CN104254329A - 用于治疗神经病变的含α-硫辛酸与和厚朴酚的组合物 - Google Patents
用于治疗神经病变的含α-硫辛酸与和厚朴酚的组合物 Download PDFInfo
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- CN104254329A CN104254329A CN201380020986.2A CN201380020986A CN104254329A CN 104254329 A CN104254329 A CN 104254329A CN 201380020986 A CN201380020986 A CN 201380020986A CN 104254329 A CN104254329 A CN 104254329A
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Abstract
本发明涉及一种含有α-硫辛酸或其盐或其复合物与和厚朴酚的组合物，其中，基于和厚朴酚和硫辛酸的总质量，所述和厚朴酚的含量为1％-30％。
Description
本发明涉及一种治疗神经病变的组合物，尤其是治疗周围神经病变的疼痛感觉综合征的组合物。
现已知有很多种组合物可用于对患有神经病变的患者给药。
具体地，已知含有α-硫辛酸的组合物对治疗神经病变，尤其是获得性周围神经病变具有良好的效果。事实上，α-硫辛酸加强了抗氧化屏障并通过提高谷胱甘肽的水平降低氧化应激，提高神经传导(nerve communication)速度，从而优化其功能，并最终发挥其抵御神经敏感(nervous sensitivity)的正常化作用，同时缓解疼痛和感觉模糊(sensory turbidity)。
最近的体内研究证明，α-硫辛酸具有神经保护和心脏保护作用。
已知含有膳食性α-硫辛酸的速释或常规释放组合物，其用于每天一次施用300mg或600mgα-硫辛酸。
据已出版的研究“α-硫辛酸口服治疗改善糖尿病性多神经病变症状-悉尼2号试验(Oral Treatment Withα-Lipoic Acid Improves Symptomatic DiabeticPolyneuropathy-The SYDNEY 2trial)”(Dan Ziegler等，糖尿病护理(DiabetesCare)，2006年11约，29卷，11号，2365-2370页)，以及“硫辛酸和乙酰左旋肉毒碱治疗椎间盘突出引起的坐骨神经痛(Thioctic Acid andAcetyl-L-Carnitine in the Treatment of Sciatic Pain Caused by aHerniated Disc)”(Memeo Antonio和Mario Loiero,临床药品调查(Clin.DrugInvestigation，2008,28卷，495-500页)报道，对于治疗糖尿病性多神经病变和坐骨神经痛的症状，600mg日剂量的α-硫辛酸具有最佳的风险/收益比。根据第一项研究，相对于600mg的日剂量，更高剂量的1200mg和1800mg均未显示出改善糖尿病多神经病变症状的更好反应。该研究还显示随着剂量增加的α-硫辛酸相关副作用，例如恶心、呕吐以及头晕。
已知厚朴(Magnolia)树皮(一种获自厚朴(Magnolia Officinalis)的植物派生物，其属于木兰科)含有两种酚类化合物，和厚朴酚与木兰醇。厚朴树皮被认为具有许多药理学特性，例如抗焦虑、抗炎、抗菌、抗氧化、抗血小板以及神经营养特性。
据“和厚朴酚对胎儿大鼠皮层神经元培养的神经营养活性(Neurotrophicactivity of honokiol on the cultures of fetal rat cortical neurons)”(Y.Fukuyama,Nakade K.,Minoshima Y.,Yokoyama,A.,H.Zhai,Y.Mitsumoto，Bioorg.Med Chem.Lett 2002.4月22日；12(8):1163-6)的描述，浓度为0.1-10μM的和厚朴酚对于培养的大鼠皮层神经元具有神经营养活性。在皮层神经元中，和厚朴酚能够促进神经突的生长。此外，还证实和厚朴酚能够促进原代培养神经元的存活和发育。
就和厚朴酚的神经营养活性而言，“木兰科化合物的治疗性应用(Therapeutic applications of compounds in the magnolia family)”(LeeYJ等，Ther.2011,130(2):157-76)披露了其在大鼠中的有效剂量为0.01g/kg和0.25g/kg。目前尚无研究披露对于人类的有效剂量。
