CN103945857A - 用于治疗代谢疾病、心血管疾病、以及炎症的蝶芪和他汀组合 - Google Patents
用于治疗代谢疾病、心血管疾病、以及炎症的蝶芪和他汀组合 Download PDFInfo
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Abstract
本发明提供了一种药物组合物,该药物组合物包括治疗有效量的蝶芪、治疗有效量的他汀化合物、以及药学上可接受的载体。这些药物组合物的实施例可以具有降低脂类的特性,或可替代地,可以具有通过减少促成神经退行性疾病的炎症或炎性过程而治疗氧化应激的特性。还提供了一种降低个体的脂类水平的方法,该方法包括向需要如此治疗的该个体给予一种药物组合物,该药物组合物包括治疗有效量的蝶芪、治疗有效量的他汀化合物、以及药学上可接受的载体,其中脂类水平是降低的。
Description
技术领域
提供了一种蝶芪和他汀化合物的组合。该组合有效治疗血脂异常、治疗心血管障碍、治疗与氧化应激相关的神经退行性障碍,并且有效减少或抑制炎症。背景技术
他汀发挥作用以减少主要位于肝脏中的胆固醇生物合成,连同抑制调节脂类代谢作用的3-羟基-3-甲基戊二酰辅酶A还原酶(HMG-CoA还原酶)。HMG-CoA还原酶抑制剂的有益效果通常归因于它们通过超过3-羟基-3-甲基戊二酰-CoA并且因此竞争性地抑制HMG-CoA还原酶来减少内源胆固醇合成的能力。
HMG-CoA还原酶催化产生甲羟戊酸(mevalonate,mevalonic acid)的反应,甲羟戊酸是胆固醇连同许多其他非甾体类异戊二烯(isoprenoidic)化合物的前体(Hunninghake(汉宁海克)D.B.,HMG-CoA还原酶抑制剂,Curr.Opin.Lipidol.(当代脂质视点),3:22-8,1992)。因为这一上游调节效应,所以HMG-CoA还原酶的他汀抑制不止影响一个生化途径。在类脂的情况下,他汀发挥作用以抑制胆固醇生物合成、增加低密度脂蛋白(LDL)的摄取和降解,抑制脂蛋白的分泌,并且抑制LDL氧化。他汀还影响细胞内信号传导途径,导致巨噬细胞中的酯化胆固醇的积累下降(即eNOS(内皮NO合酶)增加)以协助血管扩张、炎性过程的减少、以及血小板活性和凝固过程的恢复(Bellosta(贝勒斯塔)S.,Ferri(费里)N.,Bernini(贝尔尼尼)F.,Paoletti(保莱蒂)R.,Corsini(科尔西尼)A.,Non-lipid-related effects of statins(他汀的非类脂有关的效果),Ann.Med.(医学年鉴),32:164-176,2000)。
他汀通过结合在与HMG-CoA相同的活性位点中来抑制HMG-CoA还原酶。这一结合发挥作用以抑制HMG-CoA的结合,连同阻止HMG-CoA还原酶获得功能性结构。细胞内胆固醇的随附减少诱导一种蛋白酶的激活,该蛋白酶将固醇调节元件结合蛋白(SREBP)从内质网剪切下来并且允许它们在细胞核水平上易位,这些结合蛋白在细胞核中增加针对LDL受体的基因表达。肝LDL受体的增加减少循环的LDL及其前体(例如I-LDL和V-LDL胆固醇)(Sehayek(赛哈伊克)E.,Butbul(布塔布拉)E.,Avner(阿夫纳)R.,Enhanced cellularmetabolism of very low density lipoprotein by simvastatin:a novel mechanism ofaction of HMG-CoA reductase inhibitors(辛伐他汀增强极低密度脂蛋白的细胞代谢:HMG-CoA还原酶抑制剂的一种新颖的作用机制),Eur.J.Clin.Invest.(欧洲临床研究杂志),24:173-8,1994)。
蝶芪(3,5-二甲氧基-4'-羟基-反式-芪)是发现于某些浆果(例如蓝莓,小红莓,火花莓(sparkleberry),越橘)中、并且发现于非常少量的葡萄中的白藜芦醇的一种天然类似物。像白藜芦醇一样,蝶芪属于一类被叫做植物抗毒素的化合物,植物抗毒素是当处于病原体(例如细菌或真菌)的攻击下时,由植物天然产生的。然而,与白藜芦醇相反,动物研究已经显示蝶芪拥有经由一种细胞核受体(即过氧化物酶体增殖物激活受体α同种型,PPAR-α)的激活来降低脂类和葡萄糖的作用(Rimando(里曼多)等人,J.Agric.Food Chem(农业化学与食品化学杂志)(2005)53:3403-3407和US2011/0060060,两者通过引用结合在此)。虽然白藜芦醇仅仅展示出弱的PPAR-α激活,但是已知它是一种PPAR-γ激活剂。当然蝶芪展示出相反的选择性,并且它仅仅是一种弱的PPAR-γ激活剂。
蝶芪发挥作用以激活PPAR-α,在肝脏中PPAR-α导致脂肪酸的β-氧化增加以及甘油三酸酯和极低密度脂蛋白(VLDL)的合成降低(Fruchart(福鲁查特),J.-C.;Duriez(达利艾兹),P.Anti-cholesterol agents,new therapeutic approaches.(抗胆固醇剂,新的治疗途径)Ann.Pharm.Fr.(法国药学年鉴)(2004)62:3-18)。过氧化物酶体增殖物激活受体(PPAR)同种型属于配体激活的转录因子的细胞核受体超家族,转录因子通过与靶基因的启动子区中的特异性应答元件相互作用来控制基因表达(Tugwood(塔格伍德)JD,Aldridge(奥尔德里奇)TC,Lambe(蓝贝)KG,Macdonald(麦克唐纳)N,Woodyatt(伍德亚特)NJ.Peroxisomeproliferator-activated receptors:Structures and function.(过氧化物酶体增殖物激活受体:结构与功能)Ann.N.Y.Acad.Sci.(纽约科学院年鉴)804,252,1996)。在脂肪酸和脂类分解代谢中涉及的并且在涉及肝脏中的脂肪酸氧化的基因的激活中涉及的主要同种型是PPAR-α(福鲁查特J-C,Staels(斯泰拉斯)B,达利艾兹P.PPAR-alpha in lipid and lipoprotein metabolism,vascular inflammation andatherosclerosis.