CN111110689A - 一种活血化瘀通脉止痛的药物组合物及药物制剂 - Google Patents
一种活血化瘀通脉止痛的药物组合物及药物制剂 Download PDFInfo
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- CN111110689A CN111110689A CN202010031510.0A CN202010031510A CN111110689A CN 111110689 A CN111110689 A CN 111110689A CN 202010031510 A CN202010031510 A CN 202010031510A CN 111110689 A CN111110689 A CN 111110689A
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及中医药技术领域,特别涉及一种活血化瘀通脉止痛的药物组合物及药物制剂。以重量百分比计,以重量百分比计,由丹酚酸B 20%~60%、三七皂苷R1 10%~25%、丹参素10%~20%、丹参酮IIA 5%~12%、人参皂苷Rg1 1%~10%、人参皂苷Rb1 1%~10%、三七素1%~10%、原儿茶醛0.5%~2.5%、丹酚酸A 0.5%~2.5%组成。本发明是以纯度较高且药理作用、安全剂量及毒副用明确的药物按科学的配比进行组方,提供一种组方合理、药效成分清晰、杂质少,起效快、药物药效时间长,服用剂量小、药效物质基础明确的具有活血化瘀,通脉止痛功能的药物组合物,精准用药,精准治疗。
Description
技术领域
本发明涉及中医药技术领域,特别涉及一种活血化瘀通脉止痛的药物组合物及药物制剂。
背景技术
血瘀证是临床常见的病症,其发病是由于多种致瘀因素导致血行缓慢、脉道壅塞而致。根据致病因素不同,可分为寒凝血瘀、气滞血瘀、气虚血瘀等类型,病变可累及心、脑、肺、肾、肝、生殖等多个系统,轻者可影响患者的日常生活,重则危及患者生命。因此,对血瘀证及活血化瘀药物的相关研究是医药领域中最紧迫的内容之一,应按其症候进行精准治疗。
丹七方是活血化瘀通脉止痛药物中的经典方,由丹参、三七组成,现有技术多在此方基础上加减裁化,主要以具有活血化瘀功能的药材或药材提取物进行组方,各方药物配比各不相同,提取物虽经过纯化和富集,各种组方中相同药材的提取和纯化方法各异,提取物中化学成分较多,纯度较低,药效成分提取率、转移率差异较大,有效成分得率还受到药材来源、批次、加工温度、提取溶剂等因素的影响。各组方质量控制标准中含量测定指标及限度也不同,用药剂量不精确,从而导致同类药品临床疗效参差不齐。且仅能明确提取物中单个或几个已知成分,药效成分不明确,药物药效持续时间短,服用剂量较大,不能准确评估未知成分对药效以及安全性方面的影响。
现有公开专利CN 104415045B、CN 104274518B、CN 104274520B组合物中组分复杂,组方中包含16种丹参和三七药材中已知的化学成分及冰片,组分复杂,用药剂量大,而且不能充分说明组方中每种成分与药效的相关性。
发明内容
有鉴于此,本发明提供了一种活血化瘀通脉止痛的药物组合物及药物制剂。该发明中组方合理、药效成分清晰、杂质少,起效快、药物药效时间长,服用剂量小、药效物质基础明确的具有活血化瘀,通脉止痛功能的药物组合物,精准用药,精准治疗。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种活血化瘀通脉止痛的药物组合物,以重量百分比计,由下列组分组成:
作为优选,以重量百分比计,该药物组合物由下列组分组成:
优选地,以重量百分比计,该药物组合物由下列组分组成:
在本发明提供的一具体实施例中,以重量百分比计,该药物组合物由下列组分组成:
在本发明提供的另一具体实施例中,以重量百分比计,该药物组合物由下列组分组成:
本发明还提供了一种药物制剂,包括上述药物组合物,及药学上可接受的药物基质、载体或赋形剂中的一种或几种。
作为优选,药物制剂的剂型为口服制剂或吸入制剂,口服制剂为滴丸剂或软胶囊剂,吸入制制为气雾剂。
作为优选,药物基质为水溶性基质或非水溶性基质,水溶性基质为聚乙二醇4000、聚乙二醇6000、硬脂酸钠、泊洛沙姆、甘油明胶中的一种或几种;非水溶性基质为硬脂酸、单硬脂酸甘油酯、虫蜡、蜂蜡、十八醇、氢化植物油中的一种或几种。
作为优选,载体为抛射剂、混悬剂、潜溶剂中的一种或几种,抛射剂为四氟乙烷和/或七氟乙烷;混悬剂为食用油、甘油、胶体二氧化硅、油酸、司盘85、油醇、月桂醇、氯化钠中的一种或几种;潜溶剂为丙二醇、乙醇、聚乙二醇4000、聚乙二醇6000、甘油中的一种或几种。
作为优选,赋形剂为填充剂和/或矫味剂,填充剂为淀粉、甘露醇、蔗糖、乳糖、滑石粉中的一种或几种;矫味剂为香精、甜菊素、阿司帕坦、果糖中的一种或几种。
本发明提供了一种活血化瘀通脉止痛的药物组合物及药物制剂。以重量百分比计,由丹酚酸B 20%~60%、三七皂苷R1 10%~25%、丹参素10%~ 20%、丹参酮IIA 5%~12%、人参皂苷Rg1 1%~10%、人参皂苷Rb1 1%~10%、三七素1%~10%、原儿茶醛0.5%~2.5%、丹酚酸A 0.5%~2.5%组成。
本发明具有的技术效果为:
本发明采用网络药理学手段,通过OMIM、Drugbank等疾病数据库对丹参、三七药材中具有活血化瘀、通脉止痛的化学成分与作用靶点进行网络关联,从众多化学成分中筛选出关联性极强的9种成分来进行组方,提供一种新的活血化瘀通脉止痛的药物组合物,经药效对比验证本组合物使用剂量少于对照药,且药效及药效持续时间明显优于对照组。
本发明是以纯度较高且药理作用、安全剂量及毒副用明确的药物按科学的配比进行组方,提供一种组方合理、药效成分清晰、杂质少,起效快、药物药效时间长,服用剂量小、药效物质基础明确的具有活血化瘀,通脉止痛功能的药物组合物,精准用药,精准治疗。
附图说明
图1示各有效成分的作用靶点与疾病靶点的网络药理学分析图。
具体实施方式
本发明公开了一种活血化瘀通脉止痛的药物组合物及药物制剂,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
本发明提供了一种具有活血化瘀通脉止痛的药物组合物。该药物组合物由下列重量百分比的组分组成:
其中所述丹酚酸B为类白色至淡黄色粉末,含量为95%~99%;三七皂苷R1为白色粉末,含量为95%~98%;丹参素为白色针状结晶,含量为95%~ 98%;丹参酮IIA为樱红色针状结晶,含量为96%~99%;人参皂苷Rg1为白色粉末,含量为96%~99%;人参皂苷Rb1为白色粉末,含量为95%~98%;三七素为无色的结晶,含量为96%~99%;原儿茶醛为淡米色针状结晶或灰白色粉末,含量为95%~98%;丹酚酸A为淡黄色结晶,含量为96%~99%。上述组分均可通过购买上市原料获得。
优选地,该药物组合物各组分的重量百分比为:
本发明组合物可与各种药物基质、载体及赋形剂制成供口服或吸入的药物制剂。口服制剂分为滴丸剂和软胶囊剂;吸入制制为气雾剂。
本发明所述的药物基质为水溶性基质和非水溶性基质,水溶性基质包括聚乙二醇4000、聚乙二醇6000、硬脂酸钠、泊洛沙姆、甘油明胶中的一种或几种;非水溶性基质包括硬脂酸、单硬脂酸甘油酯、虫蜡、蜂蜡、十八醇、氢化植物油中的一种或几种。
本发明所述的载体为抛射剂、混悬剂、潜溶剂,抛射剂包括四氟乙烷、七氟乙烷;混悬剂包括食用油、甘油、胶体二氧化硅、油酸、司盘85、油醇、月桂醇、氯化钠中的一种或几种;潜溶剂包括丙二醇、乙醇、聚乙二醇4000、聚乙二醇6000、甘油中的一种或几种。
