CN101252837A - 用二氢吡啶类钙通道阻断剂和Omega-3脂肪酸及其组合产品的治疗 - Google Patents
用二氢吡啶类钙通道阻断剂和Omega-3脂肪酸及其组合产品的治疗 Download PDFInfo
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Abstract
一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸混合物的组合,施用该组合的方法,以及该组合的单位剂型。
Description
本申请是2005年7月28日提交的临时专利申请60/703,002的非临时申请。在此通过参考的方式将在先申请的全部内容并入本文。
技术领域
本发明涉及通过一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸混合物(其包括二十碳五烯酸(EPA)和二十二碳六烯酸(DHA),优选Omacor omega-3脂肪酸)的组合的单次施用或单位剂型治疗以下疾病中任意一种的方法:高甘油三酯血症、高血压、狭心症(angina)、心脏衰竭、血管疾病、动脉硬化症及其相关疾病,预防或减少心血管和血管疾病,以及降低胆固醇和甘油三酯水平、胰岛素抗性、禁食葡萄糖水平和饭后葡萄糖水平。本发明也涉及单次施用一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸混合物的组合产品,其中的omega-3脂肪酸包括二十碳五烯酸(EPA)和二十二碳六烯酸(DHA),优选Omacor omega-3脂肪酸。
背景技术
在人类中,胆固醇和甘油三酯是血流中脂蛋白复合物的一部分,而且可以通过超速离心法分成高密度脂蛋白(HDL)部分、中密度脂蛋白(IDL)部分、低密度脂蛋白(LDL)部分和极低密度脂蛋白(VLDL)部分。胆固醇和甘油三酯在肝中合成,并入VLDL,释放到血浆中。高水平的总胆固醇(total-C)、LDL-C、和载脂蛋白B(LDL-C的膜复合体)会促进人类的动脉硬化以及降低HDL-C及其转移复合物-载脂蛋白A的水平,载脂蛋白A与动脉硬化的发展相关。另外,人类心血管发病率和死亡率与总胆固醇和LDL-C水平成正比,与HDL-C水平成反比。
二氢吡啶类(DHP)钙通道阻断剂广泛用于治疗高血压、狭心症、心律不齐、充血性心脏衰竭、心肌症、动脉硬化以及脑和外周血管疾病的治疗方法中。
二氢吡啶类钙通道阻断剂的形式包括Bay K 8644、氨氯地平(amlodipine)、非洛地平(felodipine)、拉西地平(lacidipine)、乐卡地平(lercanidipine)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)和伊拉地平(Isradipine)。
伊拉地平表现出高亲和力和特异性地与钙通道结合,并阻止钙流入心肌和平滑肌。一种形式的伊拉地平以DynaCirc的商标出售。DynaCirc以口服施用的胶囊形式提供,其包含例如2.5mg-5mg的伊拉地平。另一种形式的伊拉地平以DynaCirc CR的商标出售。DynaCirc以口服施用的控释片形式提供,其包含例如5mg-10mg的伊拉地平。海洋生物油,通常也称为鱼油,是两种omega-3脂肪酸的良好来源,所述的两种omega-3脂肪酸为二十碳五烯酸(EPA)和二十二碳六烯酸(DHA),其可调节脂类代谢。已发现omega-3脂肪酸对心血管疾病,特别是轻度高血压、高甘油三酯血症的风险因子以及对凝血因子VII磷脂复合物的活性有有益效果。Omega-3脂肪酸降低血清LDL-胆固醇,增加血清HDL-胆固醇,降低血清甘油三酯、降低收缩血压和舒张血压以及脉搏率,并且降低血液凝血因子VII-磷脂复合物的活性。而且,omega-3脂肪酸似乎有良好的耐受性,不会引起任何严重的副作用。
Omega-3脂肪酸的一种形式是从含有DHA和EPA的鱼油获得的omega-3长链多不饱和脂肪酸的浓缩物,而且以Omacor的商标出售。该形式的omega-3脂肪酸在例如美国专利5,502,077、5,656,667和5,698,594中有说明,在此通过参考的方式将这些专利的全部内容并入本文。
Finkel等人表明二氢吡啶类钙通道阻断剂Bay K 8644是浓度依赖的正性肌力(positive inotrope),即增加心脏的收缩力,从而增加心输出量。相反,EPA和omega-6脂肪酸花生四烯酸是浓度依赖的负性肌力(negativeinotrope)。Finkel等人表明花生四烯酸和EPA的组合产生浓度依赖的负性肌力。然而,Bay K 8644和EPA的组合产生浓度依赖的正性肌力。见Finkel等人的J.of Cardiovascular Pharmacol.,20:563-571(1992)。
Hallaq等人报道了omega-3脂肪酸EPA和DHA阻止高浓度强心苷乌本苷(cardiac glycoside ouabain)的毒性。相似地,添加EPA和DHA可阻止钙内流和由二氢吡啶类钙通道阻断剂Bay K 8644引起的细胞收缩的升高。Omega-3脂肪酸的阻止作用与降低钙内流速率的能力相关,该能力阻止高水平胞质的游离钙的产生。相反的,二氢吡啶类钙通道阻断剂尼群地平抑制胞质游离钙,并由于进入细胞的钙数量不足而完全阻止细胞收缩。同时添加EPA和DHA以及尼群地平可以阻止对细胞的这种抑制作用。这样,当过多的钙进入细胞时,同时添加EPA和DHA以及例如乌本苷或Bay K 8644可以降低钙内流。但当进入细胞的钙不足时,添加EPA和DHA以及例如尼群地平也可以打开钙通道。见Hallaq等人的Proc.Natl.Acad.Sci.Pharmacology,89:1760-1764(1992);和Hallaq等人的Fish Oil Vase.Dis.,85-88(1992)。
