CN1310643C - 含有胆固醇吸收抑制剂、HMG-CoA还原酶抑制剂和一种稳定剂的组合物 - Google Patents
含有胆固醇吸收抑制剂、HMG-CoA还原酶抑制剂和一种稳定剂的组合物 Download PDFInfo
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- CN1310643C CN1310643C CNB038178443A CN03817844A CN1310643C CN 1310643 C CN1310643 C CN 1310643C CN B038178443 A CNB038178443 A CN B038178443A CN 03817844 A CN03817844 A CN 03817844A CN 1310643 C CN1310643 C CN 1310643C
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Abstract
本发明提供一种药物组合物,其中含有一种胆固醇吸收抑制剂和一种HMG-CoA还原酶抑制剂,一种或多种抗氧化剂、微晶纤维素、羟丙基甲基纤维素、硬脂酸镁和乳糖。该组合物不需要含有抗坏血酸来获得所要求的稳定性。
Description
发明背景
本发明涉及一种用于散装组合物和口服剂量单元的药物制剂,其中含有3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂(特别是辛伐他汀)和一种胆固醇吸收抑制剂(特别是伊泽替米贝)或这些化合物的可药用盐、溶剂化物或酯的混合物,它可用于调节血脂和用于防止和治疗动脉粥样硬化病及有关的症状和疾病。
几十年来已经知道,血胆固醇增高是冠心病(CHD)的主要危险因素,很多研究显示CHD的危险率可以通过降脂疗法来降低。在1987年以前,降脂手段基本上限于低饱和脂肪和低胆固醇饮食、胆酸螯合剂(考来烯胺和考来替泊)、烟酸(niacin)、贝特类药物和普罗布考。遗憾的是,所有这些疗法的效力或耐受性或者二者均有限。将降脂饮食和胆酸螯合剂组合,加或不加烟酸,可以实现LDL(低密度脂蛋白)胆固醇的显著降低,同时HDL(高密度脂蛋白)胆固醇增加。然而,此种疗法不易实施或耐受,因此除了在专家血脂诊所以外,常常失败。贝特类药物使LDL胆固醇适度减少和HDL胆固醇增加,并显著降低甘油三酯,而且由于它们能很好地被耐受故此在药物应用较广。普罗布考只使LDL胆固醇稍有降低而且也降低HDL胆固醇,因为在HDL胆固醇含量与CHD危险率之间有很强的反比关系,所以一般认为它是不理想的。随着洛伐他汀的引入,第一种HMG-CoA还原酶抑制剂在1987年成为可用的处方药,医生们第一次能够作到大大降低血浆胆固醇而不良作用很小。
近来的研究明确地表明,洛伐他汀、辛伐他汀和普伐他汀(全是HMG-CoA还原酶抑制剂)减慢了冠状动脉和颈动脉中粥样硬化损伤的发展。辛伐他汀和普伐他汀还显示出减少冠心病发生的危险,而且在辛伐他汀的情形,“斯堪的那维亚辛伐他汀存活者研究”表明了死于冠状动脉血栓病的危险和总死亡率有很显著的下降。这项研究也提供了心血管病发生病下降的一些证据。
尽管辛伐他汀显著降低了冠状动脉血栓病的发病和死亡的危险,但这种危险对于受治疗的患者仍相当大。例如,在“斯堪的那维亚辛伐他汀存活者研究”中,死于冠状动脉血栓形成的危险率降低42%仍留下5%受治疗的患者在这项5年的研究期间死于他们的疾病。进一步降低危险率显然是需要的。
