CN1489461A - 甘油三酸酯降低剂组合物 - Google Patents

甘油三酸酯降低剂组合物 Download PDF

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CN1489461A
CN1489461A CNA018226949A CN01822694A CN1489461A CN 1489461 A CN1489461 A CN 1489461A CN A018226949 A CNA018226949 A CN A018226949A CN 01822694 A CN01822694 A CN 01822694A CN 1489461 A CN1489461 A CN 1489461A
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pravastatin
ascorbic acid
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triglyceride
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大泽常起
夫
高木郁夫
平
清水一平
仁
近藤达仁
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中山正人
博
鸟住保博
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Sankyo Co Ltd
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Abstract

本发明涉及一种血中甘油三酸酯降低剂组合物，该组合物含有普伐他汀，和选自①双泛酰硫乙胺、②烟酸肌醇酯、③含核黄素化合物、生育酚化合物和抗坏血酸化合物的合剂以及④含生育酚化合物和抗坏血化合物的合剂中的1种或2种以上。

Description

甘油三酸酯降低剂组合物
                       技术领域
本发明涉及血中甘油三酸酯降低剂组合物，该组合物含有普伐他汀(pravastatin)，和选自①双泛酰硫乙胺、②烟酸肌醇酯、③由核黄素类、生育酚类和抗坏血酸类构成的合剂以及④由生育酚类和抗坏血酸类构成的合剂中的1种或2种以上。
                         背景技术
血中甘油三酸酯值与动脉硬化性疾病的关系，还没有达到像血中胆固醇与冠状动脉硬化性疾病之间看到那样的明确的关联性的确定。但是，在临床上已经弄清楚的是，血中甘油三酸酯作为动脉硬化性疾病的危险因素的重要性，而且还弄清楚了，难度高甘油三酸酯血脂症会引起胰岛素阻抗性，以及与动脉硬化的深渊关系(文献：例如，ModernPhysician，Vol.18 No.11998，p.53-56和p.69-71)。
另一方面，普伐他汀是具有通过在生物体中阻碍HMG-CoA还原酶，而使血中胆固醇总量降低的作用的药物，而且也已知道还具有降低血中甘油三酸酯量的作用。
另外已知，双泛酰硫乙胺、烟酸肌醇酯、核黄素类·生育酚类·抗坏血酸类的合剂和生育酚类·抗坏血酸类的合剂，分别具有降低血中甘油三酸酯值的作用。
然而不知道，通过并用普伐他汀、和双泛酰硫乙胺、烟酸肌醇酯、核黄素类·生育酚类·抗坏血酸类的合剂以及生育酚类·抗坏血酸类的合剂，而协同地降低血中甘油三酸酯量。
                         发明内容
本发明人，对于减少血中甘油三酸酯量的组合物，继续深入研究的结果发现，通过将普伐他汀，与选自①双泛酰硫乙胺、②烟酸肌醇酯、③由核黄素类、生育酚类和抗坏血酸类构成的合剂以及④由生育酚类和抗坏血类构成的合剂中的1种或2种以上并用，可使血中甘油三酸酯量显著下降，于是完成了本发明。
本发明涉及的是血中甘油三酸酯降低剂组合物，该组合物含有普伐他汀，和选自①双泛酰硫乙胺、②烟酸肌醇酯、③由核黄素类、生育酚类和抗坏血酸类构成的合剂以及④由生育酚类和抗坏血类构成的合剂中的1种或2种以上。
这些当中可以优选举出的有，由普伐他汀与双泛酰硫乙胺构成的血中甘油三酸酯降低剂组合物，由普伐他汀与烟酸肌醇酯构成的血中甘油三酸酯降低剂组合物，由普伐他汀与烟酸肌醇酯构成的血中甘油三酸酯降低剂组合物，由普伐他汀与核黄素类·生育酚类·抗坏血酸类的合剂构成的血中甘油三酸酯降低剂组合物，或者，由普伐他汀与育酚类·抗坏血类的合剂构成的血中甘油三酸酯降低剂组合物。
所说的普伐他汀(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)，指的是用下式表示的化合物及其盐(特别是钠盐)，其制造方法，在特开昭57-2240号等中有记载，而且市场上有售，所以容易得到。
所说的烟酸肌醇酯，指的是肌醇中存在的6个羟基用烟酸酯化了的化合物。
所说的核黄素类，指的是核黄素和核黄素酯例如丁酸核黄素酯，优选的可举出，核黄素、磷酸核黄素钠、丁酸核黄素酯、黄素腺嘌呤二核苷酸、或黄素腺嘌呤二核苷酸钠，更优选的可举出，磷酸核黄素钠或丁酸核黄素酯，特别优选的可举出丁酸核黄素酯。
所说的生育酚类，指的是，生育酚(外消旋体和旋光物)、生育酚酯如乙酸生育酚酯(外消旋体和旋光物)，优选的可举出，琥珀酸d-α-生育酚酯、琥珀酸dl-α-生育酚酯、琥珀酸dl-α-生育酚钙、乙酸d-α-生育酚酯、乙酸dl-α-生育酚酯、d-α-生育酚或dl-α-生育酚，更优选的可举出，琥珀酸dl-α-生育酚酯或乙酸d-α-生育酚酯，特别优选的可举出乙酸d-α-生育酚酯。
所说的抗坏血酸类，指的是，抗坏血酸、抗坏血酸钠盐之类的抗坏血酸盐以及抗坏血酸硬脂酸酯之类的抗坏血酸酯，优选的可举出，抗坏血酸、抗坏血酸钠或抗坏血酸钙，更优选的可举出抗坏血酸。
所说的血中甘油三酸酯量，指的是血中存在的中性脂肪的总量。
所说的血中甘油三酸酯量降低剂的「降低」，指的是降低到临床上有意义的程度。
