CN1665496B - Epa和dha在制备二级预防神经性疾患的药物中的用途 - Google Patents
Epa和dha在制备二级预防神经性疾患的药物中的用途 Download PDFInfo
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- CN1665496B CN1665496B CN03815692XA CN03815692A CN1665496B CN 1665496 B CN1665496 B CN 1665496B CN 03815692X A CN03815692X A CN 03815692XA CN 03815692 A CN03815692 A CN 03815692A CN 1665496 B CN1665496 B CN 1665496B
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及n-3PUFA EPA和/或DHA在制备预防有脑部供血动脉粥样硬化症状的患者大脑损害的口服药物中的应用。
Description
本发明涉及n-3PUFA二十碳五烯酸(EPA)和/或二十二碳六烯酸(DHA)对于脑部供血动脉有动脉粥样硬化症状的患者在预防继发性神经性疾病，特别是中风中的应用。
流行病学证据显示食用鱼或鱼油中的长链n-3多不饱和脂肪酸(PUFA)，特别是EPA和DHA，可预防西方人的心血管疾病。长链n-3PUFA可迅速降低血浆中甘油三酯(TAG)的浓度，降低食后脂血反应值。动物模型证明食用鱼油可降低动脉粥样硬化，这可能是由于类脂降低，生长因子的生成减少，炎症减少，或者是上述几种原因结合的结果。正如EP-B-1 152 755说明书和权利要求中所述，二级预防研究表明长链n-3PUFA对心肌梗塞(MI)患者产生了显著的效果。N-3PUFA尤其可有效地减少猝死，(EP-B-1 152 755)，猝死是缺乏类脂的显著降低时产生的效果。据推测，这种效应是由于n-3PUFA的抗凝血和抗心律失常作用产生的。相反，我们认为有可能是n-3PUFA的抗炎作用有助于动脉粥样硬化斑块的稳定。相反的，有迹象显示从植物油例如葵瓜子油中获得的n-6PUFA亚油酸有利于炎症，这种情况下增加摄取亚油酸将促进斑块的不稳定。
据发明人所知没有任何研究公开了n-6或n-3PUFA对斑块的稳定性作用。Rapp等人(Arterioscler.Thromb.1991，II，903-911)进行了一项研究，其中患者经过动脉内膜切除手术，在手术前一段时间内服用高剂量的鱼油(48-64g/天)，研究人员发现这些患者手术切除的斑块中的n-3PUFA，二十碳五烯酸(EPA；20:5n-3)和二十二碳六烯酸(DHA；22:6n-3)远远高于对照患者移除斑块中三种物质的水平。然而，Rapp等人没有说明斑块的结构细节。
我们现在发现，如本发明所述，给脑部供血动脉有动脉粥样硬化症状的患者施用适当剂量的鱼油不但会使低密度脂蛋白(LDL)中的EPA和DHA和动脉粥样硬化斑块类脂相结合，而且引人注目的是，提高了动脉粥样硬化斑块的稳定性。
更特别地，我们发现患者经口服鱼油后产生更多的有良好形状纤维帽的斑块，而不是细炎症帽，此外巨噬细胞没有严重的侵润斑块。众所周知，动脉粥样硬化斑块易于受损的特性包括一个细的纤维帽和数目增加的炎症细胞，如巨噬细胞。已知颈动脉斑块中的巨噬细胞和神经性疾病发病率上升有关，如中风和暂时性缺血损伤。因此，鱼油的口服给药提供了一种有效、安全的方法有助于预防神经性疾病，尤其是脑部供血动脉有动脉粥样硬化症状的患者的中风。
因此，本发明涉及EPA和/或DHA在制备口服药剂中的应用，用于预防脑部供血动脉有动脉粥样硬化症状患者的脑损伤。
在一个优选的具体实施方式中，口服药剂用于预防患有脑血管意外、一过性黑矇和/或暂时性缺血损伤症状患者的中风。
我们将详细说明实现本发明的实验研究。
患者和方法
研究计划
指定做颈动脉内膜剥离手术的患者，即有脑部供血动脉有深度动脉粥样硬化症状，同意参与实验的随机分组，进行双盲法试验，施用三种类型的油胶囊中的一种.对照油是80∶20混合的棕榈油和大豆油；混合物中脂肪酸组分接近于成年人UK饮食的平均值.另一种油是葵花子油和包含EPA/DHA的鱼油.油中脂肪酸组分如表1.每粒胶囊包含1g油和1mg维生素E.患者服用6粒胶囊/天直到进行手术；建议患者每顿饭时服用两粒胶囊，每天三次.因此，长链n-3PUFA的量为1.4g/天.亚油酸服用量为3.6g/天，这表示这种脂肪酸的吸收有40％的增加.
