CN105327115A - 一种防治ⅱ型糖尿病桑黄通泻配方及制备工艺 - Google Patents
一种防治ⅱ型糖尿病桑黄通泻配方及制备工艺 Download PDFInfo
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Abstract
本发明涉及一种防治Ⅱ型糖尿病桑黄通泻配方及制备工艺,属于中药防治Ⅱ型糖尿病技术领域。技术方案是各组分的重量百分比:桑白皮20-30%、黄连20-30%、厚朴10-20%、葛根5-10%、黄芪5-10%、山萸肉5-10%、莱菔子5-10%、知母5-10%、玉竹5-10%、苍术5-10%。本发明各药物相互配合,取长补短,协同作用,诸药合用,标本兼治,增强疗效;其降糖作用与二甲双胍效果相当,与西药相比没有毒副作用;能使Ⅱ型糖尿病患者空腹血糖和餐后2小时血糖降低,而且维持时间较长,同时也使高血脂者胆固醇和甘油三酯降低,疗效显著,产品有效成分含量高,稳定,不易变质,有利于长期保存。
Description
技术领域
本发明涉及一种防治Ⅱ型糖尿病桑黄通泻配方及制备工艺,属于中药防治Ⅱ型糖尿病技术领域。
背景技术
糖尿病是一组由于胰岛素分泌和(或)作用缺陷所引起的以慢性高血糖为特征的代谢性疾病。国际糖尿病联盟(IDF)于2013年11月14日——联合国糖尿病日公布第六版《国际糖尿病联盟糖尿病地图》显示,2013年全球约有3.82亿成年人患有糖尿病,约510万人死亡,平均每6秒钟就有1人死于糖尿病,并预计到2035年,该病患者人数会上升至5.92亿。中国的糖尿病患者人数居各国之首,宁光教授等完成的中国成人糖尿病流行与控制现状研究表明,2010年中国18岁及以上成人糖尿病患病率达11.6%(约1.139亿糖尿病患者),糖尿病前期率为50.1%(约4.934亿糖尿病前期人群)。其中,Ⅱ型糖尿病(T2DM)占糖尿病总人数的90%~95%,是一种受遗传和环境影响的多因素内分泌疾病,可引起眼、肾、神经、心脏、血管等组织器官慢性进行性病变、功能减退及衰竭,已经成为危害人类健康的主要疾病。迫于严峻的流行形势,世界各国及国际组织对T2DM的研究均给予高度关注。
T2DM发病机制非常复杂,针对Ⅱ型糖尿病发病机制,西药主要治疗靶向有以下几个方面:胰岛素分泌缺陷、胰岛素抵抗、肝糖输出过高及抑制糖的吸收、增加糖的排泄。常用药如:磺脲类药物;噻唑烷二酮类;双胍类药物;α-葡萄糖苷酶抑制剂;各种类型的胰岛素;氯回苯酸类药物。最近,新问世的西药有:二肽基肽酶-Ⅳ(DPP-Ⅳ)抑制剂、胰高血糖素样肽-1(GLP-1)类似物和肾钠-葡萄糖共转运蛋白-2(SGLT-2)抑制剂等。尽管西药针对不同的患病机制,其作用靶点比较清楚,效应较强。但是,Ⅱ型糖尿病患者是一个有机联系的整体,糖尿病患者机体的许多代谢环节同时存在失调,单纯作用于某一靶点药物难以发挥最佳治疗效果,带来副作用也相对明显,原发性失效、继发性失效问题也较严重。如果我们在Ⅱ型糖尿病早期就应用具有整体调节及多靶点治疗药物,势必提高治疗效果、控制病情发展及减少并发症的发生。因此,研究整体调节、多靶点治疗及副作用低的中药药物已成为Ⅱ型糖尿病药物研究的一个方向。
糖尿病属于中医的消渴、消瘅病证范畴。近年来,改善糖尿病的中药研究受到广泛的关注,已有越来越多的关于中药复方、单味中药及中药活性成分防治Ⅱ型糖尿病的报道:
目前市场上治疗糖尿病的药物繁多,经检索,中国专利和中国期刊公开了以下治疗糖尿病有关的中药制剂的报道,现摘录如下:
l、中国专利<申请号>00108421<发明名称>一种治疗糖尿病的药物及其制备方法<申请人>韩万明刘萍,山西省阳泉市李家庄第一人民医院分院<文摘>本发明公开了一种新的治疗糖尿病的药物,它是以生黄芪、生地、丹参、生山药、荔枝核、元参、苍术、枸杞子、乌梅、玉米须、五味子、天花粉、瓜蒂、肉桂、蚕蛹、鬼箭羽,海蛤壳、鸡内金、葛根、桑叶、黄精为原料,根据每味中药的不同特性分别经过冻干、晒干、煅烧、除尘、粉碎,按比例配制,再经熟化,灭菌后制成散剂。本发明是在搜集了上百个民间治疗糖尿病的秘方上,再根据几代人潜心钻研,临床治疗经验所得,配方独特,治疗效果显著。