Pepe等人表明二氢吡啶类钙通道阻断剂尼群地平降低峰L型Ca2+通道电流、胞质Ca2+和细胞收缩。相反的,二氢吡啶类钙通道阻断剂Bay K 8644显著升高峰L型Ca2+通道电流、胞质Ca2+和细胞收缩。当细胞同时暴露于DHA和Bay K 8644或尼群地平时,二氢吡啶类钙通道阻断剂的作用被抑制。Pepe等人推断DHA在二氢吡啶的结合位点或其附近特异地与Ca2+通道结合,并干扰L型Ca2+通道电流的调节。见Pepe等人的Proc.Natl.Acad.Sci.Physiology,91:8832-836(1994)。
国际申请PCT/IE99/00031公开了一种自乳化的预浓缩药物组合物,用水溶液稀释时,所述组合物能够形成水包油的微乳剂或乳剂。所述组合物包含:治疗有效量的低水溶性治疗剂;药学有效量的低HLB油性组分;以及由至少一种HLB为大约10-20的表面活性剂组成的表面活性剂系统。所述治疗剂包括环孢霉素、硝苯地平或吲哚美辛且所述低HLB油性组分包括EPA或DHA。
美国专利申请(公开号:2006/0034815)公开了一种药物组合物,其包括一种omega-3油和一种或多种他汀盐,其中至少约80wt%的他汀以固体颗粒的形式存在于多相悬浮液中,在此通过参考的方式并入其全部内容。在另一个实施例中,该公布文本提供了一种包括omega-3油和一种或多种他汀盐的药物组合物,其中多至15wt%的他汀为溶液,而剩余的他汀以多相悬浮液的形式存在。
然而,在先技术没有公开本发明的组合治疗,本发明的组合治疗使用一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸(优选Omacor omega-3脂肪酸)的组合。另外,在先技术没有公开单次施用或单位剂型的一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸(优选Omacor omega-3脂肪酸)的组合,其提供了全新的、更有效的高甘油三酯血症、高胆固醇血症、高血压、狭心症、血管疾病、动脉硬化症和相关疾病的药物治疗,以及有效预防和减少心血管和血管疾病,以及有效降低胰岛素抗性、禁食葡萄糖水平和饭后葡萄糖水平。
发明内容
本领域中对一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸的组合产品的需求仍未得到满足。尤其是,本领域对提供具有特异治疗特性的单次施用的omega-3脂肪酸(例如Omacor omega-3脂肪酸)与一种或多种二氢吡啶类钙通道阻断剂的组合产品,例如单位剂型的需求仍未得到满足。
本领域对单次施用或单位剂型产品的施用方法的需求也未得到满足。而且,本领域对一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸(例如Omacor omega-3脂肪酸)的单次施用或单位剂型产品的需求仍未得到满足,其中一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸组合以提供特异的治疗特性。
本发明通过共施用一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸或施用一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸的单位剂型满足了本领域以及其他领域的未满足需求,其对以下任何疾病提供了有效的药物治疗:高甘油三酯血症、高胆固醇血症、高血压、狭心症、心脏衰竭、血管疾病、动脉硬化症和相关疾病,且其有效预防和减少心血管和血管疾病,以及有效降低胆固醇和甘油三酯水平、降低胰岛素抗性、禁食葡萄糖水平和饭后葡萄糖水平。
本发明的一些具体实施方式提供了使用一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸的组合治疗以下任何疾病的方法:高甘油三酯血症、高胆固醇血症、高血压、狭心症、心脏衰竭、血管疾病、动脉硬化症和相关疾病;预防和减少心血管和血管疾病的;以及降低胆固醇和甘油三酯水平、胰岛素抗性、禁食葡萄糖水平和饭后葡萄糖水平。
本发明的其他具体实施方式针对包括一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸的组合产品,例如单位剂型。在具体实施方式的一个方面中,组合产品用于治疗以下任何疾病症:高甘油三酯血症、高胆固醇血症、高血压、狭心症、心脏衰竭、血管疾病、动脉硬化症和相关疾病,预防和减少心血管和血管疾病,以及降低胆固醇和甘油三酯水平、降低胰岛素抗性、禁食葡萄糖水平和饭后葡萄糖水平。
本发明的其他具体实施方式是治疗以下任何疾病的方法:高甘油三酯血症、高胆固醇血症、高血压、狭心症、心脏衰竭、血管疾病、动脉硬化症和相关疾病,预防和减少心血管和血管疾病的方法,以及降低胆固醇和甘油三酯水平、降低胰岛素抗性、禁食葡萄糖水平和饭后葡萄糖水平的方法,其包括组合施用一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸(优选的是特定的产品:Omacor omega-3脂肪酸)。
在本发明的一些具体实施方式中,二氢吡啶类钙通道阻断剂包括BayK 8644、氨氯地平(例如Norvasc)、非洛地平(例如Plendil)、拉西地平(例如Lacipil)、乐卡地平(例如Zanidip)、尼卡地平(例如Cardene)、硝苯地平(例如Adalat、Procardia)、尼莫地平(例如Nimotop)、尼索地平(例如Sular)、尼群地平和伊拉地平(例如DynaCirc)。