US2006251608描述了治疗皮肤衰老的制剂，其包含抗氧化剂、抗氧化的共促进剂(co-promoter)、抗炎药物、维生素、矿物质和胶原合成促进剂。但其没未提及这些制剂对治疗神经病变的任何效果。提及了α-硫辛酸与和厚朴酚在这些制剂中可作为抗氧化剂，但并未专门描述这两种化合物的组合。
对于运动员来说，营养补充剂有利于提高肌肉质量、强度以及体力，除很多其它成分外，所述营养补充剂还包含α-硫辛酸和含2％和厚朴酚的厚朴树皮。而这些补充剂对神经病变的治疗效果并未经报道，且在这些补充剂中，和厚朴酚的含量极低。具体地，在已知的这些补充剂中和厚朴酚和α-硫辛酸的比值为小于0.3％。
因此，本发明的目的在于提供一种含有α-硫辛酸的组合物，其对神经性疼痛及其症状具有更好的治疗活性。所述目的由某种组合物和药学或膳食制剂实现，所述组合物的主要特征在第一项权利要求中具体描述，而权利要求9具体描述了所述药学或膳食制剂的特征。本发明组合物及制剂的其他特征在余下的权利要求中进行具体描述。
本发明组合物包括α-硫辛酸或其盐或其复合物、与和厚朴酚，其特征在于，基于和厚朴酚与硫辛酸这两种组分的总质量，和厚朴酚的含量为1％-30％。
本发明组合物中含有的α-硫辛酸可为消旋体形式，例如，可以是R或S型两种对映体形式的混合物、和/或它们的盐或复合物，或本发明组合物可仅含有生物活性的R对映体形式，或其盐或其复合物。
事实上，本发明人意外地发现，当所述α-硫辛酸与和厚朴酚以特定比例联用时，由于存在协同效应，能够提高α-硫辛酸对于神经病变和其相关疼痛综合征的治疗效果。
具体地，本发明人进行的实验显示，在神经元的原代培养物中，施用本发明的α-硫辛酸与和厚朴酚组合物能够有效地促进神经突延伸以及细胞存活，然而，施用相似的含有α-硫辛酸和含量为0到低于1％的和厚朴酚组合物时，却没有显著的促进神经突延伸的作用。
优选地，基于和厚朴酚和α-硫辛酸的总质量，本发明组合物中和厚朴酚的含量为2％-15％，更优选地，为3％-10％。
实际上，以上所示范围是硫辛酸与和厚朴酚浓度的最佳比例，通过比较硫辛酸与和厚朴酚联用时的显著性活性与单独使用，证明了该这些比例下的两种活性物质具有明显的协同效应。
而α-硫辛酸的盐或其复合物，例如，水溶性盐(如R-硫辛酸钠或钾)，和其它R型对映体或RS消旋体的水溶性盐均可用于本发明组合物。
本发明组合物还优选含有其他活性成分，其与α-硫辛酸或其盐或其复合物以及和厚朴酚联用，能够形成特别有效的治疗非糖尿病性和外周性神经病变的组合物。
因此，本发明组合物优选包括γ-亚麻酸或其盐或其复合物，例如γ亚麻酸的钠盐。优选地，基于和厚朴酚和α-硫辛酸的总质量，本发明组合物中所述的γ-亚麻酸的含量为2％-30％。更优选地，基于和厚朴酚和α-硫辛酸的总质量，本发明组合物中所述的γ-亚麻酸的含量为15％-25％。
本发明组合物中优选还含有生理学可接受的硒来源。在本说明书以及权利要求中，“生理学可接受的硒来源”指的是任何可吸收的硒来源，其可用于膳食或药物组合物，例如，与氨基酸形成复合物的硒盐或硒。优选地，选自下组的化合物可用作生理学可接受的硒来源：硒代甲硫氨酸、亚硒酸钠、硒酸钠和酵母硒。
优选地，基于和厚朴酚和α-硫辛酸的总质量，本发明组合物中生理学可接受的硒来源的质量适合提供0.0001％-2％的硒量。更优选地，基于和厚朴酚和α-硫辛酸的总质量，本发明组合物中生理学可接受的硒来源的质量适合提供0.0001％-0.1％的硒量。
本发明组合物优选还含有至少一种选自下组的组分：维生素C、维生素E和B族维生素，例如维生素B1、B2、B5、B6和B12。
本发明组合物可制备成适于口服施用的任何剂型。具体地，在一方面，本发明涉及一种口服施用的膳食或药物组合物，其含有上述定义的组合物，形式可以为丸剂、片剂、胶囊剂、咀嚼片剂、口香糖、片芯、口服混悬剂粉末、可重建的颗粒粉末(granular powder to be reconstituted)或口含粉末、口服混悬剂、糖浆。
本发明组合物还可根据所需药物制剂类型而含有赋形剂、芳香剂以及其他经批准的食用物质。可用于制备片剂或胶囊剂的合适赋形剂为：例如马铃薯、小麦或玉米淀粉，尤其是预凝胶淀粉、微晶纤维素、磷酸氢钙、碳酸钙、多元醇(如甘露醇、山梨醇)、麦芽糊精、乳糖、胶体氧化硅、高分散二氧化硅、山嵛酸甘油酯、丙二醇、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、纤维素酯及醚(例如羧甲基纤维素、羟丙甲纤维素、羟丙基纤维素)、交联焦糖钠、海藻酸盐、角叉菜胶、硬脂酸镁、硬脂酰富马酸钠、二氧化钛、明胶、蔬菜油(例如大豆或葵花油)、聚甘油油酸酯(poliglicerol oleate)、甘油、脂肪酸甘油三酯、卵磷脂。