本发明的血中甘油三酸酯降低剂组合物在固态制剂的场合所含的普伐他汀的重量％，通常是0.01～5％，优选的是0.05～3％，另外，双泛酰硫乙胺的重量％，通常是0.5～50％，优选的是1.0～25％，另外，核黄素类的重量％，通常是0.002～40％，优选的是0.01～20％，再有，抗坏血酸类的重量％，通常是0.05～50％，优选的是0.5～25％，另外还有，生育酚类的重量％，通常是0.002～40％，优选的是0.02～20％，烟酸肌醇酯的重量％，通常是0.05～50％，优选的是0.5～25％。
本发明的血中甘油三酸酯降低剂组合物在液态制剂的场合所含的普伐他汀的含量，通常是0.01～10mg/mL，优选的是0.05～5mg/mL，另外，双泛酰硫乙胺的含量，通常是0.5～10mg/mL，优选的是1～5mg/mL，另外，核黄素类的含量，通常是0.05～5mg/mL，优选的是0.1～3mg/mL，再有，抗坏血酸类的含量，通常是1～10mg/mL，优选的是3～7mg/mL，另外还有，生育酚类的含量，通常是0.5～5mg/mL，优选的是1.5～3mg/mL，烟酸肌醇酯的含量，通常是1～40mg/mL，优选的是2～20mg/mL。
作为本发明的血中甘油三酸酯降低剂组合物的具体剂型，例如，可举出，片剂、细粒剂(含散剂)、胶囊、液剂等，可适当使用适于各种剂型的添加剂和基材，并按照日本药典等中记载的通常的方法进行制造。
在上述各剂型中，根据其剂型，可以使用通常使用的各种添加剂。
例如，在片剂的场合，可以使用，乳糖、结晶纤维素等作为赋型剂，硅铝酸镁等作为稳定剂，羟丙基纤维素等作为粘合剂，硬脂酸镁等作为润滑剂。
在细粒剂和胶囊剂的场合，可以使用，乳糖、精制白糖等作为赋型剂，硅铝酸镁(Magnesium alumino metasillicate)等作为稳定剂，玉米淀粉等作为吸附剂，羟丙基纤维素、聚山梨醇酯等作为粘合剂。
液剂的场合，可以使用，D-山梨糖醇液、蜂蜜等作为甜味剂，dl-苹果酸等作为矫味剂，依地酸钠(disodium dihydrogenethylenediamine tetraacetate)等作为稳定剂，乙醇等作为溶解助剂，硬脂酸聚氧化乙烯固化蓖麻油60等作为增溶剂。
在上述各剂型中，可根据需要添加交联聚乙烯吡咯酮等分解剂，硅酸钙等吸附剂，三氧化二铁、焦糖等着色剂，安息香酸钠等pH调解剂，香料。
将本发明中的组合物给药时，对组合物的各成分可以同时给药，或者，间隔时间地分别给药。
上面所说的「同时」给药，只要是能在大致相同的时间给药的给药方式即可，没有特别的限定，但是以单一的组合物的方式给药是优选的。
另外，上面所说的「间隔时间地分别」给药，只要是能在不同的时间分别地给药的给药方式即可，没有特别的限定，例如，可以举出，将1个成分给药，接着在规定的时间后，将其他成分给药的方法。
另外，给药的组合物成分，合起来有3种以上时，所说的「同时地，或者，间隔时间地分别」给药，包括以下的方法：将全部成分同时给药的方法，各成分间隔时间地分别给药的方法，将2种以上成分同时给药，间隔时间将剩余的药剂给药的方法，或者，将2种以上成分间隔时间地给药，将剩余的药剂同时给药的方法等。
                   实施发明的最隹方案
下面举出实施例等，更详细地说明本发明，但本发明并不限于这些实施例。
(实施例1)片剂
(1)成分
表1
                      <核黄素·抗坏血酸·生育酚>  <双泛酰硫乙胺>
                                4片中                 4片中
                                (1600mg)              (1440mg)
普伐他汀钠                      20mg                  20mg
丁酸核黄素酯                    12mg                  -
抗坏血酸                        500mg                 -
琥珀酸dl-α-生育酚酯            200mg                 -
双泛酰硫乙胺                    -                     500mg
结晶纤维素                      120mg                 12mg
硅铝酸镁                        144mg                 -
蔗糖脂肪酸酯                    -                     140mg
羟丙基纤维素                    96mg                  48mg
硬脂酸镁                        24mg                  24mg
交联聚乙烯吡咯酮                100mg                 48mg
(クロスポピドン)
乳糖                            适量                  适量
表2
                     <烟酸肌醇酯>      <抗坏血酸+生育酚>
                        4片中             4片中
                        (1400mg)          (1400mg)
普伐他汀钠              20mg              20mg
烟酸肌醇酯              500mg             -
抗坏血酸                -                 500mg
琥珀酸dl-α-生育酚酯    -                 200mg
结晶纤维素              12mg              12mg
蔗糖脂肪酸酯            140mg             140mg
羟丙基纤维素            96mg              48mg
硬脂酸镁                24mg              24mg
