CN1370180A - 植物甾醇或植物甾烷醇与抗坏血酸的偶联物及其在治疗或预防心血管疾病中的用途 - Google Patents
植物甾醇或植物甾烷醇与抗坏血酸的偶联物及其在治疗或预防心血管疾病中的用途 Download PDFInfo
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- CN1370180A CN1370180A CN00811798A CN00811798A CN1370180A CN 1370180 A CN1370180 A CN 1370180A CN 00811798 A CN00811798 A CN 00811798A CN 00811798 A CN00811798 A CN 00811798A CN 1370180 A CN1370180 A CN 1370180A
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Abstract
新的植物甾醇和/或植物甾烷醇衍生物,包括其盐,用通式(I)、(II)、(III)表示,其中R是植物甾醇或植物甾烷醇部分,R2衍生自抗坏血酸,R3是氢或任何金属、碱土金属或碱金属。这些衍生物有效地治疗和预防心血管疾病及其潜在病情(包括动脉粥样硬化和高血脂症)。
Description
发明领域
本发明涉及植物甾醇和植物甾烷醇(phytostanol)领域及其在治疗和预防心血管疾病和其它疾病中的应用。
发明背景
尽管最近的科学技术进展有助于提高人类生活的质量和延长人的寿命,但是预防动脉粥样硬化(心血管疾病(“CVD”)的潜在病因)的问题没有完全解决。动脉粥样硬化是一种由固有(遗传)因素和环境因素(如饮食和生活方式)相互影响引起的退行性过程。迄今的研究提示,胆固醇可能在动脉粥样硬化中起作用,它在血管中形成动脉粥样硬化斑,最终切断向心肌或大脑或四肢(这取决于该斑在动脉网中的位置)的供血(1,2)。观察表明,人总血清胆固醇减少1%导致冠状动脉发病危险性降低2%(3)。统计学表明,平均血清胆固醇减少10%(例如从6.0毫摩尔/升到5.3毫摩尔/升)在美国每年能防止100000人死亡(4)。
甾醇是起许多关键性细胞功能的天然存在的化合物。植物甾醇如植物中的菜油甾醇、豆甾醇和β-谷甾醇、真菌中的麦角固醇以及动物中的胆固醇是其各自细胞类型中细胞和亚细胞膜中的主要组分。人体内植物甾醇的饮食来源来自种植物,即蔬菜和植物油。据估计,常规西式饮食中的每日植物甾醇含量约为60-80毫克,相反,素食者饮食每日将提供约500毫克。
植物甾醇已经受到很大注意,因为在将其喂给许多哺乳动物(包括人)后,它们能降低血清胆固醇水平。尽管确切的作用机理尚不知道,但是胆固醇和植物甾醇之间的关系显然部分是因为两者化学结构之间有相似性(分子侧链上有差别)。估计植物甾醇代替了胶束相的胆固醇从而减少了其吸收,或可能在胆固醇吸收过程中竞争受体和/或载体部位。
根据报道(5),四十年前,Eli Lilly出售来自妥尔油的甾醇制剂,后来出售来自豆油的称为CytellinTM的制剂,发现这些制剂能使血清胆固醇减少约9%。随后的各种研究调查了谷甾醇制剂对于血浆脂质和脂蛋白浓度的影响(6),以及来自大豆和妥尔油的谷甾醇和菜油甾醇对血清胆固醇的影响(7)。发现能高度有效地减少血清胆固醇的植物甾醇组合物公开在Kutney等人的美国专利5,770,749中,该组合物包含不超过70%(重量)的β-谷甾醇、至少10%(重量)菜油甾醇和豆甾烷醇(β-谷甾烷醇)。该专利中注意到植物甾醇组分之间有某些形式的协同作用,提供了比以前更好的减少胆固醇的结果。
尽管植物甾醇,不仅在治疗CVD及其潜伏的状况(如高胆固醇血症、高血脂、动脉粥样硬化、高血压、血栓形成)方面,而且在治疗其它疾病如II型糖尿病、痴呆症、癌症和衰老方面有明显的现已熟知的优点,但是由于植物甾醇的高度疏水性(即它们在水中的溶解度很低),植物甾醇的给药和其掺入食物、药物和其它输送载体中变得复杂。现已研究了所给予的植物甾醇的形式(例如晶体、悬浮液、颗粒)对其降低血清胆固醇水平的能力的影响如何。由于植物甾醇是高度疏水性的,因此它们不能大量溶解在消化道的胶束相中,因此不能有效地阻断胆固醇吸收。油和脂肪能以有限但不令人满意的程度溶解游离的植物甾醇。由于只有溶解的植物甾醇能抑制胆固醇的吸收,因此必需要加以改进。
为了增强植物甾醇的溶解度,早期的研究侧重于对其进行研磨(美国专利3,888,005和4,195,084,均为Eli Lilly所有)。另外,研究者试图使植物甾醇酯化来增强它们的溶解度。德国专利2035069(1971年1月28日)(类似于美国专利3,751,569)描述了在食用油中添加植物甾醇脂肪酸酯。该酯化在游离的甾醇和脂肪酸酐之间进行,以高氯酸为催化剂。该方法和其它方法的明显缺点是采用了非食品级的催化剂和试剂。
美国专利4,588,717(David E.Mitchell Medical Research Institute)描述了一种包含植物甾醇的脂肪酸酯的维生素补充剂,其中该脂肪酸酯的碳链主链中有大约18-20个碳原子。
美国专利5,502,045(Raision Tehtaat Oy AB)描述了β-谷甾烷醇脂肪酸酯混合物的制备。尽管该专利的意图是制备可溶的稳定的植物甾醇输送体系,但是由于不饱和的脂肪酸部分最终会氧化,因此这些“脂肪酸”酯化的产物的长期稳定性有一些问题。
因此,非常需要有一种以前没有满意地得到的稳定的水溶性植物甾醇/植物甾烷醇衍生物,该衍生物能口服,能掺入输送体系而无需进一步修饰。
本发明目的是避免或减少上述缺点。
发明概述
本发明还包括制备具有上式的新衍生物的方法。
本发明进一步包含一种治疗或预防CVD及其潜在状况(包括动脉粥样硬化、高胆固醇血症、高血脂、高血压、血栓形成)、有关疾病如II型糖尿病以及其它疾病(包括氧化性损伤作为潜在疾病过程的一部分,如痴呆、阿尔茨海默疾病、衰老和癌症)的组合物,该组合物包含具有上述一个或多个化学式的植物甾醇和/或植物甾烷醇与抗坏血酸的一种或多种衍生物,以及药学上可接受的载体。
本发明还提供了添加了具有一个或多个上式的植物甾醇和/或植物甾烷醇以及抗坏血酸的衍生物的食物、饮料和营养药。
