配制和试验方法
在给与胶囊前-3或-4天(给药开始前第1周)、给药第4天和第8天由头静脉取血约10mL。另外,取血前约18小时,使试验动物断食。将得到的血液收集在试管中,室温下放置30分钟至1小时后,离心分离(3000rpm,10分钟),使用得到的血清,采用八木法测定血液中的过氧化脂质量。
另外,过氧化脂质量的测定中,使用日立制作所社的荧光光度计F3000。
试验结果
以给药2周以及1周前血液中过氧化脂质量的平均值为100,换算求出普伐他汀与牛磺酸、泛硫乙胺和烟酸肌醇酯各自的给药量的单剂以及配合剂的血液中过氧化脂质量。各数值为1组5只的平均值。
(普伐他汀与牛磺酸的联用效果)
表5
被测物质                         血液中的过氧化脂质量
(mg/kg)                         给药后4天     给药后8天
普伐他汀单剂(2)                 110.8         116.2
牛磺酸单剂(1000)                95.8          93.8
普伐他汀(2)+牛磺酸(1000)        89.9          77.5
(普伐他汀与泛硫乙胺的联用效果)
表6
被测物质                            血液中的过氧化脂质量
(mg/kg)                           给药后4天      给药后8天
普伐他汀单剂(2)                   110.8          116.2
泛硫乙胺单剂(300)                 82.5           105.0
普伐他汀(2)+牛磺酸(300)           83.6           75.4
(普伐他汀与烟酸肌醇酯的联用效果)
表7
被测物质                            血液中的过氧化脂质量
(mg/kg)                           给药后4天      给药后8天
普伐他汀单剂(2)                   110.8          116.2
烟酸肌醇酯单剂(400)               98.5           96.5
普伐他汀(2)+烟酸肌醇酯(400)       83.8           81.3
工业实用性
本发明的普伐他汀与牛磺酸、泛硫乙胺或烟酸肌醇酯组合而成的组合物具有优良的降低血液中过氧化脂质的作用,因此作为血液中过氧化脂质降低剂有用。

Claims (1)

1.一种血液中过氧化脂质降低剂组合物,其含有普伐他汀以及选自牛磺酸、泛硫乙胺和烟酸肌醇酯中的1种以上物质。
CNB018218024A 2000-11-07 2001-11-05 过氧化脂质降低剂组合物 Expired - Fee Related CN1240379C (zh)

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TWI284529B (en) * 2000-12-18 2007-08-01 Sankyo Co A composition for lowering triglyceride
JP2006509722A (ja) * 2002-07-03 2006-03-23 エスペリオン セラピューティクス,インコーポレイテッド 脂質代謝異常を治療するためのパンテチン含有組成物
US20050192347A1 (en) * 2003-12-23 2005-09-01 Dasseux Jean-Louis H. Urea and thiourea compounds and compositions for cholesterol management and related uses
JP5080011B2 (ja) * 2005-02-28 2012-11-21 第一三共ヘルスケア株式会社 グルタチオンペルオキシダーゼ活性を増加させるための組成物
EP2114151A4 (en) * 2007-03-01 2010-03-17 Concourse Health Sciences Llc INOSITOL NIACINATE ISOMERS AND USES THEREOF
US10874625B2 (en) * 2009-11-02 2020-12-29 Plant Sensory Systems, Llc Methods for the biosynthesis of taurine or hypotaurine in cells
WO2011053764A2 (en) * 2009-11-02 2011-05-05 Plant Sensory Systems, Llc Method for the biosynthesis of taurine or hypotaurine in cells

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JPS6019891B2 (ja) 1978-12-01 1985-05-18 第一製薬株式会社 薬物性脂肪肝用剤
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JPS5869813A (ja) 1981-10-23 1983-04-26 Sogo Yatsukou Kk 血清脂質低下剤
JPS6041611A (ja) 1983-08-17 1985-03-05 Sankyo Co Ltd 血中脂質低下剤
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US6916849B2 (en) 2000-10-23 2005-07-12 Sankyo Company, Limited Compositions for improving lipid content in the blood

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CA2428204A1 (en) 2002-05-16
US20030229124A1 (en) 2003-12-11
HK1061978A1 (en) 2004-10-15
CN1240379C (zh) 2006-02-08
AU2002211005A1 (en) 2002-05-21
US6998422B2 (en) 2006-02-14
WO2002038151A1 (fr) 2002-05-16
TWI285105B (en) 2007-08-11

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