表1.研究用胶囊中的脂肪酸组分
样本含量根据Rapp等人.，(Arteriscler.Thromb.1991 11，903-11)所述的斑块磷脂(PL)的脂肪酸组分进行计算，在本研究中考虑使用十到十五倍的低EPA+DHA剂量。在此基础上计算50样品含量需要增加一倍的斑块磷脂中的EPA，达到P＜0.05。考虑到有20％的遗漏，本项研究选用了188名患者。
研究开始时，空腹时采集的静脉血样本加入至EDTA中。患者开始如上所述服用胶囊，记录7天食物重量的日记。整个研究阶段，患者继续药物疗法，并且建议他们不要改变饮食。有规律地与患者接触提高了顺应性，顺应性根据回收的胶囊和测量LDL类脂部分的脂肪酸组分评估。不能够遵从(n＝5)的患者退出该项研究。每个治疗小组中，回收的胶囊计算得到顺应性＞85％，此外，服用鱼油的实验组中超过90％的患者血浆LDL类脂部分中EPA的比例增加超过0.5g/100g总脂肪酸。观察的结果表明每个治疗组中顺应性至少为85-90％。
患者开始接受研究后大约7到190天进行移除颈动脉斑块的手术。7天内进行手术的患者退出该研究。进行手术前一天早晨，再采集一次空腹静脉血样本。手术时聚集颈动脉斑块并进行清洗。从颈总动脉开端切割成2mm宽的切片。进行生化学分析的切片用液态氮冷冻。用于显微解剖的切片浸入甲醛然后植入石蜡中。用于免疫组织化学的切片在最适切割温度下冷冻于包埋剂(Agar Scientific，Stansted，UK)中，在-70℃冷藏。
惯常营养素摄入量分析
用FOODBASE(脑化学学会，London，UK)修饰方法对食物日记进行惯常营养素摄入量的分析，这已被确认用于测量脂肪酸摄入量。
血脂和脂蛋白
血浆总胆固醇和三酰基甘油(TAG)浓缩物可由商业可获得的的比色测定法(Sigma Chemical Co.，Poole，UK)确定。低密度脂蛋白(LDL)通过两步密度梯度法从血浆中制备，将1.7mL血浆(加入固态溴化钾调节密度为1.24g/mL)加入3.3mL磷酸盐缓冲生理盐水中，在封闭管中离心2小时，转速100,000rpm，温度15℃，在Beckman超速离心机的Beckman TLA-100.4转子中。纯化的LDL-70℃冷藏用于分析脂肪酸组分。
脂肪酸组分分析
测定PL的脂肪酸组分，胆固醇酯(CE)和LDL的TAG部分，以及接近于颈动脉斑块分岔的冷冻部分。萃取类脂，薄层色谱法分离类脂馏分，每个馏分中的脂肪酸组分用气相色谱法测定，如Thies等人(Am.J.Clin.Nutr.2001，73，539-48)所述。
颈动脉斑块形态学
植入石蜡的部分用苏木精和曙红染色。接近分岔的部分用美国心脏病协会(Stary等人.，Circulation，1995，92，1355-74)公布的标准和Virmani等人.(Arterioscler.Thromb.Vase.Biol.200020，1262-75)提出的这种系统的修饰分类。由心血管病理学家随机顺序检查这些部分，他们不知道任何患者的信息。美国心脏病协会(AHA)分类包括六级，或者说类别，分别为：第I类(初级损害)；第II类(早期损害或脂肪纹)；第III类(中级损害或早期动脉粥样化)；第IV类(动脉粥样化或动脉粥样化斑块)；第V类(纤维动脉粥样化或纤维化损害)；第VI类(伴有表面缺陷的损害和/或出血和/或血栓沉积)。由Virmani等人.提出的修饰分类包括根据严重程度进行一系列等级描述，如：病理性内膜加厚(细胞外类脂积聚区域的子宫平滑肌细胞，但无坏死或血栓)；纤维帽动脉粥样化(良好形状的坏死核，覆有纤维帽；无血栓)；细纤维帽动脉粥样化(巨噬细胞浸润的细纤维帽和伴有少量平滑肌细胞的淋巴细胞和潜在的坏死核，无血栓)；糜烂(腔血栓症)；斑块破裂(纤维动脉粥样化破裂；腔血栓与坏死核传染)；钙化性结节和纤维钙化斑块(出现钙化)。
颈动脉斑块免疫组织化学
分岔的斑块部分用于免疫组织化学。对斑块部分染色，用于显现巨噬细胞(通过其表面的CD68辨别)和T淋巴细胞(通过其表面的CD3辨别)，和两种黏附分子，血管细胞粘附分子-1(VCAM-1)和细胞间粘附分子-1(ICAM-1)，斑块部分包括在免疫细胞进入斑块的运动中。冷冻板块的冷冻切片放置在有机硅烷覆盖的载玻片上。内在的过氧物酶活性被阻断，斑块部分继续用人类不同抗体，生物素酰化的山羊抗鼠(用猪抗羊对VCAM-1染色)免疫球蛋白G(DAKO，Ely，UK)，和抗生蛋白链菌素-山葵过氧物酶(DAKO，Ely，UK)的最佳稀释度孵化。最后，过氧物酶活性完全显现，以过氧化氢为底物，3-氨-9-乙基咔唑(SigmaChemical Co.，Poole，UK)为色原体。染色部分用福尔马林固定颜色，以Harris苏木精再次染色，在10倍显微镜下观察。使用的初期抗体是小鼠抗人CD3(Leu 4；Becton Dickinson，Oxford，UK)，小鼠抗人CD68(KP1；DAKO，Ely，UK)；小鼠抗人ICAM-1(R&D Systems，Oxford，UK)，和山羊抗人VCAM-1(R&D Systems，Oxford，UK)。染色分为0级(没有染色)，1级(中度染色)或2级(重度染色)。