本发明所述的赋形剂为填充剂、矫味剂,填充剂包括淀粉、甘露醇、蔗糖、乳糖、滑石粉中的一种或几种;矫味剂包括香精、甜菊素、阿司帕坦、果糖中的一种或几种。
本发明提供的活血化瘀通脉止痛的药物组合物及药物制剂中所用原料药或辅料均可由市场购得。
下面结合实施例,进一步阐述本发明:
试验例1药物有效成分确定
本发明以丹参、三七两味药材为基础,分别对其中的成分进行分析,根据其中各成分的口服生物利用度、血脑屏障、类药性等数据进行筛选共筛选出47个有效成分及其作用靶点。同时,根据OMIM、Drugbank等疾病数据库以Cerebrovascular Diseases、Intracranial Hemorrhages等血管性疾病的作用靶点。将筛选的有效成分的作用靶点与疾病靶点做交集,最终确定了18个有效成分。
表1通过作用靶点与疾病靶点筛选出的18个有效成分
序号 | 药材 | 成分 |
1 | 三七 | Deoxyharringtonine |
2 | 三七 | Ginsenoside Rg1 |
3 | 三七 | Ginsenoside Rb1 |
4 | 三七 | Alexandrin_qt |
5 | 三七 | Panaxadiol |
6 | 三七 | Gomisin B |
7 | 三七 | Notoginsenoside R1 |
8 | 三七 | Stigmasterol |
9 | 三七 | Quercetin |
10 | 三七 | N3-Oxalyl-L-2,3-diaminopropanoate |
11 | 丹参 | Przewaquinone B |
12 | 丹参 | Danshenol B |
13 | 丹参 | Danshenol A |
14 | 丹参 | Przewaquinone c |
15 | 丹参 | Protocatechualdehyde |
16 | 丹参 | Isotanshinone II |
17 | 丹参 | Tanshinone iia |
18 | 丹参 | Salvianolic acid A |
将筛选的有效成分的作用靶点与疾病靶点采用Cytoscape进行网络分析,如图1所示。
根据网络分析采用Mcode进行计算,Degree值平均为7,因此筛选Degree 大于7的成分如下表:
表2确定的9个有效成分
本发明以筛选出的上述9个成分进行组方。
实施例1:
取丹酚酸B 20g、三七皂苷R1 9g、丹参素 7.5g、丹参酮IIA 4.5g、人参皂苷Rg12.75g、人参皂苷Rb1 2.5g、三七素 2.25g、原儿茶醛 0.75g、丹酚酸A 0.75g混合均匀,制成50g。
实施例2:
取丹酚酸B15g、三七皂苷R1 10.5g、丹参素 9g、丹参酮IIA 5g、人参皂苷Rg1 3g、人参皂苷Rb1 3g、三七素 2.5g、原儿茶醛 1g、丹酚酸A 1g 混合均匀,制成50g。
实施例3:
取丹酚酸B 25g、三七皂苷R1 7.5g、丹参素 6g、丹参酮IIA 4g、人参皂苷Rg12.5g、人参皂苷Rb1 2g、三七素 2g、原儿茶醛 0.5g、丹酚酸A 0.5g混合均匀,制成50g。
对比例1:
取丹酚酸B 10g、三七皂苷R1 11.5g、丹参素 10g、丹参酮IIA 5.5g、人参皂苷Rg13.75g、人参皂苷Rb1 3.75g、三七素 3g、原儿茶醛 1.25g、丹酚酸 A 1.25g混合均匀。
对比例2:
取丹酚酸B 30g、三七皂苷R1 6g、丹参素 4.8g、丹参酮IIA 3.2g、人参皂苷Rg12g、人参皂苷Rb1 1.6g、三七素 1.6g、原儿茶醛 0.4g、丹酚酸A 0.4g 混合均匀。
对比例3:
取丹酚酸B 20g、三七皂苷R1 9g、丹参素 7.5g、丹参酮IIA 4.5g、人参皂苷Rg12.75g、人参皂苷Rb1 2.5g、原儿茶醛 0.75g、丹酚酸A 0.75g、淀粉 2.25g混合均匀。
