CN117442687A - 治疗帕金森病的中药组合物及其应用 - Google Patents
治疗帕金森病的中药组合物及其应用 Download PDFInfo
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Abstract
本发明提供一种治疗帕金森病的中药组合物及其应用,该中药组合物按照重量份配比的组成包括:熟地10‑15份,生地10‑15份,当归10‑15份,白芍10‑15份,川芎5‑10份,黄芪5‑10份,白术5‑12份,天麻3‑10份,秦艽3‑10份,防风3‑8份,荆芥3‑8份,威灵仙1‑5份,全蝎1‑5份,细辛1‑5份。该中药组合物对帕金森模型小鼠具有很好的治疗效果,并缩短治疗周期、减少药物服用量,且效果可与左旋多巴相比,有望进一步开发成临床药剂用于帕金森病治疗。
Description
技术领域
本发明涉及中医药技术领域,具体涉及治疗帕金森病的中药组合物及其应用。
背景技术
帕金森病(Parkinson'sdisease,PD)是一种严重的退行性神经变性疾病,患病人群以中老年群体为主,有研究表明,我国60岁以上人群中,PD发病率约为1%~2%,共有约300万帕金森患者,占全球患病人数的50%,已成为全球帕金森病大国。帕金森病的病理改变多与大脑内路易小体的形成和黑质多巴胺能神经元的变性、缺失有关,其神经元变性使得多巴胺能神经递质释放减少,胆碱能神经功能占优,产生帕金森症状,但目前尚未得出帕金森的明确病因,推测可能与遗传因素、生活环境、患者年龄等有关。该病具有病程长、不可自愈、并发症多等特点,患者早期主要表现为静止性震颤,随着病程加重还会出现步态异常,行动迟缓,肌强直等症状,同时伴随认知障碍、睡眠障碍、焦虑、抑郁、便秘、感觉改变、吞咽困难等非运动症状,严重降低患者生活质量。
目前帕金森病治疗主要采用传统的药物治疗和外科手术治疗。药物治疗主要采用多巴胺替代治疗、抗胆碱能制剂、多巴胺受体激动剂、单胺氧化酶抑制剂、儿茶酚-氧位-甲基转移酶抑制剂、谷氨酸受体拮抗剂等西药进行治疗,其中以口服美多巴(左旋多巴)、息宁等多巴胺补充剂进行治疗的替代疗法,被认为是最有效的治疗办法。该类药物主要透过血脑屏障进入人体中枢,在多巴脱羧酶作用下转化为多巴胺,补充患者纹状体内的多巴胺,改善帕金森症状,具有显著的药理效果。但这类药物长期服用会引发“开关效应”、异动症、剂末恶化等毒副作用,严重降低患者的生存质量,甚至减少患者生存期。
相对而言,中药复方制剂具有多靶点、副作用少等特点,在治疗慢性疾病方面有很大优势。帕金森病在中医上归属“颤证”,近年来,许多研究人员探究了中药复方和单体成分对帕金森的治疗作用,发现中药单独或联合西药治疗帕金森病都具有很好的效果,且副作用较少,因此涌现了许多用于帕金森病治疗的中药制剂。如专利号为CN111686209A(公开日2020年9月22日)的中国发明专利申请公开了一种治疗帕金森病的中药复方制剂,原料包括:钩藤6-5份、天麻3-9份、秦艽6-12份、生黄芪10-20份、熟地黄10-20份、怀牛膝10-20份、枸杞子10-20份、当归10-20份、炒白术10-20份、炒酸枣仁6-15份、桃仁3-12份、红花3-9份、乌梢蛇20-30份。再如专利号为CN 112675254 A(公开日2021年4月20日)公开了一种治疗帕金森病胃肠功能障碍的中药组合物及其制备方法,原料包括:苍术10-20份,厚朴6-15份,陈皮6-10份,知母10-15份,黄连3-9份,木香6-12份,肉苁蓉10-30份。但是这些制剂以及一些已经上市的可治疗帕金森病的中成药如六味地黄丸、补中益气丸,参苓白术散、人参养荣丸等。一般只从补益肝肾、调理气血、解热祛痰、缓解肢体拘挛、补益大脑等单一方面入手来治疗帕金森病,且鲜有药物专治帕金森病,大部分药物治疗域较宽泛,针对性较弱。同时中药成分多为亲水成分或大分子物质,不易透过血脑屏障,治疗效果上远不及左旋多巴等常用西药。