在优选的具体实施方式中,二氢吡啶类钙通道阻断剂是伊拉地平。
通过阅读以下说明或通过实践本发明所授内容,本领域技术人员可以了解本发明的其他性质和优点。
本发明的最佳实施方式
本发明涉及使用一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸(优选Omacor omega-3脂肪酸)治疗以下任何疾病:高甘油三酯血症、高胆固醇血症、高血压、狭心症、心脏衰竭、血管疾病、动脉硬化症和相关疾病,预防和减少心血管和血管疾病,以及降低胆固醇和甘油三酯水平、降低胰岛素抗性、禁食葡萄糖水平和饭后葡萄糖水平,还涉及使用包括一种或多种二氢吡啶类钙通道阻断剂和一种或多种omega-3脂肪酸的组合产品或单位剂型。
在一些具体实施方式中,本发明提供了全新的组合产品,其用于治疗以下任何疾病:高甘油三酯血症、高胆固醇血症、高血压、狭心症、心脏衰竭、血管疾病、动脉硬化症和相关疾病,并预防和减少心血管和血管疾病,以及降低胆固醇和甘油三酯水平、降低胰岛素抗性、禁食葡萄糖水平和饭后葡萄糖水平,还包括对患者施用该组合产品。在优选的具体实施方式中,所施用的包括优选为Omacor omega-3脂肪酸形式的omega-3脂肪酸和一种或多种二氢吡啶类钙通道阻断剂,其中Omacor omega-3脂肪酸与一种或多种二氢吡啶类钙通道阻断剂同时施用。
在其他优选的具体实施方式中,所施用的包括优选为Omacor omega-3脂肪酸形式的omega-3脂肪酸和一种或多种二氢吡啶类钙通道阻断剂,其中Omacor omega-3脂肪酸与一种或多种二氢吡啶类钙通道阻断剂分别施用。例如,每周施用一次伊拉地平(例如,通过伊拉地平贴片),伴以每日摄取omega脂肪酸(例如Omacor胶囊)。本领域技术人员借助本发明的公开内容,能够认识到施用Omacor omega-3脂肪酸与一种或多种二氢吡啶类钙通道阻断剂的精确剂量和时间根据多种因素,例如施用途径和疾病的严重程度而变化。
本发明包括通常认为是安全剂量的现在已知的或未来将知的二氢吡啶类钙通道阻断剂。例如,二氢吡啶类钙通道阻断剂包括Bay K 8644、氨氯地平、非洛地平、拉西地平、乐卡地平、尼卡地平、硝苯地平、尼莫地平、尼索地平、尼群地平和伊拉地平。在一个优选的具体实施方式中,二氢吡啶类钙通道阻断剂是伊拉地平。
很明显,本发明的组合产品包含一种二氢吡啶类钙通道阻断剂或多种二氢吡啶类钙通道阻断剂。在一些具体实施方式中,多于一种的二氢吡啶类钙通道阻断剂与大量的omega-3脂肪酸组合。
本文使用的术语“omega-3脂肪酸”包括天然或合成的omega-3脂肪酸、或其药学可接受的酯、其衍生物、其结合物(参见,例如Zaloga等人的美国专利申请公布2004/0254357,和Horrobin等人的美国专利6,245,811,通过参考的方式将其并入本文)、其前体或其盐、及它们的混合物。Omega-3脂肪酸油的实例包括,但不限于:omega-3多不饱和的长链脂肪酸,例如二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和α-亚麻酸;omega-3脂肪酸与甘油的酯,例如甘油单酯、甘油二酯和甘油三酯;以及omega-3脂肪酸与伯醇、仲醇或叔醇的酯,例如脂肪酸甲酯和脂肪酸乙酯。优选的omega-3脂肪酸油是长链脂肪酸,例如EPA或DHA,其甘油三酯、其乙酯、及它们的混合物。Omega-3脂肪酸或其酯、其衍生物、其结合物、其前体、其盐、及它们的混合物可以以它们的纯品形式使用或作为例如鱼油(优选纯化的鱼油浓缩物)的油的组分使用。适用于本发明的omega-3脂肪酸的市售实例包括Incromega F2250、F2628、E2251、F2573、TG2162、TG2779、TG2928、TG3525和E5015(自英国,约克郡的Croda International PLC)、以及EPAX6000FA、EPAX5000TG、EPAX4510TG、EPAX2050TG、K85TG、K85EE、K80EE和EPAX7010EE(自挪威,利萨克的Pronova Biocare a.s.,1327)。
美国专利5,502,077、5,656,667和5,698,694中说明了omega-3脂肪酸的优选形式,在此通过参考的方式将这些专利的全部内容并入本文。
另一种优选的组合物包括浓度为至少40wt%,优选至少50wt%,更优选至少60wt%,再优选至少70wt%,最优选至少80wt%,或进一步为至少90wt%的omega-3脂肪酸。优选地,omega-3脂肪酸包括至少50wt%,更优选至少60wt%,再更优选至少70wt%,最优选至少80wt%,例如约84wt%的EPA和DHA。优选地,omega-3脂肪酸包括约5~100wt%,更优选约25~75wt%,再更优选约40~55%,且最优选约46wt%的EPA。优选地,omega-3脂肪酸包括约5~100wt%,优选约25~75wt%,更优选约30~60wt%,且最优选约38wt%的DHA。除非另有说明,以上所有重量百分比都是与组合物中含有的总脂肪酸的重量相比。重量百分比基于游离酸或酯的形式,即使其他形式也用于本发明,但优选地基于omega-3脂肪酸的乙酯形式。
EPA∶DHA的比例可以为99∶1~1∶99,优选4∶1~1∶4,更优选3∶1~1∶3,最优选2∶1~1∶2。Omega-3脂肪酸可以包括纯EPA或纯DHA。
所述omega-3脂肪酸油可任选地包括诸如α生育酚等的化学抗氧化剂,诸如大豆油和部分氢化的植物油等的油,和诸如分馏的椰子油、卵磷脂及其混合物等的润滑剂。