(在脂类和脂蛋白代谢、血管炎症以及动脉硬化中的PPAR-α)Prog.Exp.Cardiol.(实验和临床心脏病学)8,3,2003)。已经显示肝脏中PPAR-α的激活导致脂肪酸的氧化增加连同甘油三酸酯和极低密度脂蛋白(VLDL)合成降低。这加上其诱导肝载脂蛋白A-I和A-II表达从而增加血浆HDL胆固醇的能力使得它成为降胆固醇领域中的一个非常重要的靶标(Gervois(格拉沃斯)P,Torra(图拉)IP,福鲁查特JC,斯泰拉斯B.Regulation of lipid and lipoproteinmetabolism by PPAR activators.(通过PPAR激活剂调节脂类和脂蛋白代谢)Clin.Chem.Lab.Med.(临床化学与实验室医学)38,3,2000)。贝特药物家族是已知的PPAR-α激动剂,并且其降低甘油三酸酯并且升高HDL-胆固醇的效果主要归因于它们激活PPAR-α(Desai(德赛)RC,Metzger(梅茨格)E,Santini(圣蒂尼)C,Meinke(梅因克)PT,Heck(赫克)JV,Berger(伯杰)JP,MacNaul(马克纳欧)KL,Cai(蔡)T,Wright(赖特)SD,Agrawal(阿格拉沃尔)A,Moller(默勒)DE,Sahoo(赛虎)SP.Design and synthesis of potent and subtype-selectivePPARalpha agonists.(有效力的并且具有亚型选择性的PPARα激动剂的设计与合成)Bioorg.Med.Chem.Lett.(生物有机化学与医药化学快报)16,1673,2006)。然而,尽管是有前途的,但是他汀-贝特组合可以导致不希望的副作用(例如肌肉痛),或甚至导致病症(包括肌病/横纹肌溶解)。
在该描述上扩展,关于通过白藜芦醇激活PPAR-α的报道(Inoue(井上)H,Jiang(江)XF,Katayama(片山)T,Osada(长田)S,Umesono(梅园)K,Namura(名村)S.Brain protection by resveratrol and fenofibrate against stroke requiresperoxisome proliferator-activated receptor alpha in mice.(在大鼠中通过对抗中风的白藜芦醇和非诺贝特的脑保护需要过氧化物酶体增殖物激活受体)Neurosci.Lett.(神经科学快报)352,203,2003)是最终引起用蝶芪进行类似研究的发现(里曼多AM,Nagmani(耐格曼尼)R,Feller(费勒)DR,Yokoyama(横山)W.Pterostilbene,a new agonist for the peroxisome proliferatoractivated receptoralpha-isoform,lowers plasma lipoproteins and cholesterol in hypercholesterolemichamsters.(一种新的过氧化物酶体增殖物激活受体α-同种型的激动剂-蝶芪降低高胆固醇血仓鼠中的脂蛋白和胆固醇)农业化学与食品化学杂志53,3403,2005)。USDA研究人员测试了蝶芪、白藜芦醇、以及环丙贝特(贝特药物家族的一员)在H4IIEC3大鼠肝细胞中对PPAR-α激活的作用。使用包含过氧化物酶体增殖物应答元件启动区的荧光素酶报告基因构建体,他们发现100μM蝶芪超过对照8倍地诱导PPAR-α激活并且是100μM的环丙贝特的几乎2倍(白藜芦醇在100μM浓度处对细胞是有毒的)。在300μM处,蝶芪浓缩物诱导涨到超过对照的14倍。这表明蝶芪补充因此也应该产生降低的甘油三酸酯和极低密度脂蛋白(VLDL)合成以及增加的血浆HDL胆固醇,这是由PPAR-α被贝特药物家族激活引起的。
因此,不同的研究共同表明他汀和PPAR配体的组合可以提供一个有价值的治疗选择,并且在患有血脂代谢障碍的心血管炎性障碍的糖尿病受试者和非糖尿病受试者中可以是有益的。如上所讨论,关于他汀和某些PPAR配体(例如贝特)的组合对慢性治疗的不利情况是不确定的,并且需要调查。然而,他汀与其他PPAR配体(例如芪化合物)的组合可以在阻止心血管障碍的发展中提供相当大的益处。
关于衰老和神经退行性障碍,补充有水果和蔬菜的饮食具有预防并逆转与衰老问题相关的缺陷的效果。
由于其强健的抗氧化剂活性,白藜芦醇已经被鉴定为具有多种抗衰老特性。体外实验已经显示白藜芦醇是一种有效的自由基清除剂并且抑制低密度脂蛋白氧化(Brito(布里托)等人,Free Radic Res.(自由基研究)(2002)36(6):621-631)。其他芪(例如松芪、去氧丹叶大黄素(desoxyrhapontigenin)、蝶芪、白藜芦醇三甲基醚、以及白皮杉醇)具有不同程度的通过激活PPAR-α来降低脂类水平的生物活性和有效性。
如上所讨论,已经证明作为白藜芦醇的一种天然甲醚类似物的蝶芪具有与白藜芦醇类似的抗氧化剂活性(里曼多等人,(2002)农业化学与食品化学杂志,50:3453-3457;Stivala(斯蒂瓦拉)等人,(2001)J.Biol.Chem.(生物化学杂志)276(25):22586-22594)。蝶芪存在于一些小的水果中,例如葡萄(Adrian(艾德里安)等人,(2000)农业化学与食品化学杂志48:6103-6105)和越桔的浆果(Vaccinium ashei Reade和Vaccinium stamineum L.)(里曼多等人,(2004)农业化学与食品化学杂志52:4713-4719),连同在木本植物(Maurya(利亚)等人,(1977)J.Nat.Prod.(天然产物杂志)47:179-181;Amone(阿蒙)等人,(1977)J.Chem.Soc.Perkins Trans.(帕金斯反式化学学会杂志)19:2116-2118)中。然而,里曼多等人(2004)发现在葡萄中,蝶芪通常以非常微量地发现并且可以是完全不存在的。