本发明还提供了一种治疗或预防CVD及其潜在状况(包括动脉粥样硬化、高胆固醇血症、高血脂、高血压、血栓形成)、有关疾病如II型糖尿病以及其它疾病(包括氧化性损伤作为潜在疾病过程的一部分,如痴呆、衰老和癌症)的方法,该方法是给予动物具有一个或多个上式的植物甾醇和/或植物甾烷醇以及抗坏血酸的衍生物。
与本领域以前知道和描述的未修饰的植物甾醇/植物甾烷醇组合物相比,本发明的植物甾醇/植物甾烷醇/抗坏血酸衍生物及其盐具有许多优点。具体地说,发现其在水溶液(如水)中的溶解度得到提高,从而使得能够进行口服给药而不需要进一步增强或修饰。因此,本发明的衍生物可以就这样制备和使用,或能容易地掺入食物、饮料、药剂和营养药中而不管这些“载体”是否是水基的。这一增强的溶解度通常导致获得所需治疗效果的衍生物给药剂量更低。
本发明衍生物的第二个优点是植物甾醇/植物甾烷醇组分和抗坏血酸之间在降低血清胆固醇和作为抗氧化剂中有添加或协同的治疗效果。这些效果和其它显著的优点将在下文有更详细的描述。
附图简述
通过下列非限制性附图描述本发明,其中:
图1显示了制备植物甾烷醇-磷酸-抗坏血酸及其钠盐的方法;
图2显示了制备植物甾烷醇-碳酸-抗坏血酸及其钠盐的方法;
图3显示了制备植物甾烷醇-草酸-抗坏血酸及其钠盐的方法;
图4显示了Vitosterol对于喂了胆固醇的apo E-KO小鼠中血浆胆固醇水平的影响;
图5显示了Vitosterol对于喂了胆固醇的apo E-KO小鼠中血浆甘油三酯水平的影响;
图6显示了Vitosterol对于小鼠体重的影响;和
图7显示了Vitosterol对于动脉粥样硬化百分数的影响。
其中R是植物甾醇或植物甾烷醇部分,R2从抗坏血酸衍生得到,R3是氢、或任何金属、碱土金属或碱金属。衍生物的组分在下文有更详细的描述。应当注意,在整篇揭示中,术语“衍生物”、“结构”和“类似物”可互换地用来描述连接了植物甾醇或植物甾烷醇以及抗坏血酸的新的一元(unitary)化合物。
植物甾醇/植物甾烷醇
本文所用的术语“植物甾醇”没有限制地包括所有植物甾醇,例如:谷甾醇、菜油甾醇、豆甾醇、菜子甾醇、链甾醇、指海绵甾醇(chalinosterol)、海绵甾醇、穿贝海绵甾醇、和它们的所有天然或合成的形式和衍生物,包括异构体。术语“植物甾烷醇”包括所有饱和或氢化的植物甾醇,以及它们的所有的天然或合成形式和衍生物,包括异构体。应理解,对植物甾醇和植物甾烷醇加以修饰(即加入侧链)也在本发明的预计之中。还应理解,在整篇说明书中未确定时,术语“植物甾醇”包括植物甾醇和植物甾烷醇,即这些术语可互换使用,除非另有特指。
用于制成本发明衍生物的植物甾醇和植物甾烷醇可从各种天然来源制得。例如,它们可通过加工植物油(包括水生植物)获得,这些植物油例如是玉米油和其它植物油如麦芽油、大豆提取物、大米提取物、米糠、油菜籽油、向日葵油、芝麻油和鱼(及其它海产来源)油。本发明的海绵甾醇、穿贝海绵甾醇和以及它们的所有天然或合成形式和衍生物,包括异构体。术语“植物甾烷醇”包括所有饱和或氢化的植物甾醇和它们的所有天然或合成形式和衍生物,包括异构体。应理解,对植物甾醇和植物甾烷醇进行修饰,即加入侧链,也在本发明的预计范围内。还应知道,在整篇说明书中未确定时,术语“植物甾醇”包括植物甾醇和植物甾烷醇,即这些术语可互换使用,除非另有特指。
用于制成本发明衍生物的植物甾醇和植物甾烷醇可从各种天然来源制得。例如,它们可通过加工植物油(包括水生植物)获得,这些植物油例如是玉米油和其它植物油如麦芽油、大豆提取物、大米提取物、米糠、油菜籽油、向日葵油、芝麻油和鱼(及其它海产来源)油。本发明不局限于任一植物甾醇来源。美国专利4,420,427提出了用甲醇等溶剂从植物油滤渣制备甾醇。另外,如美国专利5,770,749(纳入本文作为参考)所述,植物甾醇和植物甾烷醇可从妥尔油树脂或皂(林业副产物)获得。
在一个较佳的形式中,本发明衍生物用天然衍生的或合成的β-谷甾醇、菜油甾烷醇、谷甾烷醇和菜油甾醇制得,如此形成的这些衍生物的每一种可在以各种比例输送之前混合成一组合物。在另一较佳形式中,本发明衍生物用天然衍生的或合成的谷甾烷醇、用天然衍生的或合成的菜油甾烷醇或其混合物制得。
R2
R2包括抗坏血酸或其衍生物。本发明所实现的是产生了一种新的结构或化合物,在该结构或化合物中,植物甾醇或植物甾烷醇部分与抗坏血酸化学连接。该连接有益于并增强了该新结构的两个部分。以前溶解度很差的植物甾醇部分现在变成了新衍生物的一部分,该衍生物在水性和非水性介质(如油和脂肪)中更容易溶解。因此,植物甾醇的给药变得可行,而无需靠进一步增强来改善其输送。
许多年来,已经认识到L-抗坏血酸(通常称为维生素C)是平衡人体营养的重要部分,而且它起了生理学抗氧化剂的作用。然而,抗坏血酸是与其工作时最不稳定的维生素,因为它很容易与环境氧反应,产生脱氢抗坏血酸,而后者容易进一步分解成没有维生素C效果的化合物。据信本发明的新结构“保护”抗坏血酸以防发生这样的分解。另外,与植物甾醇或植物甾烷醇一起形成的一元化合物以协同或增强的方式增强了抗坏血酸的抗氧化剂效果和其它治疗效果。这些优点以前没有被认识或发现。
衍生物的形成
a)酯的形成
包含植物甾醇和/或植物甾烷醇以及抗坏血酸的新结构可通过许多方法来形成。通常,在使“酸”部分和“醇”(植物甾醇)缩合的反应条件下,将所选植物甾醇或甾烷醇(或其卤代磷酸酯、卤代碳酸酯或卤代草酸酯)与抗坏血酸混合在一起。这些条件与其它常见酯化反应(如Fisher酯化过程)中所用的相同,使酸组分和醇组分直接反应,或在合适的酸催化剂(如无机酸、硫酸、磷酸、对甲苯磺酸)存在下反应。这些酯化反应中通常所用的有机溶剂是醚如乙醚、四氢呋喃或苯、甲苯或类似芳族溶剂,反应温度可从室温到升高的温度,这取决于进行反应的反应物的反应性。
在较佳的实施方案中,形成酯衍生物的方法包括将抗坏血酸或其衍生物的羟基“保护”成酯(例如乙酸酯)或醚(例如甲醚),然后在合适的反应条件下使保护的抗坏血酸与植物甾醇/植物甾烷醇卤代磷酸酯、卤代碳酸酯或卤代草酸酯缩合。该缩合反应通常在有机溶剂如乙醚、四氢呋喃、苯、甲苯或类似芳族溶剂中进行。根据反应物的特性和反应性,反应温度可以从低温(-15℃)到高温。