优选地，本发明制剂为片剂或胶囊剂的形式，其适于每日施用200mg-1300mg量的α-硫辛酸，和2.5mg-150mg量的和厚朴酚。
较优选地，本发明制剂为片剂或胶囊剂的形式，其适于每日施用580mg-620mg量的α-硫辛酸，和45mg-60mg量的和厚朴酚，或适于每日施用280mg-320mg量的α-硫辛酸，和20mg-30mg量的和厚朴酚。
更优选地，本发明制剂为片剂或胶囊剂的形式，其适于每日施用600mg量的α-硫辛酸，和54mg量的和厚朴酚，或适于每日施用300mg量的α-硫辛酸，和27mg量的和厚朴酚。
在本说明书以及权利要求中，“适于每日施用”指的是每个胶囊或片剂含有所规定的活性组分的总量，或含有相同量的一部分，例如通过多个胶囊或片剂施用该总量。例如，含有约300mg的α-硫辛酸和15mg的和厚朴酚被认为适于每日施用600mgα-硫辛酸和30mg和厚朴酚。
本发明制剂中γ-亚麻酸或其盐或其复合物的含量为10mg-300mg。
本发明的优选制剂适合每日施用580mg-620mg量的α-硫辛酸、45mg-60mg量的和厚朴酚，和125mg-140mg量的γ亚麻酸，其为明胶软胶囊形式。明胶软胶囊形式的另一优选的本发明制剂适于每日施用280mg-320mg量的硫辛酸、20mg-30mg量的和厚朴酚，和60-70mg量的γ亚麻酸。
本发明制剂中含有上述生物学可接受的硒来源，其含量提供1μg-90μg的硒量。
本发明制剂优选含有维生素C，其含量为20mg-1000mg。
本发明制剂优选含有维生素E，其含量为1mg-100mg。
本发明制剂优选含有维生素B1，其含量为1mg-5mg。
本发明制剂优选含有维生素B2，其含量为1mg-5mg。
本发明制剂优选含有维生素B5，其含量为1mg-20mg。
本发明制剂优选含有维生素B6，其含量为1mg-8mg。
本发明制剂优选含有维生素B12，其含量为0.001mg-0.020mg。
本发明的优选制剂包括约600mg的α-硫辛酸，约54mg的和厚朴酚，约140mg的γ-亚麻酸，和约0.110mg的亚硒酸钠。
本发明的另一种优选制剂包括约300mg的硫辛酸，约27mg的和厚朴酚，约66mg的γ-亚麻酸，和约0.055mg的亚硒酸钠。
可通过施用类型以及其它实际考虑选择本发明组合物的制备技术。
本领域技术人员所知的任何用于制备含有低熔点活性成分片剂的技术均可以用于制备本发明制剂，例如，在粉末混合后直接压片、制粒后湿压或干压(如在流化床中)、压成颗粒或片芯。胶囊可如下制备：例如，通过将粉末、颗粒、小片或片芯灌装入预成形的外壳(体)，然后加装胶囊帽封闭；通过形成掺有合适增塑剂的可着色明胶片，同时用液体(Sherer法)或固体(Accogel法)灌装；通过在冷却的油性溶液中，滴加含增塑剂的明胶和可能的活性成分(如滴加法)。
参考附图，本领域技术人员可从以下实施例明白本发明组合物和制剂的优点，所述附图中：
-图1a显示了在0.5％EtOH中培养7天后，大鼠皮层神经元的原代细胞培养物照片；
-图1b显示了在0.5％EtOH外加40ng ml-1的bFGF中培养7天后，大鼠皮层神经元的原代细胞培养物照片；
-图1c显示了在0.5％EtOH外加含有99.7％α-硫辛酸以及0.3％和厚朴酚的10μM溶液中培养7天后，大鼠皮层神经元的原代细胞培养物照片；
-图1d显示了在0.5％EtOH外加含有95.5％α-硫辛酸以及4.5％和厚朴酚的10μM溶液中培养7天后，大鼠皮层神经元的原代细胞培养物照片；
-图1e显示了在0.5％EtOH外加含有91％α-硫辛酸以及9％和厚朴酚的10μM溶液中培养7天后，大鼠皮层神经元的原代细胞培养物照片；
-图1f显示了在0.5％EtOH外加含有46％α-硫辛酸以及54％和厚朴酚的10μM溶液中培养7天后，大鼠皮层神经元的原代细胞培养物照片；
-图1d显示了在0.5％EtOH单独外加10μMα-硫辛酸溶液中培养7天后，大鼠皮层神经元的原代细胞培养物照片；
-图1h显示了在0.5％EtOH单独外加10μM和厚朴酚溶液中培养7天后，大鼠皮层神经元的原代细胞培养物照片；
-图2a显示了在0.5％EtOH中培养4天后，大鼠皮层神经元的原代培养物照片；
-图2b显示了在0.5％EtOH外加含有99.7％α-硫辛酸以及0.3％和厚朴酚的10μM溶液中培养4天后，大鼠皮层神经元的原代细胞培养物照片；