另外地,多种植物性药材包含蝶芪,这些植物性药材包括榆绿木(Anogeissus acuminata)、剑叶龙血树(Dracaena cochinchinensis)、古山龙血树(Dracaena loureiri)、特氏古夷苏木(Guibourtia tessmannii)、大果紫檀(Pterocarpus macrocarpus)、花榈木(Pterocarpus marsupium)、小叶紫檀(Pterocarpus santalinus)、兔眼蓝莓(Vaccinium ashei)、高丛蓝莓(Vacciniumcorymbosum)、甜越橘(Vaccinium deliciosum)、膜质越橘(Vacciniummembranaceum)、常青越桔(Vaccinium ovatum)、Vaccinium ovalifoilum、小花越橘(Vaccinium parviflorum)、长蕊越橘(Vaccinium stamineum)、笃斯越橘、以及古山葡萄(Vitis vinifrea)。蝶芪还发现于非植物性药材来源(例如蜂胶)中。
蓝莓物种的蝶芪浓度的量不同。已经报道99ng至475ng范围的蝶芪可以来源于一克的冻干蓝莓。
研究已经将抗氧化剂的作用与脑衰老和行为的有害作用联系在一起。抗氧化剂/抗炎性多酚的组合在预防这些有害作用中具有展示出的疗效,多酚包括以“次级化学品”的形式存在于水果和蔬菜中的蝶芪,“次级化学品”通常不在植物初级代谢中涉及。像这样,需要进一步鉴定可以保护免受衰老和认知缺陷的水果和植物,尤其是化合物。参见通过引用结合在此的US2009/0069444。
此外,已知因素(例如生活方式和饮食)可以消极地或积极地影响血管疾病的后果。锻炼和饮食可以显著地降低蚀斑形成的速率和范围。似乎饮食还可以有力地影响现存的斑块将形成严重的血凝块的可能性。因此,许多食物中的化合物模拟由药物治疗导致的抗凝和抗血小板聚集不是出人意料的。最近的研究已经证明了多种食物(包括浆果和葡萄)的抗血栓形成特性和抗血小板特性。
鉴于以上情况,提供一种具有蝶芪和他汀的有益特性的药物组合物将是令人希望的。
如果可以找到一种以协同方式增强蝶芪的降脂类特性(经由PPAR-α激活途径)以及他汀的降脂类特性(经由HMG-CoA还原酶抑制途径)的方法,这将代表对本领域的一个有价值的贡献。
如果可以找到用一种具有蝶芪和他汀的有益特性的药物组合物增强eNOS的活性,由此增加血管扩张,并且使得炎性过程和蚀斑形成的减少的方法,这将代表对本领域的一个有价值的贡献。
此外,如果可以找到一种通过将蝶芪与他汀组合来减少或抑制促成个体的癌症、神经退行性疾病以及衰老的炎性过程的方法,这将代表对本领域的一个有价值的贡献。
发明内容
提供了一种药物组合物,该药物组合物包括治疗有效量的蝶芪、治疗有效量的他汀化合物、以及药学上可接受的载体。在另一个实施例中,一种药物组合物包括治疗有效量的蝶芪和他汀化合物的组合。
药物组合物的实施例可以具有降低脂类的特性。
在替代性实施例中,这些药物组合物可以具有可以通过例如减少促成神经退行性疾病的炎症或炎性过程而可以治疗氧化应激的特性。
提供了一种降低个体的脂类水平的方法,该方法包括向需要如此治疗的这位个体给予一种药物组合物,该药物组合物包括治疗有效量的蝶芪、治疗有效量的他汀化合物、以及药学上可接受的载体,其中脂类水平是降低的。
附图说明
图1描绘了一个实施例中的总胆固醇(TC,以mg/dL),显示出以下组合的效果:具有和不具有他汀的蝶芪(高剂量)以及具有和不具有他汀的蝶芪(低剂量)。深色实心条:原始的基线测量;浅色实心条:治疗6-8周后的最终测量。
图2描绘了一个实施例中的总LDL-C(mg/dL),显示出以下组合的效果:具有和不具有他汀的蝶芪(高剂量)以及具有和不具有他汀的蝶芪(低剂量)。深色实心条:原始的基线测量;浅色实心条:治疗6-8周后的最终测量。
具体实施方式
已经提供了一种安全且有效的药物组合物或营养组合物,该组合物包含蝶芪和一种他汀化合物。在一个实施例中,一种治疗个体的血脂异常的方法包括向需要如此治疗的这位个体给予一种药物组合物的步骤,该药物组合物包括治疗有效量的蝶芪、治疗有效量的他汀化合物、以及药学上可接受的载体。
在另一个实施例中,一种降低个体的脂类水平的方法包括向需要如此治疗的这位个体给予一种药物组合物的步骤,该药物组合物包括治疗有效量的蝶芪、治疗有效量的他汀化合物、以及药学上可接受的载体,其中脂类水平是降低的。
不被理论所束缚,认为他汀与蝶芪(或其他PPAR-α激活剂,例如贝特家族成员)的组合将赋予除了仅仅降低胆固醇和甘油三酸酯以外的心脏健康益处。PPAR-α激活剂和他汀都已经显示出赋予对抗动脉硬化的保护、通过激活eNOS(内皮氧化氮合酶)而作为一种血管舒张剂,并且发挥作用以减少/抑制炎症。
蝶芪对PPAR-α激活的作用是得到确认的。过氧化物酶体增殖物激活受体(PPAR)同种型属于配体激活的转录因子的细胞核受体超家族,转录因子通过与靶基因的启动子区中的特异性应答元件相互作用来控制基因表达。在脂肪酸和脂类分解代谢中涉及的并且在涉及肝脏中的脂肪酸氧化的基因的激活中涉及的主要同种型是PPAR-α。已经显示肝脏中PPAR-α的激活导致脂肪酸的氧化增加连同甘油三酸酯和极低密度脂蛋白(VLDL)合成降低(福鲁查特等人,法国药学年鉴(2004)62:3)。这一激活加上其诱导肝载脂蛋白A-I和A-II表达从而增加血浆HDL胆固醇的能力使得它成为降胆固醇领域中的一个非常重要的靶标(格拉沃斯等人,临床化学与实验室医学,(2000)38:3)。比较地,贝特药物家族是已知的PPAR-α激动剂,并且其降低甘油三酸酯并且升高HDL-胆固醇的效果主要归因于它们激活PPAR-α(德赛等人,生物有机化学与医药化学快报,(2006)16:1673)。
血脂异常是脂蛋白代谢的障碍,包括脂蛋白的过度产生或缺乏。这些障碍可以通过评价血清总胆固醇(TC)、低密度脂蛋白(LDL)胆固醇和甘油三酸酯浓度、以及高密度脂蛋白(HDL)胆固醇浓度的降低来显现。极低密度脂蛋白(VLDL)和总脂蛋白也可以被影响。
在本发明的某些实施例中,可以将降低的脂类水平表示为选自以下各项的血浆或血清的减少:总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、甘油三酸酯(TG)、以及低密度脂蛋白胆固醇与高密度脂蛋白胆固醇的比例(LDL-C/HDL-C)。测量并且诊断确定上述脂类组分在不同动物物种、哺乳动物、以及人类个体中的血中浓度在本领域中是熟知的。