图1显示了“保护的”抗坏血酸的形成(步骤a)、中间的氯代磷酸/甾烷醇衍生物的形成(步骤b)、缩合反应(任选的步骤c或d),结果产生一种新的基于式I的本发明衍生物:植物甾烷醇-磷酸-抗坏血酸(结构6所示)。
图1所示的更详细的方法如下:最初通过形成5,6-异亚丙基-抗坏血酸(结构2),使抗坏血酸得到保护以防分解。这可在合适的反应条件下混合丙酮和抗坏血酸以及酸性催化剂(如硫酸或盐酸)来实现(见实施例1)。形成在甲苯和吡啶中的植物甾烷醇溶液(但也可采用其它含氮碱,如脂族和芳族胺),用磷衍生物如磷酰氯处理该溶液,制得植物甾烷醇氯代磷酸酯(结构4)。过滤并浓缩母液后形成的残余物是植物甾烷醇氯代磷酸酯(结构4)。然后将后者与5,6-异亚丙基-抗坏血酸混合,在加入合适的醇如乙醇以及盐酸(步骤d)后,浓缩。或者,可加入吡啶/THF(步骤c),使产物浓缩。在最后的洗涤和干燥(步骤e)后,步骤c或d得到的新产物均为植物甾烷醇-磷酸-抗坏血酸(结构6)。
在本发明方法的另一较佳形式中,抗坏血酸在羟基部位并不保护成5,6-异亚丙基-抗坏血酸,而是保护成酯(例如乙酸酯、磷酸酯等)。然后可用已知的酯化方法使后者与经上述衍生处理的植物甾醇或植物甾烷醇缩合,最终得到本发明的结构。抗坏血酸的单磷酸酯和二磷酸酯的形成在文献中有充分的描述。例如,美国专利4,939,128(授予Kato等人)(该文纳入本文作为参考)指出了抗坏血酸磷酸酯的形成。同样,美国专利4,999,437(授予Dobler等人)(该文也全部纳入本文作为参考)描述了抗坏血酸2-磷酸酯的制备。在Dobler等人的专利中,通过在反应溶液中加入镁化合物(如镁化合物的水溶液),结果改善在叔胺存在下磷酸化抗坏血酸或抗坏血酸与POCl3的核心反应(在德国待批申请DOS 2,719,303中有所描述)。任何这些已知的抗坏血酸衍生物均可用于本发明。
图2显示了“保护的”抗坏血酸的形成(步骤a)、中间的氯代碳酸/甾烷醇衍生物的形成(步骤b)和缩合反应(任选的步骤c或d),结果产生了结构9(与10相同),它是一种新的基于式II的本发明衍生物:植物甾烷醇-碳酸-抗坏血酸。这些氯代碳酸衍生物可用上文参照图1详细描述的相同方法制得;然而,用光气代替磷酰氯(如图2步骤b所示)。
图3显示了“保护的”抗坏血酸的形成(步骤a)、中间的氯代草酸/甾烷醇衍生物的形成(步骤b)和缩合反应(任选的步骤c或d),结果产生了新结构13(与14相同),它是一种新的基于式III的本发明衍生物:植物甾烷醇-草酸-抗坏血酸。这些氯代草酸衍生物可用上文参照图1详细描述的相同方法制得;然而,用草酰氯代替磷酰氯(如图2步骤b所示)。
b)盐的形成
本发明不仅包括含有植物甾醇或植物甾烷醇和抗坏血酸的母体结构(例如,如图1结构5和6,图2结构9和10,图3结构13和14所示的那些较佳的结构),而且还包括它们的盐。这些盐比它们对应的母体化合物更易溶于水,因此它们在体外和体内的效果和评价得到更多改善。
本发明衍生物的盐形成很容易进行,用一系列碱(例如甲醇钠或其它金属醇盐)处理母体化合物,以产生对应的碱金属盐。其它钙、镁、锰、铜、锌等的金属盐可通过母体化合物与合适的金属醇盐反应产生。对于式I,R3表示氢(母体化合物)或任何金属、碱土金属或碱金属(盐)。
c)用催化(加氢)和化学方法还原
任选的,本发明的植物甾醇衍生物或其组成部分(植物甾醇或抗坏血酸)可在形成衍生物之前或之后氢化或饱和化。杂环体系氢化成部分或全部还原的类似物是熟知的方法。例如,抗坏血酸环催化和/或化学还原成对应的二氢类似物很容易在氢气氛以及金属催化剂(如铂、钯或瑞尼镍)下实现。该还原反应通常在有机溶剂(如乙醇、乙酸乙酯或类似介质)中、环境压力或低压(3-5psi)、室温或稍稍升高的温度下进行。
这些体系的化学反应涉及用“氢化物”试剂家族(如氢硼化钠、氢化铝锂及其类似物)进行还原。这些还原通常在无水惰性介质(包括乙醚、四氢呋喃、二噁烷或苯、甲苯、类似芳族溶剂)中室温至回流温度下进行。
类似的催化或化学反应适用于本发明的所有植物甾醇类似物。因此,本发明包括所有全部或部分还原的衍生物,其中抗坏血酸环被部分或全部还原,和/或其中植物甾醇部分被部分或全部氢化。
衍生物
本发明包含用以下通式表示的所有含有植物甾醇和/或植物甾烷醇和抗坏血酸的衍生物,包括其盐:其中R是植物甾醇或植物甾烷醇氯代部分;R2从抗坏血酸衍生获得,R3是氢或任何金属、碱土金属或碱金属。最佳的是,本发明包含图1-3所示的结构5、6、7、9、10、11、13、14和15的卤代磷酸酯、卤代碳酸酯和卤代草酸酯/植物甾烷醇/抗坏血酸衍生物。然而,可以清楚地明白,这些结构仅是在式I、II和III范围内的许多新衍生物中的一些选择。还应理解,尽管结构7、11和15中显示了钠盐,但是上述其它盐也包括在本发明范围内。
衍生物与HMG-辅酶A还原酶抑制剂的联合
在另一个实施方案中,本发明的衍生物可在给药前与一种或多种抑制胆固醇合成的药物或化合物联合。这些化合物包括,但不局限于,3-羟基-3-甲基戊二酰基辅酶A(HMG-CoA)还原酶抑制剂。这些限制胆固醇合成的化合物与本发明的植物甾醇衍生物的联合具有协同性,它们引发并维持了“全身性的或肠内”和“外来的”效果。
尽管本发明衍生物的作用机理不确定,据信胆固醇水平通过称为“胆转向(biliarydiversion)”的过程(胆肠细胞(enterocyte)和肝细胞之间联系的解偶)而降低。肠胆固醇产生可能会增加,但是胆固醇在胆汁中释放,而不通过肠细胞被重新吸收。任何限制胆固醇合成的化合物将与这些衍生物一起工作,因为前者的机理是减少肠胆固醇的合成和胆固醇的胆分泌。由于胆固醇合成减少,植物甾醇/胆固醇在肠内的比例增加,从而减少了胆固醇吸收,增加了植物甾醇通过肠细胞穿梭机制被运输。本发明的植物甾醇衍生物与抑制胆固醇合成的化合物(如抑制素)之间具有协同效果的发现是非常重要的,因为当与本文描述的衍生物一起给药时,抑制胆固醇合成的这些化合物的剂量就可显著降低。最近已经发现,与抑制素(如洛伐他汀Lovastatin)有一些关键的副作用,因此,与本文所述的衍生物的协同作用所提供的剂量减少效果是特别令人信服的。可与本发明衍生物联合的其它抑制素的例子包括:阿曲伐他汀(atorvastatin(LipitorTM))、苏普他汀(superstatin)、西伐他汀(simvastatin(ZocorTM))和普伐他汀(pravastatin(PravacholTM))。