交联聚乙烯吡咯酮        100mg             48mg
乳糖                    适量              适量
(2)制法
取上述成分及用量，按照日本药典制剂总则「片剂」项制备片剂。
(实施例2)细粒剂
(1)成分
表3
                      <核黄素·抗坏血酸·生育酚>   <双泛酰硫乙胺>
                                4包中                 4包中
                                (5.5g)                (5.2g)
普伐他汀钠                      20mg                  20mg
丁酸核黄素酯                    12mg                  -
抗坏血酸                        1.0g                  -
琥珀酸dl-α-生育酚酯            200mg                 -
双泛酰硫乙胺                    -                     500mg
精制白糖                        1.4g                  1.6g
斯特维亚菊萃取生成物            -                     16mg
玉米淀粉                        1.2g                  1.2g
聚山梨醇酯80                    80mg                  48mg
硅铝酸镁                        144mg                 -
硬脂酸镁                        24mg                  24mg
乳糖                            适量                  适量
表4
                      <烟酸肌醇酯>    <抗坏血酸+生育酚>
                          4包中             4包中
                          (5g)              (5g)
普伐他汀钠                20mg              20mg
烟酸肌醇酯                1000mg            -
抗坏血酸                  -                 1000mg
琥珀酸dl-α-生育酚酯      -                 200mg
精制白糖                  1400mg            1600mg
斯特维亚菊萃取生成物      16mg              16mg
玉米淀粉                  1200mg            1200mg
聚山梨醇酯80              80mg              48mg
硅铝酸镁                  144mg             144mg
硬脂酸镁                  24mg              24mg
乳糖                      适量              适量
(2)制法
取上述成分及用量，按照日本药典制剂总则「颗粒剂」项制备细粒剂。
(实施例3)胶囊剂
(1)成分
表5
                     <核黄素·抗坏血酸·生育酚>   <双泛酰硫乙胺>
                            8个胶囊中                8个胶囊中
普伐他汀钠                  20mg                     20mg
丁酸核黄素酯                12mg                     -
抗坏血酸                    500mg                    -
琥珀酸dl-α-生育酚酯        200mg                    -
双泛酰硫乙胺                -                        500mg
玉米淀粉                    960mg                    960mg
聚山梨醇酯80                80mg                     48mg
硅铝酸镁                    144mg                    -
硬脂酸镁                    24mg                     24mg
乳糖                        适量                     适量
小计                        2000mg                   1940mg
胶囊                        640mg                    640mg
合计                        2640mg                   2580mg
表6
                      <烟酸肌醇酯>    <抗坏血酸+生育酚>
                        8个胶囊中         8个胶囊中
普伐他汀钠              20mg              20mg
烟酸肌醇酯              500mg             -