因此,开发疗效好且副作用小、适合长期服用的药物来治疗帕金森病仍然是目前的迫切需求。
发明内容
本发明的目的是提供治疗帕金森病的中药组合物及其应用,动物实验表明,该中药组合物对MPTP诱导的帕金森模型小鼠具有很好的治疗效果,且效果可与左旋多巴相比,有望进一步开发成临床药剂用于帕金森病治疗。本发明的技术方案为:
第一方面,本发明提供一种治疗帕金森病的中药组合物,按照重量份配比的组成包括:熟地10-15份,生地10-15份,当归10-15份,白芍10-15份,川芎5-10份,黄芪5-10份,白术5-12份,天麻3-10份,秦艽3-10份,防风3-8份,荆芥3-8份,威灵仙1-5份,全蝎1-5份,细辛1-5份。
优选地,所述中药组合物按照重量份配比的组成包括:熟地12份,生地12份,当归12份,白芍12份,川芎9份,黄芪9份,白术9份,天麻6份,秦艽6份,防风5份,荆芥5份,威灵仙3份,全蝎3份,细辛3份。
进一步地,所述中药组合物还包括以下群体中的一种:冰片包合物2-3份,薄荷脑包合物1-2份,麝香酮包合物1-2份。
优选地,所述中药组合物中,冰片包合物为3份,或者薄荷脑包合物为1份,或者麝香酮包合物为1份。
进一步地,所述包合物是采用冰片或者薄荷脑或者麝香酮与β环糊精按照重量比1:10形成的包合物。
第二方面,本发明提供一种治疗帕金森病的药物制剂,包括上述中药组合物和药学上可接受的辅料。
进一步地,所述药学上可接受的辅料包括稀释剂、粘合剂、矫味剂、赋形剂、PH调节剂、澄清剂等,如蔗糖、糊精、淀粉、乳糖、木糖醇、甘露醇、山梨醇、可溶性淀粉、微晶纤维素、阿司帕坦、甜菊素、无水乙醇、枸橼酸、枸橼酸钠、壳聚糖、苯甲酸钠等。
进一步地,所述药物制剂包括固体制剂和液体制剂,所述固体制剂包括:硬胶囊剂、颗粒剂、片剂、分散片、软胶囊剂、微丸、蜜丸;所述液体制剂包括:糖浆剂、煎膏剂、口服液、合剂。
第三方面,本发明提供上述治疗帕金森病的药物制剂的制备方法,包括以下步骤:
步骤1,按照中药组合物的重量份组成:熟地10-15份,生地10-15份,当归10-15份,白芍10-15份,川芎5-10份,黄芪5-10份,白术5-12份,天麻3-10份,秦艽3-10份,防风3-8份,荆芥3-8份,威灵仙1-5份,全蝎1-5份,细辛1-5份,冰片包合物1-3份或者薄荷脑包合物1-2份或者麝香酮包合物1-2份配料,先将熟地、生地、当归、白芍、川芎、黄芪、白术、天麻、秦艽、防风、荆芥、威灵仙、全蝎、细辛加8-12倍量水浸泡0.5-1.5h,煎煮,过滤出提取液;
步骤2,将提取液浓缩至稠膏,将稠膏烘干得干膏,碾碎干膏过80目备用;或者将提取液浓缩至适宜体积得浓缩液;
步骤3,向干膏粉或浓缩液中加入冰片包合物细粉或薄荷脑包合物或麝香酮包合物混合均匀,再加入辅料混合均匀,制成对应的药物制剂。
进一步地,所述制备方法还包括配料前制备冰片包合物或者薄荷脑包合物或者麝香酮包合物,包括:
(1)将冰片或者薄荷脑或者麝香酮和其10倍重量的β环糊精混合均匀,然后加入β环糊精重量2倍重量的纯化水制成混悬液;
(2)将混悬液使用高速分散器进行剪切并研磨,过滤后干燥至水分不大于10%,即得。
进一步地,所述(2)中剪切并研磨的控制参数为:转速2000~3500rpm,时间20~30min。
进一步地,所述(2)中干燥温度为40-45℃。
进一步地,所述步骤1中煎煮1-3次,每次煎煮0.5-2h,且每次均加同倍量水。
进一步地,所述步骤1中当归的炮制方法为:将当归片与黄酒按照质量比10:1混合拌匀,待酒被吸尽后,置炒制容器内,用文火加热,炒至深黄色,取出,晾凉。