统计分析
只显示完成此项研究的患者的数据(对照组中n＝57；葵花子油组中n＝52；鱼油组中n＝53)。不同治疗组的年龄，体重指数(BMI)，研究开始时的血脂浓度，临床史，使用的药物疗法和惯常营养素摄入量根据单一因素方差分析法进行比较。测定血脂浓度和LDL类脂部分脂肪酸组分的治疗效果作为与基线值的偏差。不同治疗组中与基线值的偏差根据单一因素方差分析法进行比较，利用基线值和治疗持续时间作为共同变量；治疗具有显著效果，利用student’s t-检验辨别组间差异。在一些例子中，在同一治疗组中利用成对的student’s t-检验比较治疗后与基线的偏差值，在不同治疗组中利用单一因素方差分析法和post-hoc student’s t-检验比较治疗后与基线的偏差值。不同治疗组中颈动脉斑块类脂部分的脂肪酸组分利用单一因素方差分析法比较，以油组的持续时间为协同变异；治疗具有显著效果，利用student’s t-检验辨别各组差异。不同治疗组中染色强度(免疫组织化学)和噬菌斑的分布根据卡方检验进行比较。测定每个治疗组中分布的平均等级，根据Jonckheere-Terpstra测验进行比较。测定相关性作为Spearman’s相关系数(ρ)。全部分析均根据SPSS版本11(SPSS，Chicago，IL，USA)操作，在所有例子中P＜0.05就显示具有统计学显著性差异。
结果
患者概貌
有18位患者退出此项研究，其中13人由于临床原因，5人因为他们不能服从研究协议。另有8名患者因为在研究开始的7天内进行了手术而排除在此项研究外。
完成该项研究的患者素质如表2.所列举。各治疗组之间在研究开始时在以下方面没有显著性差异：性别，年龄，BMI，空腹血浆TAG和胆固醇浓度，能量和个体大量或微量营养素包括个体脂肪酸吸收，吸烟者/戒烟者数量，受损颈动脉狭窄等级，临床史和应用药物疗法(所有的P至少＞0.1438；单一因素方差分析)(表2.)。每组的供油时间相似(表2.)。葵花子油组的患者额外供有3.6g亚油酸/天，这种脂肪酸每天增加大约40％。鱼油组的患者额外供有1.4g长链n-3PUFA/天，EPA摄入量增加约10倍，DHA摄入量增加约4倍。
表2.研究开始时患者素质
年龄，BMI，血脂和营养素摄入量数据是平均值±SD(年龄和BMI波动范围如括号中所示)。
狭窄数据是括号中所示的25th和75th百分数的中间值。
有治疗组持续时间的数据是括号中所示的10th和90th百分数的中间值。
数据由7天称重食物日记计算得到。
*大多数戒烟者在本研究开始前已经戒烟超过3年。
即中风。
血脂浓度
血浆胆固醇浓度无显著性治疗效果(未给出数据)。然而，血浆TAG浓度产生显著性治疗效果(P＝0.0184；单一因素方差分析)。鱼油造成血浆TAG浓度有显著性降低(-0.48±1.06mmol/L)，而在其它组中无显著变化。因此，经鱼油治疗后血浆TAG浓度(1.2±0.8mmol/L)显著低于基线(P＝0.0032；成对的student’s t-检验)。此外，鱼油组中血浆TAG浓度在研究结尾时显著地低于其他两组(与对照组P＝0.0294，与葵花子油组P＝0.0347；单一因素方差分析)。在鱼油治疗持续时间和血浆TAG浓度变化之间存在显著线性相关(ρ＝-0.44；P＝0.0118)。
LDL类脂部分的脂肪酸组分
对于LDL PL，CE和TAG中的一些脂肪酸的比例存在显著的治疗效果。鱼油治疗后在三种LDL类脂部分中EPA和DHA的比例均有所增加(表3.)。这些比例与基线(每部分中EPA的P＜0.0001，CE中DHA的P＝0.0031，PL和TAG中DHA的P＜0.0001；成对student’s t-检验)存在显著性差异，与治疗后其他两组中比例也存在显著差异(P至少＜0.0003，单一因素方差分析)。鱼油组LDL PL中长链n-3PUFA比例的增加伴随有亚油酸，二-homo-γ-亚麻酸(20∶3n-6)和花生四烯酸(20∶4n-6)比例的显著性降低。鱼油组LDL CE和TAG中长链n-3PUFA比例的增加伴随有亚油酸和油酸(18∶1n-9)比例分别显著降低。葵花子油治疗造成LDL CE中亚油酸比例增加，很大程度上在于油酸的消耗。结果如表3.列举。
数据是平均值±SD
以不同上标标示的同一行的数值与其它值均有明显不同(以基线值和治疗时间为共变量进行单一因素方差分析).
颈动脉斑块脂肪酸组分
对于每一个斑块类脂部分的EPA和DHA的比例和斑块PL中的亚油酸比例产生了显著的治疗效果。鱼油治疗组中患者颈动脉斑块的PL，CE和TAG中EPA的比例高于对照组(PL，CE和TAG分别为P＜0.0001，0.0053和0.0007；单一因素方差分析)和葵花籽组(PL，CE和TAG分别为P＜0.0001，0.0278和0.0024；单一因素方差分析)。斑块PL中EPA比例和鱼油治疗组(ρ＝0.41，P＝0.0051)之间存在显著的正向线性关系。鱼油治疗组中患者颈动脉斑块的CE和TAG中DHA的比例高于对照组(CE和TAG分别为P＝0.0042和0.0241；单一因素方差分析)。此外，鱼油治疗组中患者颈动脉斑块的PL和CE中DHA的比例高于葵花籽组(PL和CE分别为P＝0.0100，0.0278；单一因素方差分析)。鱼油治疗组患者斑块的PL中亚油酸的比例低于其他两组(与对照组相比P＝0.0118，与葵花籽油组相比P＝0.0015；单一因素方差分析)。对照组和葵花籽油中斑块类脂部分的脂肪酸组分无显著性差异。结果如表4.列举。