新的植物甾醇类似物的潜在优点
抗坏血酸与植物甾醇部分相连的本发明的新衍生物,与使用没有这种连接的植物甾醇/植物甾烷醇相比,提供了许多饮食和治疗上的优点。首先最重要的是,新衍生物在水溶液和非水性介质(如油和脂肪)中的溶解度大大提高。该较高的溶解度使得有效的饮食和治疗剂量降低,成本也随之降低。第二,当植物甾醇部分和抗坏血酸结合在一个结构中来治疗或预防心血管疾病和其潜在状况(包括动脉粥样硬化和高血脂)以及病理学中有氧化性损伤的疾病(如癌、衰老、痴呆和阿尔茨海默疾病)时,两者之间非常可能有协同或附加的效果。第三,这些衍生物的形成在消除分解的同时使抗坏血酸实现了全部潜力。第四,这些衍生物是热稳定的(对氧化和水解稳定),而这是在诸如挤压机和食品加工机中进一步加工所必需的。
输送体系
尽管本发明范围内完全考虑了衍生物可直接不作任何进一步修饰来给予动物(尤其是人),但是也可采用进一步的措施来增强输送,确保衍生物在要加入的食物、饮料、药物、营养物等中均匀分布。然而,应当理解,这些步骤纯粹是任选的。这些增强可通过许多合适的方法来实现,例如使衍生物溶解或分散形成乳液、溶液和分散液或自乳化体系;将其冻干、喷雾干燥、控制沉淀或其组合;形成固体分散体、悬浮液、水化的脂质体系;和环糊精形成包涵络合物(inclusion complexations);用具有胆汁酸及其衍生物的水溶助长剂(hydrotopes)和制剂。
可用于本发明的各种技术如下所述。
乳液
乳液是包含两个不混溶相(例如水和油)的细分或胶态分散液,其中一个相(内相或不连续相)以液滴形式分散在另一相(外相或不连续相)中。因此,水包油乳液由作为内相的油和作为不连续相或外相的水组成,而油包水乳液则相反。可制成包含植物甾醇或植物甾烷醇衍生物的各种乳化体系,包括标准乳液、微乳液和自乳化(在接触搅动的水性液体如胃液或肠液时乳化)的那些体系。
乳液通常可包括油相和水相、乳化剂、乳液稳定剂和任选的防腐剂、调味剂、pH调节剂和缓冲液、螯合剂、防沫剂、张力调节剂和抗氧化剂。合适的乳化剂(其中括号内的数字指较佳的HLB值)包括:阴离子表面活性剂,如醇醚硫酸盐、烷基硫酸盐(30-40)、皂类(12-20)和磺基琥珀酸盐;阳离子表面活性剂,如季铵化合物;两性离子表面活性剂,如烷基甜菜碱衍生物;两性表面活性剂,如脂肪胺硫酸盐,二脂肪烷基三乙醇胺衍生物(16-17);和非离子表面活性剂,如脂族或环脂族醇的聚乙二醇衍生物,饱和脂肪酸和烷基苯酚(alkyphenol)、加成到聚丙二醇和烷基聚丙二醇上的水溶性聚乙烯氧(polyethyleneoxy)加成物、壬基苯酚聚乙氧基乙醇、蓖麻油聚乙二醇醚、聚环氧丙烷/聚环氧乙烷加成物、三丁基苯氧基-聚乙氧基乙醇、聚乙二醇、辛基苯氧基-聚乙氧基乙醇、羊毛脂醇、聚氧乙基化(POE)烷基苯酚(12-13)、POE脂肪族酰胺、POE脂肪族醇醚、POE脂肪族胺、POE脂肪族酯、泊洛沙姆(7-19)、POE乙二醇一醚(13-16)、多氧乙基醚(17-19)和脱水山梨糖醇酯(2-9)。该列表并非穷尽的,因为其它乳化剂同样也是合适的。
合适的乳液稳定剂包括,但不局限于,亲液胶体如多糖、阿拉伯胶、琼脂、海藻酸、角叉菜胶、瓜尔胶、刺梧桐胶、西黄蓍胶、黄原胶;两性物(例如明胶)和合成或半合成的聚合物(例如卡波姆(carbomer)树脂、纤维素醚和酯、羧甲基壳多糖、聚乙二醇-n(环氧乙烷聚合物H(OCH2CH2)nOH);细分的固体,包括粘土(如绿坡缕石、澎润土、锂蒙脱石、高岭土、硅酸铝镁和蒙脱土)、微晶纤维素氧化物和氢氧化物(例如氢氧化铝、氢氧化镁和氧化硅);和群聚的促进剂/胶凝剂(包括氨基酸、肽、蛋白质卵磷脂和其它磷脂和泊洛沙姆)。
用于形成乳液的合适的抗氧化剂包括:螯合剂,如柠檬酸、EDTA、苯丙氨酸、磷酸、酒石酸和色氨酸;优先氧化的化合物,如抗坏血酸、亚硫酸氢钠和亚硫酸钠;水溶性链终止剂如硫醇和脂溶性链终止剂如没食子酸烷酯、棕榈酸抗坏血酸酯、叔丁基氢醌、丁基化羟基苯甲醚、丁基化羟基甲苯、氢醌、去甲基二氢愈创木酸和α-生育酚。合适的防腐剂、pH调节剂和缓冲液、螯合剂、渗透剂、着色剂和调味剂在下文“悬浮液”中有所描述,但是同样适用于乳液的形成。
乳液的通常制备如下:将两相(油相和水相)分开加热至合适的温度,在两种情况下是相同的,在固体或半固体油的情况下,通常比熔点最高的组分的熔点高5-10℃,或当油相是液体时,经常规实验测得的合适温度。水溶性组分溶解在水相(水)中,油溶性组分溶解在油相中。为了产生水包油乳液,将油相剧烈混合到水相中,产生合适的分散液,搅拌同时使产物以控制的速度冷却。油包水乳液以相反方式形成,即,将水相加入油相。当亲水性胶体作为乳液稳定剂成为体系的一部分时,可采用相转化技术,即在加入至水相之前,将胶体加入油相而非水相中。当使用植物甾醇或植物甾烷醇衍生物时,宜在加热前将这些衍生物加入油相中。
也可形成包含植物甾醇或植物甾烷醇衍生物的微乳液,该微乳液的特征是粒径比标准乳液小至少一个数量级(10-100nm),其定义为“水、油和两亲物的体系,它是单一的光学各向同性的热动力学稳定的液体”(8)。在较佳形式中,微乳液包含表面活性剂或表面活性剂混合物、辅助表面活性剂(通常是短链醇)、所选植物甾醇或植物甾烷醇衍生物、水和任选的其它添加剂。
作为本发明的衍生物输送体系,该体系有几个优点。首先,微乳液有自发形成的趋势,即,不需要形成标准乳液所需的剧烈混合。从商业角度来看,这简化了生产过程。第二,由于微液滴的直径小,因此微乳液可用微过滤技术来除菌,而不会破坏微结构。第三,微乳液是高度热动力学稳定的。第四,微乳液具有很高增溶能力,这特别重要,因为它们能进一步增强衍生物的溶解。
适用于形成微乳液的表面活性剂或表面活性剂混合物可以是阴离子、阳离子、两性或非离子表面活性剂,且其HLB(亲水-亲油平衡值)在1-20之间,更佳的在2-6和8-17之间。特别佳的试剂是非离子表面活性剂,它选自脂族或环脂族醇的聚乙二醇衍生物、饱和脂肪酸和烷基苯酚(alkyphenol)、加成到聚丙二醇和烷基聚丙二醇上的水溶性聚乙烯氧(polyethyleneoxy)加成物、壬基苯酚聚乙氧基乙醇、蓖麻油聚乙二醇醚、聚环氧丙烷/聚环氧乙烷加成物、三丁基苯氧基-聚乙氧基乙醇、聚乙二醇、辛基苯氧基-聚乙氧基乙醇、羊毛脂醇、聚氧乙基化(POE)烷基苯酚(12-13)、POE脂肪族酰胺、POE脂肪族醇醚、POE脂肪族胺、POE脂肪族酯、泊洛沙姆(7-19)、POE乙二醇一醚(13-16)、多氧乙基醚(10-17)和脱水山梨糖醇酯(2-9)。