Omega-3脂肪酸的最优选形式是Omacor omega-3酸(自挪威,利萨克的,Pronova Biocare A.S.的K85EE),且优选包括如下特征(每个剂型):
测试 | 最小值 | 最大值 |
二十碳五烯酸C20:5 | 430mg/g | 495mg/g |
二十二碳六烯酸C22:6 | 347mg/g | 403mg/g |
EPA和DHA | 800mg/g | 880mg/g |
总n-3脂肪酸 | 90%(w/w) |
一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸(优选Omacor omega-3酸)的组合产品可通过本领域已知的任何方法给药。这些模式包括口服给药、直肠给药、鼻腔给药、局部(包括口腔和舌下)给药或肠胃外(包括皮下、肌肉内、静脉和皮内)给药。这些组合物优选以口服给药。
本发明的组合物中的活性组分的剂量可变化;然而,活性组分的量应当是能够获得合适的剂型的量。所选的剂量依赖所需的治疗效果,给药途径以及治疗期限。本发明的组合物的一些具体实施方式主要包括有效剂量、药物有效量或治疗有效量的一种或多种二氢吡啶类钙通道阻断剂。
一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸的组合产品以本领域已知的以下形式施用:胶囊、片剂、可分散在饮料中的粉末、液体、软胶囊或其他方便的剂型(诸如于胶囊中的口服液体)。在一些实施方式中,胶囊包括硬明胶。组合产品还可包含在适用于注射或输液的液体中。
本发明的活性成分(一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸)还可以与一种或多种非活性药物成分(一般也称作“赋形剂”)组合施用。非活性成分例如有助于溶解、悬浮、增稠、稀释、乳化、稳定、保藏、保护、着色、调味、以及将所述活性成分制成适用的安全方便等可应用的、有效的制剂。因此,非活性成分可包括胶态二氧化硅、交联聚维酮、乳糖一水合物、卵磷脂、微晶纤维素、聚乙烯醇、聚维酮、十二烷基硫酸钠、硬脂富马酸钠、滑石粉、二氧化钛和黄原胶。
在大多数的具体实施方式中,赋形剂主要包括表面活性剂,例如丙二醇单辛酸酯、长链脂肪酸的甘油酯和长链脂肪酸的聚乙二醇酯的混合物、聚乙氧基蓖麻油(polyethoxylated castor oils)、甘油酯、油酰聚乙二醇甘油酯(oleoyl macrogol glycerides)、丙二醇单月桂酸酯(propylene glycolmonolaurate)、丙二醇二辛酸酯/二癸酸酯、聚乙二醇-聚丙二醇共聚物(polyethylene-polypropylene glycol copolymer)和聚氧乙烯山梨糖醇酐单油酸酯(polyoxyethylene sorbitan monooleate);潜溶剂,例如乙醇、甘油、聚乙二醇和丙二醇;以及油,例如椰子油、橄榄油或红花油。表面活性剂、潜溶剂、油或它们的组合的使用是药物学领域普遍已知的,并且本领域技术人员应认识到任何合适的表面活性剂可与本发明及其具体实施方式联合使用。
Omega-3脂肪酸每天可施用的量为约0.1g~约10g,更优选约0.5g~约8g,最优选约0.75g~约4g。优选地,单位剂型中的omega-3脂肪酸剂的含量为约0.1g~约2g,优选约0.5g~约1.5g,更优选约1g。
在本发明的一个具体实施方式中,二氢吡啶类钙通道阻断剂的含量一般为约0.5mg~约100mg,优选为约1mg~约50mg,最优选为约2.5mg~20mg。
在本发明的一些变体中,一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸(例如Omacor omega-3酸)的组合被制成单次施用形式或单位剂型,其使用选自如下群组中的二氢吡啶类钙通道阻断剂:Bay K8644、氨氯地平(例如Norvasc)、非洛地平(例如Plendil)、拉西地平(例如Lacipil)、乐卡地平(例如Zanidip)、尼卡地平(例如Cardene)、硝苯地平(例如Adalat、Procardia)、尼莫地平(例如Nimotop)、尼索地平(例如Sular)、尼群地平和伊拉地平(例如DynaCirc)。
一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸的每日剂量可以一共以每日1~10个剂量数施用,优选的剂量数是每天1到4次。尽管可以使用其他施用方式提供一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸的单位剂型,但优选以口服给药方式施用。
在一些优选具体实施方式中,使用软胶囊。软胶囊的制造是本领域普通技术人员普遍已知的。可参考例如Ebert(1978),″Soft Elastic GelatinCapsules:A Unique Dosage Form,″Pharmaceutical Technology 1(5),在此通过参考的方式将其并入本文。在一些具体实施方式中,一种或多种二氢吡啶类钙通道阻断剂和/或omega-3脂肪酸包含在软胶囊中。在某些具体实施方式中,软胶囊中的活性组分与增溶剂组合。增溶剂包括表面活性剂、亲水或疏水溶剂、油或它们的组合。