试验例2药效试验:
药效对比样品:
药物组合物1是指按本发明实施例1所制备的药物组合物;药物组合物2是指按本发明实施例2所制备的药物组合物;药物组合物3是指按本发明实施例3 所制备的药物组合物;依据本发明对比例1所制备样品获得对比样品1;依据本发明对比例2制备样品获得对比样品2;依据本发明对比例3制备样品获得对比样品3;依据授权公开号CN100389789C说明书实施例1制备样品得到丹七胶囊;依据授权公开号CN100404042C说明书实施例1制备样品得到丹七软胶囊。药物组合物滴丸是指按本发明实施例4所制备的滴丸剂;丹七片为市售品,生产厂家为修正药业集团股份有限公司。
仪器试剂:酶标仪,厂家:Manufactured in China Designed in CaliforniaUSA,型号:SMP500-18272-LSIO;全自动血液流变仪,厂家:北京普利生仪器有限公司,型号:LBY-N6;电子天平,厂家:美国双杰兄弟有限公司,型号:T1000。肌酸激酶(CK)ELISA检测试剂盒;肌酸激酶同工酶(CK-MB) ELISA检测试剂盒;Na+-K+-ATP酶ELISA检测试剂盒;内皮素-1(ET-1) ELISA检测试剂盒;一氧化氮(NO)ELISA检测试剂盒;肿瘤坏死因子(TNF-a)ELISA检测试剂盒和白介素-6(IL-6)ELISA检测试剂盒。
实验动物:SPF级Wistar大鼠,雌雄各半,体重200~220g,购自长春市亿斯实验动物技术有限责任公司。
本方明药物组合物1、2、3与对比样品1、2、3以及丹七胶囊、丹七软胶囊、丹七片进行药效实验对比研究,方法及结果如下:
一、血瘀模型大鼠血液流变学检测:
取检疫合格的Wistar大鼠110只,体重200~220g,雌雄各半。设立11个试验组,分别为空白组、模型组、丹七软胶囊组、丹七胶囊组、丹七片组、药物组合物1组、药物组合物2组、药物组合物3组、对比样1组、对比样2组以及对比样3组,每组10只大鼠,雌雄各半,将碎冰放入水深15~20cm内壁光滑的塑料圆桶中,待冰水温度至0~1℃,除空白组外,将各组大鼠放入圆桶,10min后,将全身僵直大鼠取出,每天冰水浴后给予鼠粮正常饲养。除空白组外,各组大鼠隔日注射盐酸肾上腺素(0.8mg/kg)。按照上述造模方法造模,连续造模10d,1~5d只造模不给药,5~10d给药组给予相对应药物,模型组给予纯化水,各组动物灌胃给药体积为10mL/kg,连续给药5天。末次造模后禁食不禁水12h,末次给药1h后,腹腔注射戊巴比妥钠(1.5mL/kg)麻醉,仰卧于手术台,腹主动脉取血,置于枸橼酸钠抗凝管中,立即进行血流变学检测。
实验结果:模型组与空白组比较全血粘度(低切、中切、高切)有明显差异(P<0.05,P<0.01);与模型组比较,各给药组全血粘度(低切)均有不同程度差异(P<0.05);除丹七胶囊、丹七软胶囊与对比样品2组外,其余各组全血粘度(中切)与模型组比较,均有不同程度差异(P<0.05);除丹七软胶囊、对比样品1组与对比样品2组外,其余各组与模型组比较各组全血粘度 (高切)均有明显差异(P<0.05,P<0.01),详见表3。
组别 | 剂量(g/kg) | 低切(10s) | 中切(60s) | 高切(150s) |
空白组 | -- | 5.35±0.42 | 4.36±1.73 | 3.21±0.51 |
模型组 | -- | 6.81±1.78<sup>#</sup> | 5.76±1.05<sup>#</sup> | 4.58±1.03<sup>##</sup> |
丹七胶囊组 | 0.810 | 5.46±1.04<sup>*</sup> | 5.00±0.92 | 3.81±0.83<sup>*</sup> |