表4.不同油治疗组中颈动脉斑块类脂部分的脂肪酸组分
数据是平均值±SD
以不同上标标示的同一行的数值与其它值均有明显不同(以基线值和治疗时间为共变量进行单一因素方差分析)。
颈动脉斑块形态学分类
以AHA分类法确定的损害类型的分布情况在鱼油组患者和对照组、葵花籽油组患者之间存在显著性差异(与对照组相比P＝0.0234，与葵花籽油组相比P＝0.0107；卡方检验)。这是由于鱼油组中IV型损害(“动脉粥样化”)比例较高和V型损害(“纤维动脉粥样化和纤维变形损害”)比例较低造成的。与持续时间的中间值相比，各组中治疗时间较短或较长的患者的损害类型分布情况作了比较。对于与持续时间中间值相比治疗时间较短的患者的斑块，各治疗组之间没有显著性差异。然而，鱼油组中治疗时间较中间值长的患者的损害分布情况与对照组和葵花籽油组相比均产生显著性差异(P分别为0.0111和0.0432；卡方检验)。所有患者中，IV型斑块的EPA和DHA含量最高，VI型最低。
以改良的AHA分类法确定的损害类型的分布情况在鱼油组患者和对照组、葵花籽油组患者之间存在显著性差异(与对照组相比P＝0.0344，与葵花籽油组相比P＝0.0313；卡方检验)。这种差异是由于鱼油组中有良好形状纤维帽和无血栓(纤维帽动脉粥样化)的损害比例较高和炎症的细纤维帽(细纤维帽动脉粥样化)损害比例较低造成的。
对照组和葵花籽油组的斑块损害类型分布之间不存在显著性差异。结果如表5.和表6.列举。
颈动脉斑块的淋巴细胞和巨噬细胞
不同治疗组患者的斑块中ICAM-1或VCAM-1没有区别(未显示数据).同样，对斑块中的T淋巴细胞也没有治疗效果.相反，鱼油组患者的斑块切片用抗-CD68染色的程度较低，一种巨噬细胞标记，该组染色分布与其它组相比存在区别(与对照组相比P＜0.0001，于葵花子油组相比P＝0.0016，卡方检验)，并且染色密度平均等级明显较低(P＝0.0246).鱼油组治疗时间与抗-CD68染色密度为显著负性相关(p＝-0.352；P＝0.0301).鱼油组中治疗时间短于平均值的患者的抗-CD68染色密度(25％染色密度1，75％染色密度2)比治疗时间长于平均值的患者的抗-CD68染色密度(47％染色密度1，53％染色密度2)更高.然而，这些染色密度分布不存在显著差异(P＝0.0827；卡方检验).对各治疗组中治疗时间短于或长于平均值的患者的斑块抗-CD68染色密度分布进行了比较.鱼油组中的分布情况与对照组(治疗时间短于或长于平均值的患者的P值分别＜0.0001和0.0048)和葵花子油组(治疗时间短于或长于平均值的患者的P值分别＝0.0109和0.0363)均存在显著差异.(卡方检验)
在全部患者的斑块中，巨噬细胞浸润高(即抗-CD68染色密度为2)与浸润适中的斑块(即抗-CD68染色密度为l)相比较含有的EPA和DHA更少。(表6.)
对照组和葵花子油组的抗-CD68染色分布或染色密度的平均等级之间不存在显著差异。
T-淋巴细胞和巨噬细胞染色情况如表7.列举。
讨论
本研究中葵花子油组患者在饮食时补充给予3.6g亚油酸/天，对于结果计算只产生了很有限的影响.这可能是由于这些患者在平时的饮食中已经摄取足够量的亚油酸；这种摄取与UK中对成年人的报道相一致.我们的研究表明深度颈动脉粥样硬化中增加亚油酸摄入量40％，并且消耗一定量的这种脂肪酸，不会导致增加的亚油酸进入颈动脉斑块中，也不会导致斑块稳定性发生变化，至少在整个研究阶段是这样的.
饮食中补充给予鱼油显著降低了血浆TAG浓度。TAG的降低程度与其他给予鱼油的研究中的结果相一致，并与给予鱼油的持续时间相关。
长链n-3PUFA例如EPA和DHA通常以小份量给予，因此在血浆和组织类脂中的比例相对较低。然而，这些脂肪酸增加的消耗量通过不同的血液和组织类脂群中脂肪酸比例的增加标记，就象本研究中的LDL类脂部分。本研究中的关键部分是当长链n-3PUFA以适当量被吸收时，他们很容易地渗入动脉粥样硬化斑块类脂中。EPA对于斑块类脂的渗入，特别是PL，与时间呈线性相关。我们已知的考察鱼油补充给药法对动脉粥样硬化斑块脂肪酸组分的作用的研究是Rapp等人.见 上，其表明了摄取大剂量鱼油后EPA和DHA对斑块类脂渗入的基本情况。然而，Rapp等人.没有研究噬菌斑现象的EPA/DHA摄入作用。本研究表明给予n-3PUFA至接近界标二级预防研究(see，e.g.EP-A-1,152,755)中应用的水平可渗入斑块类脂群。此外，即使在我们使用过的最适当剂量水平，n-3PUFA也在相对较短时间内发生渗入。这就说明动脉粥样硬化斑块是相当动态的，伴随一定程度的类脂循环，甚至在晚期动脉粥样硬化阶段。