-图2c显示了在0.5％EtOH外加含有91％α-硫辛酸以及9％和厚朴酚的10μM溶液中培养4天后，大鼠皮层神经元的原代细胞培养物照片；
-图2d显示了在0.5％EtOH外加含有46％α-硫辛酸以及54％和厚朴酚的10μM溶液中培养7天后，大鼠皮层神经元的原代细胞培养物照片。
材料和方法
所用化合物的纯度通过高效液相色谱(HPLC，单峰)、核磁共振(H1和C3)、以及高分辨率质谱分析法测定。
培养基是达尔伯克(氏)改性培养基(DMEM)、胎牛血清(FBS)，B27补充剂获自Gibco BRL(纽约,美国)。试剂PD98059[2-2(2-氨基-3-甲氧基苯基)-4H-1-苯并吡喃-4-酮]、LY294002[2-(4-吗啉基)-8-苯基-1(4H)-苯并吡喃-4酮]，以及KN93[N-[2-[N-(4-氯代肉桂基)-N-甲基氨甲基]苯基]-N(2-羟乙基)-4-甲氧基苯磺酰胺磷酸盐]购自美国密苏里州西格马公司(Sigma，MO，USA)。人重组纤维母细胞生长因子(bFGF)由美国纽约北方生物科技有限公司(Upstate Biotechnology Inc，NY，USA)供应。其它所用的试剂均为市场上纯度最高的试剂。
实施例1形态学
根据“重组纤维母细胞生长因子及其修饰蛋白CS23对胎儿大鼠大脑不同部位来源的原代培养神经元存活的影响(Effects of recombinant human basicfibroblast growth factor and its modified protein CS23on survival of primarycultured neurons from various regions of fetal rat brain.)”(Abe K等，Jpn JPharmacol 1990,53(2):221-7)中的描述，制备了8份原代细胞培养物。所有操作均在无菌环境下进行。
自18天的大鼠胎儿(Japan SLC,Inc)大脑半球中分离出神经元细胞，并悬浮于10％FBS/MEM，然后按9000个细胞cm-2接种在多聚-L-赖氨酸平板上。
24小时后，培养基换成添加有B27的无血清培养基，特别用于神经元的生长(神经基质培养基)。
然后，取第一培养物(A)作为对照培养物。
第二培养物(B)中加入了40ng mL-1的bFGF。
第三培养物(C)中加入了99.7wt％的α-硫辛酸和0.3wt％的和厚朴酚，至总浓度为10μM。
第四培养物(D)中加入了95.5wt％的α-硫辛酸和4.5wt％的和厚朴酚，至总浓度为10μM。
第五培养物(E)中加入了91wt％的α-硫辛酸和9wt％的和厚朴酚，至总浓度为10μM。
第六培养物(F)中加入了46wt％的α-硫辛酸和54wt％的和厚朴酚，至总浓度为10μM。
第七培养物(G)中仅加入了α-硫辛酸，至总浓度为10μM。
第八培养物(H)中仅加入了和厚朴酚，至总浓度为10μM。
孵育6天后，用4％的甲醛固定8份培养物中的细胞。
然后，在显微镜水平下，评估8份培养物的神经突长度。根据“和厚朴酚在胎鼠皮质神经元培养物中的神经营养活性(Neurotrophic activity of honokiolon the cultures of fetal rat cortical neurons)”(Fukuyama Y等，Bioorg.Med Chem.Lett 12,1163-66(2002))中描述的神经突长度的组化方法，对神经元进行微管结合蛋白-2(MAP2)的免疫组化染色。根据上述Y.Fukuyama等.(2002)中的方法，利用软件程序“Lumina Vision”和“Mac-SCOPE”测量和计算整个细胞体中最长的神经突长度。通过利用“Lumina Vision”和“Mac-SCOPE”软件(Yoshiyasu Fukuyama等.2002)测量各神经元的最长神经突的长度，从而进行形态学分析。
结果如表1所示，其中p表示显著性差异，ns表示“非显著”。
表1
利用本发明组合物(和厚朴酚浓度4.5％-9％)处理的培养物中，神经突的长度增长显著(p＜0.0001)，而利用含有99.7％α-硫辛酸和0.3％和厚朴酚的组合物处理后的培养物未显示神经突长度增长没有显著性差异。与对照(培养物A)和加入了生长因子的培养物(培养物B)相比，尤其与额外加入了含有99.7wt％α-硫辛酸以及0.3wt％和厚朴酚组合物的培养物(培养物C)相比，含有95.5(wt)％α-硫辛酸和4.5wt％和厚朴酚的组合物，以及含有91(wt)％α-硫辛酸和9wt％和厚朴酚的组合物均能有效促进神经突显著延伸。应注意，本发明组合物，无论是含有比例为95.5％的α-硫辛酸和4.5％的和厚朴酚，还是含有91％的α-硫辛酸和9％的和厚朴酚，均比加入生长因子bFGF的组合物具有更显著的效果。含有46wt％的α-硫辛酸和54％的和厚朴酚的组合物则抑制了培养物F中的神经突长出。