丹七软胶囊组 | 1.944 | 5.51±0.60<sup>*</sup> | 5.10±0.54 | 4.37±0.42 |
丹七片组 | 0.810 | 5.54±1.80<sup>*</sup> | 4.56±0.88<sup>*</sup> | 3.61±0.73<sup>*</sup> |
药物组合物1 | 0.018 | 5.38±1.16<sup>*</sup> | 4.40±0.75<sup>*</sup> | 3.31±0.69<sup>**</sup> |
药物组合物2 | 0.018 | 5.41±1.04<sup>*</sup> | 4.39±0.66<sup>*</sup> | 3.82±0.71<sup>*</sup> |
药物组合物3 | 0.018 | 5.40±1.11<sup>*</sup> | 4.40±0.94<sup>*</sup> | 3.77±0.84<sup>*</sup> |
对比样品1 | 0.018 | 5.46±0.52<sup>*</sup> | 4.59±0.99<sup>*</sup> | 4.33±0.70 |
对比样品2 | 0.018 | 5.63±1.78<sup>*</sup> | 5.01±0.83 | 4.33±0.52 |
对比样品3 | 0.018 | 5.40±1.62<sup>*</sup> | 4.42±0.83<sup>*</sup> | 3.46±0.63<sup>*</sup> |
注:与空白对照组比较,#P<0.05,##P<0.01;与模型对照组比较,*P<0.05,**P<0.01。
二、血瘀模型大鼠血清生化学指标检测:
取检疫合格的Wistar大鼠110只,体重200~220g,雌雄各半。设立11 个试验组,分别为空白组、模型组、丹七软胶囊组、丹七胶囊组、丹七片组、药物组合物1组、药物组合物2组、药物组合物3组、对比样1组、对比样2 组以及对比样品3组,每组10只大鼠,雌雄各半,将碎冰放入水深15~20cm 内壁光滑的塑料圆桶中,待冰水温度至0~1℃,除空白组外,将各组大鼠放入圆桶,10min后,将全身僵直大鼠取出,每天冰水浴后给予鼠粮正常饲养。除空白组外,各组大鼠隔日皮下注射盐酸肾上腺素(0.8mg/kg)。按照上述造模方法造模,连续造模10d,1~5d只造模不给药,5~10d给药组给予相对应药物,模型组给予纯化水,各组动物灌胃给药体积为10mL/kg,连续给药 5d。末次造模后禁食不禁水12h,末次给药1h后,腹腔注射戊巴比妥钠 (1.5mL/kg)麻醉,仰卧于手术台,腹主动脉取血,3000r/min,离心10min,取上清进行血清生化学指标检测。具体检测指标:ELISA法检测血清中肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)、钠-钾-三磷酸腺苷酶(Na+-K+-ATP)、内皮素(ET-1)、一氧化氮(NO)以及肿瘤坏死因子(TNF-a)和白介素-6 (IL-6)。
结果:模型组与空白组比较,各项指标均有明显差异(P<0.01,P<0.001);与模型组比较,各组CK、CK-MB、Na+-K+-ATP均有明显升高或降低(P<0.05, P<0.01,P<0.001);除丹七胶囊组、丹七片组和对比样品1、2、3组外,其余各组与模型组比较,NO均有明显升高(P<0.05,P<0.01);除对样品1、对比样品2组外,各组与模型组比较,ET-1均有明显降低(P<0.05,P<0.01),详见表4。
注:与空白对照组比较,##P<0.01,###P<0.001;与模型对照组比较,*P<0.05,**P<0.01,***P<0.001。