现在已知某些羟基取代的氮杂环丁烷酮例如伊泽替米贝(在美国专利5,767,115和Re.37721中提到)被用来作为降血胆固醇药治疗和预防动脉粥样硬化。胆固醇酯是动脉粥样硬化损伤的主要成分和胆固醇在动脉壁细胞上的主要储存形式。胆固醇的形成也是饮食胆固醇的肠吸收的关键步骤。因此,抑制胆固醇酯形成和降低血清胆固醇很可能抑制动脉粥样硬化损伤形成的进展,减少胆固醇酯在动脉壁中的积累,和阻断饮食胆固醇的肠吸收。
利用HMG-CoA还原酶抑制剂(如辛伐他汀)与胆固醇吸收抑制剂(如伊泽替米贝)相组合的疗法来调节血脂以及治疗或降低动脉粥样硬化病的危险,可以实现危险率的进一步降低,这两种活性药物的结合使用描述于美国专利5,846,966。因为伊泽替米贝像NMG-CoA还原酶抑制剂(如辛伐他汀)一样,可以每日口服一次,所以利用一种稳定并且减小活性成分降解的配方将这两种活性组分结合在单独一个可口服的药物剂量单元(例如药片)中,会是有益的。
本发明通过提供一种用于散装药物组合物和口服药物剂量单元的包含辛伐他汀和伊泽替米贝的新颖制剂解决了这一需要,它可以用一种粗放的方法制备,得到高质量的终产品,具有最少的不想要的降解副产物和理想的储存稳定性。
发明概要
本发明提供一种含有胆固醇吸收抑制剂和HMG-CoA还原酶抑制剂的新颖的药物制剂,它具有理想的稳定性,但不需要存在抗坏血酸,也无需存在预胶化的淀粉。
更具体地说,本发明提供一种药物组合物,其中含有1-20%重量的一种胆固醇吸收抑制剂,例如伊泽替米贝;1-80%重量的一种HMG-CoA还原酶抑制剂,例如辛伐他汀;和0.01-2%重量的一种稳定剂剂,例如BHA。它还含有1-80%重量的微晶纤维素;0.5-10%重量的羟丙基甲基纤维素;0.1-4%重量的硬脂酸镁;和25-70%重量的乳糖。该组合物还可以任选地含有一种或多种交联的羧甲基纤维素钠、柠檬酸、抗坏血酸和没食子酸丙酯。虽然本发明组合物可以包含抗坏血酸,但不是非要包含抗坏血酸才能得到所要的结果。类似地,虽然组合物中可以包含预胶化的淀粉,但并非一定要包含预胶化的淀粉才能得到所要的结果。本发明组合物可以制备成散装形式,它适合形成个别的口服剂量单元,例如片剂,可用于治疗血管病症,例如高脂血,包括高胆固醇血,以及治疗和预防动脉粥样硬化疾病和发作,例如心肌梗塞。
本发明的另一方面是一种药物组合物,其中含有1-20%重量的一种胆固醇吸收抑制剂,例如伊泽替米贝;1-80%重量的至少一种HMG-CoA还原酶抑制剂;和0.005-10%重量的至少一种稳定剂。本发明的其它方面将在以下的详细描述中显而易见。
发明详述
本发明涉及HMG-CoA还原酶抑制剂和胆固醇吸收剂抑制剂的制剂。更具体地说,该HMG-CoA还原酶抑制剂是一种他汀类药物,包括例如,辛伐他汀、洛伐他汀、阿托伐他汀、氟伐他汀、普伐他汀、西立伐他汀、匹伐他汀和罗苏伐他汀。胆固醇吸收抑制剂可以选自下述专利中公开的任何一种:美国专利RE 37,721、5,688,990、5,656,624、5,624,920、5,698,548、5,627,176、5,633,246、5,688,785、5,688,787、5,744,467、5,756,470、5,767,115和2002年6月11日提交的美国专利申请10/166,942,这些专利在本申请中引用作为参考。制备这些化合物的方法也公开于这些专利中。本发明特别涉及辛伐他汀和伊泽替米贝的制剂。
辛伐他汀在全世界销售,在美国是以ZOCOR的商品名称出售。其制备方法描述在美国专利4,444,784、4,916,239、4,820,850以及其他专利和文献出版物中。辛伐他汀具有以下的结构式I:
伊泽替米贝现在以ZETIA的商品名称在美国出售。ZETIA制剂包含伊泽替米贝作为仅有的活性成分。在美国专利5,631,365、RE.37721、5,846,966、5,767,115、6,207,822、2002年3月25日提交的美国专利申请10/105,710和PCT 93/02048中描述了伊泽替米贝的制造方法。伊泽替米贝具有以下的结构式II,可以是无水形式或水合形式:
除了HMG-CoA还原酶抑制剂和胆固醇吸收抑制剂活性药物,特别是辛伐他汀和伊泽替米贝以外,本发明的口服药物组合物还可以含有微晶纤维素、羟丙基甲基纤维素(HPMC)、硬脂酸镁、乳糖和聚乙烯吡咯烷酮(PVP)中的一种或几种。组合物中还含有一种或多种稳定剂,包括抗氧化剂,例如,丁基化羟基苯甲醚(BHA)、2,6-二叔丁基-4-甲基苯酚(BHT)、没食子酸丙酯、抗坏血酸、柠檬酸、依地酸二钠和偏亚硫酸氢钙,优选BHA、没食子酸丙酯及其混合物,最优选的是BHA与没食子酸丙酯的混合物。组合物中还可以任选地包含交联羧甲基纤维素钠(ccNa)、柠檬酸、乳酸、苹果酸、琥珀酸、酒石酸和乙二胺四乙酸(EDTA)以及其盐中的一种或几种。特别是,虽然本发明组合物中可以含有抗坏血酸、但它并不需要加入抗坏血酸作为达到好结果的必需成分。类似地,本发明组合物不需要加入预胶化的淀粉作为取得好结果的组分,虽然预胶化的淀粉在需要时可以包含在组合物中。“抗坏血酸”一词在本申请中使用时,意思是包括游离酸及其盐形式,例如抗坏血酸钠。
已知抗坏血酸在作为一种组分时会使组合物,药物和其它物质退色。当在药片中使用时,这种退色作用可能需要使用盖住药片的包衣来遮盖退色作用。因为本发明组合物可以不用抗坏血酸配制,这些不加抗坏血酸形成的药剂制备时可以免去额外的加上包衣的步骤。当然,如果需要,可以加上包衣,例如为了美观、但不再需要加上包衣来遮盖由抗坏血酸引起的退色。
这里所用的术语“药物组合物”和“组合物”包括散装组合物和个别的口服剂量单元(片剂、丸剂等),其中含有两种药学活性物,例如辛伐他汀和伊泽替米贝,及本申请所述的无药学活性的赋形剂(活性剂和赋形剂在这里统称为本发明组合物的“组分”)。散装组合物是还没有形成为个别口服剂量单元的材料。药物组合物的口服剂量单元形式优选为片剂。
除了在操作实施例中或另外指出以外,在说明书和权利要求中使用的所有表示组分数量、反应条件等的数字都应理解成在一切情况下均加一“约”字。
在本发明的含义中,单个口服剂量单元的总重量,例如一只药片的重量,由该剂量单元中所有组分(即,两种活性物和赋形剂)的重量加起来决定,不包括在由散装组合物形成剂量单元后可任选地施加于其外部的任何涂层的重量。它也不包括在造粒过程中使用并随后在干燥期间除掉的任何溶剂。如上定义的单个口服剂量单元的总重量被用来作为计算构成剂量单元的各种组分的重量百分数的基础。然而,包含本发明所述组分的未包衣的剂量单元和用蜡、着色剂等包衣的剂量单元都属于本发明的范围。
含有本发明所述组分的散装组合物的总重量必然会随希望制备的散装组合物的重量而变。为了计算构成任何给定数量散装组合物的各组分的重量百分数,要将在给定数量散装组合物内所有组分(即,两种活性物和所述的赋形剂)的重量加在一起以确定散装组合物的总重量。正如本领域都清楚的,散装组合物既不包括造粒过程中使用的溶剂,也不包括包衣材料作为其组分,因此这些包衣材料和溶剂不包括在散装组合物的总重量计算之内。
在本领域都认为,用来描述单个口服剂量单元的成分的组分重量范围和具体重量可以按比例放大以制备散装组合物。当然,这里采用的组分重量百分数既适用于个别的口服剂量单元,也适用于散装组合物。
