CN106456577A - 姜黄素‑肽缀合物及其制剂 - Google Patents
姜黄素‑肽缀合物及其制剂 Download PDFInfo
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- CN106456577A CN106456577A CN201580030155.2A CN201580030155A CN106456577A CN 106456577 A CN106456577 A CN 106456577A CN 201580030155 A CN201580030155 A CN 201580030155A CN 106456577 A CN106456577 A CN 106456577A
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Abstract
在此公开了包含类姜黄素‑肽复合物的组合物。还公开了制备类姜黄素‑肽复合物的方法,其包括获得类姜黄素、获得肽并将所述类姜黄素和所述肽混合在溶剂中。还公开了治疗受试者的方法,所述方法包括鉴别需要治疗姜黄素相关病症的受试者并将包含所述类姜黄素‑肽复合物的治疗组合物施用于所述受试者。还公开了包含所述类姜黄素‑肽复合物和药学上可接受的赋形剂、稀释剂或载体的治疗组合物。
Description
相关申请
本申请要求由Payne等人于2014年5月12号提交并且标题为“姜黄素-肽缀合物及其制剂(CURCUMIN-PEPTIDE CONJUGATES AND FORMULATIONS THEREOF)”的美国临时申请序列号61/992,123的优先权,所述申请的全部公开内容(包括附图)以引用方式并入本文。
发明领域
本发明涉及营养品制剂领域,并且更具体地说,涉及具有生物可利用的类姜黄素(curcuminoid)的制剂领域。
公开背景
姜黄(Turmeric)是从姜科姜黄(Curcuma longa)根茎获得的咖喱香料并且在印度草药医学和传统的亚洲膳食中具有悠久的使用历史。姜黄的主要生物活性成分是姜黄素(1,7-双[4-羟基-3-甲氧基苯基]-1,6-庚二烯-3,5-二酮),1910年首次被鉴别出的黄色颜料。在美国,姜黄素被广泛用于食物着色(例如,在芥菜、乳酪、香料、谷类、马铃薯片、汤、泡菜、冰淇淋和酸奶中),并且也用作营养品。最近,姜黄素成了药物开发的焦点。2011年6月的报告陈述:在美国国立卫生研究院注册的关于在治疗多种临床病症中使用膳食姜黄素的61例临床试验已完成或在进行中。
商业姜黄素包含姜黄素本身(77%)、脱甲氧基姜黄素(DMC,17%)和双脱甲氧基姜黄素(BDMC,3%),后两者与姜黄素的差别仅在于分别缺少一个或两个甲氧基。作为一个群体,用于药物用途的这些化合物和它们的衍生物被称为类姜黄素。这三种化合物的主要细胞代谢产物包括两个亚乙烯基被还原的四氢类姜黄素(tetrahydrocurcuminoid),即THC(四氢姜黄素)、TDMC(四氢脱甲氧基姜黄素)和TBDMC(四氢双脱甲氧基姜黄素)。四氢类姜黄素保留了生物活性,但是为无色的并且比类姜黄素更具有化学稳定性。
姜黄素的药用特性包括所报告的抗氧化、抗炎、抗病毒、抗细菌和抗真菌、抗致畸、抗增殖和抗转移的作用,并且它即使是在持续时间内以8g/天的水平摄入,对人类食用也是安全的。研究显示,姜黄素在不同程度上促进创伤愈合并且对糖尿病、哮喘、过敏症、白内障、动脉粥样硬化、阿尔茨海默氏病、帕金森氏病、骨髓增生异常综合征、囊性纤维化、心肌梗塞、高胆固醇、中风、疟疾、HIV、HSV-1、牛皮癣等等具有治疗性和或预防性作用。姜黄素对其具有改善作用的疾病包括自身免疫疾病,其包括多发性硬化症、类风湿性关节炎、牛皮癣、炎性肠病、干燥综合征( syndrome)、系统性红斑狼疮、I型糖尿病、神经变性疾病和几种类型的癌症。
姜黄素的药学用途一直受到限制,因为这种化合物在酸性和生理pH下几乎不溶于水(仅溶解大约600ng/mL)并在碱性pH下快速水解。人类高口服剂量(8-12g/天)的姜黄素的血浆浓度仅仅在纳摩尔范围内。关于姜黄素的大多数治疗性体外研究已将其溶解在有机溶剂中。这些溶剂包括二甲基亚砜(DMSO)、丙酮和乙醇,但是它们自身对于体内研究具有有限的适用性。姜黄素的不良溶解性降低了它在身体各处,具体地在大脑中的生物利用率,在大脑中,姜黄素不易穿过血脑屏障。
因此,持续需要提高姜黄素生物利用率的方法和工艺。
发明概述
