CN107468701A - 化合物20(R)‑三七皂苷Ft1及其药物组合物在制备抗炎药物中的应用 - Google Patents
化合物20(R)‑三七皂苷Ft1及其药物组合物在制备抗炎药物中的应用 Download PDFInfo
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Abstract
本发明提供化合物20(R)‑三七皂苷Ft1在制备抗炎药物中的应用,以及一种抗炎功能的药物组合物,该药物组合物以化合物20(R)‑三七皂苷Ft1(20(R)‑notoginsenoside Ft1)为有效成分,并含有常规药用载体。本发明同时还提供化合物20(R)‑三七皂苷Ft1在制备抗炎功能性食品中的应用。
Description
技术领域:
本发明属于药物技术领域,具体涉及有效成分20(R)-三七皂苷Ft1(20(R)-notoginsenoside Ft1)及其药物组合物在制备抗炎的药物及功能性食品中的应用。
背景技术:
炎症是临床常见的一个病理过程,可以生于机体各部位的组织和各器官。急性炎症通常具有红、肿、热、痛、机能障碍等变化,同时往往伴有发热、白细胞增多等全身反应,是机体与致炎因子进行斗争的客观反映并贯串在炎症过程的始终。致炎因子作用于机体后,一方面引起组织细胞的损害,使局部组织细胞发生变性、坏死;另一方面,激起机体抗病机能增强,以利于消灭致炎因子,使受损害的组织得到修复,从而使机体受到损害之后,机体的内坏境以及内环境和外坏境之间达到新的平衡。
一般来说,炎症是机体的一种抗病反应,是对机体有利的,例如炎性充血,能使局部组织得到较多的氧、营养物质和防御物质;局部组织代谢和抵抗力增强;渗出液能稀释毒素,其中所含的抗体能消灭细菌并中和毒素;渗出的纤维蛋白元凝结而成假膜,形成成一道屏障,能阻止病原菌向深部蔓延;渗出物中的中性白细胞和巨噬细胞能吞噬细菌,还能吞噬清除坏死崩解的细胞碎屑;炎区的浆细胞和淋巴细胞能产生抗体中和毒素;组织增生能修复炎区所造成缺损。但是炎症也是有危害的,甚至是致命性的。例如,渗出液过多则往往造成有关器官的机能障碍,如胸腔积液可压迫肺,出现呼吸困难;心包积液影响心脏搏动,同样炎症后期的结缔组织增生及机化虽然有利于组织修复,但又往往造成粘连或实质性器官的硬变,严重地影响该器官的功能。此外,特殊部位或器官所发生的炎症可造成严重后果,如脑或脑的炎症可压迫生命中枢,声带炎症阻塞喉部导致窒息,严重的心肌炎可以影响心脏功能,此时,应使用抗炎症药物抑制炎症反应。
抗炎药主要有两大类,一类是甾体抗炎药,是一类含有甾体结构的抗炎药,主要是肾上腺皮质所分泌的糖皮质激素氢化可的松及其人工合成的衍生物。另一类是非甾体抗炎药,是一类不含有甾体结构的抗炎药,阿司匹林、对乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布、塞来昔布等,该类药物具有抗炎、抗风湿、止痛、退热和抗凝血等作用,在临床上广泛用于骨关节炎、类风湿性关节炎、多种发热和各种疼痛症状的缓解。
迄今,尚未发现20(R)-三七皂苷Ft1作为有效成分在抗炎症功能方面的应用和报道,也未发现该化合物在制备抗炎症功能的药物及功能性食品中应用的报道。实验表明20(R)-三七皂苷Ft1具有较好的抗炎症作用,其疗效与阳性对照药相当,同时兼备安全性优的特点,具有较好的应用前景。
发明内容:
本发明的目的在于提供一种抗炎症功能的药物组合物,其中含有抗炎症功能的化合物20(R)-三七皂苷Ft1及药用载体和/或赋形剂,提供该化合物及其药物组合物在制备抗炎药物以及功能性食品中的应用。
为了实现本发明的上述目的,本发明提供了如下的技术方案:
化合物20(R)-三七皂苷Ft1在制备治疗炎症的药物中的应用。
根据所述的化合物20(R)-三七皂苷Ft1在制备治疗炎症的药物中的应用,其中所述的炎症为急性或亚急性或慢性炎症。
本发明还提供了化合物20(R)-三七皂苷Ft1在制备治疗关节炎、风湿性关节炎的药物中的应用。
根据所述的化合物20(R)-三七皂苷Ft1在制备治疗炎症或治疗关节炎、风湿性关节炎的药物中的应用,其中化合物20(R)-三七皂苷Ft1是通过抑制二甲苯所致机体耳肿胀且呈剂量依赖性,实现抗炎作用。