免疫组织化学染色法和噬菌斑现象测量显示出n-3PUFA的显著冲击。鱼油组比其他两个组的任何一个都有更多的良好形状的纤维帽，而非细纤维帽。此外，鱼油治疗的患者的斑块被巨噬细胞浸润的程度较轻。本研究中作为鱼油补充给药法结果的噬菌斑现象的变化情况因此也显示了一种更稳定的斑块，其较为不易受损破裂。这些区别(即程度较轻的巨噬细胞浸润和更多有良好形状纤维帽的斑块)是由于斑块类脂中EPA和DHA含量较高导致的，表明n-3PUFA决定斑块的稳定性。
药物制备和给药模式
本发明中药物活性成分是EPA，DHA或二者的混合物。n-3PUFA脂肪酸可为天然存在的甘油三酯形式，或药物可接受的盐或衍生物，尤其是乙酯或其他烷基酯。
合适的，活性成分来自鱼油，虽然EPA和DHA的来源未来可由商业途径获得。从生鱼油中制备药用鱼油等级的方法，和改变产品中EPA和/或DHA含量浓度的方法，对于本领域技术人员是公知的。从使n-3PUFA吸收更快和确保患者顺从的观点出发，鱼油中EPA和/或DHA浓度应当高，可以通过各种办法以达到足够的剂量，例如，每天一粒或两粒胶囊。优选的，以含有混合物的20％-100％重量的EPA和DHA作为活性成分，更优选的，含有混合物的超过70％重量的EPA和DHA，最优选的，含有混合物的70％-90％重量的EPA和DHA。同时混合物中EPA和DHA的比例不是关键性因素，通常优选EPA∶DHA是1∶2至2∶1，更优选约3∶2。
虽然优选的药物活性成分应当含有EPA和DHA的混合物，本发明领域技术人员可根据常识选择n-3PUFA酸中的任意一种。制备基本上纯的EPA或DHA方法是已知的，在文献中有记载。
本发明药物是口服形式，合适的口服剂型是硬或软胶囊，如果需要其他口服剂型如粉末，可通过微囊化制得。
药物除了包含活性成分EPA和DHA，还可添加本领域已知的一种或多种药物可接受的载体。包括填充剂，稳定剂，膨胀剂，粘合剂，增湿剂，表面活性剂，润滑剂等，如药物组合物配制领域中所公知的。
另外加入抗氧剂，如苯甲醇，丁酸盐，苯醌，维生素E，抗坏血酸等，防腐剂，着色剂，芳香剂，调味剂，以及其他可用的药物试剂。抗氧剂是药物特别优选的组分。
口服制剂制备实施例
软明胶胶囊含有1g/胶囊
组分：
EPA乙酯 525mg/胶囊
DHA乙酯 315mg/胶囊
d-α维生素E 4IU/胶囊
明胶 246mg/胶囊
甘油 118mg/胶囊
活性成分和辅料称重，快速搅拌使均匀。混合物用胶体磨粉碎，在不锈钢管道中包囊。混合物用标准包囊机填入20号明胶胶囊中(平均重量为1.4g)。
本发明药物可以以任何适当剂量给予患者，治疗脑部供血动脉粥样硬化症状。n-3PUFA基本无毒性，甚至在相当高的剂量下无毒性。在上述的实验中，例如每天共给予1.4gEPA和DHA，有利于增加斑块的稳定性。一般来说，每天的EPA和/或DHA的剂量是0.5-5.0g，优选1.0-3.0g/天。
本发明药物适于治疗患者脑部供血动脉粥样硬化症状，例如中风或暂时性缺血损伤，以达到降低更多的，可能致命的损伤的危险性的目的。本药物可与其他药物联合应用，例如阿司匹林和华法林，降低这类患者继发性神经性疾病的危险性。
Claims (8)
1.EPA和DHA的混合物，或其药物上可接受的盐，或其中EPA或DHA，或EPA和DHA是其乙酯，在制备预防有暂时性缺血损伤和/或一时性黑曚症状的患者中风的口服药物中的应用，其中剂量范围是每天0.5至5g的EPA和/或DHA，且其中所述混合物中EPA和DHA的比例是1∶2-2∶1。
2.根据权利要求1的应用，其中所述比例为3∶2。
3.根据权利要求1或2的应用，其中所述药物包含所述混合物的20％-100％重量作为活性成分。
4.根据权利要求3的应用，其中所述药物包含所述混合物的超过70％重量作为活性成分。
5.根据权利要求4的应用，其中所述药物包含所述混合物的70％-90％重量作为活性成分。
6.如权利要求1或2的应用，其中所述药物还包含EPA和DHA的抗氧剂。
7.根据权利要求1或2的应用，其中药物给药剂量为1.0-3.0g/天的EPA和DHA。
8.如权利要求1或2的应用，其中口服药物是胶囊。
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Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003048831A (ja) | 2001-08-02 | 2003-02-21 | Suntory Ltd | 脳機能の低下に起因する症状あるいは疾患の予防又は改善作用を有する組成物 |
| JP4993852B2 (ja) | 2004-09-17 | 2012-08-08 | サントリーホールディングス株式会社 | ストレスに起因する行動異常を伴う症状あるいは疾患の予防又は改善作用を有する組成物 |
| US7550613B2 (en) | 2005-05-04 | 2009-06-23 | Pronova Biopharma Norge As | Compounds |
