CN101010080B - 高脂血症治疗剂 - Google Patents
高脂血症治疗剂 Download PDFInfo
- Publication number
- CN101010080B CN101010080B CN2005800291311A CN200580029131A CN101010080B CN 101010080 B CN101010080 B CN 101010080B CN 2005800291311 A CN2005800291311 A CN 2005800291311A CN 200580029131 A CN200580029131 A CN 200580029131A CN 101010080 B CN101010080 B CN 101010080B
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- Prior art keywords
- pitavastatin
- ezetimibe
- blood
- cholesterol
- hyperlipemia
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Classifications
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- 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
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Abstract
本发明提供一种高脂血症治疗剂和高胆固醇血症治疗剂，其特征在于，含有依泽替米贝和匹伐他汀、匹伐他汀的盐或匹伐他汀的内酯体。
Description
技术领域
本发明涉及一种对血液中的胆固醇具有优良的降低作用的高脂血症治疗剂。
背景技术
高脂血症是血液中的脂蛋白异常增高的症状，特别是指血液中的胆固醇高的症状。已知高脂血症与动脉硬化、心肌梗塞等疾病密切相关，因此认为其治疗是极为重要的。
多种药剂用于高脂血症和高胆固醇血症的治疗，目前，洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗苏伐他汀、匹伐他汀等的HMG-CoA还原酶抑制剂作为其治疗剂的主要成分。其中，已知匹伐他汀((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)具有强的HMG-CoA还原酶抑制作用，可用作高脂血症治疗剂(专利文献1～3)。
若将HMG-CoA还原酶抑制剂给药高脂血症患者，则血液中胆固醇降低。但是，血液中的胆固醇值非常高的患者也是非常多的，这样的患者中多数利用HMG-CoA还原酶抑制剂不能充分降低血液中的胆固醇值。在这种情况下，增加HMG-CoA还原酶抑制剂的给药量的治疗方法存在安全性的问题等，因此也不推荐。
另一方面，已知依泽替米贝((3R，4S)-1-(4-氟苯基)-3-[(3S)-3-(4-氟苯基)-3-羟丙基]-4-(4-羟苯基)-2-氮杂环丁酮)是抑制来自食物和来自胆汁酸的胆固醇在肠道中的吸收，以不同于HMG-CoA还原酶抑制剂的机制降低血液中胆固醇的高脂血症治疗剂(专利文献4)。
已公开了并用HMG-CoA还原酶抑制剂和依泽替米贝对降低血液中胆固醇和治疗动脉粥样硬化症是有效的(专利文献4)。此外，也报导了通过并用HMG-CoA还原酶抑制剂和依泽替米贝来降低血液中胆固醇的作用(非专利文献1)。
但是，尚不知道并用匹伐他汀和依泽替米贝对高脂血症表现出怎样的并用效果。
专利文献1：日本专利第2569746号公报
专利文献2：美国专利第5102888号公报
专利文献3：欧洲专利第304063号公报
专利文献4：WO95/08532小册子
非专利文献1：Metab.Clin.Exp.，50(10)，1234-1241(2001)
发明内容
本发明的目的在于提供一种对血液中胆固醇具有优良降低作用的高脂血症治疗剂和高胆固醇血症治疗剂。
本发明者等鉴于上述情况进行了深入研究，结果发现，并用匹伐他汀和依泽替米贝对降低血液中胆固醇具有显著优良的作用，可用于高脂血症和高胆固醇血症的治疗，从而完成本发明。
即，本发明提供一种高脂血症治疗剂，其特征在于，含有依泽替米贝和匹伐他汀、匹伐他汀的盐或匹伐他汀的内酯体。
本发明也提供一种高胆固醇血症治疗剂，其特征在于，含有依泽替米贝和匹伐他汀、匹伐他汀的盐或匹伐他汀的内酯体。
此外，本发明提供依泽替米贝和匹伐他汀、匹伐他汀的盐或匹伐他汀的内酯体在制造高脂血症治疗剂中的使用。
此外，本发明提供依泽替米贝和匹伐他汀、匹伐他汀的盐或匹伐他汀的内酯体在制造高胆固醇血症治疗剂中的使用。