抗坏血酸                -                 500mg
琥珀酸dl-α-生育酚酯    -                 200mg
玉米淀粉                960mg             960mg
聚山梨醇酯80            80mg              48mg
硅铝酸镁                144mg             144mg
硬脂酸镁                24mg              24mg
乳糖                    适量              适量
小计                    2000mg            2000mg
胶囊                    640mg             640mg
合计                    2640mg            2640mg
(2)制法
取上述成分及用量，按照日本药典制剂总则「颗粒剂」项制造细粒剂之后，填充到胶囊中制造硬胶囊剂。
(实施例4)液剂
(1)成分
表7
                   <核黄素·抗坏血酸·生育酚> <双泛酰硫乙胺>
                            100mL中              100mL中
普伐他汀钠                  20mg                 20mg
磷酸核黄素钠                20mg                 -
抗坏血酸                    500mg                -
乙酸d-α-生育酚酯           50mg                 -
双泛酰硫乙胺                -                    500mg
D-山梨糖醇液(70％)          4g                   6g
蜂蜜                        7g                   8g
dl-苹果酸                   200mg                -
依地酸钠                    20mg                 20mg
乙醇                        2mL                  2mL
硬脂酸聚氧化乙烯            100mg                100mg
硬化蓖麻油60
安息香酸钠                  60mg                 60mg
香料                        微量                 微量
精制水                      适量                 适量
表8
                   <烟酸肌醇酯>    <抗坏血酸+生育酚>
                      100mL中           100mL中
普伐他汀钠            20mg              20mg
烟酸肌醇酯            500mg             -
抗坏血酸              -                 500mg
乙酸d-α-生育酚酯     -                 50mg
D-山梨糖醇液(70％)    4g                6g
蜂蜜                  7g                8g
dl-苹果酸             200mg             200mg
依地酸钠              20mg              20mg
乙醇                  2mL               2mL
硬脂酸聚氧化乙烯      100mg             100mg
硬化蓖麻油60
安息香酸钠            60mg              60mg
香料                  微量              微量
精制水                适量              适量
(2)制法
取上述成分及用量，按照日本药典制剂总则「液剂」项制造液剂。
(试验例)血中脂质量的评价试验
<试验方法>
(1)被试验物质
普伐他汀，使用三共株式会社的纯度99.4％的产品。
双泛酰硫乙胺、烟酸肌醇酯、丁酸核黄素酯、乙酸d-α-生育酚酯以及抗坏血酸，分别使用，购自第一制药、白鸟制药制、三菱东京制药制、エ-ザイ制和日本ロツシユ制的产品。
(2)试验动物
作为试验动物，从Covance Research Products Inc.购入5月龄比格尔(ビ-グル)雄犬，检疫和驯化饲养约1个月后使用。
(3)给药剂型、制剂的配制方法和制剂的保存方法
向从TORPAC社购入的明胶胶囊(1/2盎司)中，填充普伐他汀或各配合剂(其填充量是根据每个试验动物的体重计算出对于普伐他汀或各配合剂所必需的量)。而且，普伐他汀填充好了的胶囊，要冷藏，配合剂填充胶囊要在室温下，保存到将要给药之前。
另外，配合剂的场合，是填充到相同的明胶胶囊中。
(4)给药途径和给药期间
将填充了普伐他汀或配合剂的胶囊，1日1次9:00～12:30期间，经口强制对试验动物给药。而且，让试验动物在给药前绝食2～3小时。
给药期间为11天。
(5)被试试样的配制和试验方法
在胶囊给药前14天和7天(给药开始前第2周和第1周)、给药后4天、8天、和12天，从桡侧皮静脉采血约10ml。而且，采血前约18小时让试验动物绝食。得到的血液放入试管中，室温下放置30分～1小时后，进行离心分离(3000rpm，10分钟)，使用得到的血清，用GK-GPO-POD法测定甘油三酸酯。
另外，各含量的测定中，使用Instrumentation Laboratory公司的全自动分析装置Monarch.