虽然药物剂量单元的总重量可以根据需要而变化,但基于实用考虑,优选口服单个剂量单元的总重量在50-1000mg的范围内,特别是从100mg至800mg。
在本发明的一项实施方案中,药物组合物中含有胆固醇吸收抑制剂活性物,例如伊泽替米贝,其数量为组合物重量的1-20%,特别是1.25-10%;HMG-CoA还原酶抑制剂活性物,例如辛伐他汀,其数量为组合物重量的1-80%,特别是1-20%,尤其是5-10%;以及至少一种稳定剂,例如BHA,其数量为组合物重量的0.005-20%,特别是0.01-2%,尤其是0.01-0.05%,最好是约0.02%。在此实施方案的一个方面,组合物中还含有0-0.2%(即,0.2或更少),特别是0.001-0.05%,尤其是约0.005%重量的没食子酸丙酯。例如,一种总重量为100-800mg的口服剂量单元可以含有1.25-10%重量的伊泽替米贝,5-10%重量的辛伐他汀,约0.02%的BHA,以及任选存在的约0.005%重量的没食子酸丙酯。
在此实施方案内,该药物组合物,例如但不限于总重量为100-800mg的口服剂量单元,还进一步含有百分含量如下的以下赋形剂;1-80%,特别是5-20%,尤其是约15%的微晶纤维素;0.5-10%,特别是1-4%,尤其是约2%的HPMC;0.1-4%,特别是0.5-2%,尤其是约1.5%的硬脂酸镁。
乳糖也是本发明组合物的一个组分,可以以不同的用量使用以达到所希望的药片总重量。例如,如果对于单个剂量单元除乳糖外的所有组分的总重为36.77mg,则可以加入63.23mg乳糖使剂量单元总重量达到100mg。如果对于单个剂量单元除乳糖外的所有组分的总重为73.54mg,则可以加入126.46mg乳糖使剂量单元总重量达到200mg。应该理解,这些组分重量可以按比例放大以制备散装组合物。一般来说,组合物重量的约25-70%由乳糖构成。
在此实施方案的一个方面,组合物中可任选地包含交联的羧甲基纤维素钠作为一个组分。因此,组合物中可以包含约0-10%(即,10%或更少),特别是2-4%,尤其是约3%重量的交联羧甲基纤维素钠。
在此实施方案的另一方面,本发明组合物中可以任选地包含柠檬酸作为一个组分。因此,组合物中可以含有0-10%(即,10%或更少),特别是0.1-1.25%,尤其是约0.25%重量的柠檬酸。
另外,组合物中可以任选地含有乳酸、苹果酸、琥珀酸、酒石酸和BDTA中的一种或几种。
在本发明的第二个实施方案中,药物组合物中含有占组合物重量1-20%的一种胆固醇吸收抑制剂,例如伊泽替米贝;占组合物重量1-80%的至少一种HMG-CoA还原酶抑制剂,例如一种他汀类药物;以及占组合物重量0.005-10%,特别是0.01-5%,尤其是0.01-2%的至少一种稳定剂。
在此实施方案的一个方面,稳定剂是一种抗氧化剂。进一步说,该抗氧化剂是选自丁基化羟基苯甲醚、柠檬酸和依地酸二钠及它们的混合物。
在此实施方案的另一方面,组合物还含有选自十二烷基硫酸钠、交联的羧甲基纤维素钠、聚乙烯吡咯烷酮、微晶纤维素和乳糖-水合物的一种或多种组分。
在本发明的第三实施方案中,提供了一种口服剂量单元,其中含有5-20mg、特别是10mg伊泽替米贝;5-80mg,特别是5、10、20、40和80mg的辛伐他汀;以及每mg辛伐他汀0.002-0.004mg的BHA。更具体地说,组合物中还任选含有每mg辛伐他汀0.0005-0.001mg的没食子酸丙酯。例如,组合物中可以含有0.01-16mg,特别是0.02-0.16mg的BHA,另外还可含有0.001-0.05mg,特别是0.005-0.04mg的没食子酸丙酯。虽然并不必需,但组合物中优选含有没食子酸丙酯。
