CN111093398A - 含有益智提取物作为有效成分的用于预防、改善或治疗骨关节炎的组合物 - Google Patents
含有益智提取物作为有效成分的用于预防、改善或治疗骨关节炎的组合物 Download PDFInfo
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- CN111093398A CN111093398A CN201880058695.5A CN201880058695A CN111093398A CN 111093398 A CN111093398 A CN 111093398A CN 201880058695 A CN201880058695 A CN 201880058695A CN 111093398 A CN111093398 A CN 111093398A
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Abstract
本发明涉及一种含有益智提取物作为有效成分的用于预防、改善或治疗骨关节炎的组合物,详细来说,能够减少作为炎症因子的白细胞介素1β、白细胞介素6、肿瘤坏死因子α以及环氧化酶2的表达,并且能够减少作为诱发软骨退行性变因子的基质金属蛋白酶9的表达,恢复软骨损伤,能够有用的作为用于预防或改善骨关节炎的保健食品或者用于预防或治疗骨关节炎的治疗剂来使用。
Description
技术领域
本发明涉及一种含有益智提取物作为有效成分的用于预防、改善或治疗骨关节炎的组合物。
背景技术
关节炎为关节发生炎症以及疼痛而致的疾病,有骨关节炎(osteoarthristis)、类风湿性关节炎(rheumatoid arthritis)、痛风、干性关节炎,关节炎患者的95%都患有骨关节炎。骨关节炎为随着关节软骨磨损殆尽而显出局部退行性变化的疾病,又称为退行性关节炎(degenerative arthritis)。骨关节炎为与老龄化有一定关联的典型的退行性疾病,疾患率约占总人口的10~15%,尤其在65岁以上的高龄人群中,约60~80%患有骨关节炎。
骨关节炎的病因与老化现象或过重的体重有较深的关系,随着年龄增长,女性患者更多且症状更为严重。初期症状为一个或两个关节显出强直症状并伴有疼痛,随着病程延长,会在关节周边引起骨的过度形成以及关节的变形等。诱发骨关节炎的机理为肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)、白细胞介素6(IL-6)之类的促炎性细胞因子(pro-inflammatory cytokine)生成的增加,且骨胶原酶(collagenase)、基质分解素(stromelysin)等之类的基质金属蛋白酶(MMPs)的分泌增加而诱发关节软骨的损伤。
现在临床上使用的骨关节炎的治疗利用镇痛剂、类固醇剂、非甾体剂之类的药物治疗,或者利用透明质酸、氨基葡萄糖、软骨素等软骨保护剂,或者通过关节镜手术、近端胫骨切开术、关节置换术、全膝关节置换术等外科治疗。但是,使用药物治疗剂时,只具有非特异性地缓解疼痛或炎症反应的效果,而软骨保护剂只能向软骨提供营养,或者只能起到通过缓解冲击来保护软骨的作用。并且,长期服用类固醇制剂时,具有引起因钙的损失导致的骨质疏松症、高血压、糖尿病等的副作用。因此,药物治疗大部分只为减少疼痛而使用,虽然以进行永久性人造关节置换术为主,但到现在为止还未出现具有根治效果的药物或手术方法。
另外,益智仁(Alpiniae Oxyphyllae Fructus)为姜科(Zingiberaceae)植物益智(Alpinia oxyphylla Miq)的果实,生长于中国广东省和海南岛。益智仁的形状呈两头略尖的球形或椭圆形,长度约1~2cm,直径约7~10mm。外表面呈褐色或深褐色,具有多个纵向连接的小结节状隆起的条纹。果皮的厚度约为0.3~0.5mm,与种子紧贴,不易剥离。里面通过薄膜纵向分为三个房,5~8个种子通过假种皮相互依附着存在于各房中。种子为褐色至深褐色,呈不规则的多面体,直径约为3.5mm,质地坚硬。气味奇特,味道略苦。