根据所述的化合物20(R)-三七皂苷Ft1在制备治疗炎症或治疗关节炎、风湿性关节炎的药物中的应用,其中化合物20(R)-三七皂苷Ft1是通过抑制角叉菜胶所致机体足肿胀且呈剂量依赖性,实现抗炎作用,抗炎作用优于阳性药吲哚美辛。
本发明另外还提供了化合物20(R)-三七皂苷Ft1在制备抗炎功能性食品中的应用。
本发明同时还提供了一种抗炎的药物组合物,含有式(A)所示的化合物20-(R)-三七皂苷Ft1及可药用载体或赋形剂,
以及,所述的药物组合物在制备治疗炎症的药物中的应用,其中所述的炎症指急性或亚急性或慢性炎症。
本发明同时还提供了所述的药物组合物在制备治疗关节炎、风湿性关节炎药物中的应用。
本发明化合物作为药物时,可直接使用,或者以药物组合物的形式使用。该药物组合物中含有0.1-99%的20(R)-三七皂苷Ft1,优选为0.5-90%的有效成分20(R)-三七皂苷Ft1,其余为药物学和药剂学上可接受的,对人和动物无毒的药用辅料或载体。
所述的药用载体为一种或多种固体、半固体和/或液体稀释剂,填料以及药物制品辅料。本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经注射(肌注和静注)和口服两种形式给药,功能性食品以口服形式给药。
炎症是一种普遍性的疾病,有的炎症疾病如关节炎,风湿性关节炎等往往较难治愈。20(R)-三七皂苷Ft1各剂量组均可不同程度抑制二甲苯所致小鼠的耳肿胀且呈剂量依赖性,高剂量组(200mg/kg)抑制率54.12%,优于阳性药阿司匹林(200mg/kg)的抑制率49.36%。20(R)-三七皂苷Ft1各给药组均能不同程度抑制角叉菜胶所致小鼠的足肿胀且呈剂量依赖性,灌胃给药高剂量组(200mg/kg)抑制率39.07%,腹腔注射给药剂量组(20mg/kg)抑制率52.40%,作用显著,优于阳性药吲哚美辛(10mg/kg)的抑制率42.73%。20(R)-三七皂苷Ft1在所设剂量范围内对小鼠急性、亚急性炎症显示了较好的疗效,其疗效优于阳性药,同时兼备安全性优的特点,在治疗炎症方面具有较好的应用前景。
具体实施方式:
下面的实施例可更详细地说明本发明,但不以任何形式限制本发明。
实施例1:
20(R)-三七皂苷Ft1的制备:
三七茎叶用10倍量1%HCl溶液提取,提取2次,每次2小时,合并滤液,用3%NaOH溶液调pH至7,经浓缩干燥,得干膏。干膏100g,以硅胶(200-300目)拌样并进行硅胶柱层析,以氯仿∶甲醇:水(8:2:0.2)为洗脱剂,薄层层析检查并合并色点相同的流份,得Fr1-5流份。Fr4(5g)以氯仿:甲醇:水(8:2:0.2)为洗脱剂进行反复硅胶柱层析,以及反相硅胶RP-18柱层析(甲醇∶水/7:3),得20(R)-三七皂苷Ft1(0.12g)。
20(R)-三七皂苷Ft1的结构鉴定:
仪器:质谱(MS)用VGAutopec-3000型质谱仪测定;核磁共振谱{1H-、13C-NMR(DEPT)}用Bruker AM-400型和DRX-500型超导核磁共振波谱仪测定,以TMS(四甲基硅烷)为内标。
结构:如化学式
分子式:C47H80O17
分子量:916
13C-NMR(C5D5N):δ39.2(C-1),26.8(C-2),89.0(C-3),39.8(C-4),56.4(C-5),18.5(C-6),35.2(C-7),40.0(C-8),50.4(C-9),37.0(C-10),31.5(C-11),70.8(C-12),49.2(C-13),51.8(C-14),32.2(C-15),26.7(C-16),50.7(C-17),17.4(C-18),16.4(C-19),73.0(C-20),22.7(C-21),43.3(C-22),22.7(C-23),126.1(C-24),130.8(C-25),25.9(C-26),18.5(C-27),28.1(C-28),16.7(C-29),17.8(C-30),104.8(C-1′),82.9(C-2′),77.8(C-3′),71.8(C-4′),76.0(C-5′),63.0(C-6′),103.2(C-1″),84.6(C-2″),78.4(C-3″),71.1(C-4″),78.0(C-5″),62.9(C-6″),106.5(C-1′′′),76.0(C-2′′′),78.7(C-3′′′),70.9(C-4′′′),67.5(C-5′′′)。