2、中国专利<申请号>99120424<发明名称>一种治疗糖尿病的药物及其制备方法<申请人>邵玉君<文摘>本发明公开了一种治疗糖尿病的中成药及其制备方法,这种中成药将松花粉、鸡内金、黄芪、太子参、黄柏、玉米须、知母、地黄、黄精、桑白皮、山药、荔枝核、丹参、山茱萸、大黄和五味子16味中药料,根据其有效成分和理化性质分为四组,分别采用水煎、水煎醇沉、乙醇提取和粉碎后直接入药的工艺,制备成胶囊,治疗糖尿病,疗效既显著,又无任何毒副作用。
3、桑白皮不同部位对实验性高脂糖尿病小鼠的影响,张静,高英,罗娇艳,荣向路,张娟,李艳,李卫民;广州中医药大学中药学院,广州中医药大学国家中医药管理局调肝降脂重点实验室;刊名中药新药与临床药理.2014,25(2):159-164.目的:建立实验性高脂糖尿病小鼠模型,分析桑白皮不同部位对其糖、脂质代谢以及股骨的影响。结果:与正常对照组比较,模型组的血糖、血脂指标明显升高(P<0.01);与模型组比较,桑白皮总黄酮(MTF)组、桑白皮总生物碱(MTA)组均能明显控制高脂饲料喂养的小鼠体质量(P<0.05,P<0.01),其中MTF组能显著降低糖尿病小鼠FBG,TC,TG,LDL-C水平(P<0.05,P<0.01);MTA组能明显降低小鼠FBG、TC、TG水平(P<0.05);桑白皮总多糖(MTP)组能明显抑制糖尿病小鼠TC、TG水平(P<0.05);MTF组和MTA组均能明显降低糖尿病小鼠尿酸(UA)和总胆红素(TBIL)水平(P<0.05)。病理切片表明正常对照组小鼠股骨未见异常;模型组小鼠股骨有不同程度的变形并且伴有骨密度的改变;MTF组小鼠6例中有3例不同程度病变。结论:桑白皮各部位均具有一定的降糖作用,其中MTF对糖尿病小鼠的各项指标改善最为显著,同时对糖尿病导致的骨质疏松以及股骨头病变有抑制作用;其次是MTA,对FBG、TC、TG指标的改善作用也非常明显,MTP对指标的改善作用没有MTF和MTA显著,主要改善小鼠TG、TC水平。而桑白皮药材提取物(ME)组对小鼠的各项指标均无明显影响,可能与给药剂量和提取方法有关。
4、桑白皮水煎液及化学拆分组分降糖作用研究;郑晓珂,袁培培,克迎迎,王绅,高爱社,赫金丽,曹彦刚,张娜,李玲玲,牛艳,冯卫生;河南中医学院药学院;刊名世界科学技术-中医药现代化.2014,16(9):1957-1967.目的:研究桑白皮水煎液及各化学拆分组分对糖尿病小鼠模型的降糖作用。结果:桑白皮水煎液高剂量组能增加Ⅰ型糖尿病小鼠体质量,明显降低饮水量、饮食量,并能不同程度地降低FBG、TC、TG、LDL-c水平(P<0.05或P<0.01),升高C肽、HDL-c水平(P<0.05或P<0.01)。桑白皮30%乙醇组分及脂肪油组分给药量约为桑白皮水煎液的1/2和1/4时,均能显著改善糖尿病小鼠糖脂紊乱状况,修复肝脏细胞,改善肝脏组织损伤,且作用优于桑白皮水煎液。结论:桑白皮水煎液具有较好的降糖作用,其有效部位为30%乙醇组分和脂肪油组分,降糖作用机制可能与促进胰岛素分泌、调节血脂紊乱,保护肝脏结构和功能有关。
5、黄连素治疗Ⅱ型糖尿病的疗效分析;米米尔艾合买提江·艾买提,艾尔肯·乌布力;新疆喀什疏附县托克扎克镇卫生院;刊名糖尿病新世界.2015.目的:观察临床中采用黄连素对2型糖尿病患者血糖水平的影响,分析并探讨应用此治疗方法治疗2型糖尿病的安全性和可行性。结果:研究组的降糖效果要好于空白对照组(P<0.05);研究组和黄金对照组治疗后患者餐后血糖均明显下降(P<0.05),但两组间降糖效果比较差异无统计学意义(P>0.05)。结论:采用黄连素治疗Ⅱ型糖尿病患者具有较好的疗效和可行性,在各医院应该得到推广和应用。