在此公开了包含类姜黄素-肽复合物的组合物。还公开了制备类姜黄素-肽复合物的方法,其包括获得类姜黄素、获得肽并将类姜黄素和肽混合在溶剂中。还公开了治疗受试者的方法,所述方法包括鉴别需要治疗姜黄素相关病症的受试者并将包含所述类姜黄素-肽复合物的营养组合物施用于受试者。还公开了包含所述类姜黄素-肽复合物和药学上可接受的赋形剂、稀释剂或载体的治疗组合物。
附图简述
图1是示出姜黄素结合到乳清蛋白的凝胶电泳实验的照片。
实施方案详述
本发明人已发现,姜黄素-肽复合物的摄入相比于未复合的姜黄素的摄入显著地增加姜黄素的血清生物利用率。
因此,在一个方面,本文公开了包含连接至肽化合物的类姜黄素化合物的类姜黄素-肽复合物。
对于“肽化合物”或“肽复合物”的上下文中的“肽”,它意指由一个或多个氨基酸构成的化合物。当肽具有不止一个氨基酸时,所述肽具有至少两个通过肽键连接在一起的氨基酸。在一些实施方案中,肽包含20种天然存在的氨基酸或修饰氨基酸中的任一种。在某些实施方案中,化合物是低聚肽,例如具有两个氨基酸的二肽、具有三个氨基酸的三肽、4聚体、5聚体等等。在一些实施方案中,低聚肽包含2-20个之间的氨基酸。在其他实施方案中,肽化合物是具有21-100个之间的氨基酸的多肽。对于“N聚体”,其中N是整数,它意指具有N个氨基酸的低聚肽或多肽。
在其他实施方案中,肽化合物是蛋白质或蛋白质片段。在一些实施方案中,蛋白质是天然存在的并且是由细胞表达的全序列多肽。在其他实施方案中,蛋白质是具有非天然存在的序列的合成蛋白。在一些实施方案中,合成蛋白是使用重组技术由细胞表达的,而在其他实施方案中,合成蛋白是使用肽合成仪合成的。蛋白质片段是具有与蛋白质中发现的序列片段相同的序列的低聚肽或多肽。
本公开和权利要求范围内的所有氨基酸、蛋白质或肽可以是人工产生的或天然存在的或具有任何形式的修饰(翻译后的化学修饰或酶法修饰)。
在一些实施方案中,类姜黄素化合物结合到肽化合物以形成复合物。在这些实施方案中,类姜黄素化合物直接结合到肽的氨基酸或通过接头化合物进行结合。在一些实施方案中,接头是烷基、烯基或炔基部分,其可被选自由-OH、-SH、-COOH、-N-C(O)H、-N-C(O)OH、-C(O)NH等组成的组的取代基取代。在一些实施方案中,接头通过取代基结合到氨基酸或类姜黄素化合物。
在其他实施方案中,类姜黄素化合物通过氢键合连接到肽化合物以形成复合物。在其他实施方案中,类姜黄素化合物通过静电力连接到肽化合物以形成复合物。在其他实施方案中,类姜黄素化合物通过亲脂相互作用(例如,范德华力或π堆叠)连接到肽化合物以形成复合物。在其他实施方案中,类姜黄素化合物通过共价键合连接到肽化合物以形成复合物。
在一些实施方案中,肽是全长蛋白。在某些实施方案中,所述蛋白质是发现于哺乳动物血清中的蛋白质。在其他实施方案中,蛋白质来源于哺乳动物之外的动物源。在这些实施方案的一部分中,蛋白质来源于禽源,例如卵蛋白。在另一些其他实施方案中,蛋白质来源于植物,如谷物、坚果、豆类、水果、蔬菜等等。在一些实施方案中,蛋白质是从乳清、大米、豌豆、亚麻籽、大豆、卵获得的。在一些实施方案中,蛋白质是白蛋白。在其他实施方案中,肽包含半胱氨酸或酪氨酸。在某些实施方案中,肽是N-乙酰半胱氨酸。在某些实施方案中,仅使用单一氨基酸,例如半胱氨酸或酪氨酸。
在一些实施方案中,从自然源获得的蛋白质不是分离和纯化的蛋白质。相反,蛋白质是各种分离的蛋白质一起的混合物。这些蛋白质是特定源的分离物。因此,例如,乳清分离蛋白(WPI)是从乳清中获得的分离蛋白的混合物,而大米分离蛋白(RPI)是从大米中获得的分离蛋白的混合物。本领域的普通技术人员已知如何获得分离蛋白,例如WPI。贯穿本公开,术语“乳清蛋白”、“乳清分离蛋白”和“WPI”可互换使用。
本文所描述的复合物中使用的低聚肽和多肽及全长蛋白的实例包括但不限于乳清蛋白、肿瘤坏死因子(TNF-α);环氧合酶(COX)(包括COX-1和COX-2);α1-酸性糖蛋白(AGP)(也称为血清类粘蛋白);髓样分化蛋白2(MD-2);称为组蛋白乙酰转移酶(HAT)的酶的组中的任一种,如p300/CBP;称为组蛋白脱乙酰酶(HDAC)的酶的组中的任一种;乙二醛酶I(GLOI);黄嘌呤氧化酶(XO);蛋白酶体;肌(内)质网Ca2+ATP酶(SERCA);人免疫缺陷病毒1型(HIV-1)蛋白酶;DNA甲基转移酶(DNMT)中的任一种,例如DNMT1;DNA聚合酶(pol)λ;核糖核酸酶(RNase)中的任一种,例如RNase A;脂氧合酶(LOX)中的任一种;基质金属蛋白酶(MMP)中的任一种;溶菌酶;蛋白激酶C(PKC)酶家族中的任一种;细胞肉瘤(c-Src);糖原合酶激酶(GSK)-3β;ErbB2;磷酸化酶激酶;蛋白还原酶中的任一种,例如硫氧还蛋白还原酶(TrxR)和醛糖还原酶(ALR2);硫氧还蛋白还原酶;酪蛋白中的任一种;人血清白蛋白(HSA);牛血清白蛋白(BSA);纤维蛋白原;β-乳球蛋白(β-LG);α-乳清蛋白;人血清免疫球蛋白(Ig);FtsZ;转甲状腺素蛋白(TTR);谷胱甘肽(GSH);和Kelch状ECH相关蛋白1(Keap1)。