益智仁的成分已知含有诺卡酮(nootkatone)、表圆柚醇(epinootkatol)、β努特卡醇(β-nootkatol)、β蒎烯(β-pinene)、对异丙基甲苯(p-cymene)、4-萜烯醇(terpinen-4-ol)、二苯基庚烷类(diarylheptanoid)化合物益智酮(yakuchinone)A和B,还含有黄酮属的杨芽素(tectochrysin)、白杨素(chrysin)、良姜素(izalpinin)、3,5-二羟基-7,4'-二甲氧基黄酮(3,5-dihydroxy-7,4'-dimethoxyflavone)等。上述诺卡酮(nootkatone)具有抗胃溃疡作用,上述益智酮(yakuchinone)A和B具有抗炎症作用,抑制皮肤癌的生成,降低环氧化酶2(COX-2)和诱导型一氧化氮合酶(iNOS)的表达和核因子κB(NFκB)的活性。另外,已知益智酮(yakuchinone)A、诺卡酮(nootkatone)以及表圆柚醇(epinootkatol)还具有杀虫效果、脑细胞保护作用、抗过敏作用、美白作用等。
并且,益智仁的精油成分增加皮肤渗透力,通过以竞争的方式抑制钙离子流入细胞内,显出平滑肌松弛作用和心肌抑制作用,已知还具有抗利尿作用、抗溃疡作用、抗痴呆作用、学习能力改善作用。
另外,韩国公开专利第2012-0109140号公开了有关包含益智仁提取物的用于治疗肺癌的组合物及保健食品的内容,韩国授权专利第1235238号公开了对退行性关节炎具有良好疗效的白芍药提取物以及包含其的药剂学组合物,但还没有公开如本发明的含有益智提取物作为有效成分的用于预防、改善或治疗骨关节炎的组合物。
发明内容
技术问题
本发明为适应上述要求而提出,本发明提供一种含有益智仁提取物作为有效成分的用于预防、改善或治疗骨关节炎的组合物,本发明的作为有效成分的益智仁提取物在动物模型中减少了炎症因子及诱发关节软骨损伤的基质金属蛋白酶9(MMP-9)的表达,通过确认其对软骨损伤的恢复来完成了本发明。
解决问题的手段
为了达成上述目的,本发明提供一种含有益智仁提取物作为有效成分的用于预防或改善骨关节炎的保健食品组合物。
并且,本发明还提供一种含有益智仁提取物作为有效成分的用于预防或治疗骨关节炎的药学组合物。
发明的效果
本发明涉及含有益智提取物作为有效成分的用于预防、改善或治疗骨关节炎的组合物,益智仁作为源自天然植物的物质,安全且易于提供原料,能够减少作为炎症因子的白细胞介素1β、白细胞介素6、肿瘤坏死因子α以及环氧化酶2的表达,并且能够减少作为软骨退行性变诱发因子的基质金属蛋白酶9的表达,恢复软骨损伤的效果良好,能够有用的作为用于预防或改善骨关节炎的保健食品或者用于预防或治疗骨关节炎的治疗剂的原材料来使用。
附图说明
图1为示出SD大鼠后腿的体重负荷率(%)的结果。Con为阴性对照组,MIA(碘乙酸单钠,monosodium iodoacetate)为骨关节炎诱发组,MIA+吲哚美辛为阳性对照组,MIA+益智仁300mg/kg为使用MIA及300mg/kg的益智仁提取物进行并行处理的组,MIA+益智仁150mg/kg为使用MIA及150mg/kg的益智仁提取物进行并行处理的组。#、###、####表示使用MIA诱发骨关节炎的组的体重负荷率相对于阴性对照组有意义的减少,其中,#指p<0.05,###指p<0.001,####指p<0.0001,***表示使用MIA和吲哚美辛进行并行处理的阳性对照组的体重负荷率比通过MIA处理的骨关节诱发组增加,***指p<0.001。
图2为示出在骨关节炎动物模型中益智仁提取物对炎症诱发因子(白细胞介素1β、白细胞介素6、肿瘤坏死因子α以及环氧化酶2)以及软骨退行性变诱发因子(基质金属蛋白酶9)的表达的确认结果。Con为阴性对照组,MIA为通过MIA处理的骨关节炎诱发组,IM为使用MIA以及吲哚美辛进行并行处理的阳性对照组,300为使用MIA及300mg/kg的益智仁提取物进行并行处理的组,150为使用MIA及150mg/kg的益智仁提取物进行并行处理的组。#、##表示使用MIA进行处理时相对于阴性对照组con对于炎症诱发因子以及软骨退行性变诱发因子的表达有意义的增加,#指p<0.05,##指p<0.01,*、**表示因MIA而增加的炎症诱发因子以及软骨退行性变诱发因子的表达在使用吲哚美辛或益智仁提取物进行处理时有意义的减少,*指p<0.05,**指p<0.01。