<试验结果>
以给药2周和1周前的血清脂质量的平均值作为100，进行换算求出双泛酰硫乙胺、烟酸肌醇酯、丁酸核黄素酯·乙酸d-α-生育酚酯·抗坏血酸的合剂、以及乙酸d-α-生育酚酯·抗坏血酸的合剂各自的各给药量中的血中脂质量和与普伐他汀配合中的血中脂质量等。各值是一组5条(犬)的平均值。
(普伐他汀与双泛酰硫乙胺的并用效果)
表9
    被试验物质                      血中甘油三酸酯量
     (mg/Kg)                 给药后4天  给药后8天    给药后12天
纯普伐他汀试剂(2)             108.9      104.0         91.1
纯双泛酰硫乙胺试剂(300)       104.4      103.9         96.6
普伐他汀(2)                   85.4       84.4          74.6
+双泛酰硫乙胺(300)
(普伐他汀与烟酸肌醇酯的并用效果)
表10
   被试验物质                血中甘油三酸酯量
    (mg/Kg)          给药后4天  给药后8天    给药后12天
纯普伐他汀试剂(2)      108.9      104.0         91.1
烟酸肌醇酯(400)        109.3      94.8          111.7
普伐他汀试剂(2)        79.48      1.18          6.7
+烟酸肌醇酯(400)
(普伐他汀与丁酸核黄素酯、乙酸-d-α-生育酚酯以及抗坏血酸的并用效果)
表11
    被试验物质                   血中甘油三酸酯量
     (mg/Kg)           给药后4天    给药后8天    给药后12天
纯普伐他汀试剂(2)        108.9        104.0         91.1
丁酸核黄素酯(6)          104.2        98.8          86.0
+乙酸d-α-生育酚酯(150)
+抗坏血酸(500)
普伐他汀(2)              77.4         80.3          74.8
+丁酸核黄素酯(6)
+乙酸d-α-生育酚酯(150)
+抗坏血酸(500))
(普伐他汀、乙酸-d-α-生育酚酯以及抗坏血酸的并用效果)
表12
   被试验物质                    血中甘油三酸酯量
     (mg/Kg)           给药后4天    给药后8天    给药后12天
纯普伐他汀试剂(2)        108.9        104.0        91.1
乙酸d-α-生育酚酯(10)    104.2        104.8        104.1
+抗坏血酸(50)
普伐他汀(2)              86.9         88.1         88.1
+乙酸-d-α-生育酚酯(10)
+抗坏血酸(50)
(工业实用性)
本发明涉及的普伐他汀与双泛酰硫乙胺等组合的组合物，具有优良的降低血中甘油三酸酯量的作用，所以作为血中甘油三酸酯降低剂是有用的。

Claims (5)

1.一种血中甘油三酸酯降低剂组合物，该组合物含有普伐他汀，和选自①双泛酰硫乙胺、②烟酸肌醇酯、③由核黄素类、生育酚类和抗坏血酸类构成的合剂以及④由生育酚类和抗坏血类构成的合剂中的1种或2种以上。
2.一种血中甘油三酸酯降低剂组合物，该组合物含有普伐他汀和双泛酰硫乙胺。
3.一种血中甘油三酸酯降低剂组合物，该组合物含有普伐他汀和烟酸肌醇酯。
4.一种血中甘油三酸酯降低剂组合物，该组合物含有普伐他汀、和核黄素类·生育酚类·抗坏血酸类的合剂。
5.一种血中甘油三酸酯降低剂组合物，该组合物含有普伐他汀和生育酚类·抗坏血类的合剂。
CNB018226949A 2000-12-18 2001-12-12 甘油三酸酯降低剂组合物 Expired - Fee Related CN1307990C (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104799302A (zh) * 2014-01-25 2015-07-29 天津中瑞药业股份有限公司 一种肌醇烟酸酯营养强化胶囊的制备方法
CN104799269A (zh) * 2014-01-25 2015-07-29 天津中瑞药业股份有限公司 一种含硒的肌醇烟酸酯营养强化胶囊制备方法

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA05000050A (es) * 2002-07-03 2005-04-08 Esperion Therapeutics Inc Composiciones farmaceuticas y metodos para tratar, prevenir y manejar el colesterol, dislipidemia y enfermedades relacionadas.