本领域技术人员知道和使用许多方法来制备微乳液。在形成本发明微乳液的较佳方法中,混合表面活性剂、辅助表面活性剂和植物甾醇或植物甾烷醇衍生物(预先以合适比例溶解在合适油中),然后用水滴定,直至获得具有所需透明度的体系。
在另一较佳的实施方案中,可通过混合植物甾醇或植物甾烷醇衍生物与水溶助长剂和食物级表面活性剂来形成微乳液(参见9)。
溶液和分散液
可将植物甾醇或植物甾烷醇溶解或分散在合适的油载体中,加入或不加入赋形剂,以此形式用于例如普通的食品用途、用于给肉和鱼涂油、以及用于掺入动物饲料中。
合适的增溶剂包括所有食品级油如植物油、海产油(如鱼油)和植物油、甘油单酯、甘油二酯、甘油三酯、生育酚等以及它们的混合物。
自乳化的体系
植物甾醇或植物甾醇衍生物可与合适赋形剂如表面活性剂、乳液稳定剂(上述)等混合,加热(如果需要)和冷却,形成在接触水性介质时能自发形成乳液的半固体产物。该半固体产物可以其它许多形式使用,例如作为二片式硬或软明胶胶囊中的填充物,或可加以改变用于其它输送体系。
固体分散体
进一步增加本发明衍生物的溶解度/可分散性的其它方式涉及使用固体分散体体系。这些分散液可包括分子溶液(低共溶混合物)、物理分散液或两者的组合。
例如,固体分散体通常可用水溶性聚合物作为载体制得。这些载体包括,但不局限于,下列单独的物质或其组合:加入或未加入液体级PEG的固体级聚乙二醇(PEG);聚乙烯吡咯烷酮或其与乙酸乙烯酯以及纤维素醚和酯的共聚物。其它赋形剂,如乙二醇家族的其它成员(如丙二醇、多元醇如甘油等),也可加入该分散体中。
固体分散体可用本领域技术人员熟知的许多方法来制备。这些方法包括,但不局限于,下列方法:
(a)使组分熔化,然后控制冷却使其固化,随后机械研磨产生合适的粉末。或者,可将熔融(熔化)的分散液在喷雾干燥器中喷入冷却的空气流中,形成固体颗粒(造粒)或使其通过挤出机和成球仪(spheroniser),形成粒径控制的固体物质。在另一方案中,将熔融的分散液直接填入两半式硬明胶胶囊中;
(b)将组分溶解在合适的溶剂体系(如有机物、有机混合物、有机物-水)中,然后例如通过在环境压力下或真空蒸发、喷雾干燥、冻干等方法除去溶剂;或采用前述的变化方案,和
(c)将组分溶解在合适的溶剂体系中,随后用不互溶的溶剂(组分在其中的溶解度很低或不溶解)使它们从溶液中沉淀出来,过滤,除去溶剂,干燥并任选地研磨,得到合适的粉末形式。
悬浮液
可用来进一步增强衍生物溶解度和/或可分散性的悬浮液包括固体(可能是细分的)内相,该内相分散在油性或水性外相(赋形剂)中。另外,在其形成期间,固体内相可加入上述乳液中,得到具有与悬浮液和乳液共同性质的输送体系。
本领域常用的许多赋形剂适用于制备在本发明范围内的悬浮液。悬浮液通常包含油性或水性赋形剂、分散(悬浮)的内相、分散和/或润湿剂(表面活性剂)、pH调节剂/缓冲剂、螯合剂、抗氧化剂、调节离子强度的试剂(渗透剂)、着色剂、调味剂、使悬浮液稳定并增加粘度的物质(悬浮剂)和防腐剂。
合适的赋形剂包括,但不局限于:水、油、醇、多元醇、植物甾醇组合物在其中部分溶解或不溶解的其它食用或食物级化合物及其混合物。合适的分散剂包括,但不局限于:卵磷脂;磷脂;非离子表面活性剂如聚山梨酯65、辛苯聚醇-9、壬苯聚醇-10、聚山梨酯60、聚山梨酯80、聚山梨酯40、泊洛沙姆235、聚山梨酯20和泊洛沙姆188;阴离子表面活性剂如月桂基硫酸钠和多库酯钠(docusate sodium);脂肪酸、脂肪酸盐、其它脂肪酸酯和它们的混合物。
调节pH的试剂/缓冲剂包括柠檬酸及其盐、酒石酸及其盐、磷酸及其盐、乙酸及其盐、盐酸、氢氧化钠和碳酸氢钠。合适的螯合剂包括EDTA盐(二钠、二钠钙等)、柠檬酸和酒石酸。合适的抗氧化剂包括抗坏血酸及其盐、棕榈酸抗坏血酸酯、生育酚(尤其是α-生育酚)、丁基化羟基甲苯、丁基化羟基苯甲醚、亚硫酸氢钠和偏亚硫酸氢钠。合适的渗透剂包括单价、二价和三价电解质、单糖和二糖。合适的防腐剂包括羟基苯甲酸(甲酯、乙酯、丙酯、丁酯及其混合物)、山梨酸、硫柳汞、季铵盐、苄醇、苯甲酸、葡糖酸洗必太和苯乙醇。着色剂和调味剂可按需加入,可选自所有天然、与天然相同和合成的种类。
水化的脂质体系
在本发明的另一实施方案中,本发明衍生物的溶解度/可分散性可通过物理包容形成磷脂体系(如脂质体或其它水化的脂相)来进一步增强。包涵(包络)指捕获分子但不形成共价键,该方法被广泛用来提高活性组分的溶解度,随后改善其溶解。
水化脂质体系(包括脂质体)可用各种脂质和脂质混合物制得,这些脂质包括磷脂如磷脂酰胆碱(卵磷脂)、磷酸甘油二酯和鞘酯、糖脂等。脂质宜和带电荷物质(如带电荷磷脂、脂肪酸、它们的钾盐和钠盐)一起使用,以使所得脂质体系稳定。形成脂质体的典型方法如下:
1)将一种或多种脂质以及植物甾醇或植物甾烷醇或它们的混合物和生育三稀酚组分分散在有机溶剂(例如氯仿、二氯甲烷、乙醚、乙醇或其它醇,或它们的组合)中。在形成脂质体期间,可加入带电荷物质以减少随后的聚集。还可加入抗氧化剂(如棕榈酸抗坏血酸酯、α-生育酚、丁基化羟基甲苯和丁基化羟基苯甲醚),以保护任何未饱和的脂质(如果有的话);
2)过滤该混合物,除去少量不可溶的组分;
3)在一定条件(压力、温度)下除去溶剂,以确保组分没有发生相分离;
4)通过接触含有溶解溶质(包括缓冲盐、螯合剂、低温保护剂等)的水性介质,使“干的”脂质混合物水化;和
5)用合适的技术(如匀浆化、挤出等)减小脂质体粒径,改变片层体(lamellarity)的状态。
本发明中可采用本领域已知的产生和加载具有活性组分的水化脂质的任何方法。例如,制备脂质体的合适方法在参考文献10和11中有所描述,这两篇文献均纳入本文作为参考。这些方法的变化方案在美国专利5,096,629中也有所描述,该文也纳入本文作为参考。
美国专利4,508,703(纳入本文作为参考)描述了使两亲性脂质组分和疏水性组分溶解形成溶液、然后使该溶液在气流中雾化产生粉末化混合物来制备脂质体的方法。
环糊精络合物