6、黄连相关中药复方治疗糖尿病及其并发症的临床观察;黄莉文,麦熙,何淑云;广州医学院羊城医院;刊名中国医药指南.2014,10(20):205.目的:对黄连相关中药复方治疗糖尿病及其并发症的临床效果进行评价分析,为今后的临床治疗工作提供可靠的参考依据。结果:观察组患者治疗有效率较对照组发生显著升高(P<0.05),治疗后观察组患者空腹血糖水平、餐后2h血糖水平均较对照组发生明显降低(P<0.05)。结论:经黄连相关中药复方与降糖药物联合可使糖尿病患者的临床疗效得到改善,对血糖的调节具有一定的促进作用,值得关注。
7、厚朴酚对2型糖尿病大鼠血糖的影响;孙长颢,宁华,那立欣,李颖,李松涛,牛玉存;哈尔滨医科大学公共卫生学院营养与食品卫生学教研室;刊名卫生研究.2014,43(2):313-316.目的:研究厚朴酚对2型糖尿病大鼠血糖的影响。结果:干预3周后,OGTT实验中,与模型组相比,厚朴酚组大鼠血糖在30和120min时间点显著低于糖尿病模型组;ITT实验中,厚朴酚组大鼠对胰岛素敏感性在15、30和45min时显著高于模型组。干预4周后,与模型组相比,厚朴酚组大鼠空腹血糖显著下降,血清和胰腺胰岛素水平显著升高。胰岛形态学改变改善。结论:厚朴酚可能通过改善胰岛素抵抗和保护胰岛β细胞而控制血糖,延缓2型糖尿病发展。
8、葛根素注射液治疗糖尿病周围神经病变的Meta分析,作者赵勇、徐文华,湖北中医药大学湖北省中医院,刊名:中成药.2014,36(12):2657~2661,目的:运用Meta分析评价葛根素注射液治疗糖尿病周围神经病变的疗效及安全性。结果:纳入本研究共14篇文献,Meta分析结果表明葛根素注射液治疗糖尿病周围神经病变的总有效率、腓总及正中神经传导速度改善均优于对照组,7例出现不良反应。结论:葛根素注射液治疗糖尿病周围神经病变有效,尚需高质量、大样本、多中心的随机对照双盲研究进一步证实。
9.葛根总黄酮纳米混悬液的制备及其降血糖作用研究,作者傅前霞、周群、王治平、樊化,湖北省荆州市公安卫校。刊名:时珍国医国药.2014,25(11):2664~2666.目的:制备葛根总黄酮(PF)纳米混悬液(NS-PF),并考察其降血糖作用。结果:制备的NS-PF的粒径、多分散指数及Zeta电位分别为(158.18±3.16)nm、(0.383±0.013)、-(29.76±3.81)mV。PF、NS-PF及二甲双胍给药组对正常小鼠无明显急性降糖作用,对糖尿病小鼠体重也无影响,NS-PF组对糖尿病小鼠的随机血糖和空腹血糖均具有明显降低效果,并对其糖耐量有一定改善作用,整体降糖效果显著优于PF(P<0.01)。结论:葛根总黄酮纳米混悬液能显著提高葛根总黄酮降低血糖作用。
10、黄芪黄酮与葛根黄酮配伍对肝脏糖脂代谢的影响;李艳敏,范颖,刘烨,郝明芬,李新,刘丽,訾慧,李军;辽宁中医药大学辽宁中医药大学,省部共建中医脏象理论及应用教育部重点实验室;刊名中国实验方剂学杂志.2015,21(10):109-112.目的:明确黄芪黄酮与葛根黄酮配伍对糖尿病大鼠糖脂代谢的影响。结果:与正常组比较,模型组大鼠血糖、血清胆固醇(CHO),油三酯(triglyceride,TG)均升高(P<0.05),肝组织胰岛素(insulin,INS),葡萄糖转运体4(glucosetransporter4,GLUT4),脂联素(adiponectin,ADPN)及瘦素(leptin,LEP)浓度均下降(P<0.05)。与模型组比较,黄芪黄酮组糖尿病大鼠血糖水平明显降低(P<0.05),葛根黄酮组变化不明显,二药合用未呈现协同作用;黄芪黄酮组、葛根黄酮组CHO,TG含量均明显降低,但合用效果不如单味药;黄芪黄酮、葛根黄酮均能明显升高肝脏GLUT4水平(P<0.05);二药对肝脏INS,GLUT4及LEP的影响,合用比单味药效果好,二药存在协同作用。结论:黄芪黄酮与葛根黄酮配伍能够协同调节INS,GLUT4及LEP水平而实现改善糖尿病糖脂代谢紊乱的作用。