UDP-葡萄糖醛酸转移酶(UGT)催化葡糖醛酸从高能辅因子(UDP-葡糖醛酸)向包含可供使用的亲核中心(例如羟基、羧基、氨基、或硫醇基)的外源性物质(xenobiotic)、药物、或内源底物转移。UGT和II期生物转化酶类主要在肝脏和肠中表达,并且是位于内质网腔表面上的膜合酶类。相对于亲本底物,葡糖醛酸化的终产物典型地更具极性并且更适于经由尿液或胆汁被排泄并除去。
内源UGT底物包括胆红素、中性类固醇、胆汁酸、脂肪酸、以及类视色素。外源性UGT底物范围从环境毒物(例如苯并[a]芘)到常见的药物制剂(例如扑热息痛以及其他NSAID)。单独的UGT同种型展示出不同模式的底物特异性和可诱导的调节。不同UGT以物种特异性方式和组织特异性方式被表达。主要的两个UGT基因家族是UGT1和UGT2。
已知在UGT的调节中涉及PPAR。具体地,UGT是PPAR-α的靶标,如与PPAR-γ相反。作为一种已知的PPAR-γ激活剂的白藜芦醇已经显示出对UGT的一些诱导,但不是一种强的PPAR-α激活剂。在一组类似的芪的研究中,只有蝶芪以一种类似于环丙贝特的方式激活PPAR-α(里曼多等人,农业化学与食品化学杂志,(2005)53:3403-3407)。不认为蝶芪是一种强的PPAR-γ激活剂。认为这一亚型选择性在用于使用蝶芪激活或诱导UGT的表达的当前方法中是有利的。因此,蝶芪的增强的降脂类特性是由这些涉及PPAR-α激活的互相关联的途径介导的。
另外,蝶芪可以用于治疗或预防血管疾病。已经显示蝶芪在体外抑制大鼠平滑肌细胞的增殖,这给了它作为用于治疗动脉硬化的抗增殖剂的可能性(Park(帕克)等人,Vascul.Pharmacol.(心血管药理学)(2010)53:61)。已经显示PPAR-α激活剂和他汀都赋予对抗动脉硬化的保护。在另一个实施例中,治疗有效量的蝶芪和治疗有效量的他汀化合物的组合可以用于治疗动脉硬化。就治疗动脉硬化而言,期待的是蝶芪和他汀的该组合将提供协同效应。因此,在这一实施例中,蝶芪和他汀的该组合可以通过激活eNOS(内皮氧化氮合酶)而作为血管舒张剂来协同地发挥作用,和/或发挥作用以减少或抑制炎症。
结肠环境中慢性的炎性病症存在与结肠直肠癌的发展有关,并且针对炎性标志物的治疗方案减少结肠癌的风险。已经显示蝶芪在体外和体内减少促炎细胞因子标志物(例如COX-2、TNF-α、IL-4、IL-1-β、以及iNOS)的水平。(参见例如,Hougee(胡戈)等人,Planta Med.(药用植物)(2005)71(5):387-392;Paul(保罗)等人,Cancer Prev.Res.(癌症预防研究)(Phila(费拉)),(2009)2(7):650-657;保罗等人,Carcinogenesis(致癌作用)(2010)31(7):1272-1278,每个都通过引用结合在此)。
蝶芪作为细胞色素P450的抑制剂也是熟知的(R.Mikstacka(密斯科塔卡)等人,Mol.Nutr.Food Res.(分子营养与食品研究)(2007)51:517)。所有他汀(普伐他汀除外)都主要在肝脏中经历由超家族CYP450同工酶的I期代谢(M.Bottorff(柏图夫)等人,Arch Intern Med.(内科医学档案)(2000)160:2273-80;B.A.Hamelin(哈梅林)等人,Trends Pharmacol Sci.(药理科学趋势)(1998)19:26-37)。不被理论所束缚,认为通过抑制细胞色素P450,蝶芪可以增加体内他汀的生物利用度,这样允许它们在血液中循环更长时间并且因此加强有益的生物化学端点。问题是蝶芪是否抑制代谢他汀的相同的P450同工酶。CYP3A4同工酶负责代谢阿托伐他汀、洛伐他汀、以及辛伐他汀,然而氟伐他汀和罗苏伐他汀都主要由CYP2C9同工酶代谢。已经显示蝶芪抑制CYP1A1和CYP1B1同工酶(R.密斯科塔卡等人,“Inhibition of human recombinant cytochromes P450CYP1A1and CYP1B1by trans-resveratrol methyl ethers(由反式白藜芦醇甲醚抑制人类重组细胞色素P450CYP1A1和CYP1B1),”分子营养与食品研究(2007)51:517),但是不抑制CYP2E1(R.密斯科塔卡等人,“Effect of natural analoguesof trans-resveratrol on cytochromes P4501A2and2E1catalytic activities(反式白藜芦醇的天然类似物对细胞色素P4501A2和2E1的催化活性的作用),”Xenobiotica(异生化合物)(2006)36:269)。
在另一个实施例中,治疗有效量的蝶芪和治疗有效量的他汀的组合可以用于治疗血脂异常。在另一个实施例中,治疗有效量的蝶芪和治疗有效量的他汀的组合可以用于降低脂类,例如减少内源胆固醇合成。就治疗血脂异常和降低脂类而言,期待的是蝶芪和他汀的该组合将提供协同效应。
在另一个实施例中,治疗有效量的蝶芪和治疗有效量的他汀的组合可以用于减少促炎细胞因子的水平。就治疗、预防和/或减少炎症而言,期待的是蝶芪和他汀的该组合将提供协同效应。
有用的他汀化合物包括但不限于:阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀、辛伐他汀,及其衍生物、盐、溶剂化物、以及前药。
在一个实施例中,能以从约1mg至约150mg的每日剂量,特别是例如在人类患者中提供他汀。另一个适合的剂量范围是每日从约15mg至约150mg。另一个适合的剂量范围是每日从约1mg至约100mg。另一个适合的剂量范围是每日从约1mg至约50mg。另一个适合的剂量范围是每日从约5mg至约100mg。另一个适合的剂量范围是每日从约5mg至约80mg。另一个适合的剂量范围是每日从约10mg至约80mg。