可以使用的一种增溶剂类型是维生素E物质。该组增溶剂包括属于α-、β-、γ-、δ-、ζ1-、ζ2-和η-生育酚、其dl、d和l形式以及它们的结构类似物(如生育三烯酚)的物质;与有机酸产生的相应的衍生物,例如酯;以及它们的混合物。优选的维生素E物质增溶剂包括生育酚、生育三烯酚和与有机酸产生的生育酚衍生物,有机酸例如乙酸、丙酸、胆汁酸、乳酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、反丁烯二酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、聚乙二醇琥珀酸酯和水杨酸。特别优选的维生素E物质增溶剂包括α-生育酚、α-生育酚醋酸酯、α-生育酚琥珀酸酯、α-生育酚聚乙二醇1000琥珀酸酯及它们的混合物。
另一组增溶剂是有机酸的一元醇酯。一元醇可以例如是乙醇、异丙醇、叔丁醇、脂肪醇、苯酚、甲酚、苄醇或环烷基醇。有机酸可以例如是乙酸、丙酸、丁酸、具有6-22个碳原子的脂肪酸、胆汁酸、乳酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、反丁烯二酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸和水杨酸。本组中优选的增溶剂包括柠檬酸三烷基酯、低级醇脂肪酸酯和内酯。优选的柠檬酸三烷基酯包括柠檬酸三乙酯、乙酰柠檬酸三乙酯、柠檬酸三丁酯、乙酰柠檬酸三丁酯及其混合物,其中特别优选柠檬酸三乙酯。特别优选的低级醇脂肪酸酯包括油酸乙酯、亚油酸乙酯、辛酸乙酯、癸酸乙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯及它们的混合物。内酯也可作为增溶剂。实例包括ε-己内酯、δ-戊内酯、β-丁内酯、它们的异构体、以及它们的混合物。
增溶剂可以是含氮溶剂。优选的含氮溶剂包括二甲基甲酰胺、二甲基乙酰胺、N-烷基吡咯烷酮、N-羟烷基吡咯烷酮、N-烷基哌啶酮、N-烷基己内酰胺及它们的混合物,其中烷基是C1-12支链或直链烷基。特别优选的含氮溶剂包括N-甲基-2-吡咯烷酮、N-乙基-2-吡咯烷酮或它们的混合物。另外,含氮溶剂可以是聚合物形式,例如聚乙烯吡咯烷酮。
另一组增溶剂包括磷脂。优选的磷脂包括磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、卵磷脂、溶血卵磷脂、溶血磷脂酰胆碱、聚乙二醇化磷脂/聚乙二醇化溶血磷脂(polyethylene glycolatedphospholipids/lysophospholipids)、聚乙二醇化卵磷脂/聚乙二醇化溶血卵磷脂及它们的混合物。
另一组优选的增溶剂是乙酸甘油酯和乙酰化甘油脂肪酸酯。优选的乙酸甘油酯包括醋精、二醋精、三醋精及它们的混合物,其中三醋精是特别优选的。优选的乙酰化甘油脂肪酸酯包括乙酰化甘油单酯、乙酰化甘油二酯及它们的混合物。
另外,增溶剂可以是甘油脂肪酸酯。脂肪酸组分大约有6-22个碳原子。甘油脂肪酸酯可以是甘油单酯、甘油二酯、甘油三酯及它们的混合物。优选的甘油脂肪酸酯包括甘油单酯、甘油二酯、脂肪酸具有6-12个碳的中链甘油三酯及它们的混合物。特别优选的甘油脂肪酸酯包括脂肪酸含6-12个碳的中链甘油单酯、脂肪酸含6-12个碳的中链甘油二酯及它们的混合物。
增溶剂可以是丙二醇酯。优选的丙二醇酯包括碳酸丙二酯、丙二醇单乙酸酯、丙二醇二乙酸酯、丙二醇脂肪酸酯、乙酰化丙二醇脂肪酸酯及它们的混合物。另外,丙二醇脂肪酸酯可以是丙二醇脂肪酸单酯、丙二醇脂肪酸二酯或它们的混合物。脂肪酸含有大约6-22个碳原子。特别优选的丙二醇酯是丙二醇单辛酸酯(CAPRYOL)。其他优选的丙二醇酯包括丙二醇二辛酸酯、丙二醇二癸酸酯、丙二醇二辛酸酯/丙二醇二癸酸酯及它们的混合物。
另外一组增溶剂是乙二醇酯。乙二醇酯包括单乙二醇单乙酸酯、二乙二醇酯、聚乙二醇酯及它们的混合物。其他的实例包括乙二醇单乙酸酯、乙二醇二乙酸酯、乙二醇脂肪酸单酯、乙二醇脂肪酸二酯及它们的混合物。另外,乙二醇酯可以是聚乙二醇脂肪酸单酯、聚乙二醇脂肪酸二酯或它们的混合物。同样地,脂肪酸组分包含大约6-22个碳原子。特别优选的乙二醇酯是以Labrafil和Labrasol命名的乙二醇酯。
例如含4-25个烯烃的聚氧乙烯-山梨醇-脂肪酸酯(也称为聚山梨醇酯)也适于作为表面活性剂,例如已知的商品名为Tween的市售的单月桂酸酯和三月桂酸酯、棕榈酸酯、硬脂酸酯和油酸酯。
可使用的亲水溶剂包括醇,例如与水混溶的乙醇,例如无水乙醇,或甘油。其他醇包括甘醇,例如从氧化物(如乙烯氧化物)可得到的任何甘醇,例如1,2-丙二醇。其他实例是多元醇,例如聚烷撑二醇,例如聚(C2-3)烷撑二醇。典型的例子是聚乙二醇。可选地,亲水组分优选地包括N-烷基吡咯烷酮,例如N-(C1-14烷基)吡咯烷酮,例如N-甲基吡咯烷酮、三(C1-4烷基)柠檬酸,例如柠檬酸三乙酯、二甲基异山梨醇、(C5-C13)链烷酸,例如辛酸或碳酸丙二酯。
亲水溶剂可包含一种主要组分或单一组分,例如一种醇,例如C1-4-醇(例如乙醇),或包含例如可选自部分低级醚或低级链烷醇的其他共组分。优选的部分醚例如是Transcutol(其分子式为C2H5-[O-(CH2)2]2-OH)、Glycofurol(也称为四氢糠醇聚乙二醇醚)或者低链烷醇,如乙醇。
一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸的组合产品受助于一种或多种二氢吡啶类钙通道阻断剂在omega-3脂肪酸油中的溶解度。在本发明的一些具体实施方式中,单位剂型的药物组合物包括均相溶液,该均相溶液包括基本溶解在溶剂系统中的一种或多种二氢吡啶类钙通道阻断剂,该溶剂系统包括天然或合成的omega-3脂肪酸或其药学可接受的酯、衍生物、结合物、前体或盐,或者它们的混合物,其中溶剂系统中不溶解的一种或多种二氢吡啶类钙通道阻断剂少于10%。一种或多种二氢吡啶类钙通道阻断剂基本溶解在omega-3脂肪酸油中以提供基本均质的组合物。优选地,本发明的这一方面不含有用以溶解一种或多种二氢吡啶类钙通道阻断剂的大量增溶剂。优选地,一种或多种二氢吡啶类钙通道阻断剂在不使用大量增溶剂(除了omega-3脂肪酸)情况下包含在药物组合物中,并基本溶解(即,溶剂系统中不溶解的阻断剂少于10%,优选地少于5%)。