| JP5967855B2 (ja) | 2005-06-30 | 2016-08-10 | サントリーホールディングス株式会社 | 日中活動量の低下および／又はうつ症状の改善作用を有する組成物 |
| JP5697293B2 (ja) * | 2005-06-30 | 2015-04-08 | サントリーホールディングス株式会社 | 器質的脳障害に起因する高次脳機能の低下に対する改善作用を有する組成物 |
| CA2571462C (en) * | 2006-02-07 | 2013-08-13 | Mochida Pharmaceutical Co., Ltd. | Composition for preventing recurrence of stroke |
| CN101049297B (zh) * | 2006-04-06 | 2010-11-24 | 北京百慧生化制药有限责任公司 | 一种高dha型-乙酯和epa-乙酯的脂肪酸乙酯及其制造方法和制剂 |
| BRPI0717883A2 (pt) | 2006-11-01 | 2013-10-29 | Pronova Biopharma Norge As | Compostos lipídicos, composição contendo os mesmos e uso dos referidos compostos |
| JP5552313B2 (ja) | 2006-11-01 | 2014-07-16 | プロノヴァ・バイオファーマ・ノルゲ・アーエス | 脂質化合物 |
| BRPI0718393A2 (pt) * | 2006-11-03 | 2013-11-26 | Pronova Biopharma Norge As | Álcoois de ácido graxo |
| EP3593797A1 (en) | 2006-12-28 | 2020-01-15 | Suntory Holdings Limited | Nerve-regenerating agent |
| AU2009315314B2 (en) * | 2008-11-14 | 2013-04-18 | Bomi P. Framroze | A method of lowering circulating oxidized low density lipoprotein-beta-2-glycoprotein 1 complex for treatment of atherosclerosclerosis |
| BRPI1011876B1 (pt) | 2009-04-29 | 2020-03-31 | Amarin Pharma, Inc. | Composições farmacêuticas estáveis compreendendo etilácido eicosapentaenoico (etil-epa) e uso das mesmas para tratar ou prevenir uma doença relacionada ao cardiovascular |
| EP2424521A4 (en) | 2009-04-29 | 2015-03-04 | Amarin Pharmaceuticals Ie Ltd | PHARMACEUTICAL COMPOSITIONS COMPRISING EPA AND CARDIOVASCULAR AGENT AND METHODS OF USE |
| DK2443246T3 (en) | 2009-06-15 | 2018-03-26 | Amarin Pharmaceuticals Ie Ltd | COMPOSITIONS AND METHODS FOR REDUCING TRIGLYCERIDES WITHOUT INCREASING LDL-C LEVELS IN AN INDIVIDUAL WITH CURRENT STATE THERAPY |
| RU2012116079A (ru) | 2009-09-23 | 2013-10-27 | АМАРИН КОРПОРЕЙШН ПиЭлСи | Фармацевтическая композиция, включающая омега-3 жирную кислоту и гидроксипроизводное статина и способы ее применения |
| KR102354949B1 (ko) * | 2009-10-23 | 2022-01-24 | 바스프 에이에스 | 지방산 오일 혼합물의 코팅된 캡슐 및 정제 |
| US20110178105A1 (en) * | 2010-01-15 | 2011-07-21 | E.I. Du Pont De Nemours And Company | Clinical benefits of eicosapentaenoic acid in humans |