进一步地,所述步骤1中白芍的炮制方法为:取净白芍,用30-40℃温水浸2-3小时,并润过夜,用糠头(谷壳)拌炒,炒至白芍外表显紫褐色,内部显深黄色或黄褐色,取出,筛去糠头,放凉,切瓜子片,晒干,即得。
进一步地,所述步骤1中熟地的炮制方法为:取洗净生地,置容器内隔水蒸至黑润,取出,晒至八成干,切厚片,干燥后筛去碎屑,即得。
进一步地,所述步骤1中威灵仙的炮制方法为:取威灵仙净片于容器内,喷淋定量黄酒拌匀(威灵仙与黄酒质量比为10:1)、闷润后置炒药锅内,用微火加热,翻炒至显微黄火色,微干,取出,摊晾凉,即得。
在本发明的研究中,选择了熟地、生地、当归、白芍、川芎、黄芪、白术、天麻、秦艽、防风、荆芥、威灵仙、全蝎、细辛这十四味中药材进行复配,并将冰片、薄荷脑、麝香酮与β环糊精制备成包合物的形式,β环糊精的分子结构为一宽一窄的中空圆筒状,具有“内疏水,外亲水”的特性,是一种理想的药物载体。再将冰片、薄荷脑、麝香酮包合物中的一种与这十四味中药配伍使用,既有平肝熄风、补益肝肾的治本之效,又兼有养血柔筋、祛风通络的治标之功。还可促进药物透过血脑屏障进入大脑,协同增强对于帕金森病的作用疗效。帕金森动物模型实验表明,本发明的药物组合物可显著提高治疗效果,并缩短治疗周期、减少药物服用量。并且与左旋多巴相比,本发明药物组合物在改善小鼠运动的协调能力、肌肉力量、神经细胞保护等方面,显示了更好的抗帕金森病作用。
附图说明
图1为本发明实施例10中各组小鼠震颤评分图。
图2为本发明实施例10中各组小鼠爬杆实验评分结果。其中,与同时间模型组相比,#表示P<0.05,##表示P<0.01;与自身第7天造模后相比,*表示P<0.05,**表示P<0.01。
图3为本发明实施例10中各组小鼠悬挂实验评分结果。其中,与同时间模型组相比,#表示P<0.05,##表示P<0.01;与自身第7天造模后相比,*表示P<0.05,**表示P<0.01。
图4为本发明实施例10中各组小鼠转棒实验评分结果。其中,与同时间模型组相比,#表示P<0.05,##表示P<0.01;与自身第7天造模后相比,*表示P<0.05,**表示P<0.01。
图5为本发明实施例10中各组小鼠旷场活动图,其中,图A:阴性对照组;图B:模型组;图C:中药组;图D:无包合物药物组;图E:本发明1/2剂量药物组;图F:本发明2/3剂量药物组;图G:本发明正常剂量药物组;图H阳性药物组。
图6为本发明实施例10中各组小鼠旷场实验活动距离比较结果。其中,与同时间模型组相比,#表示P<0.05,##表示P<0.01;与自身第7天造模后相比,*表示P<0.05,**表示P<0.01。图7为本发明实施例10中各组小鼠强迫游泳实验评分结果。其中,与同时间模型组相比,#表示P<0.05,##表示P<0.01;与自身第7天造模后相比,*表示P<0.05,**表示P<0.01。图8为本发明实施例10中小鼠黑质部HE染色图片。其中,图A:阴性对照组;图B:模型组;图C:中药组;图D:无包合物药物组;图E:本发明1/2剂量药物组;图F:本发明2/3剂量药物组;图G:本发明正常剂量药物组;图H:阳性药物组。
图9为本发明实施例10中小鼠黑质部TH染色图片。其中,图A:阴性对照组;图B:模型组;图C:中药组;图D:无包合物药物组;图E:本发明1/2剂量药物组;图F:本发明2/3剂量药物组;图G:本发明正常剂量药物组;图H:阳性药物组。
具体实施方式
在本发明的描述中,需要说明的是,实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
下面结合附图和具体实施例,进一步阐述本发明。
实施例1