进而，本发明提供一种高脂血症的处置方法，其特征在于，给药有效量的依泽替米贝和匹伐他汀、匹伐他汀的盐或匹伐他汀的内酯体。
进而，本发明提供一种高胆固醇血症的处置方法，其特征在于，给药有效量的依泽替米贝和匹伐他汀、匹伐他汀的盐或匹伐他汀的内酯体。
发明的效果
本发明的高脂血症治疗剂和高胆固醇血症治疗剂对血液中的胆固醇具有优良降低作用，对治疗高脂血症和高胆固醇血症是有效的。
附图说明
图1是表示通过匹伐他汀钙盐和依泽替米贝的并用给药降低血液中胆固醇的作用的图。
图2是表示通过阿托伐他汀钙盐和依泽替米贝的并用给药降低血液中胆固醇的作用的图。
具体实施方式
已知本发明所使用的匹伐他汀、匹伐他汀的盐或匹伐他汀的内酯体(以下有时记作匹伐他汀类)是具有基于HMG-CoA还原酶抑制的胆固醇合成抑制活性的高脂血症治疗剂。在这些匹伐他汀类中，优选为匹伐他汀的盐，特别优选为钙盐、钠盐。
已知本发明所使用的依泽替米贝是通过抑制胆固醇在肠道中的吸收而发挥其效果的药剂。
本发明将匹伐他汀类和依泽替米贝组合来进行治疗，如后述的实施例所述，在使用豚鼠(marmot)的评价系统中，相比于分别单独给药匹伐他汀类和依泽替米贝的情况，两种药剂并用给药具有显著降低血液中胆固醇的作用。
本发明的匹伐他汀类和依泽替米贝的给药形态可以适当选择，例如，散剂、颗粒剂、干糖浆剂、片剂、胶囊剂和注射剂等均可，这些给药形态能够通过本领域技术人员所公知惯用的制剂方法，将药学容许的载体与匹伐他汀类和依泽替米贝配合而制造。
当调制口服用固体制剂时，在添加赋形剂、根据需要添加粘合剂、崩解剂、润滑剂、着色剂、矫味剂、矫臭剂等之后，能够以常规方法制造片剂、颗粒剂、散剂、胶囊剂等。作为这些添加剂，使用在该领域中通常使用的物质即可，例如，作为赋形剂，能够例示乳糖、氯化钠、葡萄糖、淀粉、微晶纤维素、硅酸等；作为粘合剂，能够例示水、乙醇、丙醇、单糖浆、明胶液、羟丙基纤维素、甲基纤维素、乙基纤维素、虫胶、磷酸钙、聚乙烯吡咯烷酮等；作为崩解剂，能够例示琼脂粉、碳酸氢钠、十二烷基硫酸钠、硬脂酸甘油一酸酯等；作为润滑剂，能够例示精制滑石、硬脂酸盐、硼砂、聚乙二醇等；作为着色剂，能够例示β-胡萝卜素、黄色三氧化二铁、焦糖(caramelo)等；作为矫味剂，能够例示白糖、橙皮等。
当调制口服用液体制剂时，添加矫味剂、缓冲剂、稳定剂、保存剂等，能够以常规方法制造内服液剂、糖浆剂、酏剂等。作为这些添加剂，使用在该领域中通常使用的物质即可，例如，作为矫味剂，能够举出白糖等；作为缓冲剂，能够举出柠檬酸钠等；作为稳定剂，能够举出西黄蓍胶等，作为保存剂，能够举出对羟基苯甲酸酯等。
当调制注射剂时，添加pH调节剂、稳定剂、等张调节剂等，能够以常规方法制造皮下、肌肉和静脉注射剂。作为这些添加剂，使用在该领域中通常使用的物质即可，例如，作为pH调节剂，能够例示磷酸钠等；作为稳定剂，能够例示焦亚硫酸钠等；作为等张调节剂，能够例示氯化钠等。
本发明的药剂的使用方式没有特别的限定，除了将两种药剂同时给药之外，也可以隔开间隔分别给药。即，将匹伐他汀类和依泽替米贝两种药剂制成单一制剂，或者也可以将两种药物分别制成制剂而以组合的形式使用。此外，当将两种药物分别制成制剂时，两种制剂也可以不制成相同的剂型。
本发明的药剂的给药量可以根据症状进行适当地选择，匹伐他汀类以每天0.1～50mg，优选1～20mg的剂量给药；依泽替米贝以每天0.1～500mg，优选1～100mg的剂量给药即可。此外，可以一天给药一次，也可以分成两次以上给药。
实施例
以下，例举实施例对本发明做更加具体的说明，但是本发明不限于这些实施例。
实施例1
匹伐他汀钙盐和依泽替米贝并用给药降低血液中胆固醇的效果
以下面的试验方法测定将匹伐他汀钙盐和依泽替米贝并用给药时的降低血液中胆固醇的效果。作为比较例，代替匹伐他汀钙，并用给要阿托伐他汀钙盐，此时也以相同的方法进行测定。
1.试验动物和饲养环境
使用6周龄Hartley系雄性豚鼠(日本SLC(株))进行试验。在实验期间进行饲养，其饲养室内保持明暗循环(以室内光的明亮期间：上午7:00～下午7:00)，温度维持在23±3℃，湿度维持在55±15％，自由摄取固体饲料(RC-4：Oriental Yeast Co.，ltd.)和自来水。
2.制剂调制
本发明：匹伐他汀钙盐和依泽替米贝悬浮在羧甲基纤维素钠(岩井化学药品(株))的0.5质量％水溶液中，匹伐他汀钙盐调制为1mg/mL，依泽替米贝调制为3mg/mL。匹伐他汀钙盐含9.43质量％的水分，因此，称量给药量的1.1质量倍以进行校正。悬浮液冷藏(4℃)保存于遮光的瓶中，每7天调制一次。
比较例：使用阿托伐他汀钙盐代替匹伐他汀钙盐，同样制造比较试验用制剂。
3.试验方法