图3为示出通过H&E(苏木素-伊红)染色对在骨关节炎动物模型中使用益智仁提取物的组织病理学变化进行确认的结果。SD rat:Normal为阴性对照组,Control为通过MIA处理的骨关节炎诱发组,益智仁300mg/kg为使用MIA和300mg/kg的益智仁提取物进行并行处理的组,益智仁150mg/kg为使用MIA和150mg/kg的益智仁提取物进行并行处理的组,吲哚美辛为使用MIA和吲哚美辛进行并行处理的阳性对照组。
图4为示出通过番红O染色法对在骨关节炎动物模型中使用益智仁提取物的组织病理学变化进行确认的结果。染成红色的部分为软骨的主要成分蛋白聚糖(proteoglycan)层。SD rat:Normal为阴性对照组,Control为通过MIA处理的骨关节炎诱发组,益智仁300mg/kg为使用MIA和300mg/kg的益智仁提取物进行并行处理的组,益智仁150mg/kg为使用MIA和150mg/kg的益智仁提取物进行并行处理的组,吲哚美辛为使用MIA和吲哚美辛进行并行处理的阳性对照组。
具体实施方式
本发明提供一种含有益智仁提取物作为有效成分的用于预防或改善骨关节炎的保健食品组合物。
本发明的益智仁提取物以使用C1~C4的低级醇、水或它们的混合物作为溶剂来提取为优选,更为优选地,以乙醇为溶剂进行提取,但不限于此。
在本发明的一实例中,上述保健食品组合物制备成粉末、颗粒、丸、片剂、胶囊、糖衣、糖浆以及饮料的剂型为优选,但不限于此。
在将本发明的保健食品组合物作为食品添加物来使用时,可以直接添加上述益智仁提取物,或者与其他食品或食品成分一同使用,可以根据通常的方法适当的使用。有效成分的混合量可根据其使用目的(预防、健康或治疗性处置)来恰当的决定。通常,在制备食品或饮料时,本发明的组合物占原料的15重量份以下,优选地,添加10重量份以下的量。但在以健康及卫生为目的,或以健康调节为目的来长期摄取时,上述的量可以在上述范围以下,因为在安全方面没有任何问题,所以也可以以上述范围以上的量来使用。
上述食品的种类没有特别的限制。能够添加上述提取物或其分馏物的食品,举例来说,有肉类、香肠、面包、巧克力、糖果类、快餐类、饼干类、披萨、拉面、其他面类、香口胶类、包括冰淇淋的奶制品、各种汤、饮料、茶、补液、酒精饮料以及维生素复合体等,包括所有通常意义的保健食品。
在把本发明的组合物作为饮料来使用时,可以如普通饮料一样追加含有多种香味剂或天然碳水化合物等。上述天然碳水化合物为葡萄糖、果糖之类的单糖,麦芽糖、蔗糖之类的二糖,糊精、环式糊精之类的多聚糖,木糖醇、山梨糖醇、赤藓糖醇等的糖醇。甜味剂可以使用索马甜、甜叶菊提取物之类的天然甜味剂,糖精、阿巴斯甜之类的合成甜味剂。上述天然碳水化合物的比率可为每100g本发明的组合物添加约0.01~0.04g,优选地,添加约0.02~0.03g。除上述外,本发明的组合物还可以含有多种营养剂、维生素、电解质、增味剂、着色剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护性体胶增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇类、用于碳酸饮料的碳酸化剂等。此外,本发明的组合物还可以含有天然果汁、用于果汁饮料以及蔬菜饮料的制备的果肉。这样的成分可单独或混合使用。虽然这样的添加剂的比率不是很重要,但通常可在本发明的组合物每100重量份中的0.01~0.1重量份的范围内进行选择。
并且,本发明涉及一种含有益智仁提取物作为有效成分的用于预防或治疗骨关节炎的药学组合物。
本发明的药学组合物的特征在于,减少作为炎症因子的白细胞介素1β、白细胞介素6、肿瘤坏死因子α以及环氧化酶2的表达和作为软骨退行性变诱发因子的基质金属蛋白酶9的表达,但不限于此。