本实施例提供一种治疗帕金森病的颗粒剂的制备方法,包括以下步骤:
S1:按下列重量比准确称取熟地黄12份,生地黄12份,当归12份,白芍12份,川芎9份,黄芪9份,白术9份,天麻6份,秦艽6份,防风5份,荆芥5份,威灵仙3份,全蝎3份,细辛3份。
S2:将称量好的药材加8倍量水浸泡1h后,煎煮3次,每次0.5h(每次均加8倍量水煎煮),合并提取液滤过,滤液浓缩至稠膏,放入烘箱烘至干膏,碾碎干膏过80目备用。
S3:称取适量冰片和其10倍重量的β环糊精,先将冰片与等量的β环糊精粉碎混合均匀,然后将混合粉末与剩余β环糊精置于处方量β环糊精重量2倍量的纯化水中制成混悬液;之后将混悬液以50转/min的转数搅拌5min后,使用高速分散器进行剪切以3500转/min的速度研磨30min,取研磨后包合物抽滤,在40℃条件下烘干2h至水分不大于10%,即得冰片包合物。
S4:向S2所得的干膏粉中加入过80目筛的冰片包合物3份混合均匀,再加入与混合药粉比例为5:3的微晶纤维素和乳糖混合物(微晶纤维素:乳糖=1:1)制成颗粒,干燥,即得颗粒剂。
本实施例获得的颗粒呈棕褐色,大小均匀,色泽一致,无结块、吸潮、软化现象,具有冰片香气,味微苦。颗粒粒度、水分、溶化性和薄层鉴别结果均合格。
实施例2
本实施例提供一种治疗帕金森病的颗粒剂的制备方法,与实施例1的区别是:采用薄荷脑包合物1份;辅料为与混合药粉比例为1:1的微晶纤维素和木糖醇混合物(微晶纤维素:木糖醇=1:1)。
本实施例获得的颗粒呈棕褐色,大小均匀,色泽一致,无结块、吸潮、软化现象,具有薄荷香气,味微苦。颗粒粒度、水分、溶化性和薄层鉴别结果均合格。
实施例3
本实施例提供一种治疗帕金森病的颗粒剂的制备方法,与实施例1的区别是:采用麝香酮包合物1份;辅料为与混合药粉比例为3:2的糊精和乳糖混合物(糊精:乳糖=1:1)。
本实施例获得的颗粒呈棕褐色,大小均匀,色泽一致,无结块、吸潮、软化现象,味微苦。颗粒粒度、水分、溶化性和薄层鉴别结果均合格。
实施例4
本实施例提供一种治疗帕金森病的微丸的制备方法,与实施例1的区别是:
S4:向S2所得的干膏粉中加入过80目筛的冰片包合物3份混合均匀,再加入与干膏粉比例为1:2的微晶纤维素和乳糖混合物(微晶纤维素:乳糖=1:1)糊精和微晶纤维素制成软材,利用挤出滚圆机进行制粒,获得成品微丸制剂。
本实施例获得的微丸呈棕色,大小均匀,表面光滑,流动性较好,色泽一致,味微苦。微丸粒度、水分、溶化性和薄层鉴别结果均合格。
实施例5
本实施例提供一种治疗帕金森病的微丸的制备方法,与实施例4的区别是:采用麝香酮包合物1份;辅料为与混合药粉比例为1:2的糊精和微晶纤维素混合物(糊精:微晶纤维素=1:1)。
本实施例获得的微丸呈棕色,大小均匀,表面光滑,流动性较好,色泽一致,味微苦。微丸粒度、水分、溶化性和薄层鉴别结果均合格。
实施例6
本实施例提供一种治疗帕金森病的微丸的制备方法,与实施例4的区别是:采用薄荷脑包合物1份;辅料为与混合药粉比例为1:1的乳糖和糊精混合物(乳糖:糊精=1:1)。
本实施例获得的微丸呈棕色,大小均匀,表面光滑,流动性较好,色泽一致,味微苦。微丸粒度、水分、溶化性和薄层鉴别结果均合格。
实施例7
本实施例提供一种治疗帕金森病的口服液的制备方法,与实施例1的区别是:
S4:向S2所得的浓缩液中加入过80目筛的麝香酮包合物1份混合均匀,再加入0.2份壳聚糖、0.002份山梨酸和适量木糖醇,调节其澄清度并矫味,制备口服液。
本实施例获得的口服液呈棕色,气香,味微甜。口服液相对密度为1.30,PH为5.56,各项检查结果均合格。
实施例8
本实施例提供一种治疗帕金森病的口服液的制备方法,与实施例7的区别是:采用冰片包合物3份;采用离心法进行澄清,辅料为适量木糖醇。