在一些实施方案中,类姜黄素-肽复合物是姜黄素和乳清分离蛋白(WPI)的复合物。在某些实施方案中,WPI是乳源乳清蛋白。乳清蛋白是β-乳球蛋白(~65%)、α-乳清蛋白(~25%)、牛血清白蛋白(~8%)和免疫球蛋白的混合物。在这些实施方案的一部分中,复合物是通过在乙醇中混合姜黄素和WPI形成的。因此,在这些实施方案中,姜黄素与WPI之间无共价键。然而,在其他实施方案中,姜黄素和WPI形成共价键。在某些实施方案中,姜黄素与WPI的比率是1:1w/w(mg姜黄素:g的WPI)。在其他实施方案中,姜黄素与WPI的比率是1:≤10w/w(mg:g)。在另一些其他实施方案中,姜黄素与WPI的比率是10:≥1w/w(mg:g)。在某些实施方案中,姜黄素与WPI的比率是25:1w/w(mg:g)。在其他实施方案中,姜黄素与WPI的比率是1:50w/w(mg:g)。在一些实施方案中,从可商购获得的来源获得WPI,其可用粉末中包含85%WPI。在一些实施方案中,从可商购获得的来源获得姜黄素,其可用粉末中包含95%姜黄素。
在另一方面,本文公开了包含如本文所述的类姜黄素-肽复合物和药学上可接受的载体、稀释剂或赋形剂的营养组合物。
术语“载体”定义了有助于化合物并入到细胞或组织中的化合物。例如二甲亚砜(DMSO)是一种常用的载体,因为它有助于很多有机化合物摄取到生物体的细胞或组织中。一种常用的载体是水,在这种情况下,制备目标产物的水性溶液并将其施用于受试者。
术语“稀释剂”定义了会溶解目标化合物并且稳定化合物生物活性形式的稀释于水中的化合物。在本领域中,将溶解在缓冲溶液中的盐用作稀释剂。一种常用的缓冲溶液是磷酸盐缓冲盐水,因为它模拟了人血液的盐条件。因为缓冲盐可以在低浓度下控制溶液的pH值,所以缓冲稀释剂很少改变化合物的生物活性。
在某些实施方案中,同一种物质可以用作载体、稀释剂或赋形剂,或者具有任意两种作用或者具有全部的三种作用。因此,治疗组合物的单一添加剂可以具有多种功能。
术语“生理上可接受的”定义了不会消除化合物的生物活性和特性的载体或稀释剂。
可以用本身已知的方式制造本文所公开的治疗组合物,例如,通过常规混合、溶解、造粒、糖锭剂制备、研磨、乳化、干燥、包封、包埋或压片方法。
可以使用一种或多种生理学上可接受的载体(包括赋形剂和助剂)以常规方式来配制本文所公开的治疗组合物,所述载体有助于将类姜黄素-肽复合物加工成营养学上可使用的制剂。任何熟知的技术、载体和赋形剂都可以如本领域中合适的和理解的来使用;例如在上文的Remington's Pharmaceutical Sciences中。
对于口服施用,可通过将类姜黄素-肽复合物和本领域中熟知的药学上可接受的载体结合来容易地配制类姜黄素-肽复合物。这类载体使得本公开的复合物能够配制为片剂、丸剂、糖锭剂、胶囊、液体、凝胶、糖浆、浆液、混悬液等,以便受试者口服摄入。通过将一种或多种固体赋形剂和本公开的类姜黄素-肽复合物混合,任选地研磨所得混合物并在添加合适的辅助剂(如果需要)之后加工颗粒混合物以获得片剂或糖锭剂核,可以获得用于口服使用的治疗制剂。合适的赋形剂具体地说是填充剂,如糖,包括乳糖、蔗糖、甘露醇或山梨醇;纤维素制剂,例如像玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟基丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮(PVP)。如果需要,可以添加崩解剂,如交联聚乙烯吡咯烷酮、琼脂或海藻酸或其盐,如海藻酸钠。
糖锭剂核提供有合适的包衣。为此,可以使用浓缩糖溶液,其可以任选地含有阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波姆胶、聚乙二醇和/或二氧化钛、漆溶液以及合适的有机溶剂或溶剂混合物。可以向片剂或糖锭剂包衣中添加染料或色素以用于鉴别或表征活性化合物剂量的不同组合。
可口服使用的治疗制剂包括由明胶制得的推入配合型胶囊以及由明胶和塑化剂(如甘油或山梨糖醇)制得的软质密封胶囊。所述推入配合型胶囊可以含有与填充剂如乳糖、粘合剂如淀粉和/或润滑剂如滑石或硬脂酸镁以及任选地稳定剂混合的活性成分。在软胶囊中,活性化合物可以溶解或混悬于合适的液体,如脂肪油、液体石蜡或液体聚乙二醇中。此外,可以添加稳定剂。用于口服施用的所有制剂都应为适用于此类施用的剂量。