仅含有α-硫辛酸或仅含有和厚朴酚的组合物对神经突生长的刺激作用微乎其微。该实验结果值与对照组合物比较并无显著差异。
图1还显示了在细胞培养7天后，与对照培养物A(图1a)相比，在培养物C、D、E中(图1c、1d、1e)，神经元显示延伸的神经突含有更明显、颜色更深的神经元细胞体，而相对于培养物B(图1b，含有40ng ml-1的bFGF)和仅含有硫辛酸(图1d)或和厚朴酚(图1h)的培养物而言，D和E(图1d和1e)的更佳。
所测试的结果显示，本发明组合物对皮质神经元的分化具有确切的、出乎意料的效果。
实施例2神经元存活评价
根据“重组纤维母细胞生长因子及其修饰蛋白CS23对胎儿大鼠大脑不同部位来源的原代培养神经元存活的影响”(Abe K等，Jpn J Pharmacol 1990,53(2):221-7)中的描述，制备了4份原代细胞培养物。所有操作均在无菌环境下进行。自18天的大鼠胎儿(Japan SLC,Inc)大脑半球中分离出神经元细胞，并悬浮于10％FBS/MEM，然后按20000个细胞cm-1接种在多聚-L-赖氨酸平板上。
24小时后，将培养基换成添加有B27的无血清培养基，特别用于神经元的生长(神经基质培养基)。
细胞培养的方法与采用NBM/B27的实施例中所实施的基本相同，区别在于，其利用了无血清培养基、添加有N2的DMEM(“用于大鼠CNS神经元选择性培养的新和成培养基制剂(Formulation of a novel synthetic medium for selectivelyculturing rat CNS neurons)”，Cestelli A等.Dev Brain Res 1985,22.219)；从而平板的细胞密度为2×105cm-2。
然后，取培养物I作为对照培养物。
培养物(L)中加入了99.7wt％的α-硫辛酸和0.3wt％的和厚朴酚，至总浓度为10μM。
培养物(M)中加入了91wt％的α-硫辛酸和9wt％的和厚朴酚，至总浓度为10μM。
培养物(N)中加入了46wt％的α-硫辛酸和54wt％的和厚朴酚，至总浓度为10μM。
孵育3天后，用4％的甲醛固定4个培养物中的细胞。
根据“水溶性四唑鎓盐用于细胞生存率比色试验(A water-solubletetrazolium salt useful for colorimetric cell viability assay)”(Tominaga等，AnalCommun 1999,36.47)中的WST-8H法测定神经元的存活。该方法采用了2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2.4-disolfofenil)-2H四唑鎓的盐作为色源指示剂以测定WTS-8细胞的生存率，其所产生的细胞生存率结果分别与利用溴化3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H四唑鎓的MTT法，以及氚代胸腺嘧啶摄取法所获得的结果相一致。
所得结果示于表2(其中的数值表示为平均值)和图2。在表2中，p表示显著性差异，ns代表“非显著”。
表2
| 培养物 | 与对照(培养物I)相比在450nm下的吸光度％ |
| I | 100.0 |
| L | 106.0(p＝ns) |
| M | 143.1(p<0,001) |
| N | 29.7(p<0,001) |
培养物M的值显著高于对照I。
在没有活性成分的参考培养物I中，测定出仅有一小部分神经元存活。与此相反，在有10μM浓度的本发明组合物存在时，培养物M显示出很强的神经元生长和生存能力。
实施例3
按实施例2所述制备了4份原代细胞培养物(按“重组纤维母细胞生长因子及其修饰蛋白CS23对胎儿大鼠大脑不同部位来源的原代培养神经元存活的影响”(Abe K等，Jpn J Pharmacol 1990,53(2):221-7))。
然后，取培养物(O)作为对照培养物。
培养物(P)中加入了91wt％的α-硫辛酸和9wt％的和厚朴酚，至总浓度为10μM。
培养物(Q)中加入了91wt％的α-硫辛酸和9wt％的和厚朴酚，至总浓度为10μM，并加入了0.003μM的硒。
培养物(R)中加入了91wt％的α-硫辛酸和9wt％的和厚朴酚，至总浓度为10μM，并加入了0.24μM的γ-亚麻酸。
在孵育3天后，用4％的甲醛固定4个培养物中的细胞。