本实施例获得的口服液呈棕色,气香,味微甜。口服液相对密度为1.27,PH为5.66,各项检查结果均合格。
实施例9
本实施例提供一种治疗帕金森病的口服液的制备方法,与实施例7的区别是:采用薄荷脑包合物1份;辅料为0.85活性炭、0.001份苯甲钠和适量的蔗糖。
本实施例获得的口服液呈棕色,气香,味微甜。口服液相对密度为1.29,PH为5.57,各项检查结果均合格。
实施例10
药效学研究
为探究本发明制备药物对帕金森病的药效,本发明建立了C57/BL6小鼠的亚急性帕金森模型,给予本发明药物和其他药物进行帕金森行为学评价和形态学检测,并比较治疗效果。具体试验报告如下:
(一)试验目的
建立C57/BL6小鼠亚急性帕金森模型,对模型给药并进行行为学评估和形态学分析,初步判断药效。
(二)试验药物与仪器
药物和试剂:MPTP(瑞鼎化学技术上海有限公司,>99%),左旋多巴(安徽丰乐香料有限责任公司),本发明药物,无包合物药物,中药复配物,生理盐水。
所述本发明药物:中药组成为熟地12份,生地12份,当归12份,白芍12份,川芎9份,黄芪9份,白术9份,天麻6份,秦艽6份,防风5份,荆芥5份,威灵仙3份,全蝎3份,细辛3份,经提取处理得到的浓缩物,加入冰片包合物为3份,参照实施例1的颗粒剂制备方法获得颗粒剂,之后用去离子水配置成生药浓度为2.12g/ml的药液。冰片包合物是采用冰片与β环糊精按照重量比1:10形成的包合物。
无包合物药物:中药组成为熟地12份,生地12份,当归12份,白芍12份,川芎9份,黄芪9份,白术9份,天麻6份,秦艽6份,防风5份,荆芥5份,威灵仙3份,全蝎3份,细辛3份,经提取处理得到的浓缩物,用去离子水配置成生药浓度为2.12g/ml的药液。
中药复配物:中药组成为熟地12份,生地12份,当归12份,白芍12份,川芎9份,黄芪9份,白术9份,天麻6份,秦艽6份,防风5份,荆芥5份,威灵仙3份,全蝎3份,细辛3份,将上述药材打成粗粉,然后用去离子水配制成生药浓度为2.12g/ml的药液。
仪器与材料:自发活动装置;小鼠行为学评估杆与评估箱(爬杆装置和悬挂装置);转棒疲劳仪;注射器、小鼠灌胃针等。
(三)试验动物与分组
C57/BL6小鼠,雄性,体重(21.10±2.01)g,7-10周龄,共48只,SPF级饲养。实验动物共分为阴性对照组、MPTP模型组、中药组(中药复配物)、无包合物药物组、1/2剂量本发明药物组、2/3剂量本发明药物组、正常剂量本发明药物组、阳性药物组(左旋多巴)共8组;每组6只。
(四)试验方法
1.PD模型建立及给药方法
动物预饲养7天,造模5天前开始练习爬杆、悬挂、旷场实验、转棒疲劳训练和强迫游泳实验并进行测试,每日2次。分别于造模前1天,进行各项行为学观察,合格方可入组。入组后将小鼠随机分为8组:阴性对照组、MPTP模型组、中药组、无包合物药物组、1/2剂量本发明药物组、2/3剂量本发明药物组、正常剂量本发明药物组、阳性药物组,每组6只。对照组腹腔注射30mg/kg生理盐水,每日1次,连续注射7d。模型组和给药组,按30mg/kg腹腔注射MPTP,每日1次,连续注射7d。
从第8d开始进行灌胃给药。每天灌胃实验前,将各组小鼠进行称重,根据体重计算给药量。中药组、无包合物药物组和本发明正常剂量药物组按生药容量为13.78g/kg灌胃给药,本发明1/2剂量药物组按6.89g/kg生药量灌胃给药,本发明2/3剂量药物组按9.18g/kg生药量灌胃给药,阳性药物组给予100mg·kg-1左旋多巴混悬液灌胃。MPTP模型组和阴性对照组给予对应10ml·kg-1的纯净水灌胃。每日1次,连续14d。于第14、21天灌胃1h后进行行为学测试和震颤观察,记录各组数据并评分。并于21天试验结束后脱颈处死小鼠,取脑组织进行形态学分析。