| NZ727980A (en) | 2010-11-29 | 2018-08-31 | Amarin Pharmaceuticals Ie Ltd | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
| US11712429B2 (en) | 2010-11-29 | 2023-08-01 | Amarin Pharmaceuticals Ireland Limited | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
| US11291643B2 (en) | 2011-11-07 | 2022-04-05 | Amarin Pharmaceuticals Ireland Limited | Methods of treating hypertriglyceridemia |
| US20130131170A1 (en) | 2011-11-07 | 2013-05-23 | Amarin Pharmaceuticals Ireland Limited | Methods of treating hypertriglyceridemia |
| AU2013207368A1 (en) | 2012-01-06 | 2014-07-24 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering levels of high-sensitivity (hs-CRP) in a subject |
| TW201334808A (zh) * | 2012-02-29 | 2013-09-01 | Braun Melsungen Ag | 含有荷爾蒙之包含磷蝦磷脂質的乳劑 |
| EP4342546A3 (en) | 2012-06-29 | 2024-05-22 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing the risk of a cardiovascular event in a subject on statin therapy |
| WO2014074552A2 (en) | 2012-11-06 | 2014-05-15 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides without raising ldl-c levels in a subject on concomitant statin therapy |
| US20140187633A1 (en) | 2012-12-31 | 2014-07-03 | Amarin Pharmaceuticals Ireland Limited | Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis |
| US9452151B2 (en) | 2013-02-06 | 2016-09-27 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing apolipoprotein C-III |
| US9624492B2 (en) | 2013-02-13 | 2017-04-18 | Amarin Pharmaceuticals Ireland Limited | Compositions comprising eicosapentaenoic acid and mipomersen and methods of use thereof |
| US20140249225A1 (en) * | 2013-03-01 | 2014-09-04 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidative modification of membrane polyunsaturated fatty acids |
| US20140271841A1 (en) | 2013-03-15 | 2014-09-18 | Amarin Pharmaceuticals Ireland Limited | Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin |
| US10966968B2 (en) | 2013-06-06 | 2021-04-06 | Amarin Pharmaceuticals Ireland Limited | Co-administration of rosiglitazone and eicosapentaenoic acid or a derivative thereof |
| US20150065572A1 (en) | 2013-09-04 | 2015-03-05 | Amarin Pharmaceuticals Ireland Limited | Methods of treating or preventing prostate cancer |