11、黄芪消渴汤治疗糖尿病肾病的临床疗效;王宪华;河北省邢台市临西县中医院;刊名中国药物经济学.2015,5:61-63.目的:探讨黄芪消渴汤治疗糖尿病肾病的临床疗效结果:经治疗后,观察组患者治疗总有效率为92.5%,明显高于对照组的77.5%(P<0.05);观察组患者的尿蛋白排泄量和血肌酐均优于对照组(均P<0.05)。结论:黄芪消渴汤治疗糖尿病肾病可明显降低患者尿蛋白排泄量,延缓糖尿病肾病进程,疗效确切。
12、山茱萸提取物对糖尿病小鼠降血糖作用的研究;许继艳,胡哲,高燕,张丽娟;包头医学院职业技术学院,包钢第三职工医院;刊名时珍国医国药.2014,25(10):2386-2388.目的:研究山茱萸提取物环烯醚萜总苷对糖尿病小鼠血糖的影响。结果:环烯醚萜总苷给药组小鼠,低剂量组降血糖作用不显著,中、高剂量组较为显著(P<0.05)。给药停止后30、60天,中、高剂量组的血糖值及糖化血清蛋白(GSP)、糖化血红蛋白(HBA1C)较刚停药时没有显著差异,优降糖组血糖值及GSP、HBA1C有显著回升(P<0.01)。结论:环烯醚萜总苷低、中、高剂量组的降血糖作用均不及优降糖组显著,但是中高剂量组血糖维持效果较优降糖组显著。
13、Ⅱ型糖尿病胰岛素抵抗的中医药研究;毛建芳,孙丰雷;山东中医药大学;刊名吉林中医药.2012,32(2):149-150.Ⅱ型糖尿病胰岛抵抗是以脾虚为本,痰浊瘀血为标。湿热内蕴型、阴虚热盛型、气阴两虚型与阴阳两虚型均存在胰岛素抵抗异常,以阴阳两虚型和湿热内蕴型最明显。参芪复方制剂具有改善胰岛素抵抗作用,上调骨骼肌GLUT4蛋白水平可能为其机制之一。研究发现有降糖作用的中药达70余种,常用的中药如人参、黄芪、生地黄、黄精、玉竹、天花粉、知母、黄连、大黄、金银花、薏苡仁、葛根、苍术、鱼腥草等,及其有效成分如多糖、皂苷、生物碱、黄酮等均有改善胰岛素抵抗的作用。
14、茅苍术多糖对Ⅱ型糖尿病大鼠的治疗作用及机制研究;牛月华;北华大学校医院;刊名北华大学学报(自然科学版).2014,15(4):476-479.目的:探讨茅苍术多糖对Ⅱ型糖尿病大鼠的治疗作用及机制。结果:茅苍术多糖可以改善糖尿病大鼠体质量下降情况,能够降低空腹血糖含量,提升胰岛素水平;茅苍术多糖也可以降低MDA含量,增加CAT和SOD活性。结论:茅苍术多糖具有抗糖尿病作用,其作用机制可能与其抗氧化作用有关。
背景技术存在的问题是:改善糖尿病患者糖、脂代谢和延缓糖尿病并发症方面效果不理想,药物保存、携带、服用不方便。
发明内容
本发明目的是提供一种防治Ⅱ型糖尿病桑黄通泻配方及制备工艺,改善糖尿病患者糖、脂代谢和延缓糖尿病并发症,保存、携带、服用方便,具有良好的降糖、调脂效果,解决背景技术中存在的上述问题。
本发明的技术方案是:
一种防治Ⅱ型糖尿病桑黄通泻配方,各组分的重量百分比:桑白皮20-30%、黄连20-30%、厚朴10-20%、葛根5-10%、黄芪5-10%、山萸肉5-10%、莱菔子5-10%、知母5-10%、玉竹5-10%、苍术5-10%。
功效:清胃泻肺、理气化浊、补脾益肾;
应用:主要用于Ⅱ型糖尿病高血糖、高血脂症;
用法:每天3次,每次5-10g。于每餐前10-15分钟温开水送服。
一种防治Ⅱ型糖尿病桑黄通泻配方的制备工艺,包含如下工艺步骤:
①分别将桑白皮20-30%、黄连20-30%、厚朴10-20%、葛根5-10%、黄芪5-10%、山萸肉5-10%、莱菔子5-10%、知母5-10%、玉竹5-10%、苍术5-10%;粉碎备用,上述百分比为重量百分比;
②按正交试验表,采用四因素三水平进行正交试验,以确定最佳提取方法;即:乙醇浓度、溶剂与药材用量比、提取时间、提取次数四个因素;考虑到桑白皮含多糖、桑辛素,黄连中生物碱,山茱萸含有效成分熊果酸等成分,用不同浓度的乙醇回流提取,合并乙醇液,浓缩干燥;干燥提取物粉碎即得本发明产品。
所述四因素三水平正交试验,见表1:正交试验因素水平表。
本发明提取的是有效成分,然后将有效成分与赋形剂一起制成丸剂、颗粒剂、胶囊等剂型,包装为每袋2g。