造模成功标准为:小鼠出现震颤、弓背、步长缩短、动作迟缓、反应迟缓、竖毛、翘尾、易激惹等异常表现。
2.行为学评价
2.1震颤麻痹评分
腹腔注射给药后,立即进行观察并记录小鼠的震颤、竖毛、翘尾等症状,步态蹒跚、活动减少、步态等症状,持续3h。评分标准为:0分,与正常小鼠相似,无任何症状;1分,出现竖毛、弓背、间断性细小震颤,但活动自如;2分,出现吞咽频繁,频繁性震颤,后肢张开,颤尾,活动逐渐受限;3分,出现流涎、持续性震颤,四肢僵硬,活动受限;4分,因全身麻痹而死亡。
2.2爬杆实验
将一直径为2.5cm的塑料球固定于长50cm、粗1.5cm的亚克力杆顶端,缠上纱布以防打滑,然后将被测小鼠置于球上,记录由球上爬至杆子底部所需时间。评分标准为:3分,爬杆时间<4.01s;2分,爬杆时间为4.01~8.0s;1分,爬杆时间为8.01~12.0s;0分,爬杆时间>12.00s。重复测定3次,每次间隔1min。
2.3悬挂实验
实验时将被测小鼠两前爪置于30cm长,25cm高水平线中点,而后放开小鼠,记录其落地前的时间。评分标准为:0-10s-0分,10-20s-1分,20-30s-2分,30-40s-3分,40-60s-4分,60-90s-5分,超过90s-6分。(备选:被测小鼠倒置悬挂,将两前爪置于30cm长,25cm高水平电线中点,而后放开小鼠,记录其抓握情况。评分标准为:0分,两后爪均可抓住电线;1分,一只后爪可抓住电线;2分,两只后爪均不能抓住电线。如出现后爪反复抓取电线,间断可抓住现象,可记为0.5分)。重复测定2次,间隔2h。
2.4转棒实验
将小鼠置于直径为3cm的旋转杆上,转速调整为30r/min,每次同时测定6只小鼠,每个隔室中1只。记录5分钟内,小鼠从转棒开始转动至掉落转棒所经历的时间。评分标准为:0-10s-0分,10-30s-1分,30-50s-2分,50-70s-3分,70-90s-4分,90-120s-5分,超过120s-6分。
2.5旷场实验
旷场实验所用实验箱为尺寸:250×250×300mm旷场,周壁的颜色为黑色,底面为白色。正上方架摄像头,视野覆盖整个旷场。将动物放置在正中央,同时进行摄像和计时,时间为5min。通过计算机示踪分析系统来分析动物在一定时间内的活动状态。实验室保持安静,室温为20℃左右,光线充足。于实验第0d,7d,14d,21d给药1h后通过视频分析系统记录小鼠活跃度、活动次数、休息时间、活动总路程和轨迹图。
2.6强迫游泳实验
将小鼠放入20cm×30cm×20cm的玻璃水箱中,水深为15cm,水温为室温25℃。评分标准如下:1min能连续游泳者为3分,大部分时间游泳偶尔漂浮为2.5分,50%时间为漂浮状态为2分,偶尔游泳大部分时间漂浮为1.5分,无法游泳偶尔后肢游动为1分。
3.形态学检测
3.1黑质HE染色光镜观察
给药第14日,行为学评估后,将各组小鼠快速脱颈处死,取脑,置于冰上,小心剥离脑组织,置于4%多聚甲醛进行固定过夜。标本脱水后,进行石蜡包埋,在中脑黑质致密(SNPc)部进行连续的冠状面4μm厚度切片,脱蜡,染色。常规脱水,中性树脂封片,光学显微镜下观察黑质神经元的病理形态改变。
3.2免疫组织化学染色
按照免疫组化检测试剂盒步骤进行脱蜡、PBS冲洗、3%H2O2抗原修复和血清封闭。滴加一抗TH抗体(1:300),4℃过夜后顺次滴加试剂1(放大信号)和试剂2(二抗),各孵育15min,PBS冲洗后进行DAB显色、苏木精复染,脱水透明封片。观察小鼠黑质部分TH阳性细胞的形态、数量和分布。
(五)试验结果
注射造模剂7天后,各组小鼠0-7天震颤评分结果如图1所示,除阴性对照组外,各组小鼠均出现四肢不自主震颤、炸毛、精神不佳等帕金森症状,且造模的各组小鼠的震颤评分均无明显差异,造模成功。