在第三实施方案的一个方面,剂量单元中另外含有1-640mg,特别是15-120mg的微晶纤维素;0.5-80mg,特别是2-16mg的HPMC;0.1-32mg,特别是1.5-12mg的硬脂酸镁;以及乳糖。
如上所述,剂量单元中乳糖的数量取决于喜好,可以进行选择以达到所希望的药片总重量。通常,每个剂量单元可以使用约1000mg或更少的乳糖,例如约25-1000mg,来制备尺寸适用的剂量单元。
在第三实施方案的另一方面,组合物中可以任选地含有交联的羧甲基纤维素钠作为一种组分。例如,口服剂量单元可以含0-80mg(即,80mg或更少)的交联羧甲基纤维素钠,特别是3-24mg交联的羧甲基纤维素钠。
在第三实施方案的又一方面,组合物中可以任选地含有柠檬酸作为一种组分。例如,口服剂量单元可以含有0-80mg(即,80mg或更少),特别是0.25-2mg的柠檬酸。
另外,剂量单元中可以任选地含有乳酸、苹果酸、琥珀酸、酒石酸和EDTA中的一种或几种。
在本发明的第四实施方案中,提供了一种治疗有需要的患者中与血管病症有关的一种或多种疾病的方法,其作法是对患者施用治疗有效量的本发明药物组合物。
在本发明所有实施方案的一个方面,每剂量单元中伊泽替米贝的数量是10mg,每剂量单元中辛伐他汀的数量是选自:
(a)5mg,其中辛伐他汀为组合物重量的1-20%,特别是5%;
(b)10mg,其中辛伐他汀为组合物重量的1-20%,特别是10%;
(c)20mg,其中辛伐他汀为组合物重量的2-20%,特别是10%;
(d)40mg,其中辛伐他汀为组合物重量的4-20%,特别是10%;和
(e)80mg,其中辛伐他汀为组合物重量的8-20%,特别是10%。
更具体地说,当辛伐他汀的数量为组合物重量的5%时,则伊泽替米贝的数量为组合物重量的10%;而当辛伐他汀的数量为组合物重量的10%时,伊泽替米贝的数量则选自:
(a)组合物重量的1-20%,特别是10%;
(b)组合物重量的1-20%,特别是5%;
(c)组合物重量的1-20%,特别是2.5%;和
(d)组合物重量的1-20%,特别是1.25%。
在本发明所有实施方案的另一方面,组合物中含有BHA和没食子酸丙酯。
在本发明所有实施方案的又一方面,组合物中不含抗坏血酸。特别是,组合物中不含抗坏血酸,而且由散装组合物形成的片剂剂量单元在药片上没有包衣。
在本发明所有实施方案的另一方面,组合物中不含预胶化淀粉。特别是,组合物中既不含预胶化淀粉,也不含抗坏血酸。更具体地说,预胶化淀粉和抗坏血酸在组合物中都不存在,而BHA和没食子酸丙酯均包含在组合物中。
本发明范围内的一项实施例包括一种含有伊泽替米贝、辛伐他汀、BHA和没食子酸丙酯的组合物,其中该组合物不含抗坏血酸和预胶化淀粉中的一个或两个。另一实施例包括一种含伊泽替米贝、辛伐他汀、BHA和没食子酸丙酯的片剂药物剂量单元,其中该剂量单元既不含抗坏血酸,药片上也没有包衣,或者更具体地说,抗坏血酸、预胶化淀粉和药片上的包衣在该剂量单元中均不存在。
一种造粒流体被用来使散装粉末团聚,以改进散装材料的加工性能。对于本发明组合物,乙醇和水的混合物适合作为造粒流体使用。可以使用不同比例的水∶乙醇混合物,例如按体积计水和乙醇之比从10∶1至1∶3。特别是,造粒流体中水与乙醇的体积比为3∶1。加入的造粒流体的总量可以随操作的规模而变。与本发明组合物一起使用的造粒流体的常用范围是组合物重量的约15-30%,特别是约25%。在将散装材料压制成片剂之前,采用本领域已知的技术例如塔盘干燥、流化床干燥、微波干燥和真空干燥等将造粒流体除去。