采用WST-8还原测试(Tominaga等.,1999)对神经元的存活进行了测试。结果示于表3(数值以平均值示出)。此外，p表示显著性差异。
表3
| 培养物 | 与对照(培养物O)相比在450nm下的吸光度％ |
| O | 100.0 |
| P | 143,1(p<0,001) |
| Q | 178,9(p<0,001) |
| R | 176,5(p<0,001) |
表3的结果显示，本发明优选实施例的组合物(含有硒和/或γ-亚麻酸)出乎意料地对增强神经元培养物的存活尤其有效。具体地，培养物Q和R中所用的组合物比参考例O和培养物P中采用的培养组合物更有效。
Claims (13)
1.一种含有α-硫辛酸或其盐或其复合物与和厚朴酚的组合物，其特征在于，基于和厚朴酚和α-硫辛酸的总质量，所述和厚朴酚的含量为1％-30％。
2.如上述权利要求所述的组合物，其特征在于，基于和厚朴酚和α-硫辛酸的总质量，所述和厚朴酚的含量为2％-15％。
3.如上述权利要求所述的组合物，其特征在于，基于和厚朴酚和α-硫辛酸的总质量，所述和厚朴酚的含量为3％-10％。
4.如上述任一权利要求所述的组合物，其特征在于，含有γ-亚麻酸或其盐或其复合物。
5.如上述权利要求所述的组合物，其特征在于，基于和厚朴酚和α-硫辛酸的总质量，所述γ-亚麻酸的含量为2％-30％。
6.如权利要求3所述的组合物，其特征在于，还含有生理学可接受的硒来源。
7.如上述任一权利要求所述的组合物，其特征在于，还含有选自下组的至少一种组分：维生素C、维生素E、B族维生素。
8.如上述任一权利要求所述的组合物，用于治疗外周神经病变。
9.用于口服施用的膳食或药学制剂，含有以上任一权利要求所述的组合物。
10.如权利要求9所述的制剂，为片剂或胶囊形式，其适于每日施用200mg-1300mg量的α-硫辛酸，和2.5mg-150mg量的和厚朴酚。
11.如权利要求10所述的制剂，为片剂或胶囊形式，其适于每日施用580mg-620mg量的α-硫辛酸，和45mg-60mg量的和厚朴酚，或适于每日施用280mg-320mg量的α-硫辛酸，和20mg-30mg量的和厚朴酚。
12.如权利要求10所述的制剂，为明胶软胶囊形式，其适于每日施用200mg-1300mg量的α-硫辛酸，2.5mg-150mg量的和厚朴酚，和10-300mg的γ-硫辛酸或其盐或其复合物。
13.如权利要求11所述的制剂，为明胶软胶囊形式，其适于每日施用580mg-620mg量的α-硫辛酸，45mg-60mg量的和厚朴酚，和125-140mg的γ-亚麻酸；或适于每日施用280mg-320mg量的α-硫辛酸，20mg-30mg量的和厚朴酚，和60-70mg的γ-亚麻酸。
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| SM (1) | SMT201600268B (zh) |
| WO (1) | WO2013156971A1 (zh) |
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| US10053406B2 (en) | 2015-10-23 | 2018-08-21 | Colgate-Palmolive Company | Synthesis of honokiol |
| HU231044B1 (hu) * | 2016-07-22 | 2020-01-28 | Culex Patent Kft | Liponsav és szelenit szinergista hatásán alapuló készítmény és annak alkalmazása daganatos megbetegedések megelõzésében és kezelésében |
| MX2021005888A (es) | 2018-11-26 | 2021-06-23 | Procter & Gamble | Preparacion farmaceutica solida que contiene acido lipoico y uso de esta. |
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| CN101774896A (zh) * | 2007-12-25 | 2010-07-14 | 四川大学 | 和厚朴酚系列衍生物及其制备方法和用途 |
| CN102070411A (zh) * | 2011-01-22 | 2011-05-25 | 李文东 | 一种精制和厚朴酚的方法 |