本发明：24只豚鼠分成以下四组(每组6例)，即，对照组、匹伐他汀钙盐单独给药(1mg/kg)组、依泽替米贝单独给药(3mg/kg)组、和并用给药组(匹伐他汀钙盐(1mg/kg)和依泽替米贝(3mg/kg))，各组的血液中总胆固醇的值和血液中甘油三酯的值被平均化。两种药剂分别以1mL/kg每天口服给药一次，持续14天，对照组口服给药羧甲基纤维素钠0.5质量％水溶液(1mL/kg)。所有组从最后一次给药起禁食18小时后采血，测定血液中胆固醇浓度。
比较例：使用24只豚鼠，以阿托伐他汀钙盐代替匹伐他汀钙盐，进行与本发明相同的试验。阿托伐他汀钙盐的给药量在阿托伐他汀钙盐单独给药组、和阿托伐他汀钙盐与依泽替米贝并用给药组均为5mg/kg。
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比较使用Bartlett方差分析-Dunnett多重比较检验进行，危险率小于5％认为具有统计学意义的差异。
5.结果
测定结果表示于表1、2和图1、2。
降低率(％)是以(((对照组血液中总胆固醇平均值-各组血液中总胆固醇平均值)/对照组血液中总胆固醇平均值)×100)表示的值；相对指数是以(各组血液中总胆固醇平均值/对照组血液中总胆固醇平均值)表示的值。
[表1]
血液中胆固醇的降低率(％)
| 给药组 | 降低率 | 相对指数 |
| 对照组 | 0 | 1.0 |
| 依泽替米贝单独给药组 | 21 | 0.79 |
| 匹伐他汀钙单独给药组 | 29 | 0.71 |
| 依泽替米贝/匹伐他汀钙并用给药组 | 51 | 0.49 |
[表2]
血液中胆固醇的降低率(％)
| 给药组 | 降低率 | 相对指数 |
| 对照组 | 0 | 1.0 |
| 依泽替米贝单独给药组 | 19 | 0.81 |
| 阿托伐他汀钙单独给药组 | 23 | 0.77 |
| 依泽替米贝/阿托伐他汀钙并用给药组 | 26 | 0.74 |
相比于各药剂单独给药组，作为本发明的匹伐他汀钙盐和依泽替米贝两种药剂并用给药组大大增强了降低血液中胆固醇的作用(p＜0.001)。其效果是相乘的(并用给药组的相对指数(0.49)＜各单独给药组的相对指数的积(0.79×0.71＝0.56))。
与此相对，在使用HMG-CoA还原酶抑制剂中的降低血液中胆固醇作用最强的阿托伐他汀钙盐的比较例中，相比于药剂分别单独给药组，阿托伐他汀钙盐和依泽替米贝两种药剂并用给药组虽然增强了降低血液中胆固醇的作用，但是其效果是相加的(并用给药组的相对指数(0.74)＞各单独给药组的相对指数的积(0.81×0.77＝0.62))。
因此，相比于其他的HMG-CoA还原酶抑制剂和依泽替米贝的并用给药，本发明的匹伐他汀钙盐和依泽替米贝两种药剂并用给药具有显著降低血液中胆固醇的效果。
Claims (4)
1.一种高脂血症治疗剂，其特征在于：
含有依泽替米贝和匹伐他汀钙。
2.一种高胆固醇血症治疗剂，其特征在于：
含有依泽替米贝和匹伐他汀钙。
3.依泽替米贝和匹伐他汀钙在制造高脂血症治疗剂中的使用。
4.依泽替米贝和匹伐他汀钙在制造高胆固醇血症治疗剂中的使用。
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| SA06270191B1 (ar) * | 2005-06-22 | 2010-03-29 | استرازينيكا ايه بي | مشتقات من 2- أزيتيدينون جديدة باعتبارها مثبطات لامتصاص الكوليسترول لعلاج حالات فرط نسبة الدهون في الدم |
| AR057383A1 (es) * | 2005-06-22 | 2007-12-05 | Astrazeneca Ab | Compuestos quimicos derivados de 2-azetidinona, formulacion farmaceutica y un proceso de preparacion del compuesto |
| AR060623A1 (es) * | 2006-04-27 | 2008-07-02 | Astrazeneca Ab | Compuestos derivados de 2-azetidinona y un metodo de preparacion |
| UA108742C2 (uk) | 2009-09-23 | 2015-06-10 | Фармацевтична композиція для лікування запальних захворювань, опосередкованих mcp-1 | |
| WO2011088055A2 (en) * | 2010-01-12 | 2011-07-21 | Zafgen Corporation | Methods and compositions for treating cardiovascular disorders |