本发明的散装和片剂形式的药物组合物可以用以下方法制备。将乳糖、微晶纤维素、辛伐他汀、伊泽替米贝、羟丙基甲基纤维素和交联的羧甲基纤维素钠于高剪切混合器造粒机中混合,以保证各组分的均匀分布。将BHA和没食子酸丙酯溶于乙醇并将柠檬酸溶于水中制成造粒溶剂。然后将该水和乙醇溶液混合并喷洒在高剪切混合器造粒机内的粉末床上。随后将形成的湿物质干燥并过筛。然后加入硬脂酸镁将其润滑。将经过润滑处理的最终粉末掺混物压制成片。
更具体的口服剂量单元实例如下。实施例1-6中描述的口服剂量单元可以由适当等分的散装组合物用上述方法制得。
实施例1
组分 | 数量(mg) |
辛伐他汀 | 5.0 |
伊泽替米贝 | 10.0 |
微晶纤维素 | 15.0 |
乳糖 | 63.23 |
HPMC | 2.0 |
交联的羧甲基纤维素钠 | 3.0 |
柠檬酸 | 0.25 |
没食子酸丙酯 | 0.005 |
BHA | 0.02 |
硬脂酸镁 | 1.5 |
药片总重 | 100.0 |
实施例2
组分 | 数量(mg) |
辛伐他汀 | 10.0 |
伊泽替米贝 | 10.0 |
微晶纤维素 | l5.0 |
乳糖 | 58.23 |
HPMC | 2.0 |
交联的羧甲基纤维素钠 | 3.0 |
柠檬酸 | 0.25 |
没食子酸丙酯 | 0.005 |
BHA | 0.02 |
硬脂酸镁 | 1.5 |
药片总重 | 100.0 |
实施例3
组分 | 数量(mg) |
辛伐他汀 | 20.0 |
伊泽替米贝 | 10.0 |
微晶纤维素 | 30.0 |
乳糖 | 126.45 |
HPMC | 4.0 |
交联的羧甲基纤维素钠 | 6.0 |
柠檬酸 | 0.5 |
没食子酸丙酯 | 0.01 |
BHA | 0.04 |
硬脂酸镁 | 3.0 |
药片总重 | 200.0 |
实施例4
组分 | 数量(mg) |
辛伐他汀 | 40.0 |
伊泽替米贝 | 10.0 |
微晶纤维素 | 60.0 |
乳糖 | 262.90 |
HPMC | 8.0 |
交联的羧甲基纤维素钠 | 12.0 |
柠檬酸 | 1.0 |
没食子酸丙酯 | 0.02 |
BHA | 0.08 |
硬脂酸镁 | 6.0 |
药片总重 | 400.0 |
实施例5
组分 | 数量(mg) |
辛伐他汀 | 80.0 |
伊泽替米贝 | 10.0 |
微晶纤维素 | 120.0 |
乳糖 | 535.84 |
HPMC | 16.0 |
交联的羧甲基纤维素钠 | 24.0 |
柠檬酸 | 2.0 |
没食子酸丙酯 | 0.04 |
BHA | 0.16 |
硬脂酸镁 | 12.0 |
药片总重 | 800.0 |
实施例6
组分 | 数量(mg) |
辛伐他汀(0.025%BHA) | 10.0 |
伊泽替米贝 | 10.0 |
微晶纤维素 | 40.0 |
乳糖 | 98.98 |
预胶化淀粉 | 20.0 |
交联的羧甲基纤维素钠 | 20.0 |
柠檬酸 | 0 |
没食子酸丙酯 | 0 |
BHA | 0.02 |
硬脂酸镁 | 1.0 |
药片总重 | 200.0 |
实施例7中所述的口服剂量单元可以制造如下。
实施例7
伊泽替米贝粒化: | mg/片 |
组分 | |
伊泽替米贝 | 10.0 |
乳糖 | 53.74 |
微晶纤维素 | 20.0 |
交联的羧甲基纤维素钠 | 8.0 |
聚乙烯吡咯烷酮 | 4.0 |