适合以本文所公开的方法来使用的治疗组合物包括含有有效实现其预期用途的量的类姜黄素-肽复合物的组合物。更确切地说,治疗有效量意指有效预防、减轻或改善正在治疗的受试者的疾病症状或者延长存活期的类姜黄素-肽复合物的量。
典型地,对患者施用的姜黄素的剂量范围是每千克患者体重约0.5至1000mg。根据患者的需要,所述剂量可以是在一天或多天的疗程中给予的单一剂量或两个或更多个的一系列剂量。在一些实施方案中,剂量在0.1mg至50mg之间。在其他实施方案中,剂量在1mg至30mg之间。其他剂量范围包括10至50mg之间、20至50mg之间、30至50mg之间、40至50mg之间、20至40mg之间、10至20mg之间、10至30mg之间、20至30mg之间和30至40mg之间。所述剂量也可以是10mg、20mg、30mg、40mg或50mg。
在另一方面,本文公开了治疗姜黄素相关病症的方法,所述方法包括鉴别需要该治疗的受试者并将治疗有效量的本文所公开的类姜黄素-肽复合物施用于受试者。
术语“受试者”是指作为治疗、观察或实验的目标的动物,优选地为哺乳动物,并且最优选地为人。哺乳动物可选自由小鼠、大鼠、兔子、豚鼠、狗、猫、绵羊、山羊、牛、灵长类动物如猴、黑猩猩和猿以及人组成的组。
术语“治疗有效量”用于表示引发所指示的生物或药物应答的类姜黄素-肽复合物的量。这种应答可发生在研究者、兽医、医师或其他临床医生所寻求的组织、系统、动物或人内,并且包括正在治疗的疾病的症状的减轻。
术语“治疗(treat)”、“治疗(treating)”、“治疗(treatment)”或其任何其他变型不表示从病症中完全治愈。疾病或病症的症状在任何程度上的任何改善或减轻或者受试者舒适度的增加都被认为是治疗。
在另一方面,本文公开了治疗姜黄素相关病症的方法,所述方法包括鉴别需要该治疗的受试者并将治疗有效量的本文所公开的类姜黄素-肽复合物施用于受试者,其中在施用之后,姜黄素的血清Cmax为<500ng/mL。在一些实施方案中,姜黄素的血清Cmax为<0.001%的姜黄素施用剂量。
“姜黄素相关病症”是已显示通过向受试者施用姜黄素或类姜黄素化合物而被改善的病症。姜黄素相关病症的实例包括但不限于糖尿病、哮喘、过敏症、白内障、动脉粥样硬化、阿尔茨海默氏病、帕金森氏病、骨髓增生异常综合征、囊性纤维化、心肌梗塞、高胆固醇、中风、疟疾、HIV、HSV-1、牛皮癣等等。姜黄素对其具有改善作用的疾病包括自身免疫疾病,其包括多发性硬化症、类风湿性关节炎、牛皮癣、炎性肠病、干燥综合征、系统性红斑狼疮、I型糖尿病、神经变性疾病和几种类型的癌症。
药代动力学参数的Cmax的定义为本领域技术人员所熟知。简而言之,Cmax是剂量施用后的最大观察血浆浓度。
在另一方面,本文公开了制备如上所述的类姜黄素-肽复合物的方法,所述方法包括获得类姜黄素、获得肽并将类姜黄素和肽混合在溶剂中。
在一些实施方案中,溶剂是极性溶剂,而在其他实施方案中,溶剂是非极性溶剂。在一些实施方案中,极性溶剂是水,而在其他实施方案中,极性溶剂是醇。在一些实施方案中,醇是乙醇。
在其他实施方案中,溶剂是碱性溶液。在这些实施方案中,姜黄素溶解在碱性溶液中,接着加入蛋白质。在干燥姜黄素-蛋白质混合物之前,溶液被制成酸性。
实施例
实施例1:姜黄素-乳清分离蛋白复合物的制备
制备姜黄素-WPI复合物以施用于人受试者。使用以下材料:
WPI:按重量计85%蛋白质
姜黄素粉末:95%类姜黄素
乙醇:100%乙醇
1:50w/w的姜黄素:WPI比率。通过将5g姜黄素粉末与1000mL乙醇混合制备0.5%w/v酊剂(溶液)。将混合物放置于磁力搅拌热板上,速度设定值为中等并且温度设定值为50℃持续30分钟或者直到溶液变澄清。将250g WPI粉末加入所得溶液。将混合物放置在低速(20-30rpm)的旋转蒸发仪(rotary evaporator/rotovap)上,具有50℃水浴温度和低真空,持续30分钟或者直到90%的乙醇被蒸发。将所得混合物放置在窑炉烘箱中以移除乙醇的其余部分。另选地,将混合物放置在冷冻干燥机中,或另选地放置在流罩中或任其风干。
姜黄素/WPI复合物是具有黄色至橙色范围内不透明颜色的蓬松粉。与纯姜黄素相比之下,姜黄素:WPI复合物粉末与水自由地混合,形成混悬液。可用洗涤剂轻易地将姜黄素:WPI粉末从玻璃、塑胶和金属表面清除。姜黄素:WPI复合物只最低限度地使服装染色。用洗涤剂溶液进行有力的清洗通常足以移除染色。