在优选的具体实施方式中,一种或多种二氢吡啶类钙通道阻断剂是完全溶解的。在优选的具体实施方式中,如果有增溶剂,omega-3脂肪酸以外的增溶剂的量占剂型中溶剂系统总重量的50% w/w或更少,优选40%或更少,更优选30%或更少,进一步更优选20%或更少,再更优选10%或更少,且最优选5%或更少。在一些实施方式中,溶剂系统不包含omega-3脂肪酸以外的增溶剂。如本文所用的,“溶剂系统”包括通常为油形式的omega-3脂肪酸。在其它优选的具体实施方式中,omega-3脂肪酸与增溶剂的重量比是至少0.5∶1,更优选至少1∶1,进一步更优选至少5∶1,且最优选至少10∶1。
在优选的具体实施方式中,包含在剂型中的omega-3脂肪酸的量,占剂型中溶剂系统总重量的至少30% w/w,更优选至少40%,进一步优选至少50%,且最优选至少60%。在一些实施方式中,所述含量是至少70%,至少80%或至少90%。
在室温(约23℃至27℃,优选约25℃)及60%相对湿度下,包括基本为均相溶液的剂型在至少一个月,优选至少六个月,更优选至少一年,且最优选至少两年的期间是稳定的。对于“稳定”,申请人意指溶解了的一种或多种二氢吡啶类钙通道阻断剂不会从溶液中析出达可察觉的程度也不会发生化学变化达任何可察觉的程度,例如析出量少于10%,优选少于5%。
另外,包括基本为均相溶液的剂型应保护一种或多种二氢吡啶类钙通道阻断剂免于降解。一些具体实施方式包括一种或多种二氢吡啶类钙通道阻断剂与omega-3脂肪酸的单位剂型,其中在室温和60%的相对湿度下存放一个月后,剂型中在起始测量时间(t0)下测量的一种或多种二氢吡啶类钙通道阻断剂的起始量至少能够保留90%。
组合产品可通过本领域普通技术人员已知的任何方法,通过将二氢吡啶类钙通道阻断剂与omega-3脂肪酸以及任选的亲水溶剂、表面活性剂、其他增溶剂和/或前体赋形剂合并来制造。
本发明的其他具体实施方式针对一种或多种二氢吡啶类钙通道阻断剂在omega-3脂肪酸中的悬浮液。在一些具体实施方式中,悬浮液包括在omega-3脂肪酸中的一种或多种二氢吡啶类钙通道阻断剂的固体晶体颗粒,固体非晶形颗粒或它们的混合物。其他具体实施方式包括药物组合物,其包括一种或多种二氢吡啶类钙通道阻断剂在omega-3脂肪酸中的悬浮液,其中一种或多种二氢吡啶类钙通道阻断剂的一部分溶解在omega-3脂肪酸或组合物的另一组分中。例如,在一些具体实施方式中,本发明提供了包括omega-3脂肪酸和一种或多种二氢吡啶类钙通道阻断剂的药物组合物,其中约1-15% w/w的一种或多种二氢吡啶类钙通道阻断剂在溶液中,而剩余的一种或多种二氢吡啶类钙通道阻断剂在悬浮液中。
在其他具体实施方式中,本发明提供了包括omega-3脂肪酸和一种或多种二氢吡啶类钙通道阻断剂的药物组合物,其中至少约80% w/w,优选约85%w/w,更优选约90% w/w,再更优选约95% w/w,且最优选约99% w/w的一种或多种二氢吡啶类钙通道阻断剂以固体颗粒形式存在于悬浮液中。
本发明的另一个具体实施方式针对用一种或多种二氢吡啶类钙通道阻断剂包衣的软胶囊。在该具体实施方式中,施加在软胶囊外的至少一层包衣包括一种或多种二氢吡啶类钙通道阻断剂和包衣材料(例如成膜材料和/或粘合剂),以及任选的其他常规添加剂(例如润滑剂、填充剂和抗粘剂)。优选的包衣材料包括抗氧化剂、增溶剂、螯合剂和/或吸收促进剂。表面活性剂可作为增溶剂和吸收促进剂发挥作用。
可通过任何常规的技术,例如锅包衣法、流化床包衣法或喷雾包衣法进行包衣。包衣材料可以以悬浮液、喷雾液、粉尘或粉末的形式进行包衣。根据本领域已知的方法,可将包衣制成第二药物活性成分的即释、延迟/肠溶释放或缓释剂型。常规的包衣技术在例如Remington′s Pharmaceutical Sciences,18th Ed.(1990)中有描述,并通过参考的方式将其并入本文。
通常使用即释包衣以提高产品品质(elegance)并作为防潮层以及用于遮蔽味道和气味。重要的是在胃液中迅速破坏薄膜,从而导致有效的崩解和溶出。EUDRAGIT RD100(Rohm)是这样的包衣实例。其是非水溶性阳离子甲基丙烯酸酯共聚物和水溶性纤维素醚的组合。在粉末形式时,其易于分散成可喷射的悬浮液,干燥后形成平滑薄膜。这样的薄膜在水性介质中不依赖pH和薄膜厚度而迅速崩解。
如需要,可通过常规的包衣技术,例如通过锅包衣法或流化床包衣法使用聚合物在水或合适的有机溶剂中的溶液,或者使用水性聚合物分散液施加保护包衣层(即封闭层)。保护层的合适材料包括纤维素衍生物,例如羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙烯吡咯烷酮/醋酸乙烯酯的共聚物、乙基纤维素水相分散液等等。保护包衣层可包括抗氧化剂、螯合剂、颜料或染料。
可通过常规的包衣技术,例如通过锅包衣法或流化床包衣法使用聚合物在水或合适的有机溶剂中的溶液,或者使用水性聚合物分散液,将肠溶包衣层施加在具有或不具有封闭包衣层的药芯上。可包括所有市售的pH敏感聚合物。在大约低于pH4.5(但不限于此数值)的酸性胃环境下,药物的活性成分不被释放。在一定的延迟时间后,或在单位剂型通过胃之后,当pH敏感层在更高pH下溶解时释放出药物活性成分。优选的延迟时间在2-6小时的范围内。