| US9585859B2 (en) | 2013-10-10 | 2017-03-07 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy |
| US10561631B2 (en) | 2014-06-11 | 2020-02-18 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing RLP-C |
| US10172818B2 (en) * | 2014-06-16 | 2019-01-08 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids |
| US10406130B2 (en) | 2016-03-15 | 2019-09-10 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids |
| TW201900160A (zh) | 2017-05-19 | 2019-01-01 | 愛爾蘭商艾瑪琳製藥愛爾蘭有限公司 | 用於降低腎功能下降之個體中的三酸甘油酯之組合物及方法 |
| US11058661B2 (en) | 2018-03-02 | 2021-07-13 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L |
| KR20210110890A (ko) | 2018-09-24 | 2021-09-09 | 애머린 파마슈티칼스 아일랜드 리미티드 | 대상체에서 심혈관 사건의 위험도를 감소시키는 방법 |
| WO2022225896A1 (en) | 2021-04-21 | 2022-10-27 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing the risk of heart failure |
| CN113884586A (zh) * | 2021-06-17 | 2022-01-04 | 上海市肺科医院 | 一种特发性肺动脉高压的预后标记物及其应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2216421A (en) * | 1988-03-23 | 1989-10-11 | Biorex Kft | Pharmaceutical compositions acting on the heart and cardiovascular system |
| CN1338929A (zh) * | 1999-01-27 | 2002-03-06 | 拉克斯戴尔有限公司 | 治疗精神性和神经性疾病的高纯乙基epa及其他epa衍生物 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1308613B1 (it) | 1999-02-17 | 2002-01-09 | Pharmacia & Upjohn Spa | Acidi grassi essenziali nella prevenzione di eventi cardiovascolari. |
| US7226916B1 (en) * | 2000-05-08 | 2007-06-05 | N.V. Nutricia | Preparation for the prevention and/or treatment of vascular disorders |
-
2003
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2216421A (en) * | 1988-03-23 | 1989-10-11 | Biorex Kft | Pharmaceutical compositions acting on the heart and cardiovascular system |
| CN1338929A (zh) * | 1999-01-27 | 2002-03-06 | 拉克斯戴尔有限公司 | 治疗精神性和神经性疾病的高纯乙基epa及其他epa衍生物 |
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| NZ548508A (en) | 2008-04-30 |
| NO20045275L (no) | 2005-01-31 |
| EP1501493B1 (en) | 2009-10-07 |
| IL164984A0 (en) | 2005-12-18 |
| EP1501493A1 (en) | 2005-02-02 |
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