25:1w/w(mg:g)的姜黄素:WPI比率。重复以上程序,但除了25mg姜黄素粉末和1gWPI粉末。获得相似的产物。
运行姜黄素:WPI复合物的标准SDS-PAGE凝胶来测定姜黄素是否结合到蛋白质。图1示出了所得凝胶。电泳后不经固定或染色在UV下观察该凝胶。泳道6-8中所见的色斑是用姜黄素对WPI进行染色的结果。标记为M的泳道是分子量标记,其具有三个以75、50和25kD运行的荧光条带。泳道1-8分别对应于1、5、10、20、40、80、160和320微克姜黄素:WPI样品的姜黄素:WPI复合物。如泳道6-8可见,姜黄素与WPI复合。对于泳道1-5,或者没有足够的姜黄素供可视化,或者通过用SDS-PAGE裂解缓冲液处理、加热或程序中的其他步骤去除了姜黄素。
实施例2:姜黄素-氨基酸复合物的制备
按照实施例1的方法,将姜黄素溶解在95%乙醇中,随后加入N-乙酰基半胱氨酸(NAC)。使用姜黄素与n-乙酰基半胱氨酸不断增大的浓度比率来找到饱和水平。在姜黄素的0.5%(w/v)乙醇溶液中,在大约100mg的姜黄素与1000mg的NAC处发现了最佳浓度。当在宏观视场中观察到少量的姜黄素晶体形成时,记下最佳浓度。
相似地,将姜黄素溶解在95%乙醇中,随后加入半胱氨酸。使用姜黄素与半胱氨酸不断增大的浓度比率来找到饱和水平。在姜黄素的0.5%(w/v)乙醇溶液中,在大约100mg的姜黄素与1000mg的半胱氨酸处发现了最佳浓度。当在宏观视场中观察到少量的姜黄素晶体形成时,记下最佳浓度。
此外,将1.8克半胱氨酸-姜黄素复合物给药于健康的人类志愿受试者。经发现,半胱氨酸-姜黄素复合物的最大测量血液浓度为300ng/mL。这与两剂量的25mg/g姜黄素:WPI复合物(相当于50mg的姜黄素)相比较,后者产生了70ng/mL的测量血液浓度。
在相似的实验中,将姜黄素溶解在95%乙醇中,随后加入酪氨酸。未观察到姜黄素结合到络氨酸。姜黄素以单层凝固在酪氨酸层上方。当在显微镜下观察时,酪氨酸层没有可视的着色并且姜黄素晶体与酪氨酸完全分开。
实施例3:姜黄素:WPI复合物的施用
将具有25:1w/w(mg:g)姜黄素:WPI比率的单剂量的姜黄素:WPI复合物施用于两个健康个体。所述剂量包含25mg姜黄素。第20分钟、50分钟和90分钟从每个个体抽取血液并且计算血清姜黄素水平。结果在以下表1中示出。
表1
实施例4:临床研究
一位57岁男性呈现出膝和髋关节炎/滑囊炎和炎性肠病。在给药前,他具有中度膝和髋疼痛及腹部绞痛和中度腹泻。给予几种不同的剂量和剂型。给药情况和观察到的作用总结在表2中。
表2
实施例5:临床研究
病例1:一位70岁白人女性呈现出季节性抑郁症病史,已通过充分控制。将1.2g实施例1的复合物每日两次施用于所述患者,使用3天后该患者经历了症状的完全缓解。她继续服用该产品以维持症状缓解并能够停止的使用。
病例2:一位69岁白人女性呈现出髋、下背和肩的轻度骨关节炎病史。将300mg实施例1的复合物每日三次施用于所述患者,该患者经历了症状的完全缓解,包括活动范围的恢复。她停止了NSAID药物的使用。
病例3:一位67岁白人男性呈现出作为童年脊髓灰质炎感染的次级结果的关节损伤和移动能力受损。将1.2g实施例1的复合物持续两周每日两次施用于所述患者,以达到症状的完全缓解。他继续服用该产品以维持症状缓解。
病例4:一位65岁白人男性呈现出持续20多年的多重创伤性损伤造成的移动能力受损。将1.2g实施例1的复合物持续两周每日两次施用于所述患者,该患者报告症状缓解改善了50%。
病例5:一位47岁白人男性呈现出对所有NSAID治疗都难治的网球肘病史。他无法向患病手臂施加任何重量。持续两周每日两次服用等效剂量的混合在TANG中的1.5-2.0g实施例1的复合物,他报告了症状的完全缓解。他继续服用该产品以维持症状缓解。
病例6:一位28岁白人男性呈现出季节性过敏症病史。将1.2g实施例1的复合物持续两周每日两次施用于所述患者,以达到季节性过敏症症状的完全缓解。他继续使用产品以维持症状缓解。
病例7:一位47岁白人男性呈现出因1年前发生的踝关节破裂而报告的疼痛和移动能力丧失。持续两周每日两次使用1.2g实施例1的产品,所述患者报告了完全症状缓解和移动能力恢复。他继续服用产品以维持症状缓解。
病例8:一位50岁白人女性呈现出躁郁症病史。将1.2g实施例1的复合物持续两周每日两次施用于所述患者,该患者抑郁症症状中度缓解并且报告了思维更清晰和情感高涨。
病例9:一位67岁白人男性呈现出右肩轻度关节炎病史。将1.2g实施例1的复合物持续两周每日两次施用于所述患者,该患者关节炎症状显著缓解。
