CN1921860A - 高脂血症治疗药剂 - Google Patents

高脂血症治疗药剂 Download PDF

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CN1921860A
CN1921860A CNA2005800053563A CN200580005356A CN1921860A CN 1921860 A CN1921860 A CN 1921860A CN A2005800053563 A CNA2005800053563 A CN A2005800053563A CN 200580005356 A CN200580005356 A CN 200580005356A CN 1921860 A CN1921860 A CN 1921860A
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hyperlipemia
therapeutic agent
pitavastatin
eicosapentaenoic acid
triglyceride
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CN100475208C (zh
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青木太郎
山口纯司
佐佐木裕辅
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Nissan Chemical Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

本发明涉及一种包括匹伐他汀类、二十碳五烯酸或其酯类衍生物作为有效成分的高脂血症治疗药剂。根据本发明，提供了具有优异的降低血液胆固醇和甘油三酯作用的IIb型和IV型高脂血症的治疗药剂。

Description

高脂血症治疗药剂
技术领域
本发明涉及一种高脂血症治疗药剂，具体地，涉及一种对血液胆固醇和甘油三酯均表现出优异的降低作用的高脂血症治疗药剂。
背景技术
高脂血症是血液中脂蛋白异常增加的一种症状，它与一些疾病如动脉硬化和心肌梗塞密切相关，因此其治疗被认为十分重要。
多种药物被用于治疗高脂血症，主要使用HMG-CoA还原酶抑制剂(例如普伐他汀(pravastatin)、辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)和阿托伐他汀(atorvastatin))作为其治疗药剂。已知匹伐他汀(pitavastatin)具有很强的HMG-CoA还原酶抑制作用，其可用作血液胆固醇还原剂(日本专利第2569746号、美国专利第5856336号和欧洲专利第304063号)。
血液脂蛋白的主要成分是胆固醇和甘油三酯，在许多病例中，高血脂患者的血液胆固醇水平不仅增加，还伴随着甘油三酯的增加。用HMG-CoA还原酶抑制剂为高血脂患者给药时，血液胆固醇被降低到足够低，但甘油三酯却不能。此外，有一种方法，患有高水平血液胆固醇和甘油三酯的患者可以通过增加HMG-CoA还原酶抑制剂的给药剂量来降低胆固醇和甘油三酯。但这种方法在安全性方面存在问题，因此并不推荐使用。
另一方面，二十碳五烯酸(EPA)是一种长链的必需脂肪酸，它主要包含在鱼油中，据报道这种酸的作用是抑制肠道对甘油三酯的吸收，抑制肝脏内的生物合成，并通过提高血浆脂蛋白脂肪酶的活性来降低血液甘油三酯(Mizuguchi，K.等人：Eur.J.Pharmacol.235，221-227，1993；Mizuguchi，K.等人：Arteriosclerosis 18(5)，536，1990)，抑制肝脏胆固醇的合成以及通过加速胆固醇向胆汁中的排泄而降低血液总胆固醇(Mizuguchi，K.等人：Eur.J.Pharmacol.231，121-127，1993)。