本发明所用中药材的功效及其在处方中的作用阐述如下:
桑白皮:泻肺平喘,利水消肿。用于肺热喘咳,水肿胀满尿少,面目肌肤浮肿。其提取物改善链脲佐菌素致糖尿病大鼠胰岛素抵抗,乙醇提取液能明显抑制猪小肠蔗糖酶活性,从而使葡萄糖生成减少,而阻碍肠道内壁细胞对葡萄糖吸收的机制可产生降血糖作用。
黄连:清热燥湿,泻火解毒。用于湿热痞满,呕吐吞酸,泻痢,黄疸,高热神昏,心火亢盛,心烦不寐,血热吐衄,目赤,牙痛,消渴,痈肿疔疮;外治湿疹,湿疮,耳道流脓。酒黄连善清上焦火热。用于目赤,口疮。姜黄连清胃和胃止呕。用于寒热互结,湿热中阻,痞满呕吐。萸黄连舒肝和胃止呕。用于肝胃不和,呕吐吞酸。黄连及其有效成分生物碱对于改善糖尿病及其并发症的各种症状具有明显效果,其主要成分小檗碱治疗糖尿病可改善葡萄糖代谢、可抗炎改善胰岛素抵抗、可抗氧化,清除自由基及改善脂质代谢。
厚朴:燥湿消痰,下气除满。用于湿滞伤中,脘痞吐泻,食积气滞,腹胀便秘,痰饮喘咳。其中厚朴酚对过氧、超氧自由基有清除作用,对PTP1B酶活具有较强的抑制作用、增加胰岛素受体IRβ的酪氨酸磷酸化水平、增加胰岛素信号通路下游分子ERK1/2的酪氨酸磷酸化水平,明显降低STZ诱导的Ⅱ型糖尿病小鼠血糖,与黄连配伍具有明显增效作用。
葛根:口渴、消渴、麻疹不透、热痢、泄泻。其中的主要成分葛根素可治疗糖尿病,改善脑循环、周围血管及微循环,抑制糖基化对脑组织及神经细胞具有保护作用。
黄芪:有补气固表,利尿托毒之功效,用于气虚乏力,表虚自汗,内热消渴,糖尿病。
山茱萸:有补益肝肾,涩精固脱的功效。用于眩晕耳鸣、腰膝酸痛、阳痿遗精、遗尿尿频、崩漏带下、大汗虚脱、内热消渴。温肝补肾,除一切风,止月经过多。
莱菔子:消食除胀,降气化痰。用于饮食停滞,脘腹胀痛,大便秘结,积滞泻痢,痰壅喘咳。
知母:清热泻火,生津润燥。用于外感热病,高热烦渴,肺热燥咳,骨蒸潮热,内热消渴,肠燥便秘。知母聚糖A、B、C、D有降血糖作用,其中B的活性最强。
玉竹:养阴润燥,生津止渴。用于肺胃阴伤,燥热咳嗽,咽干口渴,内热消渴。
苍术:燥湿健脾,祛风散寒,明目。用于脘腹胀满,泄泻,水肿,脚气痿躄,风湿痹痛,风寒感冒,夜盲。
通过实验发现本发明桑黄通泻配方显著降低T2DM大鼠的FBG、TG、TC、LDL-C和FFA的水平,提高血清HLDL-C的水平,可显著降低大鼠血清MDA的含量,明显升高血清SOD的活性。上述实验结果说明桑黄通泻配方可改善糖尿病大鼠糖、脂代谢,抑制氧化应激反应,对Ⅱ型糖尿病大鼠具有良好的药理效应,为桑黄通泻配方的临床推广提供了实验依据。
本发明与已有技术相比,具有突出的实质性特点和显著性进步:
l、本发明根据历代医家对消渴病机的认识并结合临床研究发现,Ⅱ型糖尿病病机特点为肺胃热盛,摄纳太过,脾、肾亏虚,浊气不化。中医药理论指导下,确立清胃泻肺、理气化浊、醒脾益肾的治疗法则,并根据现代药理研究成果优选上述中药,加以科学配伍、制作,使各药物相互配合,取长补短,协同作用,诸药合用,标本兼治,增强疗效;
2、本发明所用原料多为药食同源植物药材,毒性小,克服了其它降糖药物特别是西药的毒副作用的缺点。按日剂量和疗程使用本发明产品是安全的。本产品与二甲双胍进行比较,其降糖作用与二甲双胍效果相当,与西药相比没有毒副作用;
3、经动物实验和临床验证本发明产品能使Ⅱ型糖尿病患者空腹血糖和餐后2小时血糖降低,而且维持时间较长,同时也使高血脂者胆固醇和甘油三酯降低,疗效显著;
4、组方科学,原料易得,生成工艺先进,简便易行,可操作性强,产品价格适中,适合工业化制备;
5、制备过程中根据各中药的有效成份、性质及制剂要求,采用醇提与水提法、物理灭菌方法,因而产品有效成分含量高,稳定,不易变质,有利于长期保存。
附图说明
图1是本发明实施例黄连的鉴别;
图中:1、盐酸小檗碱对照品,2、双益方样品,3、阴性对照;
阴性对照中不显示盐酸小檗碱的斑点,此方法鉴别了双益方中黄连中药材;
图2是高效液相色谱法测定盐酸小檗碱的含量(盐酸小檗碱标准品);