病例10:一位75岁女性呈现出两个脚踝的衰弱性关节炎。她休息时具有疼痛,并且主要通过轮椅走动,具有最小限度的站立或者利用助行器行走的能力。她曾每日使用各种NSAID和处方止痛麻醉剂。将25mg姜黄素持续两周每日三次(25mg姜黄素/g WPI)施用于所述患者。她获得了关节炎症状缓解,其包括疼痛减少和无需使用轮椅或助行器的移动能力增加。她中断了麻醉剂和NSAID的使用。
病例10:一位60岁女性呈现出休息时疼痛和工作活动(乡村农活)期间疼痛增加的手部关节炎。她每日使用各种NSAID。持续两周每日两次(bid)将25mg姜黄素(25mg姜黄素/gWPI)施用于所述患者。她获得了关节炎症状缓解并且能够增加工作活动。她中断了NSAID的使用。三个月姜黄素治疗后,她持续3周中断姜黄素产品的使用并且重复bid剂量的姜黄素,获得了相同结果。
病例11:一位61岁男性呈现出重度髋骨关节炎/滑囊炎,表现出休息时疼痛、移动能力降低和工作活动(乡村农活)期间疼痛增加。所述患者正每天使用各种NSAID并且计划进行髋关节置换手术。持续两周bid将25mg姜黄素(25mg姜黄素/g WPI)施用于所述患者。他经历了关节炎症状缓解,其包括移动能力增加和更容易且伴随更少疼痛进行工作活动的能力增加。
病例12:一位50岁女性呈现出肩、髋和膝关节炎和脚疼痛。所述患者表现出休息时疼痛和移动能力降低,使得该患者需要步行手杖的辅助。持续两周bid将25mg姜黄素(25mg姜黄素/g WPI)施用于所述患者。她显示出关节炎症状缓解以及伴随更少疼痛的移动能力增加。
病例13:一位55岁女性呈现出膝关节炎以及日常活动和工作活动时的膝疼痛。持续两周bid将12.5mg姜黄素(1g姜黄素:WPI产品)施用于所述患者。她显示出关节炎症状缓解以及日常活动和工作活动时更少的疼痛。
病例14:一位45岁女性呈现出膝和肩关节炎。膝和肩疼痛在正常活动和工作活动(乡村农活)时是明显的。持续两周bid将12.5mg姜黄素(1g姜黄素:WPI产品)施用于所述患者。她显示出关节炎症状缓解以及日常活动和工作活动时更少的疼痛。
病例15:一位60岁男性呈现出膝关节炎以及正常活动和工作活动(乡村农活)时的膝疼痛。持续两周bid将25mg姜黄素(1g姜黄素:WPI产品)施用于所述患者。他显示出关节炎症状缓解以及日常活动和工作活动时更少的疼痛。
病例16:一位60岁男性呈现出淋巴瘤和多病灶淋巴结肿大。持续两周bid将25mg姜黄素(25mg姜黄素/g WPI)施用于所述患者。他在两周后显示患病淋巴结的中度萎缩。进一步使用该物质没有任何进一步的作用。
病例17:一位57岁男性呈现出膝关节炎、髋滑囊炎以及正常活动和工作活动时的中度膝和髋疼痛。持续两周bid将25mg姜黄素(25mg姜黄素/g WPI)施用于所述患者。他显示出关节炎症状缓解以及日常活动和工作活动时更少的疼痛。
病例18:一位57岁男性呈现出炎性肠病以及伴随的腹部绞痛和轻度至中度腹泻。持续两周bid将25mg姜黄素(25mg姜黄素/g WPI)施用于所述患者。他显示出IBD的症状缓解以及腹部绞痛的完全缓解、坚固的大便。
病例19:一位58岁男性呈现出与正常活动和工作活动相关的膝和后背疼痛。持续两周bid将25mg姜黄素(25mg姜黄素/g WPI)施用于所述患者。他显示出关节炎症状缓解以及日常活动和工作活动时更少的疼痛。
病例20:一位67岁女性呈现出晚期阿尔茨海默氏病。给药之前,她在测试中未能完成所有的短期记忆问题。将1.2g姜黄素bid施用于患者。30天后,她在测试中通过了所有的短期记忆问题。她继续从治疗获得持久的效果。
实施例6:动物研究
病例1:一匹11岁的QH去势马呈现出右和左前脚踝的骨关节炎。它显示出脚踝弯曲时的疼痛和疾驰时的“不平步态”。每日两次对其口服施用200mg实施例1的产品。一周后,该马显示了脚踝弯曲时的疼痛减少和疾驰时的平稳步态以及平静或焦虑减少。没有不良副作用。
病例2:一只5岁绝育雌犬呈现出骨关节炎。它显示出前肢弯曲时的疼痛和减少的移动能力。每日两次对其口服施用25mg实施例1的产品。一周后,该狗显示出肢体弯曲时的疼痛减少、移动能力增加、奔跑增加和食欲增加。没有不良副作用。
病例3:一匹11岁的QH去势马呈现出前脚踝弯曲时的疼痛和减少的移动能力。通过鼻胃管一次性对其施用800mg实施例1的产品。4小时后,该马显示出脚踝弯曲时的疼痛减少以及明显的平静和镇静作用。没有不良副作用。
病例4:一匹2岁QH小雌马呈现出焦虑和不安。它在比赛训练环境中非常紧张并且在畜舍中与其他马匹具有有限互动。它也显示出下降的食欲。每日两次对其口服施用200mg实施例1的产品。一周后,该马显示出在畜舍中的焦虑和紧张减少,同时伴随食欲增加。没有不良副作用。