不被理论所束缚,认为他汀与某些生物活性剂的组合可以加强他汀的活性,由此增加疗效。例如,向他汀中添加蝶芪或与一种他汀组合可以允许减少他汀的剂量。在一个示例性实施例中,一位每天用75mg的添加有蝶芪的他汀治疗的患者可以能够减少他们摄取的他汀的量但仍继续体验相同的降胆固醇的益处。
蝶芪(3,5-二甲氧基-4'-羟基-反式-芪)是一种口服可生物利用的化合物,它在血液中的半衰期t1/2是约74-105分钟。相比之下,白藜芦醇具有贫乏的生物利用度,并且容易被UGT代谢,从而导致短得多的半衰期(在血液中的t1/2约10-14分钟),这阻碍了它作为化学预防剂的有效性。
蝶芪(99%纯度)从美国中草药公司(ChromaDex,Inc.)(尔湾,加利福尼亚州)是可商购的。
在一个实施例中,能以从约10mg至约500mg的每日剂量,特别是例如在人类患者中提供蝶芪。另一个适合的剂量范围是每日从约25mg至约500mg。另一个适合的剂量范围是每日从约50mg至约250mg。另一个适合的剂量范围是每日从约50mg至约150mg。另一个适合的剂量范围是每日从约50mg至约100mg。一个特别适合的剂量是每天给予约100mg。
当与处于固体或液体形式的蝶芪组合、或作为共混物使用时,预期他汀的剂量是特别有效的。就降低脂类并减少氧化应激的生物标志物而言,期待的是蝶芪和他汀的该组合将提供协同效应。
在另一个实施例中,一种药物组合物包括治疗有效量的蝶芪和他汀的组合。由于这些组分的预期的协同,所以蝶芪和他汀的组合的药物组合物甚至在这些单独的组分可能不提供治疗效果的情况下可以提供该治疗效果。
可以通过用于掺合和混合化合物的常规程序制备根据本发明的包含蝶芪或其衍生物、或蝶芪的药学上可接受的盐的组合物。在另一个实施例中,可以根据用于掺合和混合化合物的常规程序制备与一种他汀化合物、其衍生物或盐组合的蝶芪。优选地,该组合物还包括一种赋形剂,最优选地是一种药用赋形剂。可以通过本领域已知的程序制备包含一种赋形剂并结合蝶芪的组合物。任选地,该组合物可以包括一种或多种佐剂、赋形剂、载体、缓冲剂、稀释剂、和/或其他常规的药物辅助剂。例如,可以将蝶芪配制为用于口服给药的片剂、胶囊剂、粉剂、混悬剂、溶液以及用于非消化道给药(包括静脉内给药、真皮内给药、肌内给药、以及皮下给药)的溶液,以及将其配制为用于与常见且常规的载体、粘合剂、稀释剂、以及赋形剂透皮施用的贴剂上施用的溶液。
本发明的这些营养组合物可以与一种营养上可接受的载体组合给予。在此类配制品中可以包括从按重量计1%至按重量计99%、或可替代地按重量计0.1%至按重量计99.9%的活性成分。“营养上可接受的载体”是指与该配制品中的其他成分兼容并且对使用者无害的任何载体、稀释剂或赋形剂。有用的赋形剂包括微晶纤维素、硬脂酸镁、硬脂酸钙、任何可接受的糖(例如,甘露醇、木糖醇),并且用于美容使用,基于油的赋形剂(oil-base)是优选的。
本发明的这些药物组合物可以与一种药学上可接受的载体组合给予。在此类配制品中可以包括从按重量计1%至按重量计99%、或可替代地按重量计0.1%至按重量计99.9%的活性成分。一种“药学上可接受的载体”是指与该配制品中的其他成分兼容并且对使用者无害的任何载体、稀释剂或赋形剂。
递送系统
适合的剂型包括片剂、胶囊剂、溶液、混悬剂、粉剂、胶质、以及糖果。舌下递送系统包括,但不局限于,舌头下和舌头上的可溶药片、液滴、以及饮料。可以使用可食用膜、亲水性聚合物、口服可溶的膜或口服可溶的条。其他有用的递送系统包括口腔喷雾或鼻腔喷雾或吸入器、等。
对于口服给药而言,可以将蝶芪和/或与一种他汀组合的蝶芪进一步与一种或多种固体的无活性成分进行组合用于片剂、胶囊剂、丸剂、粉剂、颗粒剂或其他适合剂型的制备。例如,可以将该活性剂与至少一种赋形剂进行组合,这些赋形剂是例如填充剂、粘合剂、湿润剂、崩解剂、溶液阻滞剂、吸收促进剂、润湿剂(wetting agent)、吸收剂、或润滑剂。其他有用的赋形剂包括硬脂酸镁、硬脂酸钙、甘露醇、木糖醇、甜味剂、淀粉、羧甲基纤维素、微晶纤维素、硅石、明胶、二氧化硅、等。
本发明的组分连同一种常规的佐剂、载体、或稀释剂因此可以被放置为药物组合物及其单位剂量的形式。此类形式包括固体,并且特别是片剂、填充的胶囊剂、粉剂以及球粒形式,以及液体,特别是全部用于口服使用的水性或非水性溶液、混悬剂、乳剂、酏剂、以及填充有它们的胶囊剂,用于直肠给药的栓剂,以及用于非消化道使用的无菌可注射溶液。此类药物组合物及其单位剂型可以包括处于常规比例的常规成分,具有或不具有另外的活性化合物或要素,并且此类单位剂型可以包含任何适合的有效量的与待应用的预期每日剂量范围相当的活性成分。
本发明的组分能以多种多样的口服剂型和非消化道剂型给予。对本领域的普通技术人员将显而易见的是,以下剂型可以包括作为活性组分的本发明的一种化学化合物或本发明的一种化学化合物的药学上可接受的盐。
对于由本发明的一种化学化合物制备药物组合物,药学上可接受的载体可以是固体的或液体的。固体形式的制剂包括粉剂、片剂、丸剂、胶囊剂、扁囊剂、栓剂、以及可分散的颗粒剂。固体载体可以是一种或多种以下物质,这些物质还可以作为稀释剂、调味剂、增溶剂、滑润剂、助悬剂、粘合剂、防腐剂、片剂崩解剂、或一种胶囊化材料。
在粉剂中,该载体是与细碎的活性组分处于混合物形式的细碎的固体。在片剂中,该活性组分被与处于适合的比例的具有必需的结合能力的载体混合并且被压实为所希望的形状和尺寸。
这些粉剂和片剂优选地包含从百分之五或百分之十至约百分之七十的一种或多种活性化合物。适合的载体是碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可油、以及类似物。术语“制剂”旨在包括该活性化合物与作为提供胶囊的载体的胶囊化材料的配制品,在该胶囊中该活性组分(具有或不具有载体)被一种载体包围,因此该活性组分与该载体相关。类似地,包括扁囊剂和锭剂。包括片剂、粉剂、胶囊剂、丸剂、扁囊剂、以及锭剂。可以将片剂、粉剂、胶囊剂、丸剂、扁囊剂、以及锭剂用作适于口服给药的固体形式。