环糊精是一类环状寡糖分子,它包含葡萄吡喃糖亚基,具有环形圆柱状空间结构。该组中通常可获得的成员是含有6个、7个和8个葡萄吡喃糖分子的分子(分别是α-环糊精、β-环糊精和γ-环糊精),分子中极性(亲水性)羟基朝向结构外,非极性(亲油性)主链碳和醚氧衬在环的内腔中。该空腔能通过非共价方式结合形成包涵体络合物来容纳(接受)活性组分(外来分子,在这里是本发明的衍生物)的亲油性部分。
环糊精分子的外部羟基取代基可加以改性,以形成在水性介质中溶解度改善的、以及有其它所需增强效果(如毒性降低等)的衍生物。这些衍生物的例子是:烷基化衍生物,如2,6-二甲基-β-环糊精;羟基烷基化衍生物,如羟丙基-β-环糊精;支链衍生物如二葡糖基-β-环糊精;磺烷基衍生物,如磺基丁基醚-β-环糊精;和羧甲基化衍生物,如羧甲基-β-环糊精。本领域已知的其它类型的化学修饰也在本发明范围内。
环糊精络合物通常给外来分子(在这里是本发明的衍生物)带来了改善的溶解度、可分散性、稳定性(化学、物理学和微生物学的)、生物利用率和降低的毒性。
本领域已知有许多方法可产生环糊精络合物。环糊精例如可用下列基本方法来产生:在加热或不加热的条件下,将一种或多种衍生物搅拌加入环糊精的水溶液或水-有机物混合溶液中;在加热或不加热的条件下,在合适装置中捏和、浆液化或混合环糊精以及本发明组合物,并加入适量水性的、有机的或水性的-有机的混合液体;或用合适的混合装置物理掺混环糊精和本发明组合物。如此形成的包含物络合物的分离可通过下列方式来实现:共沉淀、过滤和干燥;挤出/粉末化和干燥;对潮湿的物质进行再分,然后干燥;喷雾干燥;冻干或用其它合适的技术(这取决于形成环糊精络合物所用的方法)。还可采用对分离的固体络合物进行进一步机械研磨的任选步骤。
这些环糊精络合物进一步增强了衍生物的溶解度和溶解速度,提高了衍生物的稳定性。关于环糊精络合物的综述请参见文献12。
与胆汁酸盐络合
适当配制的胆汁酸、其盐和偶联衍生物可用来使本发明的衍生物增溶,从而提高这些组合物的溶解度和分散性质。合适胆汁酸的例子包括:胆酸、鹅脱氧胆酸、脱氧胆酸、脱氢胆酸和石胆酸。合适胆汁酸盐的例子包括:胆酸钠、脱氧胆酸钠和其它盐形式。合适偶联的胆汁酸例子包括:鹅脱氧甘胆酸、甘胆酸(glycholic acid)、牛磺鹅脱氧胆酸、牛磺胆酸、牛磺脱氧胆酸及其盐。
用来进一步增强本发明衍生物溶解度的合适体系由一种或多种衍生物加上一种或多种胆汁酸、胆汁酸盐或偶联的胆汁酸组成。可加入其它物质来产生具有额外增溶能力的配方。这些物质包括,但不局限于:磷脂、糖脂和甘油单酯。这些组分可配制在固相中,或采用合适的溶剂或载体赋形剂,经适当分离,任选地用上述技术减小粒径。
由于胆汁酸及其衍生物具有令人讨厌的味道且对胃粘膜和肠胃道上部区域有刺激性,因此可用本领域已知的技术将合适的肠溶包衣施加到固体配方颗粒上。其中,典型的肠溶包衣包括:乙酸邻苯二甲酸纤维素、乙酸苯三酸纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、聚乙酸乙烯酯邻苯二甲酸、丙烯酸酯聚合物及其衍生物(例如EudragitTM系列的合适成员)、乙基纤维素或它们的组合物。在包衣配方中可加入额外的赋形剂,以修饰膜官能团或有助于包衣加工(例如表面活性剂、增塑剂、沟流剂、渗透调节剂等)。包衣配方载体可包含水体系、有机物体系或两者的混合物。
水溶助长剂络合物
能打开与疏水性(亲油性)和其它分子结合的水结构的化合物称为水溶助长剂。这些化合物可用来进一步增强衍生物的水溶解度。水溶助长剂的例子包括,苯甲酸钠、羟基苯甲酸钠、水杨酸钠、烟酰胺、烟酸钠、龙胆酸钠、龙胆酸乙醇酰胺、甲苯甲酸钠、氨基苯甲酸钠、邻氨基苯甲酸钠、丁基单乙二醇硫酸钠、间苯二酚等。
本质上非共价的络合物形成可通过将一种或多种衍生物与水溶助长剂或其混合物混合在合适液体载体中来实现,该液体载体可以是水的、有机物的或两者的组合物。可加入其它赋形剂,如表面活性剂、多元醇、二糖等,来促进络合或帮助分散。所得络合物可用本领域已知的方法(共沉淀和干燥、蒸发除去液体载体、喷雾干燥、冻干等)以干粉形式分离得到。如果需要,粒径可用本文上述的标准技术来减小。所得水溶助长剂络合物可直接使用而无需进一步修饰,或可根据需要混合到各种其它配方或载体中。
使用方法
本发明衍生物可不作任何改动地直接给予动物(尤其是人),或可如上所述那样进行处理以进一步增强该组合物的溶解度和/或可分散性。另外,在任选地结合这些增强溶解度和/或可分散性的方法的情况下,衍生物可如下文所述那样掺入各种载体中,以便治疗和/或预防CVD及其潜在状况(如高胆固醇血症、高血脂、动脉粥样硬化、高血压、血栓形成)、有关疾病如II型糖尿病以及包括氧化性损伤作为潜在疾病过程一部分的其它疾病(如痴呆、衰老)和癌症。在被认为有CVD或任何氧化相关疾病的“高危险性”人群中,预计本发明的衍生物可用于一级、二级和三级治疗程序。
在不限制前述内容普遍性的条件下,可将本发明衍生物与各种载体或佐剂掺混,以有助于直接给药或有助于将组合物掺入食物、饮料、营养药或药物中。为了评价输送衍生物用的各种可能的载体,提供了下面的清单。衍生物的剂量因输送方式、患者体型和状况、要达到的结果以及食物添加剂和药剂领域技术人员已知的其它因素而异。然而,通常较佳的是本发明衍生物以包含每日最多6克植物甾醇和/或植物甾烷醇的形式给予人。也应认识到,提供日剂量大得多的衍生物对动物宿主无害,因为过量的剂量只是通过正常的排泄通道。
1)药物剂型:
本发明衍生物可与通常的赋形剂和/或稀释剂和稳定剂一起掺入各种常规药物制剂和剂型中,这些剂型例如是用于口服、经颊或经舌给药的片剂(普通型和包衣型)、胶囊(硬和软明胶,有或没有额外的包衣)粉末、颗粒(包括泡腾颗粒)、丸粒、微粒、溶液(如胶束、糖浆、酏剂和滴剂)、锭剂、芳香熏剂、安瓿、乳液、微乳液、油膏、软膏、栓剂、凝胶、透皮贴剂和改进释放的剂型,这些均在本发明的范围内。
如上所述经过改进适用于合适剂型的本发明衍生物可通过口服、注射(静脉内、皮下、腹膜内、皮内或肌内)、外用或其它方式给予动物(包括人)。尽管其确切的作用机制还不清楚,但是静脉内给予的本发明衍生物降低了血清胆固醇水平。据信,某些基于植物甾醇的产物除了起肠内胆固醇吸收抑制剂作用外,还对通过胆汁酸合成的胆固醇体内平衡、肠细胞和胆汁胆固醇分泌、胆汁酸分泌、体内不同区室之间胆固醇输送和酶动力学的变化有全身性影响(PCT/CA97/00474,1998年1月15日出版)。另见Peter Jones的论文(正在出版)。