实施例7:姜黄素:WPI复合物的生物利用率
姜黄素:WPI复合物:六只小鼠各自被给予12.5mg的姜黄素:WPI复合物(每只小鼠~312μg的姜黄素)。每只小鼠称重为~25g。每30分钟抽取血液,总计180分钟。姜黄素的平均值(以ng/mL计)在表3中示出。平均Tmax为60分钟并且平均Cmax为163ng/mL的姜黄素。
表3:姜黄素:WPI复合物
时间(分钟) | 平均值(ng/mL) | 1 | 2 | 3 | 4 | 5 | 6 |
30 | 27 | 45 | 58 | 12 | BDL | 10 | 10 |
60 | 163 | 201 | 656 | 38 | 32 | 38 | 13 |
90 | 49 | 20 | 109 | 12 | 77 | 23 | 53 |
120 | 94 | 127 | 34 | BDL | BDL | 204 | 11 |
150 | 27 | 40 | 13 | BDL | BDL | BDL | BDL |
180 | BDL | BDL | BDL | BDL | BDL | BDL | BDL |
BDL=低于可检测限度(10ng/mL)
姜黄素:六只小鼠各自被给予0.625mg的姜黄素(约两倍于如上作为复合物施用的姜黄素量)。每只小鼠称重为~25g。每30分钟抽取血液,总计180分钟。姜黄素的平均值(以ng/mL计)在下表4中示出。
表4:姜黄素
BDL=低于可检测限度(10ng/mL)
如数据显示,游离姜黄素具有非常差的吸收性,使得它的血浆浓度总是低于可检测限度。然而,当姜黄素与乳清分离蛋白(WPI)复合时,它变成易于生物利用的。
实施例8:姜黄素:WPI复合物的药代动力学
将不同剂型的姜黄素以几个不同剂量施用于两个健康志愿者。通过刺指法在不同时间点从每个个体获得血液。计算姜黄素的血浆浓度并测定Cmax。结果在表5中示出
表5
nd=未检测出
N/A=不可用;未获得数据。
Claims (20)
1.一种包含类姜黄素-肽复合物的组合物。
2.如权利要求1所述的组合物,其中所述类姜黄素选自由姜黄素、脱甲氧基姜黄素(DMC)、双脱甲氧基姜黄素(BDMC)、四氢姜黄素(THC)、四氢脱甲氧基姜黄素(TDMC)和四氢双脱甲氧基姜黄素(TBDMC)组成的组。
3.如权利要求1所述的组合物,其中所述肽选自由二肽、三肽、低聚肽、多肽、蛋白质和蛋白质片段组成的组。
4.如权利要求1所述的组合物,其中所述肽选自由以下组成的组:乳清蛋白、肿瘤坏死因子(TNF-α);环氧合酶(COX)(包括COX-1和COX-2);α1-酸性糖蛋白(AGP)(也称为血清类粘蛋白);髓样分化蛋白2(MD-2);称为组蛋白乙酰转移酶(HAT)的酶的组中的任一种,如p300/CBP;称为组蛋白脱乙酰酶(HDAC)的酶的组中的任一种;乙二醛酶I(GLOI);黄嘌呤氧化酶(XO);蛋白酶体;肌(内)质网Ca2+ATP酶(SERCA);人免疫缺陷病毒1型(HIV-1)蛋白酶;DNA甲基转移酶(DNMT)中的任一种,例如DNMT1;DNA聚合酶(pol)λ;核糖核酸酶(RNase)中的任一种,例如RNase A;脂氧合酶(LOX)中的任一种;基质金属蛋白酶(MMP)中的任一种;溶菌酶;蛋白激酶C(PKC)酶家族中的任一种;细胞肉瘤(c-Src);糖原合酶激酶(GSK)-3β;ErbB2;磷酸化酶激酶;蛋白还原酶中的任一种,例如硫氧还蛋白还原酶(TrxR)和醛糖还原酶(ALR2);硫氧还蛋白还原酶;酪蛋白中的任一种;人血清白蛋白(HSA);牛血清白蛋白(BSA);纤维蛋白原;β-乳球蛋白(β-LG);α-乳清蛋白;人血清免疫球蛋白(Ig);FtsZ;转甲状腺素蛋白(TTR);谷胱甘肽(GSH);和Kelch状ECH相关蛋白1(Keap1)。
5.如权利要求1所述的组合物,其中所述肽是乳清蛋白、大米蛋白或豌豆蛋白。
6.如权利要求1所述的组合物,其中所述类姜黄素和所述肽是通过共价键、离子相互作用、亲脂性(范德华)相互作用或氢键缀合的。
7.如权利要求1所述的组合物,其中所述姜黄素和乳清蛋白的比率是1:1w/w(mg:g)或1:≤10w/w(mg:g)或10:≥1w/w(mg:g)或25:1w/w(mg:g)或1:50w/w(mg:g)。
8.如权利要求1所述的组合物,其中所述类姜黄素-肽复合物是通过将所述类姜黄素和所述肽混合在溶剂中的方法获得的。
9.一种制备类姜黄素-肽复合物的方法,其包括:
获得类姜黄素;
获得肽;以及
将所述类姜黄素和所述肽混合在溶剂中。