液体制剂包括溶液、混悬剂、以及乳剂,例如水或水-丙二醇溶液。例如,非消化道注射液体制剂可以被配制为处于聚乙二醇水溶液中的溶液。根据本发明的化学化合物因此可以被配制为用于非消化道给药(例如,通过注射,例如弹丸注射或连续输注)并且能以用于安瓿、预填充的注射器、小体积的输注中或用于具有添加的防腐剂的多剂量容器中的单位剂量存在。这些组合物可以采用这样一些形式,如在油性或水性运载体中的混悬剂、溶液、或乳剂,并且可以包含多种配制剂,如助悬剂、稳定剂、和/或分散剂。可替代地,该活性成分可以处于在使用之前用一种适合的运载体(例如无菌的无热原水)复水的粉末形式,该粉末通过无菌固体的无菌分离或通过从溶液中冻干而获得。
可以通过将活性组分溶解于水中并且按需要添加适合的着色剂、调味剂(flavor)、稳定剂以及增稠剂来制备适于口服使用的水溶液。可以通过用粘性材料(例如天然的或合成的胶质、树脂、甲基纤维素、羧甲基纤维素钠、或其他熟知的助悬剂)将细碎的活性组分分散于水中来制造适于口服使用的水性混悬剂。
适于在口腔中局部给药的组合物包括锭剂,它包括在调味基底(通常为蔗糖和阿拉伯胶或西黄蓍胶)中的活性剂;软锭剂,它包括在惰性基底中的活性成分,该惰性基底是例如明胶和甘油、或蔗糖和阿拉伯胶;以及漱口剂,它包括在适合的液体载体中的活性成分。
通过常规手段直接将溶液或混悬剂施用至鼻腔,例如用滴管、移液管或喷雾。这些组合物能以单一或多剂型被提供。在用来向呼吸道给予的组合物(包括鼻内组合物)中,该化合物将通常具有小的颗粒尺寸,例如5微米的量级或更小。可以通过本领域已知的手段获得这样的颗粒尺寸,例如通过微粒化。
这些药物制剂优选地处于单位剂型。在这样的形式中,该制剂被再分为包含适当数量的活性组分的单位剂量。该单位剂型可以是一种包装制剂,该包装包含不连续数量的制剂,例如小瓶或安瓿中的包装的片剂、胶囊剂、以及粉剂。而且,该单位剂型本身可以是一种胶囊剂、片剂、扁囊剂、或锭剂,或它可以是适当数目的任何这些包装形式。
用于口服给药的片剂、胶囊剂以及锭剂以及用于口服使用的液体是优选的组合物。用于施用至鼻腔或呼吸道的溶液或混悬剂是优选的组合物。用于局部给药至表皮的透皮贴剂是优选的。
用于配制和给药的技术的另外的细节可以在最新版本的雷明顿药物科学(Remington’s Pharmaceutical Sciences)(麦克出版公司(Mack Publishing Co.),伊斯顿,宾夕法尼亚)中找到。
给药途径
这些化合物可以通过任何途径来给药,包括但不局限于,口服、舌下、口腔、眼睛、肺部、直肠、以及非消化道给药,或作为口腔喷雾或鼻腔喷雾(例如喷雾状的蒸汽、液滴或固体微粒的吸入)。非消化道给药包括,例如,静脉内、肌内、动脉内、腹膜内、鼻内、阴道内、膀胱内(例如,向膀胱)、真皮内、经皮、局部、或皮下给予。还预期在本发明的范围内的是将药物组合物以控制的配制品的形式滴注至患者的体内,其中该药物的全身性或局部释放在较晚的时间发生。例如,该药物可以被定位于一个储存处用于至循环的控释,或用于释放至一个局部位点。
本发明的药物组合物可以是适于口服、直肠、支气管、鼻、肺、局部(包括口腔和舌下)、透皮、阴道或非肠道(包括皮肤、皮下、肌内、腹膜内、静脉内、动脉内、脑内(intracerebal)、眼内注射或输注)给予的那些,或处于适于通过吸入或吹入(包括粉剂和液体气溶胶)给予、或通过缓释系统给予的形式的那些。缓释系统的适合的实例包括含有本发明的化合物的固体疏水性聚合物的半透性基质,这些基质可以处于已定形的物品的形式,例如薄膜或微囊剂。
不旨在被理论所束缚,可以从在动物研究中使用的剂量评估或转化蝶芪剂量。通过利用Km因子比率将来自动物研究的剂量转化为人类剂量,其中基于其体表面积为每个动物模型分配Km因子(Reagan-Shaw(里根-肖)等人,FASEBJ.(美国实验生物学会联合会会志)(2007)22:659-661)。人等效剂量(HED)等于乘以该比率(动物的Km/人类Km)的动物剂量。例如,在高胆固醇血仓鼠胆固醇研究中,每天向仓鼠给予2.5mg/kg的蝶芪(里曼多等人,2005)。用0.135的Km比率(其中仓鼠的Km值是5/人类的Km值是37),这一研究的人等效剂量是对于成人而言每天0.337mg/kg,或对于160磅的人而言每天大约25mg。大鼠中的糖尿病和认知功能的另外的研究已经分别给出118-471mg/天和30-118mg/天的人等效剂量(Pari(帕里)等人,Life Sci.(生命科学)(2006)79:641;Joseph(约瑟夫)等人,农业化学与食品化学杂志(2008)56:10544)。小鼠中的蝶芪28天亚急性毒性研究显示在大约125mg/天、1.25g/天、以及12.5g/天的160磅人等效剂量下没有局部或全身性毒性(Ruiz(鲁伊斯)等人,农业化学与食品化学杂志(2009)57:3180)。每个参考文件都通过引用结合在此。
下面是用于人类临床试验的通用研究设计,以评价与一种他汀组合的蝶芪在除其他之外的测量的端点(包括氧化应激的标志物),降低胆固醇和/或降低血压的疗效。这一研究类型是介入性的:随机的、双盲的、安慰剂控制的研究。端点分类:安全性/疗效研究。
目的
这一研究的目的是评估单独的蝶芪还是蝶芪与一种他汀化合物的组合将帮助控制患有满足入选标准的血脂异常的患者的胆固醇和血压,以及改善氧化应激的标志物。研究者将评价蝶芪在这些患者中的安全性。此外,所有受试者中的33%(随机分布在所有研究组中)将经历同时的他汀治疗但仍满足先前的TC>200mg/dL、和/或LDL-C>100mg/dL的入选标准。
研究群体
六十位受试者,被分为三组:每个研究组20人。符合研究的年龄:18至88岁,两个性别。不接受健康志愿者。入选标准:具有未治疗或稳定治疗的先前的TC>200mg/dL、和/或LDL-C>100mg/dL的>18岁的患者。任何伴随的胆固醇药物必须在基线实验室以前至少2个月处于稳定的剂量并且未被列于排除标准中。排除标准:患有显著的肝脏、肾脏或胃肠道疾病的患者,接受噻唑烷二酮或纤维酸衍生物的患者,目前明显的心血管疾病的患者,具有繁殖潜力未接受节育的妇女,以及怀孕/哺乳期妇女。
研究设计
该研究提供了评估一种用于治疗血脂异常的方法的机会。在其他实施例中,该研究可以提供一种用于降低脂类水平或治疗其他代谢障碍的方法。在其他实施例中,该研究可以提供一种用于治疗氧化应激、或治疗与氧化应激相关的神经退行性障碍的方法。该研究利用多种来自分子标记物的分析的端点和结果,以标准化临床评价。这一设计允许用相关的关键端点生物标志物的投入的经济性、测试假定的试剂和首次临床地测试组合,针对这些生物标志物可以获得有价值的验证数据。