本发明的组合物除了上述有效成分外还可以包含药学上可接受的载体、赋形剂或稀释剂,可以为口服或非口服的多种剂型。制剂化时使用通常使用的填充剂、增量剂、结合剂、湿润剂、崩解剂、表面活性剂等稀释剂或赋形剂来制备。用于口服给药的固体制剂包括胶囊剂、散剂、颗粒剂、片剂、丸剂等,这样的固体制剂须在一种以上的化合物混合一种以上的赋形剂,比如淀粉、碳酸钙、蔗糖(sucrose)或乳糖(lactose)、明胶等。并且,除了单纯的赋形剂之外,还使用硬脂酸镁、滑石粉之类的润滑剂。用于口服给药的液体制剂为悬浊液、乳液、糖浆、气雾剂等,可以包含除了广泛使用的单纯稀释剂水、液体石蜡之外的多种赋形剂,比如湿润剂、甜味剂、芳香剂、保存剂等。用于非口服给药的制剂包括灭菌的水溶液、非水性溶剂、悬浮剂、油剂、冻结干燥制剂、佐剂。非水性溶剂及悬浮溶剂可以使用丙二醇(propyleneglycol)、聚乙二醇、橄榄油之类的植物油、油酸乙酯之类可注射的酯类等。佐剂的基剂可使用合成脂肪酸酯(witepsol)、聚乙二醇、吐温(tween)61、可可脂、月桂酸甘油酯、甘油明胶等。非口服给药时,以皮肤外用或腹腔内、直肠、静脉、肌肉、皮下、子宫内膜或脑血管内注射方式为优选,更为优选地,使用皮肤外用。
本发明的药学组合物以药剂学上有效的量进行给药。在本发明中,“药剂学上有效的量”指以能够适用于医学治疗的合理的受惠/危险比率来治疗疾病的充分的量,有效量的水准可以通过包括患者的疾病种类、重症度、药物的活性、对药物的敏感度、给药时间、给药途径及排泄比率、疗程、同时使用的药物等的要素以及其他医学领域广为人知的要素来决定。本发明的组合物可作为单独的治疗剂来给药,或者与其他治疗剂并用给药,可以与现有的治疗剂依次或同时给药,可以单一途径或多种途径给药。考虑上述所有要素后以无副作用的最小的量来获得最大的效果至关重要,相关领域的从业者很容易做出这样的决定。
本发明组合物的给药量可根据患者的体重、年龄、性别、健康状态、饮食、给药时间、给药方法、排泄率以及疾病的重症度而具有多种范围。本发明的组合物可单独使用,或者与手术、放疗、激素治疗、化疗以及使用生物学反应调节剂的方法并行使用。
以下,通过实施例对本发明进行更为详细的说明。这些实施例仅为对本发明进行更为具体的说明,相关领域的普通技术人员应该自明的是,本发明的范围并不因这些实施例而受限。
实施例1.益智仁提取物的制备
对1kg的益智仁添加15l的70%(v/v)乙醇,在85℃的温度下进行3小时的回流提取后,在50℃的温度下对过滤液进行减压浓缩,干燥后得到11.7g的益智仁提取物。
实施例2.在通过MIA(monosodium iodoacetate)诱导的骨关节炎动物模型中确认益智仁提取物给体重负荷带来的效果
为了对上述实施例1中制备的益智仁提取物对在通过MIA诱导的骨关节炎动物模型中的体重负荷带来的效果进行确认,在将诱发骨关节炎的MIA(使用0.9%的生理盐水(saline)稀释为60mg/ml的浓度)向7周龄的SD大鼠的右后腿关节腔内给药50μl来诱导骨关节炎后,以一日一次的频率口服给药益智仁提取物(150mg/kg以及300mg/kg)21日,间隔7日进行一次体重负荷率的测定。使用吲哚美辛(indomethacin,1mg/kg)作为阳性对照组。
后腿的体重负荷率使用双足平衡测痛仪(Incapacitance tester,Lintoninstrument Co.,UK,Ser No.01/45/25)进行测定。在测痛仪的夹具内,诱发了骨关节炎的大鼠由于疼痛而依靠未给药MIA的正常的腿来站立,两只足的重量由于失去平衡,相对于正常的足,测得给药MIA的足的重量相对小。在对足的重量进行测定时,在未使SD大鼠的腹部贴合于设备的传感器的状态下各对两足的重量(g)进行测定,利用上述测定的足的重量,通过下列式1的方法来计算体重负荷率(%)。上述体重负荷为以足支撑的压力,在正常情况下,两侧足的重量均衡,一只足的重量负荷率显出50%,而诱发骨关节炎的疼痛越严重,诱发骨关节炎的后腿的体重负荷率(%)越低。
式1
体重负荷率(%)=[诱发骨关节炎的后腿重量/(两侧后腿的重量)]×100