10.如权利要求9所述的方法,其中所述类姜黄素选自由姜黄素、脱甲氧基姜黄素(DMC)、双脱甲氧基姜黄素(BDMC)、四氢姜黄素(THC)、四氢脱甲氧基姜黄素(TDMC)和四氢双脱甲氧基姜黄素(TBDMC)组成的组。
11.如权利要求9所述的方法,其中所述肽选自由二肽、三肽、低聚肽、多肽、蛋白质和蛋白质片段组成的组。
12.如权利要求9所述的方法,其中所述肽选自由以下组成的组:乳清蛋白、肿瘤坏死因子(TNF-α);环氧合酶(COX)(包括COX-1和COX-2);α1-酸性糖蛋白(AGP)(也称为血清类粘蛋白);髓样分化蛋白2(MD-2);称为组蛋白乙酰转移酶(HAT)的酶的组中的任一种,如p300/CBP;称为组蛋白脱乙酰酶(HDAC)的酶的组中的任一种;乙二醛酶I(GLOI);黄嘌呤氧化酶(XO);蛋白酶体;肌(内)质网Ca2+ATP酶(SERCA);人免疫缺陷病毒1型(HIV-1)蛋白酶;DNA甲基转移酶(DNMT)中的任一种,例如DNMT1;DNA聚合酶(pol)λ;核糖核酸酶(RNase)中的任一种,例如RNase A;脂氧合酶(LOX)中的任一种;基质金属蛋白酶(MMP)中的任一种;溶菌酶;蛋白激酶C(PKC)酶家族中的任一种;细胞肉瘤(c-Src);糖原合酶激酶(GSK)-3β;ErbB2;磷酸化酶激酶;蛋白还原酶中的任一种,例如硫氧还蛋白还原酶(TrxR)和醛糖还原酶(ALR2);硫氧还蛋白还原酶;酪蛋白中的任一种;人血清白蛋白(HSA);牛血清白蛋白(BSA);纤维蛋白原;β-乳球蛋白(β-LG);α-乳清蛋白;人血清免疫球蛋白(Ig);FtsZ;转甲状腺素蛋白(TTR);谷胱甘肽(GSH);和Kelch状ECH相关蛋白1(Keap1)。
13.如权利要求9所述的方法,其中所述溶剂为极性溶剂。
14.如权利要求13所述的方法,其中所述极性溶剂为醇。
15.如权利要求14所述的方法,其中所述醇为乙醇。
16.一种治疗受试者的方法,所述方法包括:
鉴别需要治疗姜黄素相关病症的受试者,以及
将包含如权利要求1所述的类姜黄素-肽复合物的治疗组合物施用于所述受试者。
17.如权利要求16所述的方法,其中所述姜黄素相关病症选自由糖尿病、哮喘、过敏症、白内障、动脉粥样硬化、阿尔茨海默氏病、帕金森氏病、骨髓增生异常综合征、囊性纤维化、心肌梗塞、高胆固醇、中风、疟疾、HIV、HSV-1、牛皮癣等等组成的组。姜黄素对其具有改善作用的疾病包括自身免疫疾病,其包括多发性硬化症、类风湿性关节炎、牛皮癣、炎性肠病、干燥综合征、系统性红斑狼疮、I型糖尿病、神经变性疾病和几种类型的癌症。
18.如权利要求16所述的方法,其中在所述施用之后,姜黄素的血清Cmax为<500ng/mL。
19.如权利要求16所述的方法,其中在所述施用之后,姜黄素的血清Cmax为<0.001%的姜黄素施用剂量。
20.包含如权利要求1所述的类姜黄素-肽复合物和药学上可接受的赋形剂、稀释剂或载体的治疗组合物。
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CN107772479A (zh) * | 2017-11-28 | 2018-03-09 | 吉安市御美丽健康产业股份有限公司 | 一种提高免疫力的乌鸡肽保健食品及其制备方法 |
CN108771664A (zh) * | 2018-06-05 | 2018-11-09 | 中山大学 | 四氢姜黄素在改善过敏性哮喘的应用 |
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US20230025663A1 (en) | 2021-07-13 | 2023-01-26 | Zeroharm Sciences Private Limited | Nanoformulation with diverse functional molecules from turmeric and process for preparation of the same |
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CN107772479A (zh) * | 2017-11-28 | 2018-03-09 | 吉安市御美丽健康产业股份有限公司 | 一种提高免疫力的乌鸡肽保健食品及其制备方法 |
CN108771664A (zh) * | 2018-06-05 | 2018-11-09 | 中山大学 | 四氢姜黄素在改善过敏性哮喘的应用 |
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