给药14天后,如图1-图7所示,各给药组小鼠的震颤情况和行为学评估结果均有所好转,治疗效果比较顺序为:正常剂量本发明药物组>2/3剂量本发明药物组≈阳性药物组>无包合物药物组>1/2剂量本发明药物组>中药组,说明本发明药物较纯中药复配使用可以提高药物治疗效果,包合物的存在还可在药量减少的情况下发挥更好的疗效,治疗效果与阳性药物左旋多巴相当,部分实验结果甚至更好,可见本案的药物组合不但可以明显减少药物的服用剂量,还能缩短治疗周期。
形态学检测结果如表1和图8-9所示。
图8的HE染色结果显示:对照组小鼠神经细胞的大小和形态均表现为正常,整体结构清晰,轮廓边缘清楚,细胞分布均匀,细胞核未见水肿和核固缩,轴突明显。MPTP模型组小鼠黑质神经细胞数目明显减少,细胞分布不均匀,残存神经细胞细胞核大小不等,可见核固缩或肿大,核染色质减少,轴突不明显,出现明显嗜神经细胞现象。中药组小鼠神经元细胞数量有所增加,但神经元大小不等,部分细胞染色质稀疏、肿胀,可见核固缩,轴突不明显,出现嗜神经细胞现象。1/2剂量本发明药物组小鼠正常神经元细胞核固缩,染色质增多现象,神经元轴突不明显。无包合物药物组小鼠正常神经元细胞核固缩,染色质增多现象,神经元尚可见轴突。本发明正常剂量药物组和2/3剂量药物组小鼠脑神经元细胞数目明显增多,细胞体积较大,整体结构较清晰,神经细胞分布较均匀,可见胶质细胞增生和少量淋巴细胞,可见细胞轴突。阳性药物组小鼠神经细胞数目明显增多,神经细胞未见明显异常,出现间质中胶质细胞增生。
上述结果说明,MPTP的毒性对小鼠脑部黑质神经细胞损伤较大,服用不同药物后,小鼠脑内神经细胞损伤均有所改善,其中,本发明正常剂量药物组和2/3剂量药物组小鼠神经细胞数量明显增加,状态未见明显异常,与帕金森病的阳性标准药物左旋多巴治疗效果相当。
表1为各组小鼠黑质部TH阳性表达率,表中显示与模型组相比,6个给药组均有一定治疗效果,其中本发明正常剂量的TH阳性表达率与阳性药物组相近,本发明2/3剂量药物组治疗效果优于无包合物本发明药物组,说明加入引经药可明显提高药物治疗效果,并在一定程度上减少药物用量或缩短药物治疗周期。
表1:各组小鼠TH阳性神经元表达率
组别 | 平均阳性细胞数 | 平均总细胞数 | 平均TH阳性率(%) |
阴性对照组 | 80.5±7.70 | 480.3±35.3 | 16.90%±1.59% |
模型组 | 69.2±7.68 | 462.2±30.3 | 14.94%±0.97% |
纯中药组 | 71.3±1.78 | 468.2±11.3 | 15.22%±1.57% |
无包合物药物组 | 72.2±6.97 | 458.2±41.8 | 15.77%±0.69% |
本发明1/2剂量药物组 | 71.9±3.71 | 463.3±6.4 | 15.48%±0.59% |
本发明2/3剂量药物组 | 75.4±4.27 | 458.9±11.2 | 16.43%±0.58% |
本发明正常剂量药物组 | 76.8±5.23 | 464.9±38.2 | 16.52%±0.58% |
阳性药物组 | 78.0±6.23 | 470.7±29.6 | 16.57%±0.63% |
图9为各组小鼠黑质TH阳性表达结果,结果显示MPTP模型组在黑质区域存在多巴胺能神经元数量减低,能够在形态学上认定帕金森模型制作成功。6个给药组相对于模型组,TH阳性神经元数量明显增多,本发明正常剂量药物组合、本发明2/3剂量药物组与无包合物药物组相比,小鼠黑质部TH阳性表达率更高,治疗效果较好。
(六)结论