与空白对照组比较,模型组TNF-a与IL-6含量均有明显升高(P<0.01);与模型组比较,除对比样品1、3组外,其余各给药组TNF-a含量均有明显降低(P<0.05,P<0.01);除对比样品2、3外,其余各给药组IL-6含量均有明显降低(P<0.05,P<0.01)。详见表5。
组别 | 剂量(g/kg) | TNF-a(pg/mL) | IL-6(ng/mL) |
空白组 | -- | 60.25±7.43 | 1.92±0.45 |
模型组 | -- | 78.52±8.37<sup>##</sup> | 2.41±0.32<sup>##</sup> |
丹七胶囊组 | 0.810 | 66.49±8.13<sup>*</sup> | 2.05±0.47<sup>*</sup> |
丹七软胶囊组 | 1.944 | 62.66±6.47<sup>**</sup> | 1.98±0.28<sup>**</sup> |
丹七片组 | 0.810 | 67.29±6.11<sup>*</sup> | 2.08±0.24<sup>*</sup> |
药物组合物1 | 0.018 | 62.41±7.74<sup>**</sup> | 1.95±0.43<sup>**</sup> |
药物组合物2 | 0.018 | 67.15±7.56<sup>*</sup> | 1.97±0.37<sup>**</sup> |
药物组合物3 | 0.018 | 65.30±6.64<sup>**</sup> | 2.06±0.41<sup>*</sup> |
对比样品1 | 0.018 | 69.74±8.33 | 2.11±0.23<sup>*</sup> |
对比样品2 | 0.018 | 66.79±7.45<sup>*</sup> | 2.18±0.46 |
对比样品3 | 0.018 | 70.10±5.88 | 2.24±0.38 |
注:与空白对照组比较,##P<0.01;与模型对照组比较,*P<0.05,**P<0.01,***P<0.001。
由以上实验可知,药物组合物1组在抗血瘀效果上明显优于药物组合物2、 3组及其他各组,因此确定药物组合物1组的配比为最佳配比。
实施例4:
取丹酚酸B 20g、三七皂苷R1 9g、丹参素 7.5g、丹参酮IIA 4.5g、人参皂苷Rg12.75g、人参皂苷Rb1 2.5g、三七素 2.25g、原儿茶醛 0.75g、丹酚酸A 0.75g与淀粉适量混匀,按1:5的比例加入聚乙二醇4000中,混匀,60℃加热至熔融,滴入冷却剂二甲硅油中,收缩成丸,制成10000丸滴丸。
实施例5:
取丹酚酸B 20g、三七皂苷R1 9g、丹参素 7.5g、丹参酮IIA 4.5g、人参皂苷Rg12.75g、人参皂苷Rb1 2.5g、三七素 2.25g、原儿茶醛 0.75g、丹酚酸A 0.75g与甘露醇适量混合均匀,按1:5的比例加入50℃的泊洛沙姆中,混合均匀,以甘油、水、明胶为胶液,用软胶囊机制成10000粒软胶囊。
实施例6:
取丹酚酸B 20g、三七皂苷R1 9g、丹参素 7.5g、丹参酮IIA 4.5g、人参皂苷Rg12.75g、人参皂苷Rb1 2.5g、三七素 2.25g、原儿茶醛 0.75g、丹酚酸A 0.75g混合均匀,用气流粉碎机粉碎至平均粒径为2.0μm及以下的粉末,按1:20:0.2:0.5的比例加入丙二醇、司盘85、氯化钠,混合均匀,研磨,乳化,以四氟乙烷为抛射剂,用气雾剂灌装机制成10000瓶气雾剂。
试验例3整体药效学研究:
为明确药效,将最佳配比组方制成药物组合物滴丸组(实施例4),进行整体药效实验。
一、对血瘀模型大鼠血清生化学指标的影响:
取检疫合格的Wistar大鼠80只,体重200~220g,雌雄各半。设立8个试验组,分别为空白组、模型组、丹七胶囊组、丹七片组、丹七软胶囊组以及药物组合物滴丸高、中、低剂量组,每组10只大鼠,雌雄各半,将碎冰放入水深15~20cm内壁光滑的塑料圆桶中,待冰水温度至0~1℃,除空白组外,将各组大鼠放入圆桶,10min后,将全身僵直大鼠取出,每天冰水浴后给予鼠粮正常饲养。除空白组外,各组大鼠隔日皮下注射盐酸肾上腺素(0.8 mg/kg)。按照上述造模方法造模,连续造模10d,1~5d只造模不给药,5~10d 给药组给予相对应药物,模型组给予纯化水,各组动物灌胃给药体积为 10mL/kg,连续给药5d。末次造模后禁食不禁水12h,末次给药1h后,腹腔注射戊巴比妥钠(1.5mL/kg)麻醉,仰卧于手术台,腹主动脉取血,3000r/min,离心10min,取上清进行血清生化学指标检测。具体检测指标:ELISA法检测血清中肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)、钠-钾-三磷酸腺苷酶 (Na+-K+-ATP)、内皮素(ET-1)、一氧化氮(NO)以及肿瘤坏死因子(TNF-a) 和白介素-6(IL-6)。
实验结果:模型组与空白组比较,各项指标均有明显差异(P<0.01, P<0.001);与模型组比较,各组CK、CK-MB、Na+-K+-ATP、ET-1、IL-6均有明显升高或降低(P<0.05,P<0.01,P<0.001);丹七胶囊组及药物组合物滴丸高、中、低剂量组与模型组比较,NO均有明显升高(P<0.05,P<0.01),药物组合物滴丸高、中、低剂量组较丹七胶囊组、丹七软胶囊组以及丹七片组效果更优,其中以高、中剂量组尤为突出,详见表6。
注:与空白对照组比较,##P<0.01,###P<0.001;与模型对照组比较,*P<0.05,**P<0.01,***P<0.001。
与空白对照组比较,模型组TNF-a与IL-6含量均有明显升高(P<0.01,P<0.001);与模型组比较,各给药组TNF-a与IL-6含量均有明显降低(P<0.05, P<0.01,P<0.001),详见表7。
组别 | 剂量(g/kg) | TNF-a(pg/mL) | IL-6(ng/mL) |
空白组 | -- | 57.74±8.35 | 1.52±0.43 |
模型组 | -- | 76.81±7.87<sup>##</sup> | 2.35±0.28<sup>###</sup> |
丹七胶囊组 | 0.810 | 60.36±7.04<sup>*</sup> | 1.94±0.36<sup>**</sup> |
丹七软胶囊组 | 1.944 | 61.25±7.62<sup>*</sup> | 2.06±0.42<sup>*</sup> |
丹七片组 | 0.810 | 59.56±8.10<sup>**</sup> | 1.91±0.48<sup>**</sup> |
药物组合物滴丸高剂量组 | 0.252 | 59.37±6.16<sup>**</sup> | 1.84±0.52<sup>***</sup> |
药物组合物滴丸中剂量组 | 0.126 | 59.91±8.04<sup>*</sup> | 1.95±0.33<sup>**</sup> |
药物组合物滴丸低剂量组 | 0.063 | 61.40±6.13<sup>*</sup> | 2.02±0.26<sup>*</sup> |
注:与空白对照组比较,##P<0.01,###P<0.001;与模型对照组比较,*P<0.05,**P<0.01,***P<0.001。
二、对心肌缺血模型大鼠血清心肌损伤指标水平的影响:
取检疫合格的Wistar大鼠80只,体重200~220g,雌雄各半。设立8个试验组,分别为空白组、模型组、丹七胶囊组、丹七片组、丹七软胶囊组以及药物组合物滴丸高、中、低剂量组,每组10只大鼠,雌雄各半。大鼠称重后,2mL/kg腹腔注射3%戊巴比妥钠,仰卧位固定,连接心电图监测,气管插管并接呼吸机,胸骨左缘旁纵行切开第3~5肋间做横行切口,剪开并挑起心包,暴露心脏,以左心耳与肺动脉圆锥交界处的左冠状动脉前降支为标志,于左心耳下方1~2mm处进针、穿线,将一小硅胶管从丝线两端穿入,稳定 10min后结扎,缺血30min后,再灌注3h结束。假手术组只行冠状动脉穿线,不结扎。再灌注结束后,腹主动脉取血2mL,分离血清备用。检测指标:用 ELISA定量检测试剂盒分别测定各组大鼠血清肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)和心肌钙蛋白(CTnI)的水平,评估心肌细胞的损伤程度。
实验结果:模型组与空白组比较各项指标均有明显差异(P<0.01, P<0.001);与模型组比较,各组CK、CK-MB均有明显降低(P<0.05,P<0.01,P<0.001),除丹七软胶囊组、丹七片和药物组合物滴丸低剂量组外,各组LDH 均明显降低(P<0.05,P<0.01),药物组合物滴丸高、中剂量组CTnI均明显降低(P<0.05,P<0.01),详见表8。
注:与空白对照组比较,##P<0.01,###P<0.001;与模型对照组比较,*P<0.05,**P<0.01。
三、小鼠镇痛实验:
取检疫合格的ICR小鼠70只,体重20~22g,雌性。设立7个试验组,分别为空白组、丹七胶囊组、丹七片组、丹七软胶囊组以及药物组合物滴丸高、中、低剂量组,每组10只,雌雄各半。各给药组小鼠灌胃给予相应药物,空白组给予等量生理盐水,连续给药7d,末次给药后1、2、4h分别进行3次热板法镇痛实验。将小鼠置于热板仪内,温度55±0.5℃,记录小鼠出现舔足反应的时间,测定各组小鼠的痛阈值。
实验结果:与空白组比较,末次给药1h后,各组痛阈值均有明显升高 (P<0.05,P<0.01);末次给药2h后,各组痛阈值升高更为明显(P<0.05,P<0.01, P<0.001);末次给药4h后,除药物组合物滴丸高、中剂量组痛阈值明显升高外(P<0.05),其余各组均无明显差异,详见表9。
注:与空白对照组比较,*P<0.05,**P<0.01,***P<0.001。
结论:
本发明专利组可调节、改善血瘀及心肌缺血模型大鼠的相关指标,且具有明显且持续的镇痛作用,且本发明专利在同剂量下,对血瘀、心肌缺血的治疗作用及镇痛效果优于丹七胶囊、丹七软胶囊及丹七片。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
6.一种药物制剂,其特征在于,包括权利要求1至5中任一项所述药物组合物,及药学上可接受的药物基质、载体或赋形剂中的一种或几种。
7.根据权利要求6所述的药物制剂,其特征在于,所述药物制剂的剂型为口服制剂或吸入制剂,所述口服制剂为滴丸剂或软胶囊剂,所述吸入制制为气雾剂。
8.根据权利要求6所述的药物制剂,其特征在于,所述药物基质为水溶性基质或非水溶性基质,所述水溶性基质为聚乙二醇4000、聚乙二醇6000、硬脂酸钠、泊洛沙姆、甘油明胶中的一种或几种;所述非水溶性基质为硬脂酸、单硬脂酸甘油酯、虫蜡、蜂蜡、十八醇、氢化植物油中的一种或几种。
9.根据权利要求6所述的药物制剂,其特征在于,所述载体为抛射剂、混悬剂、潜溶剂中的一种或几种,所述抛射剂为四氟乙烷和/或七氟乙烷;所述混悬剂为食用油、甘油、胶体二氧化硅、油酸、司盘85、油醇、月桂醇、氯化钠中的一种或几种;所述潜溶剂为丙二醇、乙醇、聚乙二醇4000、聚乙二醇6000、甘油中的一种或几种。
10.根据权利要求6至9中任一项所述的药物制剂,其特征在于,所述赋形剂为填充剂和/或矫味剂,所述填充剂为淀粉、甘露醇、蔗糖、乳糖、滑石粉中的一种或几种;所述矫味剂为香精、甜菊素、阿司帕坦、果糖中的一种或几种。
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