肠溶聚合物包括醋酸邻苯二甲酸纤维素、醋酸偏苯三酸纤维素(celluloseacetate trimellitate)、邻苯二甲酸羟丙基甲基纤维素、聚醋酸乙烯邻苯二甲酸酯、羧甲基乙基纤维素、甲基丙烯酸/甲基丙烯酸甲酯的共聚物,例如商品名为EUDRAGIT L12.5、L100或EUDRAGIT S12.5、S100,或者用于获得肠溶式包衣的类似化合物。也可使用水性胶体聚合物分散液或重分散液(redispersions),例如EUDRAGIT L 30D-55、EUDRAGIT L100-55、EUDRAGIT S100、EUDRAGIT preparation 4110D(Rohm Pharma);AQUATERIC 1AQUACOAT CPD 30(FMC);KOLLICOAT MAE 30D和30DP(BASF);EASTACRYL 30D(Eastman Chemical)。
缓释型包衣可包括如蜡或蜡样物质的非水溶性材料、脂肪醇、虫漆、玉米蛋白、氢化植物油、非水溶性纤维素、丙烯酸和/或甲基丙烯酸的聚合物、以及本领域已知的其他慢消化或慢分散固体。用于疏水包衣材料的溶剂可以是有机溶剂或水性溶剂。优选地,疏水聚合物选自(i)非水溶性纤维素聚合物,例如烷基纤维素,优选乙基纤维素;(ii)丙烯酸聚合物;或者(iii)它们的混合物。在本发明的其他优选具体实施方式中,包括控释型包衣的疏水材料是丙烯酸类聚合物。任何药学可接受的丙烯酸类聚合物可用于本发明。丙烯酸类聚合物可以是阳离子、阴离子或非离子聚合物,且其可以是丙烯酸酯、由甲基丙烯酸或甲基丙烯酸酯形成的甲基丙烯酸酯聚合物。合适的丙烯酸类聚合物的实例包括但不局限于丙烯酸和甲基丙烯酸的共聚物、甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、乙氧基乙基甲基丙烯酸酯、氰乙基甲基丙烯酸酯(cyanoethyl methacrylate)、甲基丙烯酸甲酯、共聚物,甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸共聚物、氨烷基甲基丙烯酸酯共聚物、甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、聚(丙烯酸)、聚(甲基丙烯酸)、甲基丙烯酸烷基胺共聚物、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸)(酸酐)、甲基丙烯酸甲酯、聚甲基丙烯酸酯(polymethacrylate)、甲基丙烯酸甲酯共聚物,聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸甲酯)共聚物、聚丙烯酰胺、氨烷基甲基丙烯酸酯共聚物,聚(甲基丙烯酸酸酐)和缩水甘油甲基丙烯酸酯共聚物。
屏蔽包衣(barrier coat)可在外包衣和软胶囊壳之间。屏蔽包衣可由肠溶/延迟释放型包衣(如上所述)、或屏蔽(非功能)层组成,其作为保护包衣以防止药物活性组分从壳向外的泄漏,或反之亦然。
在本发明的一个具体实施方式中,将一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸分成第一部分和第二部分,其中一部分放置在包衣上,第二部分放置在软胶囊内。例如通过使用屏蔽层作为肠溶包衣,使该剂型的第一部分和和第二部分的施用时间之间存在落差。在一些具体实施方式中,第一部分被即释后延迟释放或缓释第二部分。在其他具体实施方式中,延迟释放第一部分后,接着释放大量的第二部分。
尽管在制药工业中广泛使用包衣技术,例如将功能性或非功能性包衣用于单一剂型中以及将APIs沉积在糖珠上,但在对软胶囊包衣时仍有几项难题。这些难题经常归因于明胶的性质和剂型形式。软胶囊通常包含溶解或分散在油或亲水液体(填充液体)中的药物。软胶囊固有的弹性源自存在于胶囊壳内的增塑剂和残余水分。这样,相比常规片剂或硬胶囊,软胶囊是更动态的系统。空气中的水分可以渗透至胶囊壳内或填充液体中。药物或填充液体也可转移到胶囊壳内,而增塑剂或残余水明胶也可转移到填充液体内。软胶囊中的挥发性组分可逃逸到空气中。
如上所述,聚合包衣通常以水性溶液、有机溶液或分散体形式使用,其中含聚合物的液滴用空气雾化并喷涂到底物上。可对包衣设备加热以利于溶剂的蒸发和薄膜的形成。对于软胶囊,必须控制喷涂速率和流化床温度的加工参数。因为明胶可溶于水,高速喷涂水性聚合物会导致明胶的溶解和胶囊的结块。床温度高会导致残余的水分从胶囊壳中蒸发,使得胶囊易碎。因此,本发明还涉及对软胶囊包衣的方法,其中避免出现上述后果。
另外,将低剂量的一种或多种二氢吡啶类钙通道阻断剂以高精度沉积在软胶囊表面受多种因素的影响。通过评估包衣均匀性来评估沉积的精确度,所述均匀性包括包衣胶囊的质量偏差和所包衣的一种或多种二氢吡啶类钙通道阻断剂的含量偏差。
本发明提供了用包含包衣材料和一种或多种二氢吡啶类钙通道阻断剂的包衣对包含omega-3脂肪酸的混合物的软胶囊进行包衣的方法,该方法包括控制包衣沉积在软胶囊上的速率和控制包衣处理期间的温度,从而产生物理和化学稳定的包衣的软胶囊。
在其他具体实施方式中,本发明的包衣也用在硬胶囊或片剂上。硬胶囊内包含的是粉末、珠粒或微片(例如类似于美国专利5,681,588中提及的系统,并通过参考的方式将其并入本文)而不是液体。
本发明的其他具体实施方式包括一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸的单位剂型,其中在室温和60%的相对湿度下存放一个月后,剂型中在起始测量时间(t0)下测量的一种或多种二氢吡啶类钙通道阻断剂的起始量至少能够保留90%。