其结果如图1所示,确认相比于正常SD大鼠的组,给药MIA诱发骨关节炎的组的体重负荷率(%)随时间的进程减少约一半。与此相反,使用MIA和益智仁提取物并行给药的组相比于MIA给药组减少的体重负荷率(%)有所增加,在给药益智仁提取物的第21日,给药150mg/kg浓度和300mg/kg浓度的益智仁提取物的组与所差浓度无关的相比于给药MIA的组,体重负荷率(%)都有所增加。
实施例3.在通过MIA(monosodium iodoacetate)诱发骨关节炎的动物模型中确认益智仁提取物对炎症诱发因子以及软骨退行性变诱发因子带来的效果
在诱发骨关节炎的关节中提取mRNA,通过PCR确认炎症诱发因子(白细胞介素1β、白细胞介素6、肿瘤坏死因子α以及环氧化酶2)以及软骨退行性变诱发因子(基质金属蛋白酶9)的表达。
其结果如图2所示,在通过MIA诱发骨关节炎的样品中确认了炎症诱发因子以及软骨退行性变诱发因子的表达增加,与此相反地,使用益智仁提取物进行并行处理时,增加的因子的表达减少了。由此可知益智仁提取物可以抑制因骨关节炎诱发的炎症以及关节软骨的损伤。
实施例4.在通过MIA(monosodium iodoacetate)诱发骨关节炎的动物模型中确认益智仁提取物引起的组织病理学变化
截断诱发骨关节炎的大鼠的膝关节部位,将其放入包含10%的乙二胺四乙酸(EDTA)的10%的福尔马林溶液中,对关节组织进行去钙化。之后将关节组织放入石蜡中进行固定后实施冠状面切片(coronal section),将石蜡固定的组织切片为7μm大小,之后实施H&E(苏木素-伊红,hematoxylin andeosin)染色法以及番红O(Safranin-O)染色来确认组织状态。通过H&E染色对有无炎症反应以及滑膜细胞的增生、炎症细胞的组织浸润与否进行确认,通过对作为软骨主要成分的蛋白聚糖(proteoglycan)层进行染色的番红O染色来确认软骨组织的损伤与否。
其结果如图3所示,在H&E染色中,正常组(SD rat:Normal)的关节滑膜组织位于正常的位置,而通过MIA诱发骨关节炎的组(Control(MIA))由于滑膜细胞过度渗透到关节周边,显出因浸润关节和骨组织而导致的滑膜组织的损失,而给药益智仁提取物时可以确认这种对关节和骨组织的浸润相对减少。
并且,进行番红O染色的结果如图4所示,诱发骨关节炎的组(Control(MIA))中本应染成红色的正常软骨组织由于通过MIA的破坏而导致蛋白聚糖组织消失,与此相反地,使用益智仁提取物进行并行处理时,染成红色的蛋白聚糖组织在滑膜周边分布有很多。由此确认通过益智仁提取物能够抑制MIA诱发的骨关节炎。
Claims (7)
1.一种用于预防或改善骨关节炎的保健食品组合物,其特征在于,含有益智仁提取物作为有效成分。
2.根据权利要求1所述的用于预防或改善骨关节炎的保健食品组合物,其特征在于,上述益智仁提取物通过使用C1~C4的低级醇、水或它们的混合物作为溶剂来提取。
3.根据权利要求1所述的用于预防或改善骨关节炎的保健食品组合物,其特征在于,上述保健食品组合物制备成选自由粉末、颗粒、丸、片剂、胶囊、糖衣、糖浆以及饮料组成的组中的一种剂型。
4.一种用于预防或治疗骨关节炎的药学组合物,其特征在于,含有益智仁提取物作为有效成分。
5.根据权利要求4所述的用于预防或治疗骨关节炎的药学组合物,其特征在于,上述药学组合物减少作为炎症因子的白细胞介素1β、白细胞介素6、肿瘤坏死因子α以及环氧化酶2的表达和作为软骨退行性变诱发因子的基质金属蛋白酶9的表达。
6.根据权利要求4所述的用于预防或治疗骨关节炎的药学组合物,其特征在于,上述药学组合物制备成选自由胶囊剂、散剂、颗粒剂、片剂以及丸剂组成的组中的一种剂型。
7.根据权利要求4所述的用于预防或治疗骨关节炎的药学组合物,其特征在于,上述药学组合物除了有效成分之外还包含药学上可接受的载体、赋形剂或稀释剂。
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WO2019054758A1 (ko) | 2019-03-21 |
US20200268827A1 (en) | 2020-08-27 |
JP2020533012A (ja) | 2020-11-19 |
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