图3是本发明采用高效液相色谱法测定桑黄通泻配方中盐酸小檗碱的含量。
具体实施方式
以下结合附图,通过实例对本发明作进一步说明。
一种防治Ⅱ型糖尿病桑黄通泻配方,各组分的重量百分比:桑白皮20-30%、黄连20-30%、厚朴10-20%、葛根5-10%、黄芪5-10%、山萸肉5-10%、莱菔子5-10%、知母5-10%、玉竹5-10%、苍术5-10%。
功效:清胃泻肺、理气化浊、补脾益肾;
应用:主要用于Ⅱ型糖尿病高血糖、高血脂症;
用法:每天3次,每次5-10g。于每餐前10-15分钟温开水送服。
一种防治Ⅱ型糖尿病桑黄通泻配方的制备工艺,包含如下工艺步骤:
①分别将桑白皮20-30%、黄连20-30%、厚朴10-20%、葛根5-10%、黄芪5-10%、山萸肉5-10%、莱菔子5-10%、知母5-10%、玉竹5-10%、苍术5-10%;粉碎备用,上述百分比为重量百分比;
②按正交试验表,采用四因素三水平进行正交试验,以确定最佳提取方法;即:乙醇浓度、溶剂与药材用量比、提取时间、提取次数四个因素;考虑到桑白皮含多糖、桑辛素,黄连中生物碱,山茱萸含有效成分熊果酸等成分,用不同浓度的乙醇回流提取,合并乙醇液,浓缩干燥;干燥提取物粉碎即得本发明产品。
所述四因素三水平正交试验,见表1:正交试验因素水平表。
结果与数据:
参照附图1,黄连的鉴别:桑黄通泻配方样品0.5g,加入甲醇5ml,振荡提取0.5h过滤,得双益方共试品溶液。以盐酸小檗碱为对照品薄层展开,展开剂为乙酸乙酯-甲醇-水-醋酸(8:3:3:2)。
阴性对照中不显示盐酸小檗碱的斑点,此方法鉴别了双益方中黄连中药材。
盐酸小檗碱的含量测定
采用高效液相色谱法测定桑黄通泻配方中盐酸小檗碱的含量,从而监测提取过程中有效成分的提取率。色谱条件为:流动相-乙腈:0.05mol磷酸二氢钾(22:78)检测波长为350nm。得到盐酸小檗碱的标准曲线方程为A=100.15C-115.67,R=0.9992。
盐酸小檗碱标准品,参照附图2。
本发明桑黄通泻配方盐酸小檗碱样品,参照附图3。
盐酸小檗碱加样回收率,见表3,
提取工艺的确定:
黄连、桑白皮、山茱萸、粉碎后,加6倍量的30%乙醇提取2小时,共提取2次。即最优组合A2B1C3D2。
由此,确定本方提取工艺为:将黄连、桑白皮、厚朴、黄芪、山茱萸、葛根、莱菔子、知母、玉竹、苍术粉碎,过60目筛,加6倍量30%乙醇浸泡0.5h,加热回流提取2次,每次2小时,滤过。滤液回收乙醇,干燥浸膏,粉碎,出粉率为20%,粉碎成细粉作为活性成分;然后将上述活性成分与赋形剂一起制成丸剂、颗粒剂、胶囊等剂型,包装为每袋2g。
本发明的动物实验报告:
近年来,随着社会环境、生活方式等改变,Ⅱ型糖尿病发病率和患病人数快速增长,已经成为人类最常见的内科疾病之一。T2DM属于中医“消渴”、“肥胖”等范畴,根据历代医家对消渴病机的认识并结合临床研究发现,消渴病多与肺胃热盛,摄纳太过,脾、肾亏虚,浊气不化有关。故此,本研究以清胃泻肺、理气化浊、补益脾肾为法,结合中医药治疗糖尿病的现代研究经验自拟桑黄通泻配方。本实验观察其对Ⅱ型糖尿病大鼠血糖、血脂及SOD、MDA、FFA的影响,为临床应用提供实验依据。
1材料
1.1实验动物雄性SD大鼠60只(体重240±25g),购自北京华阜康生生物科技股份有限公司,动物合格证号:SCXK(京)2009-0001,于华北理工大学实验动物中心屏障环境动物实验室喂养和实验。
1.2药物桑黄通泻配方由桑白皮、黄连、厚朴、山茱萸等中药组成,购自河北唐山市北京同仁堂药店,于华北理工大学中医学院实验室按设计工艺提取,出膏率约为22%。二甲双胍片:上海中美施宝有限公司,批号1005023,使用时将药片用纯净水溶解成浓度为7.14mg·ml-1的溶液。
1.3试剂链脲佐菌素(STZ):美国Sigma公司,批号B56981;柠檬酸三钠:北京市博爱科贸有限责任公司;柠檬酸:北京市博爱科贸有限责任公司;丙二醛(MDA)试剂盒,批号:20101227,超氧化物歧化酶(SOD)试剂盒,批号:20101228,均购自南京建成生物工程研究所。游离脂肪酸(FFA)酶联免疫检测试剂盒:美国RD公司进口分装。