在一些具体实施方式中,本发明的制剂可以提高每种活性成分的有效性,其中一种或两种组分以常规的全效剂量施用。在其他具体实施方式中,与在先技术的制剂相比,本发明的制剂可以降低一种或多种二氢吡啶类钙通道阻断剂和/或omega-3脂肪酸的剂量,同时维持或甚至提高每种活性成分的有效性。
相比这两种药物单独施用时的合并或叠加效果,本发明的一种或多种二氢吡啶类钙通道阻断剂和omega-3脂肪酸的组合产生的效果更大。这样,两个活性成分的组合治疗可分别或通过本发明全新的组合产品意外地提高活性组分的效果,从而提高标准剂量的有效性,或仍维持剂量降低的两个活性组分的有效性。实践中普遍接受如下观点:药物或其他活性成分的生物利用度或有效性的提高可以适当降低每日剂量。低剂量和减少所用的赋形剂(例如表面活性剂)可以降低任何不希望产生的副作用。
在此通过参考的方式将本文引用的所有文献的全部内容并入本文。
Claims (19)
1.药物组合物,其包括:
a.单位剂型,其包括天然或合成的omega-3脂肪酸或其药学可接受的酯、衍生物、结合物、前体或盐,或它们的混合物,和任选的增溶剂,以及
b.单位剂型上的一层或多层外包衣,其中至少一层外包衣包括一种或多种二氢吡啶类钙通道阻断剂,
c.任选的在单位剂型和一层或多层外包衣之间的一层或多层屏蔽包衣,以及
d.任选的单位剂型上的封闭包衣。
2.根据权利要求1所述的药物组合物,其中所述一层或多层外包衣是用于制备一种或多种二氢吡啶类钙通道阻断剂的即释、延迟/肠溶释放或缓释剂型。
3.根据权利要求1所述的药物组合物,其中所述一层或多层屏蔽包衣是用于制备天然或合成的omega-3脂肪酸或其药学可接受的酯、衍生物、结合物、前体或盐,或它们的混合物的肠溶/延迟释放剂型,或是作为非功能性的保护层。
4.根据权利要求1所述的药物组合物,其中所述单位剂型是软胶囊、硬胶囊或片剂。
5.根据权利要求1所述的药物组合物,其中所述的一种或多种二氢吡啶类钙通道阻断剂是Bay K 8644、氨氯地平、非洛地平、拉西地平、乐卡地平、尼卡地平、硝苯地平、尼莫地平、尼索地平、尼群地平和伊拉地平。
6.根据权利要求5所述的药物组合物,其中所述的一种或多种二氢吡啶类钙通道阻断剂是伊拉地平。
7.根据权利要求1所述的药物组合物,其包括约0.5mg~约100mg的一种或多种二氢吡啶类钙通道阻断剂。
8.根据权利要求1所述的药物组合物,其中所述的omega-3脂肪酸包含至少约70%的EPA和DHA。
9.根据权利要求1所述的药物组合物,其包括约0.1g~约10g的omega-3脂肪酸或其药学可接受的酯、衍生物、结合物、前体或盐,或它们的混合物。
10.根据权利要求1所述的药物组合物,其中所述的包括一种或多种二氢吡啶类钙通道阻断剂的至少一层外包衣是喷涂在单位剂型上的,在包衣过程中控制包衣沉积的速率并控制温度,从而得到物理和化学稳定的包衣的单位剂型。
11.单位剂型的药物组合物,其包括在溶剂系统中的一种或多种二氢吡啶类钙通道阻断剂的多相悬浮液或基本为均相的溶液,所述溶剂系统包括天然或合成的omega-3脂肪酸或其药学可接受的酯、衍生物、结合物、前体或盐,或它们的混合物。
12.根据权利要求11所述的药物组合物,其中所述omega-3脂肪酸包含至少约70%的EPA和DHA。
13.根据权利要求12所述的药物组合物,其中所述药物组合物包括多相悬浮液。
14.根据权利要求13所述的药物组合物,其中至少约80%的一种或多种二氢吡啶类钙通道阻断剂以固体颗粒的形式存在于悬浮液中。
15.根据权利要求11所述的药物组合物,其中所述的药物组合物包括基本为均相的溶液。
16.根据权利要求15所述的药物组合物,其中少于约10%的一种或多种二氢吡啶类钙通道阻断剂在溶剂系统中不溶解。
17.根据权利要求16所述的药物组合物,其中所述的溶剂系统进一步包括至少一种增溶剂,其占溶剂系统总重量的50%w/w或更少。
18.根据权利要求15所述的药物组合物,其中当药物组合物储存在室温和60%相对湿度下至少1个月时,从基本为均相的溶液中析出的一种或多种二氢吡啶类钙通道阻断剂不多于10%。
19.治疗一种或多种选自如下疾病的方法:高甘油三酯血症、高胆固醇血症、高血压、狭心症、冠心病(CHD)、血管疾病、动脉硬化症及其相关疾病,预防或减少心血管和血管疾病的方法,降低胰岛素抗性、降低禁食葡萄糖水平和饭后葡萄糖水平的方法,所述方法包括对患者施用有效量的一种或多种二氢吡啶类钙通道阻断剂和天然或合成的omega-3脂肪酸或其药学可接受的酯、衍生物、结合物、前体或盐,或它们的混合物。
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MX2008001282A (es) | 2008-03-24 |
EP1919285A2 (en) | 2008-05-14 |
WO2007016256A2 (en) | 2007-02-08 |
JP2009502950A (ja) | 2009-01-29 |
KR20080030691A (ko) | 2008-04-04 |
EA200800451A1 (ru) | 2008-08-29 |
US20070196465A1 (en) | 2007-08-23 |
WO2007016256A3 (en) | 2007-07-12 |
AU2006275784A1 (en) | 2007-02-08 |
NO20081067L (no) | 2008-04-18 |
CA2616806A1 (en) | 2007-02-08 |
BRPI0614417A2 (pt) | 2011-03-29 |
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