2)食品/饮料/营养药:
在本发明的另一形式中,本发明衍生物可掺入食品、饮料和营养药中,它们包括但不局限于下列这些:
1)乳制品—如奶酪、黄油、牛奶和其它乳制饮料、涂在面包上的软质食品和乳制品混合物、冰淇淋和酸奶;
2)以脂肪为基的制品—如麦淇淋、涂在面包上的软质食品、蛋黄酱、起酥、烹饪和油炸用油和调味品;
3)以谷物为基的制品—包含谷物(例如面包和面食),无论这些食物是烹饪、烘烤还是以其它方式加工的;
4)糖果—如巧克力、糖果、口香糖、甜点、非乳制浇头(topping)(例如Cool WhipTM)、果汁冰糕、糖衣和其它馅料;
5)饮料—无论是酒精类还是非酒精类饮料,包括可乐和其它软饮料、果汁、饮食添加物、代替进餐的饮料,如以商标BoostTM和EnsureTM出售的那些饮料;和
6)其它制品—包括蛋和蛋制品、加工的食品如汤、预制的面食沙司、预先制成的膳食等。
本发明衍生物可用诸如混合、灌输、注射、掺混、分散、乳化、浸泡、喷雾和捏和等方法不作进一步修饰而直接掺入食物、营养药或饮料中。或者,该衍生物可由消费者在摄食前直接涂抹到食物上或加入饮料中。这些是简单而经济的输送方式。
实施例
通过下列非限制性实施例描述本发明:
实施例1—抗坏血酸的保护
将发烟硫酸(24%,8.3克)滴加入丙酮(50毫升)中。将抗坏血酸(12克)加入0℃的该混合物中,反应混合物于0℃搅拌6小时。抽吸过滤出所得晶体,将滤饼压干,然后用丙酮(30毫升)洗涤。获得产物为5,6-异亚丙基-抗坏血酸(14克)。
实施例2—物甾烷醇的连接
将含植物甾烷醇混合物(24克)(菜油甾烷醇:36.4%;谷甾烷醇:62.3%)的甲苯(500毫升)和吡啶(25毫升)溶液滴加入0℃的含磷酰氯(9毫升)的甲苯(200毫升)混合物中。室温下搅拌该混合物3小时。过滤除去盐酸吡啶,浓缩母液,回收得到甲苯。将残余物溶解在干THF(100毫升)中,0℃下加入含上述制得的受保护的抗坏血酸(14克)的干THF(400毫升)溶液。维持室温下搅拌1小时。浓缩溶液,除去溶剂。加入乙醇(400毫升)和3N HCl(200毫升),50℃加热该混合物30分钟,浓缩。加入乙酸乙酯(600毫升),所得溶液用水(3×300毫升)洗涤,用硫酸钠干燥,浓缩,获得产物(植物甾烷醇-磷酸-抗坏血酸)为白色粉末22克。
实施例3—转变成钠盐
将上述制得的酸(17克)溶解在乙醇(100毫升)中,室温下搅拌加入含甲醇钠(2.7克)的乙醇(50毫升)溶液。维持搅拌30分钟。加入后,滤出所得白色滤饼干燥称重,得到20克白色粉末(植物甾烷醇-磷酸-抗坏血酸钠)。
实施例4—衍生物对Apo-E缺陷型小鼠中脂质水平和动脉粥样硬化病灶大小的影响
背景
维生素C(购自Aldrich-Sigma)已经与植物甾醇/植物甾烷醇的混合物化学连接,该混合物包含β-谷甾醇、谷甾烷醇、菜油甾醇和菜油甾烷醇(称为“FCP-3P4”)。作为本发明主题的新衍生物(VitroSterol或FCP-VP4)是水溶性的。研究VitoSterol及其亲代试剂(3P4和维生素C)在喂胆固醇(0.2%w/w)的雄性apo E-KO小鼠中12周内的效果。VitoSterol通过水(2%w/v)和饮食(2%w/w)给予。
目标
·测试VitoSterol降低apo E-KO小鼠中脂质的效果
·测试Vitosterol在apo E-KO小鼠中的抗动脉粥样硬化效果
具体目标
1.测试通过饮食或饮水途径给予的VitoSterol对于apo E-KO小鼠中血浆胆固醇和甘油三酯水平的影响。
2.评价VitoSterol尤其在饮水中的顺应性及其对小鼠体重的影响。
材料和方法
48只4周龄雄性载脂蛋白E剔除(apo E-KO)小鼠购自Jackson实验室,喂养于Research Center,BC Children′s Hospital的动物饲养工具中。VitoSterol由Forbes Medi-Tech Inc.(“FMI”)制备。VitoSterol的亲代材料植物甾醇(Forbes批号#98-694)和维生素C(购自Aldrich-Sigma)由FMI提供。胆固醇购自Sigma,9%(w/w)PicoLab小鼠食物购自Jameison′s Pet Food Distributor,Delta,BC。实验室化学试剂如以前所述(13-16)那样制备和使用。
实验设计:
动物和饮食:根据我们以前的实验,每组8只动物就足以检测统计学上有意义的与处理相关的对于血浆胆固醇水平的影响和动脉粥样硬化病灶的发展。因此,如下所述,将48只雄性apo E-KO小鼠分成6组,每组8只小鼠的血浆胆固醇水平和体重相似。给动物喂以实验食物14周。食物准备按以前公开的方法(13-16)进行。小鼠实验组和食物的概要显示在表1中。在基线和实验期间从小鼠尾部抽血,用于测定血浆脂质水平。在研究最后,用二氧化碳气体处死小鼠,从心脏取血。取出心脏和主动脉,固定在福尔马林中,以评价动脉粥样硬化病灶。一份血浆送至BRI实验室(Burnaby,BC)来测定维生素C和植物甾醇浓度。一份血浆送给Dr.Kitts实验室(UBC)进行抗氧化剂评价。
表1:小鼠实验组和食物
组(n) | 处理(食物类型) |
1(8) | 对照小鼠食物,含9%脂肪和0.15%(w/w)胆固醇(MC) |
2(8) | MC+2%(w/w)Vitosterol |
3(8) | MC+2%(w/w)Vitosterol,以饮用水配 |
4(8) | MC+1.3%(w/w)植物甾醇(与组2给予的量相等) |
5(8) | MC+0.7%(w/w)维生素C(与组2给予的量相等) |
6(8) | MC+1.3%(w/w)植物甾醇和0.7%(w/w)维生素C(与组2给予的量相等) |
生物化学和组织学评价:
如前所述(13-16),在St.Paul′s医院的临床实验室中,在基线和实验间4-6周间隔和实验最后估计血浆胆固醇水平。用BRI中的液相色谱技术测定一份血浆样品的维生素C和植物甾醇浓度。如前所述(13-14),用主动脉根部切片来评价动脉粥样硬化病灶的发展。