BHA | 0.01 |
抗坏血酸 | 2.5 |
柠檬酸 | 1.25 |
辛伐他汀粒化: | |
组分 | |
辛伐他汀(0.025%BHA) | 10.0 |
乳糖 | 21.87 |
微晶纤维素 | 10.0 |
交联的羧甲基纤维素钠 | 4.0 |
聚乙烯吡咯烷酮 | 2.0 |
BHA | 0.005 |
抗坏血酸 | 1.25 |
柠檬酸 | 0.625 |
润滑剂 | |
硬脂酸镁 | 0.75 |
总重 | 150.0 |
伊泽替米贝粒化:按照上述用于伊泽替米贝的数量将BHA和柠檬酸溶于70∶30的水∶乙醇混合物中。按照上述用于伊泽替米贝粒化的数量将聚乙烯吡咯烷酮(PVP)和抗坏血酸溶于水中。按照上述用于伊泽替米贝粒化的数量,将伊泽替米贝、乳糖、交联羧甲基纤维素钠的一半和微晶纤维素的一半于Hobart混合器内混合。在掺混期间向伊泽替米贝混合物中加入上述的BHA溶液。形成的混合物用上这的聚乙烯吡咯烷酮/抗坏血酸溶液粒化。得到的湿物质如上所述地造粒,然后掺入另一半交联羧甲基纤维素钠和微晶纤维素。
辛伐他汀粒化:按上述用于辛伐他汀粒化的数量将BHA和柠檬酸溶于7∶3的水∶乙醇混合物中。按上述用于辛伐他汀粒化的数量将聚乙烯吡咯烷酮(PVP)和抗坏血酸溶于水中。按照上述用于辛伐他汀粒化的数量,将辛伐他汀、乳糖、交联羧甲基纤维素钠的一半和微晶纤维素的一半于Hobart混合器内混合。在掺混期间向辛伐他汀混合物中加入上述的BHA溶液。形成的混合物用上述的聚乙烯吡咯烷酮/抗坏血酸溶液粒化。得到的湿物质按上述造粒,然后掺入另一半的交联羧甲基纤维素钠和微晶纤维素。
组合物颗粒:将伊泽替米贝颗粒和辛伐他汀颗粒在Turbula混合器内混合。在该颗粒混合物中混入硬脂酸镁,按照与上述相似的方式压制成片。
因此,在另一实施方案中,本发明提供了一种治疗组合物,其中含有(a)由1-20%重量的至少一种固醇吸收抑制剂或其可药用盐或溶剂化物和0.005%-10%重量的至少一种第一稳定剂构成的第一数量,和(b)由1-80%重量的至少一种HMG-CoA还原酶抑制剂和0.005-10%重量的至少一种第二稳定剂构成的第二数量,其中该第一数量和第二数量合起来构成治疗有效量。第一稳定剂和第二稳定剂可以相同或者化学上不同,包括例如以上列出的稳定剂。
这里所说的“治疗组合物”意味着服用两种或多种治疗药物,例如固醇吸收抑制剂和HMG CoA还原酶抑制剂,用以预防或治疗动脉粥样硬化或任何相关病症,例如以上讨论的病症。这种服用方法包括将这些治疗药物以基本上同时的方式共同给药,例如以含有固定比例的活性组分的单一药片或胶囊的形式,或者以各治疗药物用分离胶囊的多重制剂的形式给药。另外,这种服用方法包括各种治疗药物按顺序服用。无论何种形式,采用组合疗法来治疗对于治疗动脉粥样硬化病症会产生有益作用。本发明公开的组合疗法的一个潜在的优点可能是降低为有效治疗动脉粥样硬化症状所需的各个治疗化合物的数量或治疗化合物总量。通过采用治疗剂的组合,各化合物的副作用可以比单一药物疗法减小,这会改善患者顺应性。另外,可以选择治疗药物以产生更宽范围的互补作用或互补作用模式。
本发明已参照某些具体实施方案作了描述和说明,本领域技术人员将会理解,可以在不偏离本发明的精神和范围的情况下作出各种变化、修改和替换。例如,由于治疗任何适应症的哺乳动物对于本发明中使用的上述活性药物的响应不同,在本发明中上述特定剂量之外的有效剂量可能适用。因此,本发明将由随后的权利要求的范围限定,这些权利要求应以适当宽的方式理解。
Claims (17)