| TWI586380B (zh) * | 2013-12-18 | 2017-06-11 | 夢製藥公司 | 包含ＨＭＧ－ＣｏＡ還原酶抑制劑及膽固醇吸收抑制劑之醫藥組合製劑 |
| US10413543B2 (en) * | 2015-09-01 | 2019-09-17 | Sun Pharma Advanced Research Company Ltd. | Stable multiparticulate pharmaceutical composition of rosuvastatin |
| JP6937195B2 (ja) * | 2017-09-01 | 2021-09-22 | 興和株式会社 | 医薬組成物 |
| JPWO2020178878A1 (zh) * | 2019-03-01 | 2020-09-10 | ||
| US11833133B2 (en) * | 2020-08-13 | 2023-12-05 | Orient Pharma Co., Ltd. | Solid oral pharmaceutical composition |
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| JP2569746B2 (ja) * | 1987-08-20 | 1997-01-08 | 日産化学工業株式会社 | キノリン系メバロノラクトン類 |
| US5185328A (en) * | 1987-08-20 | 1993-02-09 | Nissan Chemical Industries Ltd. | Quinoline type mevalonolactones useful for treating hyperlipidemia, hyperlipoproteinemia or atherosclerosis |
| US5854259A (en) * | 1987-08-20 | 1998-12-29 | Nissan Chemical Industries Ltd. | Quinoline type mevalonolactones |
| LT3300B (en) * | 1992-12-23 | 1995-06-26 | Schering Corp | Combination of a cholesterol biosynhtesis inhibitor and a beta- lactam cholesterol absorbtion inhibitor |
| US5631365A (en) | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| US6465477B1 (en) * | 1997-08-18 | 2002-10-15 | Kowa Company, Ltd. | Stable pharmaceutical composition |
| US7148197B2 (en) * | 2000-08-24 | 2006-12-12 | The Regents Of The University Of California | Orally administered small peptides synergize statin activity |
| KR20040026705A (ko) * | 2001-08-16 | 2004-03-31 | 테바 파마슈티컬 인더스트리즈 리미티드 | 스타틴의 칼슘 염 형태의 제조 방법 |
| AR040588A1 (es) * | 2002-07-26 | 2005-04-13 | Schering Corp | Formulacion farmaceutica que comprende un inhibidor de la absorcion del colesterol y un inhibidor de una hmg- co a reductasa |
| CA2594433C (en) * | 2005-01-10 | 2014-12-30 | Cortendo Invest Ab | Compositions comprising the 2s,4r ketoconazole enantiomer for treating diabetes, metabolic syndrome and other conditions |
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- 2004-11-29 US US10/997,878 patent/US20060046996A1/en not_active Abandoned