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| US20060018975A1 (en) * | 2004-07-20 | 2006-01-26 | Talbott Shawn M | Methods and compositions for weight management and mood enhancement |
| US7776915B2 (en) * | 2005-03-24 | 2010-08-17 | Tracie Martyn International, Llc | Topical formulations and methods of use |
| CA2546464A1 (en) * | 2005-05-04 | 2006-11-04 | Richard Wachsberg | Sequential application of oral and topical formulations for treating wrinkles and other damage to skin |
| EP2192910A1 (en) * | 2007-10-01 | 2010-06-09 | Colgate-Palmolive Company | Oral compositions containing botanical extracts |
| BR112015002309A2 (pt) * | 2012-08-07 | 2017-07-04 | Buck Inst Res Aging | formulação de múltiplos componentes para aprimorar a função neurológica |
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- 2013-04-19 CN CN201380020986.2A patent/CN104254329B/zh active Active
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- 2013-04-19 US US14/395,265 patent/US9642834B2/en active Active
- 2013-04-19 RU RU2014146562A patent/RU2636613C2/ru active
- 2013-04-19 EP EP13725811.7A patent/EP2838529B1/en active Active
- 2013-04-19 ES ES13725811.7T patent/ES2577385T3/es active Active
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101774896A (zh) * | 2007-12-25 | 2010-07-14 | 四川大学 | 和厚朴酚系列衍生物及其制备方法和用途 |
| CN102070411A (zh) * | 2011-01-22 | 2011-05-25 | 李文东 | 一种精制和厚朴酚的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104254329B (zh) | 2016-09-28 |
| RU2636613C2 (ru) | 2017-11-24 |
| PT2838529E (pt) | 2016-06-24 |
| US20150093454A1 (en) | 2015-04-02 |
| ES2577385T3 (es) | 2016-07-14 |
| PL2838529T3 (pl) | 2017-04-28 |
| EP2838529B1 (en) | 2016-03-16 |
| ITMI20120661A1 (it) | 2013-10-21 |
| RU2014146562A (ru) | 2016-06-10 |
| WO2013156971A1 (en) | 2013-10-24 |
| EP2838529A1 (en) | 2015-02-25 |
| SMT201600268B (it) | 2016-08-31 |
| US9642834B2 (en) | 2017-05-09 |
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