上述药效学试验结果可以说明,本发明药物对于帕金森模型小鼠具有很好的治疗效果,且“引经药”的加入可使2/3剂量药物发挥比正常剂量无包合物药物更好的治疗效果,可明显改善帕金森病引发的小鼠行为障碍震颤情况,并在一定程度上恢复受损神经元,减少药物服用剂量、缩短治疗周期。本产品主要成分均为中药成分,具有安全、缓和、治补双效等优点,副作用较少,效果可与西医常用药左旋多巴相比。利于临床上对老年帕金森患者的治疗,受众较广。不仅更有益于患者,而且可以进一步扩大市场占有量,增加经济效益。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.一种治疗帕金森病的中药组合物,其特征在于:按照重量份配比的组成包括:熟地10-15份,生地10-15份,当归10-15份,白芍10-15份,川芎5-10份,黄芪5-10份,白术5-12份,天麻3-10份,秦艽3-10份,防风3-8份,荆芥3-8份,威灵仙1-5份,全蝎1-5份,细辛1-5份。
2.根据权利要求1所述的一种治疗帕金森病的中药组合物,其特征在于:所述中药组合物按照重量份配比的组成包括:熟地12份,生地12份,当归12份,白芍12份,川芎9份,黄芪9份,白术9份,天麻6份,秦艽6份,防风5份,荆芥5份,威灵仙3份,全蝎3份,细辛3份。
3.根据权利要求1或2所述的一种治疗帕金森病的中药组合物,其特征在于:所述中药组合物还包括以下群体中的一种:冰片包合物2-3份,薄荷脑包合物1-2份,麝香酮包合物1-2份。
4.根据权利要求3所述的一种治疗帕金森病的中药组合物,其特征在于:所述中药组合物中,冰片包合物为3份,或者薄荷脑包合物为1份,或者麝香酮包合物为1份。
5.根据权利要求3所述的一种治疗帕金森病的中药组合物,其特征在于:所述包合物是采用冰片或者薄荷脑或者麝香酮与β环糊精按照重量比1:10形成的包合物。
6.一种治疗帕金森病的药物制剂,其特征在于:包括:权利要求1~5任意一项所述的中药组合物和药学上可接受的辅料。
7.权利要求6所述的治疗帕金森病的药物制剂的制备方法,其特征在于:包括以下步骤:
步骤1,按照中药组合物的重量份组成:熟地10-15份,生地10-15份,当归10-15份,白芍10-15份,川芎5-10份,黄芪5-10份,白术5-12份,天麻3-10份,秦艽3-10份,防风3-8份,荆芥3-8份,威灵仙1-5份,全蝎1-5份,细辛1-5份,冰片包合物1-3份或者薄荷脑包合物1-2份或者麝香酮包合物1-2份配料,先将熟地、生地、当归、白芍、川芎、黄芪、白术、天麻、秦艽、防风、荆芥、威灵仙、全蝎、细辛加8-12倍量水浸泡0.5-1.5h,煎煮,过滤出提取液;
步骤2,将提取液浓缩至稠膏,将稠膏烘干得干膏,碾碎干膏过80目备用;或者将提取液浓缩至适宜体积得浓缩液;
步骤3,向干膏粉或浓缩液中加入冰片包合物或薄荷脑包合物或麝香酮包合物混合均匀,再加入辅料混合均匀,制成对应的药物制剂。
8.根据权利要求7所述的治疗帕金森病的药物制剂的制备方法,其特征在于:所述制备方法还包括配料前制备冰片包合物或者薄荷脑包合物或者麝香酮包合物,包括:
(1)将冰片或者薄荷脑或者麝香酮和其10倍重量的β环糊精混合均匀,然后加入β环糊精重量2倍重量的纯化水制成混悬液;
(2)将混悬液使用高速分散器进行剪切并研磨,过滤后干燥至水分不大于10%,即得。
9.根据权利要求8所述的治疗帕金森病的药物制剂的制备方法,其特征在于:所述(2)中剪切并研磨的控制参数为:转速2000~3500rpm,时间20~30min。
10.根据权利要求8所述的治疗帕金森病的药物制剂的制备方法,其特征在于:所述(2)中干燥温度为40~45℃。
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