用于临床测量的评估标准:1.主要结果测量:脂类实验室标志物(即,基线TC、LDL-C、甘油三酸酯(TG)、HDL-C、非HDL-C的变化);2.次要结果测量:血压(即,基线收缩压和/或舒张压的变化);基础代谢检查(basic metabolicpanel);AST(天冬氨酸转氨酶);ALT(丙氨酸转氨酶);和/或氧化应激标志物(即,应激的基线尿液衍生的标志物(例如,异前列腺素:iPF2-α-III/creat;iPF2-α-VI/creat;2,3Dinor-iPF2-α-III/creat)的变化)。
将受试者分为三组(group)或部(arm)或:(1)高剂量蝶芪,125mg,每天两次,经由口腔,持续6至8周;(2)低剂量蝶芪,50mg,每天两次,经由口腔,持续6至8周;(3)相配的安慰剂,每天摄取两次,经由口腔,持续6至8周;在饭前一小时或饭后两小时。此外,如上所述,所有受试者中的33%(随机分布在所有研究组中)将经历同时的他汀治疗。这一亚类的患者将接受处于从约1mg至约150mg范围内的每日剂量的他汀化合物的每日剂量。蝶芪将由美国中草药公司(尔湾,加利福尼亚州)标准化。所有产品的外观将是类似的。在登记时将收集血液和尿液,以建立原始的基线水平以及最终的研究拜访,以确定最终的结果水平。如果患者的LDL-C或TC不在基于登记时抽取的血液的入选标准内,那么这位患者将不被允许开始研究药物。患者将积极地参与6至8周。根据需要,将询问患者以监测任何症状的不良反应以及家庭血压。所有的研究拜访将由以下各项组成:简短的临床检查(包括生命体征),完成的调查问卷(如果适当的话),主观的不良事件报道,以及用于临床实验室测试的空腹捐赠的血液以及尿液。在登记拜访时,向所有组给出用于介入治疗的生活方式的标准建议,例如以打印的讲义提供。将在现场实验室进行所有的血液临床实验室测试。将在专供氧化应激分析的非现场实验室进行所有的尿液临床实验室测试。在拜访期间在这位患者空腹的早晨收集至少4mL的尿液。将遵循所有用于减少尿液污染的策略和标准的保护措施。在收集的3天内,将把尿液样品从收集实验室转移到-80℃冷冻机中。然后,将尿液样品装好,以干冰冷冻,用于分析。将针对每位研究受试者进行丸剂计数,以评价顺应性。
在上面的研究设计中,无需避免已知的食物效应。不被理论所束缚,在本领域中已知食物的摄食可以干扰体内多酚化合物的吸收。期待的是,该研究在给予蝶芪、或蝶芪与一种他汀的组合过程中将考虑这一食物效应。
用于检测上面列出的异前列腺素应激标志物的有用的方法从克罗诺斯科学公司(Kronos Science)(菲尼克斯,亚利桑那州)是可获得的,利用LC/MS/MS方法论,以测量尿液和血清中的异前列腺素。其他用于测量氧化应激标志物的有用的商业化检测试剂盒是容易获得的并且是熟知的。
异前列腺素是由必需脂肪酸(主要是花生油酸)的自由基催化的过氧化作用而形成的前列腺素样化合物,无需环氧合酶(COX)酶的直接作用。异前列腺素是非经典的类二十烷酸并且拥有作为增加疼痛的感受的炎症介质的有效力的生物活性。异前列腺素在氧化应激的动物和人类模型中是脂类过氧化的精确标志物,例如当可以在癌症的发展或恶化中涉及的脂类过氧化产物过量产生时,异前列腺素分析可以测量这一过程。异前列腺素能以这种方式被使用而用于心血管疾病以及神经疾病。尽管异前列腺素具有一个短的半衰期,但是它们中的一些具有有效力的生物活性,尤其是在肺和肾脏中,并且甚至能以正常的生理学发挥作用。异前列腺素是氧化应激的有用的标志物,并且重要的是,可以通过非侵入性手段测定它们。
到目前为止,已经在所有被分析的生物学流体和组织中检测到异前列腺素。正逐渐被接受的是:测量尿液中的相对稳定的F2-异前列腺素、以及8-IsoPF2α(iPF2-α-III)是一种用于确定患者的氧化应激程度的可靠的非侵入性途径。已经定义了健康人类中的异前列腺素的正常水平,以便可以确定疾病状态以及随后的治疗介入的效果。因此,已经在许多与自由基的过量产生相关的病症中测量到增加水平的尿异前列腺素,这些病症包括四氯化碳中毒、吸烟、酗酒、肝硬化、脑变性、局部缺血-再灌注损伤、动脉硬化以及糖尿病。尿异前列腺素分析还被用来评价体内抗氧化剂的疗效并且用来建立临床试验中抗氧化剂给予的值。
可以与以下实例相联系来进一步理解上面所描述的方法。如在此使用,术语“HPMC”是指羟丙基甲基纤维素。
实例1
根据临床试验患者组,将蝶芪如下作为高的每日剂量(250mg)或低的每日剂量(100mg)口服给予。高剂量:将125mg蝶芪和35mg微晶纤维素组合在绿色的不透明的尺寸2HPMC的胶囊中,并且每天给予两次。低剂量:将50mg蝶芪和120mg微晶纤维素合并在绿色的不透明的尺寸2HPMC的胶囊中,并且每天给予两次。安慰剂:在绿色的不透明的尺寸2HPMC的胶囊中的170mg微晶纤维素,每天给予两次。所有受试者中的33%(随机分布在所有患者组中)经历同时的他汀治疗(在基线/原始测量之前持续至少约2个月)。将他汀以在约1mg至约100mg的范围内的剂量每天给予给这一亚组的患者。
如在图1和图2中所示,在监测研究8周(最终的测量)后,蝶芪的给予导致患者研究组中的TC和LDL-C水平的轻微增加。在低剂量的蝶芪下,当与他汀组合时,TC和LDL-C增加被有效地减弱。因此,这表明人类受试者比单独给予蝶芪的受试者展示出更大程度的相对降低的血浆脂类水平(TC和/或LDL-C),如在患者的血液中所测试的。
在同一研究中,给予高剂量的蝶芪的患者(包括接受他汀的患者)展示出减少的收缩压(-7.8mmHg;p<0.01)和/舒张压(-7.3mmHg;p<0.001)。
实例2
重复实例1。在监测研究约8周后,期待的是单独的人类受试者将比单独给予蝶芪的患者展示出更大程度的降低的氧化应激标志物,如在患者的尿液中所测试的。
尽管在前述说明书中,已经就本发明的某些实施例对其进行了描述,并且为了说明的目的已经提出了许多细节,但是对本领域普通技术人员显而易见的是本发明易受额外的实施例的影响并且在此所描述得某些细节可以在不偏离本发明的基本原则下进行相当大的改变。