发明内容
考虑到这些存在的问题，本发明人进行深入研究，并得出结论：当与二十碳五烯酸或其酯类衍生物结合使用时，在多种HMG-CoA还原酶抑制剂当中，匹伐他汀类提供了优异的降低血液胆固醇和甘油三酯的作用，其可用于治疗高脂血症。从而完成本发明。
因此，本发明提供了一种包括匹伐他汀类和二十碳五烯酸或其酯类衍生物作为有效成分的高脂血症治疗药剂。
另外，本发明提供一种治疗高脂血症的组合物，其包括匹伐他汀类、二十碳五烯酸或其酯类衍生物、以及药物可接受载体。
进一步，本发明提供匹伐他汀类和二十碳五烯酸或其酯类衍生物在制造治疗高脂血症的药物中的用途。
本发明的高脂血症治疗药剂具有优异的降低血液胆固醇和甘油三酯的作用，其可用于治疗IIb型和IV型高脂血症。
附图说明
图1中的图说明了通过将二十碳五烯酸乙酯与匹伐他汀钙结合给药降低血液甘油三酯的作用。
具体实施方式
本发明中施用的匹伐他汀类包括匹伐他汀((3R，5S，6E)-7-[2-环丙基-4-(4-氟苯基)3-喹啉基]-3，5-二羟基-6-庚烯酸：日本专利第2569746号、美国专利第5856336号和欧洲专利第304063号)、其形成内酯环的物质和匹伐他汀盐，匹伐他汀盐包括匹伐他汀钠和匹伐他汀钙。另外，它们包括其水合物和具有允许作为药物的溶剂的溶剂化物。匹伐他汀钙是最优选的匹伐他汀类。
匹伐他汀类可以通过日本专利第2569746号、美国专利第5856336号和欧洲专利第304063号中描述的方法制造。
本发明中的二十碳五烯酸是指全顺式-5，8，11，14，17-二十碳五烯酸，其很容易通过将来自鱼油及其它来源的天然甘油酯水解去掉其甘油部分而获得，也可以使用市售商品。另外，上述的二十碳五烯酸可以与诸如钠和钙形成盐。
甘油酯和低级烷基酯可以作为二十碳五烯酸的酯类衍生物。能够作为低级烷基酯的是，例如，甲酯、乙酯、丙酯、异丙酯、正丁酯、异丁酯、和叔丁酯，优选甲酯、乙酯、和丙酯，尤其优选乙酯。
如上文所述，甘油酯很容易从天然来源中以天然甘油酯的形式被提取。另一方面，低级烷基酯可以很容易地通过二十碳五烯酸与低级脂肪醇的脱水缩合而制造。
上述二十碳五烯酸及其酯类衍生物的纯度不应加以具体限定，从剂量降低的观点而言优选纯度高的产物。
就降低血液胆固醇和甘油三酯的作用、特别是降低甘油三酯的作用而言，本发明的高脂血症治疗药剂中所含的匹伐他汀类(A)和二十碳五烯酸或其酯类衍生物(B)的质量比A∶B＝1∶1至1∶5000，进一步优选为1∶10至1∶2000。
如下文所述的实施例所示，与单独用匹伐他汀钙给药相比，本发明的其中匹伐他汀类与二十碳五烯酸或其酯类衍生物结合使用的高脂血症治疗药剂降低大鼠血液甘油三酯的作用大为提高。因此，本发明的高脂血症治疗药剂可以有效地治疗高脂血症，特别是治疗血液胆固醇和甘油三酯均显示高值的IIB型和IV型高脂血症。
本发明的高脂血症治疗药剂可以根据常规方法通过将有效成分用有效成分之外的(根据其制剂剂型可以使用的)赋形剂、衰变剂(decayagent)、粘合剂、增滑剂、稀释剂、缓冲液、等渗剂、防腐剂、润滑剂、乳化剂、分散剂、稳定剂和溶解助剂适当地混合、稀释或溶解而制造。二十碳五烯酸或其酯类衍生物很容易被氧化，因此如果需要的话可以加入抗氧化剂，例如BHA、BHT和维生素E。
就本发明的高脂血症药剂的剂型而言，可以使用多种剂型的药物制剂，例如，粉末剂、颗粒剂、干糖浆、片剂、胶囊剂和注射剂。
本发明的高脂血症治疗药剂的使用形式不应加以具体限定，可以将两种药物同时给药，或者间隔一段时间分别给药。即，匹伐他汀类和二十碳五烯酸或其酯类衍生物可以与药物可接受的稀释剂和赋形剂混合，形成单一药物制剂，或者可以从两种药物分别制成药物制剂，以组合的形式使用。当从两种药物分别制造药物制剂时，两种药物制剂可以剂型不同。