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2005
- 2005-08-30 EP EP05777087A patent/EP1785137B1/en not_active Revoked
- 2005-08-30 PL PL05777087T patent/PL1785137T3/pl unknown
- 2005-08-30 PT PT05777087T patent/PT1785137E/pt unknown
- 2005-08-30 WO PCT/JP2005/015756 patent/WO2006025378A1/ja active Application Filing
- 2005-08-30 AT AT05777087T patent/ATE489093T1/de active
- 2005-08-30 CN CN2005800291311A patent/CN101010080B/zh active Active
- 2005-08-30 KR KR1020077001596A patent/KR101244508B1/ko active IP Right Review Request
- 2005-08-30 DE DE602005024981T patent/DE602005024981D1/de active Active
- 2005-08-30 JP JP2006532716A patent/JP4886516B2/ja active Active
- 2005-08-30 ES ES05777087T patent/ES2354366T3/es active Active
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2006
- 2006-10-12 US US11/546,248 patent/US7459447B2/en active Active
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2008
- 2008-01-18 HK HK08100666.5A patent/HK1110200A1/xx not_active IP Right Cessation
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2011
- 2011-02-01 CY CY20111100106T patent/CY1111150T1/el unknown
Non-Patent Citations (1)
| Title |
|---|
| WO 2004010993 A1,page 3, line 29-33, line 18-21. |
Also Published As
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|---|---|
| HK1110200A1 (en) | 2008-07-11 |
| US20070032467A1 (en) | 2007-02-08 |
| PL1785137T3 (pl) | 2011-04-29 |
| EP1785137A1 (en) | 2007-05-16 |
| EP1785137A4 (en) | 2007-12-19 |
| CY1111150T1 (el) | 2015-06-11 |
| ATE489093T1 (de) | 2010-12-15 |
| US7459447B2 (en) | 2008-12-02 |
| WO2006025378A1 (ja) | 2006-03-09 |
| KR101244508B1 (ko) | 2013-03-18 |
| EP1785137B1 (en) | 2010-11-24 |
| JP4886516B2 (ja) | 2012-02-29 |
| KR20070047766A (ko) | 2007-05-07 |
| US20060046996A1 (en) | 2006-03-02 |
| PT1785137E (pt) | 2010-12-23 |
| CN101010080A (zh) | 2007-08-01 |
| JPWO2006025378A1 (ja) | 2008-05-08 |
| ES2354366T3 (es) | 2011-03-14 |
| DE602005024981D1 (de) | 2011-01-05 |
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