在此所引用的所有参考文件通过引用以其全文被结合。在不偏离本发明的精神或基本属性下,可以将其体现为其他特定形式,并且因此应该参考指明本发明的范围的所附权利要求书,而非参考前述说明书。
Claims (13)
1.一种降低脂类的药物组合物,该药物组合物包括治疗有效量的蝶芪、治疗有效量的他汀、以及药学上可接受的载体。
2.如权利要求1所述的降低脂类的药物组合物,其中蝶芪以从约25mg至约500mg的量存在,并且该他汀以从约1mg至约100mg的量存在。
3.如权利要求1所述的降低脂类的药物组合物,其中蝶芪以从约50mg至约150mg的量存在。
4.如权利要求1所述的降低脂类的药物组合物,其中该他汀选自下组,该组由以下各项组成:阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀、以及辛伐他汀。
5.一种抗炎药物组合物,该药物组合物包括一个治疗有效量的蝶芪、一个治疗有效量的他汀、以及一种药学上可接受的载体。
6.如权利要求5所述的抗炎药物组合物,其中蝶芪以从约25mg至约500mg的量存在,并且该他汀以从约1mg至约100mg的量存在。
7.如权利要求5所述的抗炎药物组合物,其中蝶芪以从约50mg至约150mg的量存在。
8.如权利要求5所述的降低脂类的药物组合物,其中该他汀选自下组,该组由以下各项组成:阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀、以及辛伐他汀。
9.一种降低个体的脂类水平的方法,该方法包括向需要如此治疗的该个体给予一种药物组合物,该药物组合物包括治疗有效量的蝶芪、治疗有效量的他汀、以及药学上可接受的载体,其中脂类水平是降低的。
10.如权利要求9所述的方法,其中针对一个总每日剂量的蝶芪的治疗有效量在约50mg至约250mg的范围内,并且针对一个总每日剂量的该他汀的治疗有效量在约1mg至约100mg的范围内。
11.如权利要求9所述的方法,其中将该降低的脂类水平表示为血清中选自下组的减少,该组由以下各项组成:总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、甘油三酸酯(TG)、以及低密度脂蛋白胆固醇与高密度脂蛋白胆固醇的比例(LDL-C/HDL-C)。
12.如权利要求10所述的方法,其中该个体是人类。
13.如权利要求11所述的方法,其中该个体是人类。
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- 2012-09-17 KR KR1020147009807A patent/KR20140065442A/ko not_active Application Discontinuation
- 2012-09-17 CN CN201280055384.6A patent/CN103945857A/zh active Pending
- 2012-09-17 CA CA2848880A patent/CA2848880A1/en not_active Abandoned
- 2012-09-17 MX MX2014003093A patent/MX2014003093A/es unknown
- 2012-09-17 BR BR112014006115A patent/BR112014006115A2/pt not_active Application Discontinuation
- 2012-09-17 JP JP2014530931A patent/JP2014526521A/ja active Pending
- 2012-09-17 EP EP12831470.5A patent/EP2755671A4/en not_active Withdrawn
- 2012-09-17 WO PCT/US2012/055784 patent/WO2013040574A1/en active Application Filing
- 2012-09-17 AU AU2012308222A patent/AU2012308222A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1481239A (zh) * | 2000-10-23 | 2004-03-10 | 三共株式会社 | 血中脂类改善剂组合物 |
CN1568993A (zh) * | 2004-04-30 | 2005-01-26 | 鲁南制药股份有限公司 | 治疗高血脂症的组合物 |
CN1759834A (zh) * | 2004-09-17 | 2006-04-19 | 中国医学科学院医药生物技术研究所 | 黄连素或其与辛伐他汀联合在制备用于预防或治疗与血脂有关疾病或症状的产品中用途 |
US20110189276A1 (en) * | 2010-02-03 | 2011-08-04 | Schultheiss Nathan C | Pterostilbene cocrystals |
Also Published As
Publication number | Publication date |
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KR20140065442A (ko) | 2014-05-29 |
BR112014006115A2 (pt) | 2017-04-04 |
AU2012308222A1 (en) | 2014-04-10 |
MX2014003093A (es) | 2014-07-28 |
EP2755671A1 (en) | 2014-07-23 |
US20130072509A1 (en) | 2013-03-21 |
CA2848880A1 (en) | 2013-03-21 |
WO2013040574A1 (en) | 2013-03-21 |
JP2014526521A (ja) | 2014-10-06 |
EP2755671A4 (en) | 2015-03-11 |
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