本发明的高脂血症治疗药剂的剂量根据症状加以适当选择。匹伐他汀类以每天0.1至100mg、优选1至50mg、更优选1至20mg的剂量给药，二十碳五烯酸或其酯类衍生物以每天500至100000mg、优选1000至60000mg的剂量给药。它们可以一天给药一次，或者分成两次或更多次给药。
下文参考实施例对本发明进行更具体的说明，但是本发明不受这些实施例所限制。
实施例
根据下列方法测定用二十碳五烯酸乙酯(EPA-E)和匹伐他汀钙给药时观察到的其对血液甘油三酯的作用。
1.待测动物和饲养环境
使用6周龄雄性Wistar大鼠(Japan Medical Science ExperimentalAnimal Co.，Ltd.)进行试验。它们饲养在实验期间保持正常光照循环(室内光作为光照期：7:00a.m.至7:00p.m.)的房间内，室内温度为23±3℃，湿度为55±15％，大鼠自由进食(CE-2；Nippon Clear Co.，Ltd.)，饮用自来水。
2.药物制备
将匹伐他汀钙悬浮在0.5质量％的羧甲基纤维素钠水溶液(IwaiKagaku Yakuhin Co.，Ltd.)中，控制剂量为2ml/kg。匹伐他汀钙含有9.43质量％的水，因此称量质量1.1倍于剂量的量，以校正实际剂量。悬液冷冻(4℃)在暗色瓶中，每7天制备一次。EPA-E在使用时取自Epadel胶囊(Dainippon Seiyaku Co.，Ltd.)，将其悬浮在蒸馏水中，控制剂量为2ml/kg。
3.检测方法
32只大鼠分成下列四组(每组8例)，即，对照组、匹伐他汀钙单用(10mg/kg)组、EPA-E单用(1000mg/kg)组、和匹伐他汀钙(10mg/kg)和EPA-E(1000mg/kg)联用组，各组间总胆固醇和甘油三酯的平均值相同。两种药物均每天口服给药一次(4:00p.m.)，持续21天，对照组用羟甲基纤维素钠的0.5质量％水溶液1ml/kg口服给药。所有组从最后一次给药起禁食18小时后采血，测定血液甘油三酯浓度。
4.统计学分析和数据处理方法
对照组和给药组之间的多组间差异使用Dunnett’s多重比较检验进行分析，之前进行Bartlett方差分析。p值小于5％被视为统计学显著。
5.试验结果
如图1和表1中所示，在匹伐他汀钙单用组和EPA-E单用组中血液甘油三酯均有降低趋势(85.3％和72.1％)。此时，与匹伐他汀钙单用组或EPA-E单用组相比，两种药物联用组的血液甘油三酯降低程度更大(60.3％)，证实了具有协同作用(Bürgi′s equation：K.Takagi等人：Pharmacology，1987，Nanzan Do)(60.3％＜85.3×72.1＝61.5％)(p＜0.01)。
                            表1
  血液甘油三酯(mg/dL)   相对值(％)
  对照组   68±6   100.0
  匹伐他汀钙   58±6   85.3
  EPA-E   49±5   72.1
  匹伐他汀钙+EPA-E   41±2   60.3

Claims (6)

1.一种高脂血症治疗药剂，其包括匹伐他汀类和二十碳五烯酸或其酯类衍生物作为有效成分。
2.根据权利要求1所述的高脂血症治疗药剂，其中所述的匹伐他汀类为匹伐他汀钙。
3.根据权利要求1或2所述的高脂血症治疗药剂，其中所述的二十碳五烯酸酯类衍生物为二十碳五烯酸乙酯。
4.根据权利要求1-3中任意一项中所述的高脂血症治疗药剂，其为降低血液甘油三酯的药剂。
5.一种治疗高脂血症的组合物，其包括匹伐他汀类、二十碳五烯酸或其酯类衍生物、和药物可接受载体。
6.匹伐他汀类和二十碳五烯酸或其酯类衍生物在制造治疗高脂血症的药物中的用途。
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