1.一种药物组合物,其中含有1-20%重量的依泽替米贝,1-80%重量的辛伐他汀,和0.01-2%重量的BHA,条件是其中不含抗坏血酸,其中含有0.1-1.25%重量的柠檬酸,其中该组合物是一种片剂,条件是该片剂没有包衣。
2.权利要求1的组合物,其中含有1.25-10%的伊泽替米贝和1-20%的辛伐他汀。
3.权利要求2的组合物,其中含5-10%的辛伐他汀。
4.权利要求1的组合物,其中含0.01-0.05%的BHA。
5.权利要求4的组合物,其中含约0.02%的BHA。
6.权利要求1的组合物,其中还含有0.2%或更少重量的没食子酸丙酯。
7.权利要求6的组合物,其中含0.001-0.05%重量的没食子酸丙酯。
8.权利要求7的组合物,其中含约0.005%重量的没食子酸丙酯。
9.权利要求1的组合物,其中还含有5-20%重量的微晶纤维素,1-4%重量的羟丙基甲基纤维素和0.5-2%重量的硬脂酸镁。
10.权利要求1的组合物,其中还含有10%或更少重量的交联的羧甲基纤维素钠。
11.权利要求10的组合物,其中含2-4%重量的交联的羧甲基纤维素钠。
12.权利要求1的组合物,条件是其中不含预胶化的淀粉。
13.权利要求1的药物组合物作为制备有需要治疗的患者治疗高脂血症或动脉粥样硬化疾病药物中的应用。
14.权利要求1的药物组合物,其中基本含有
10.0mg的辛伐他汀、
10.0mg的依泽替米贝、
15.0mg的微晶纤维素、
58.23mg的乳糖、
2.0mg的HPMC、
3.0mg的交联羧甲基纤维素钠、
0.25mg的柠檬酸、
0.005mg的没食子酸丙酯、
0.02mg的BHA和
1.5mg的硬脂酸镁。
15.权利要求1的药物组合物,其中基本含有
20.0mg的辛伐他汀、
10.0mg的依泽替米贝、
30.0mg的微晶纤维素、
126.45mg的乳糖、
4.0mg的HPMC、
6.0mg的交联羧甲基纤维素钠、
0.5mg的柠檬酸、
0.01mg的没食子酸丙酯、
0.04mg的BHA和
3.0mg的硬脂酸镁。
16.权利要求1的药物组合物,其中基本含有
40.0mg的辛伐他汀、
10.0mg的依泽替米贝、
60.0mg的微晶纤维素、
262.90mg的乳糖、
8.0mg的HPMC、
12.0mg的交联羧甲基纤维素钠、
1.0mg的柠檬酸、
0.02mg的没食子酸丙酯、
0.08mg的BHA和
6.0mg的硬脂酸镁。
17.权利要求1的药物组合物,其中基本含有
80.0mg的辛伐他汀、
10.0mg的依泽替米贝、
120.0mg的微晶纤维素、
535.84mg的乳糖、
16.0mg的HPMC、
24.0mg的交联羧甲基纤维素钠、
2.0mg的柠檬酸、
0.04mg的没食子酸丙酯、
0.16mg的BHA和
12.0mg的硬脂酸镁。
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CN (2) | CN1310643C (zh) |
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CN102266323A (zh) * | 2011-08-04 | 2011-12-07 | 海南锦瑞制药股份有限公司 | 依折麦布和辛伐他汀组合物及其制备方法 |
CN102266323B (zh) * | 2011-08-04 | 2013-03-27 | 海南锦瑞制药股份有限公司 | 依折麦布和辛伐他汀组合物及其制备方法 |
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