JP2005187454A (ja) * 2003-12-05 2005-07-14 Sankyo Co Ltd ビタミンｅ含有ｌｄｌ低下剤及び／又は動脈硬化抑制剤組成物
US20050192347A1 (en) * 2003-12-23 2005-09-01 Dasseux Jean-Louis H. Urea and thiourea compounds and compositions for cholesterol management and related uses
JP2008509154A (ja) * 2004-08-06 2008-03-27 トランスフオーム・フアーマシユーチカルズ・インコーポレーテツド 新規なスタチン薬剤組成物および関連治療方法
NZ552390A (en) * 2004-08-06 2010-01-29 Transform Pharmaceuticals Inc Novel fenofibrate formulations and related methods of treatment
US20090042979A1 (en) * 2004-08-06 2009-02-12 Transform Pharmaceuticals Inc. Novel Statin Pharmaceutical Compositions and Related Methods of Treatment
KR101112549B1 (ko) * 2005-01-31 2012-06-12 삼성전자주식회사 박막 트랜지스터 표시판
KR20220041879A (ko) 2019-07-29 2022-04-01 마티아스 라쓰 스타틴 유도된 혈관 석회화의 예방에서의 아스코르베이트
US11547693B2 (en) 2019-07-29 2023-01-10 Matthias Rath Ascorbate in the prevention of statin induced vascular calcification
WO2022129003A1 (en) * 2020-12-15 2022-06-23 Dsm Ip Assets B.V. Multiparticulate solid oral dosage form comprising statin and vitamin e

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6019891B2 (ja) * 1978-12-01 1985-05-18 第一製薬株式会社 薬物性脂肪肝用剤
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
US5260305A (en) * 1988-12-12 1993-11-09 E. R. Squibb & Sons, Inc. Combination of pravastatin and nicotinic acid or related acid and method for lowering serum cholesterol using such combination
US5662934A (en) * 1993-01-05 1997-09-02 Najarian; Thomas Compositions and methods for lowering cholesterol while maintaining antioxidant levels
JP2618202B2 (ja) * 1994-06-23 1997-06-11 株式会社ロッテ 血中脂質降下剤およびこれを含有する飲食品
TW474809B (en) * 1995-07-03 2002-02-01 Sankyo Co A pharmaceutical composition for arteriosclerosis or xanthoma consisting of HMG-CoA reductase inhibitors and insulin sensitizers
US5965621A (en) * 1995-08-17 1999-10-12 Allergan Methods and compositions for reducing or maintaining body weight in a mammal
AU732465B2 (en) * 1996-04-17 2001-04-26 Merck & Co., Inc. Combination therapy for reducing the risks associated with cardiovascular disease
PT1017390E (pt) * 1997-07-31 2007-07-24 Kos Life Sciences Inc Comprimido revestido que compreende ácido nicotínico ou um composto metabolizado a ácido nicotínico sob uma forma de libertação prolongada, e um revestimento que contém um inibidor da hmg-coa-redutase sob uma forma de libertação imediata.
US6245797B1 (en) * 1997-10-22 2001-06-12 Merck & Co., Inc. Combination therapy for reducing the risks associated with cardio-and-cerebrovascular disease
JP2000044470A (ja) * 1998-08-04 2000-02-15 Nof Corp 高脂血症薬
CN1092986C (zh) * 1999-08-16 2002-10-23 上海本草生物医学工程研究所 一种用于降血脂的辅酶a口服制剂及制备方法和应用
US6436406B1 (en) * 2000-06-15 2002-08-20 A. Glenn Braswell Compositions and methods for reducing or controlling blood cholesterol, lipoproteins, triglycerides and atherosclerosis
US6916849B2 (en) * 2000-10-23 2005-07-12 Sankyo Company, Limited Compositions for improving lipid content in the blood
AU2002211005A1 (en) * 2000-11-07 2002-05-21 Sankyo Company Limited Lipid peroxide-lowering compositions
US7037934B2 (en) * 2000-12-14 2006-05-02 Sankyo Company, Limited Blood lipid ameliorant composition
WO2002047682A1 (fr) * 2000-12-14 2002-06-20 Sankyo Company, Limited Composition ameliorant les lipides sanguins
MXPA05000050A (es) * 2002-07-03 2005-04-08 Esperion Therapeutics Inc Composiciones farmaceuticas y metodos para tratar, prevenir y manejar el colesterol, dislipidemia y enfermedades relacionadas.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104799302A (zh) * 2014-01-25 2015-07-29 天津中瑞药业股份有限公司 一种肌醇烟酸酯营养强化胶囊的制备方法
CN104799269A (zh) * 2014-01-25 2015-07-29 天津中瑞药业股份有限公司 一种含硒的肌醇烟酸酯营养强化胶囊制备方法

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