结果
A:血浆总胆固醇水平
图1显示了VitoSterol及其亲代药物对于血浆总胆固醇水平的影响。水溶液和膳食VitoSterol均有显著的降胆固醇效应。该显著效果在研究的12周内是一致的。
B:血浆甘油三酯
图2显示了化合物对血浆甘油三酯水平的影响。VitoSterol稍有降低甘油三酯的效果。在第12周,VitoSterol的降甘油三酯效果明显减少。
C:体重
图3显示了体重。膳食VitoSterol组中的体重降低可能是由于食物制品。体重降低似乎与摄食和膳食制品有关。
D:粪便胆固醇水平
初步结果显示VitoSterol显著抑制了胆固醇的吸收。结果总结如下:
组 | 粪便胆固醇(%W/W) |
对照 | 0.12 |
膳食VitoSterol | 0.8 |
水VitoSterol | 0.7 |
3P4 | 0.2 |
E:动脉粥样硬化病灶体积
图4显示FM-VP4使动脉粥样硬化病灶体积比对照组减小75%。处理组以下列方式计数:
表2:病灶体积研究采用的小鼠实验组和膳食
组(n) | 处理(饮食类型) |
1(8) | 对照小鼠食物,含9%脂肪和0.2%(w/w)胆固醇(MC) |
2(8) | MC+0.2%胆固醇+2%(w/w)Vitosterol(即,在食物中) |
3(8) | MC+0.2%(w/w)胆固醇和1.2%(w/w)植物甾醇 |
4(8) | MC+0.2%(w/w)胆固醇和0.5%(w/w)维生素C |
5(8) | MC+0.2%(w/w)胆固醇+1.2%植物甾醇+0.5%维生素C |
6(8) | MC+0.2%(w/w)胆固醇+2%VitoSterol(w/v),在水中 |
结论
VitoSterol是具有额外的降低甘油三酯效应的强效的降胆固醇剂。我们发现在12周实验期间没有明显的副作用。发现VitoSterol使胆固醇水平降低75%,甘油三酯水平降低44%。这些是很好的结果。另外,发现对动脉粥样硬化病灶体积有显著的效果(与对照组相比,VitoSterol(新衍生物)处理组的体积减小71-86%)。
参考文献
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Claims (23)
2.根据权利要求1所述的结构,其中植物甾醇选自谷甾醇、菜油甾醇、豆甾醇、菜子甾醇、链甾醇、指海绵甾醇、海绵甾醇、穿贝海绵甾醇、和它们所有的天然或合成的形式和衍生物,包括异构体。
3.根据权利要求1所述的结构,其中植物甾烷醇选自所有饱和的或氢化的植物甾醇以及它们所有的天然或合成的形式和衍生物,包括异构体。
4.根据权利要求1所述的结构,其中植物甾烷醇是谷甾烷醇。
5.根据权利要求1所示的结构,其中R3选自钙、镁、锰、铜、锌、钠、钾和锂。
6.一种用来治疗和预防心血管疾病及其包括动脉粥样硬化和高血脂在内的潜在病情的组合物,该组合物包含一种或多种具有下式的结构以及这些结构的所有盐:其中R是植物甾醇或植物甾烷醇部分,R2衍生自抗坏血酸,R3是氢或任何金属、碱土金属或碱金属;以及药学上可接受的载体。
7.根据权利要求6所述的组合物,其中植物甾醇选自谷甾醇、菜油甾醇、豆甾醇、菜子甾醇、链甾醇、指海绵甾醇、海绵甾醇、穿贝海绵甾醇、和它们所有的天然或合成的形式和衍生物,包括异构体。
8.根据权利要求6所述的组合物,其中植物甾烷醇选自所有饱和的或氢化的植物甾醇以及它们所有的天然或合成的形式和衍生物,包括异构体。
9.根据权利要求6所述的组合物,其中植物甾烷醇是谷甾烷醇。
10.根据权利要求6所述的组合物,其中R3选自钙、镁、锰、铜、锌、钠、钾和锂。
11.根据权利要求6所述的组合物,该组合物还包含至少一种减少人体内胆固醇合成的药剂。
12.根据权利要求11所述的组合物,其中所述药剂是3-羟基-3-甲基戊二酰基辅酶A-HMG-CoA,还原酶抑制剂。
14.根据权利要求13所述的食品或饮料,其中植物甾醇选自谷甾醇、菜油甾醇、豆甾醇、菜子甾醇、链甾醇、指海绵甾醇、海绵甾醇、穿贝海绵甾醇、和它们所有的天然或合成的形式和衍生物,包括异构体。
15.根据权利要求13所述的食品或饮料,其中植物甾烷醇选自所有饱和的或氢化的植物甾醇以及它们所有的天然或合成的形式和衍生物,包括异构体。
16.根据权利要求13所述的食品或饮料,其中植物甾烷醇是谷甾烷醇。
17.根据权利要求13所述的食品或饮料,其中R3选自钙、镁、锰、铜、锌、钠、钾和锂。
18.一种治疗或预防动物心血管疾病及包括动脉粥样硬化和高胆固醇血症的其潜在病情的方法,该方法包括给予该动物一种或多种具有下式的植物甾醇和/或植物甾烷醇衍生物及其所有的盐:其中R是植物甾醇或植物甾烷醇部分,R2衍生自抗坏血酸,R3是氢或任何金属、碱土金属或碱金属。
19.根据权利要求18所述的方法,其中所述动物是人。
20.根据权利要求18所述的方法,其中植物甾醇选自谷甾醇、菜油甾醇、豆甾醇、菜子甾醇、链甾醇、指海绵甾醇、海绵甾醇、穿贝海绵甾醇、和它们所有的天然或合成的形式和衍生物,包括异构体。
21.根据权利要求18所述的方法,其中植物甾烷醇选自所有饱和的或氢化的植物甾醇以及它们所有的天然或合成的形式和衍生物,包括异构体。
22.根据权利要求18所述的方法,其中所述植物甾烷醇是谷甾烷醇。
23.根据权利要求18所述的方法,其中R3选自钙、镁、锰、铜、锌、钠、钾和锂。
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EP1420026A3 (en) | 2004-12-15 |
BR0011863A (pt) | 2003-10-14 |
DE60013130T2 (de) | 2005-01-05 |
AU5383700A (en) | 2001-01-31 |
WO2001000653A1 (en) | 2001-01-04 |
NO20016294D0 (no) | 2001-12-20 |
EP1189924A1 (en) | 2002-03-27 |
DE60013130D1 (de) | 2004-09-23 |
JP2003522124A (ja) | 2003-07-22 |
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