1.4仪器酶标仪:美国,型号CA94089,AGM-2300型血糖仪:韩国糖博士公司,数显恒温水浴锅:国华电器有限公司;AnkeTGL-16G高速离心机:上海安亭科学仪器厂。
2方法
2.1T2DM大鼠模型建立与分组60只健康SD大鼠适应性喂养1周,随机抽取10只大鼠为N组,喂以基础饲料,其余50只大鼠喂以高脂饲料(脂肪41%、蛋白17%、碳水化合物42%),自由进食饮水。4周后,大鼠禁食8h,喂高脂饲料组大鼠按25mg/kg一次性尾注射2%STZ溶液(临用前用柠檬酸-柠檬酸钠缓冲液配制),N组注射相当剂量的柠檬酸缓冲液。5天后从大鼠尾部取血测定空腹血糖,血糖≥11.1mmol/L的为成模大鼠[2]共40只,分为M组、Met组、SL、SH组各10只。
2.2给药方案造模成功后次日给药,Met组给药剂量为0.14g/(kg·d),SL、SH组给药量分别为1.8、7.2g/kg(按人等效剂量的5、20倍生药量计算)。药物用纯净水配成不同浓度的混悬液灌胃(给药容量均为每100g体重1ml)。每周为大鼠称量体重1次,以调整用药量。N组和M组以等量纯净水灌胃。共4周。
2.3标本收集4周后,所有大鼠禁食(不禁水)8h后,用10%水合氯醛腹腔注射麻醉,抽取腹主动脉血液约6-8ml注入一次性采血管中,2000转/分,离心10min,无菌吸取上层血清,分装于1.5mlEP管中,一部分血清送华北理工大学附属医院检验科检测TG、TC、HDL-C和LDL-C;剩余血清在-20℃条件中储存,待测MDA、SOD和FFA。
2.4指标检测方法
2.4.1空腹血糖检测:各组大鼠于给药前、给药后2周和4周,空腹8h后断尾采血,用快速糖测试仪测定血糖。
2.4.2血脂检测甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)于华北理工大学附属医院检验科进行检测。
2.4.3血清SOD、MDA、FFA检测用黄嘌呤氧化酶法检测血清中SOD活性;用硫代巴比妥酸法检测血清中MDA含量;用酶联免疫法检测血清中FFA含量。(具体检测方法参照试剂说明进行)
2.4.4统计学方法实验数据以均数±标准差表示,用SPSS13.0进行统计分析,组间比较采用t检验,多个样本均数比较,采用单项方差分析(One-WayANOVA),以P<0.05为差异有统计学意义。
3结果
3.1桑黄通泻配方对Ⅱ型糖尿病大鼠空腹血糖的影响
与N组比较,成模大鼠FBG水平显著升高(P<0.01),说明糖尿病模型制备成功;与DM对照组比较,给药后2周、4周Met组、SL组、SH组大鼠FBG水平显著减低(P<0.01),结果表明桑黄通泻配方具有降低FBG的作用。(结果见表4)
3.2桑黄通泻配方对Ⅱ型糖尿病大鼠血脂代谢的影响
与N组比较,DM组各项血脂指标除了HDL-C降低外,其余指标均显著增高(P<0.01),Met组、SL组、SH组与DM组比较,TG、TC、LDL-C三项指标显著降低(P<0.05),尤以SL组突出;SH组的HDL-C的增量较其他组更明显。(结果见表5)
3.3大鼠血清FFA、SOD活性和MDA含量的变化
与N组比较,DM组血清中SOD的活性明显下降(P<0.01),而FFA、MDA的含量明显增加(P<0.01)。与DM组比较,Met组、SL、SH组SOD水平显著升高(P<0.01或P<0.05),Met组、SH组MDA水平显著降低(P<0.01);与DM模型组比较,Met、SL、SH组的FFA显著降低(P<0.01或P<0.05)。(结果见表6)
4讨论
历代医家非常重视肥美饮食及脾肾二脏虚弱在消渴发病中的作用。如《素问·奇病论》曰:“脾瘅,此肥美之所发也,此人必数食甘美而多肥也,肥者令人内热,甘者令人中满,故其气上溢,转为消渴。”《灵枢·本脏》曰:“脾脆,则善病消瘅易伤。”这些《内经》中的记载不仅提出了过食肥美湿浊内热是发病的主要病理环节,而且明确了脾虚易为湿浊所困为消渴病的发病基础。另外,《外台秘要·消渴消中门》云:“房室过度,致令肾气虚耗故也,下焦生热,热则肾燥,肾燥则渴。”《医贯》又云:“下焦命门火不归元,游于肺则为上消,游于胃则为中消。”这些论述则说明肾亏虚也是导致消渴之本,肺胃有热则是消渴之标。桑黄通泻配方急则治标,以桑白皮、黄连为君,清肺泻胃,厚朴、莱菔子理气泻浊;葛根、知母、玉竹清润肺胃为臣,黄芪、山茱萸、苍术补益脾肾、醒脾化浊为左使。通过现代药理研究证实,方中主药桑白皮具有良好糖苷酶抑制作用,明显降低餐后高血糖,黄连具有改善胰岛素抵抗作用,黄芪、山茱萸、葛根、知母、玉竹等在降糖、降脂方面有较好作用。
现代医学认为T2DM是一组由于组织对胰岛素生物学效应减弱以及胰岛β细胞功能缺陷而形成的以空腹和餐后高血糖为主要特征的代谢异常综合征[5]。T2DM在高血糖的同时,往往合并脂代谢紊乱,胰岛素抵抗和胰岛素缺乏是导致糖、脂代谢紊乱的中心环节。而导致胰岛素抵抗的主要因素包括FFA的升高、氧化应激、炎症反应以及细胞内在机制异常等。FFA是细胞膜脂质结构和前列腺素合成的供体,为脂肪代谢的中间产物,是机体主要供给能量的来源。升高的FFA可以使胰岛素受体底物(IRS)的丝氨酸残基磷酸化作用增强,影响了胰岛素介导的葡萄糖转运,导致糖代谢障碍[6],它抑制葡萄糖氧化,加速肝脏糖异生,增加肝脏葡萄糖的释出,导致肝脏IR,同时FFA可降低骨骼肌对胰岛素的敏感性,引起骨骼肌胰岛素抵抗和糖代谢障碍。氧化应激是指活性氧族(ROS)产生过多或发生代谢障碍并超过内源性抗氧化防御系统对其的消除能力时,过剩的ROS参与氧化生物大分子的过程,其最终产生细胞脂质过氧化并致使溶酶体、线粒体损伤。SOD是体内合成的氧自由基清除剂,其活性可反映机体抗氧化的能力。MDA是生物膜中多价不饱和脂肪酸受自由基作用生成的脂质过氧化代谢产物,其含量反映机体脂质过氧化的速度和程度,代表自由基的活性。SOD/MDA值则能更准确地反映机体氧化与抗氧化之间的平衡关系。
通过实验发现桑黄通泻配方显著降低T2DM大鼠的FBG、TG、TC、LDL-C和FFA的水平,提高血清HLDL-C的水平,可显著降低大鼠血清MDA的含量,明显升高血清SOD的活性。上述实验结果说明桑黄通泻配方可改善糖尿病大鼠糖、脂代谢,抑制氧化应激反应,对Ⅱ型糖尿病大鼠具有良好的药理效应,为桑黄通泻配方的临床推广提供了实验依据。
Claims (3)
1.一种防治Ⅱ型糖尿病桑黄通泻配方,其特征在于各组分的重量百分比:桑白皮20-30%、黄连20-30%、厚朴10-20%、葛根5-10%、黄芪5-10%、山萸肉5-10%、莱菔子5-10%、知母5-10%、玉竹5-10%、苍术5-10%。
2.一种防治Ⅱ型糖尿病桑黄通泻配方的制备工艺,其特征在于包含如下工艺步骤:
①分别将桑白皮20-30%、黄连20-30%、厚朴10-20%、葛根5-10%、黄芪5-10%、山萸肉5-10%、莱菔子5-10%、知母5-10%、玉竹5-10%、苍术5-10%;粉碎备用,上述百分比为重量百分比;
②按正交试验表,采用四因素三水平进行正交试验,以确定最佳提取方法;即:乙醇浓度、溶剂与药材用量比、提取时间、提取次数四个因素;用不同浓度的乙醇回流提取,合并乙醇液,浓缩干燥;干燥提取物粉碎即得本发明产品。
3.根据权利要求2所述的一种防治Ⅱ型糖尿病桑黄通泻配方的制备工艺,其特征在于:将黄连、桑白皮、厚朴、黄芪、山茱萸、葛根、莱菔子、知母、玉竹、苍术粉碎,过60目筛,加6倍量30%乙醇浸泡0.5h,加热回流提取2次,每次2小时,滤过;滤液回收乙醇,干燥浸膏,粉碎,出粉率为20%,粉碎成细粉作为活性成分;然后将上述活性成分与赋形剂一起制成丸剂、颗粒剂、胶囊剂型,包装为每袋2g。
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