实施例2:
20(R)-三七皂苷Ft1的体内抗炎活性实验:
1药物
(1)受试药物
20(R)-三七皂苷Ft1,白色粉末;实验时以0.05%羧甲基纤维素钠研磨配制成混悬液。
(2)对照药品
吲哚美辛肠溶片,国药准字H50020263,25mg/片,成人常用量为每次1~2片,每日2~3次;重庆科瑞制药生产,批号259002,遮光、密封保存。
拜阿斯匹林肠溶片,国药准字J20130078,进口药品注册证号H20130192,100mg/片,密封,25℃以下保存。
(3)剂量设置及配制方法
吲哚美辛肠溶片,临床用量为150mg/日/人,试验剂量设为10mg/kg,相当于临床用量的4倍,用纯水配制成0.5mg/mL浓度的混悬液。
拜阿司匹林肠溶片,临床用量为100-300mg/日/人,试验剂量设为200mg/kg,相当于临床用量的40倍,用纯水配制成10mg/mL浓度的混悬液。
20(R)-三七皂苷Ft1共设置三个剂量组,分别为200、100、40mg/kg(灌胃给药),10、20mg/kg用生理盐水配制腹腔注射给药。
为保证试验样品的稳定性,以上所有样品均每日现配现用。
2动物
(1)品系及来源
SPF级雄性ICR小鼠,体重19~24g;购自北京华阜康生物科技股份有限公司,生产许可证号:SCXK(京)2014-0004,质量检测单位:中国医学科学院医学实验动物研究所,动物购进适应性饲养5天进入实验。
(2)饲养条件
小鼠饲养于IVC动物实验室,温度20~25℃(日温差≤3℃);湿度40%~70%;照明12h:12h明暗交替,照度150~300lx;噪音≤60dB。实验动物使用许可证:SYXK(滇)K2013-0002,发证单位:昆明市科学技术局。
(3)饲养管理
采用PVC透明塑料盒群养,每箱≤10只,每日喂饲鼠用配合饲料,自由饮水,视情况更换笼具和垫料。饲料来源于昆明医科大学实验动物中心,生产许可证:SCXK(滇)2011-0005,发证单位:云南省科学科技厅。
3主要仪器
MS104S/PL600-S型电子分析天平,瑞士METTLER TOLEDO;Millipore Rios3水纯化系统,Millipore;YLS-Q4型耳肿打耳器,济南益延科技有限公司;QT-1漩涡混合器,上海琪特仪器分析仪器有限公司。
4主要试剂
二甲苯,分析纯化学试剂,GB/716494-1996,四川西陇化工有限公司。角叉菜胶,Sigma-C1013,CAS:9000-07-1,25g。
5数据处理
计量资料用平均数±标准差表示,方差齐时组间比较采用LSD检验,方差不齐时组间比较采用Dunnett’s T3检验;偏态分布用秩和检验。P<0.05有统计学意义,P<0.01有显著统计学意义。
6实验方法
(1)对二甲苯致小鼠耳肿胀的影响
选19~21g雄性ICR小鼠,按体重随机分为6组:对照组;阳性对照阿司匹林肠溶片200mg/kg;20(R)-三七皂苷Ft1 200、100、40mg/kg组(ig);20(R)-三七皂苷Ft1 20mg/kg(ip)每组10只。除拜阿司匹林片仅于实验当天灌胃给药一次外,其余各组动物均每日按剂量灌胃给药一次,连续7天,对照组给予20mL/kg.bw的纯水。末次给药后30分钟,于各组小鼠右耳两面涂二甲苯0.05mL。致炎后1h脱颈椎处死动物,剪下左右耳廓,用直径8mm打耳器分别在两耳同一部位打下圆耳片,用分析天平称重,以两耳重量之差作为肿胀度。为减小系统误差,试验采用平行操作。结果见表1。
由表1可见,20(R)-三七皂苷Ft1各剂量组均可不同程度抑制二甲苯所致小鼠的耳肿胀,阳性药阿司匹林200mg/kg,20(R)-三七皂苷Ft1 200mg/kg(ig)、20(R)-三七皂苷Ft120mg/kg(ip)剂量组作用显著,与对溶媒照组相比差异均具有统计学意义。20(R)-三七皂苷Ft1 100mg/kg剂量组具有作用趋势。
表1 20(R)-三七皂苷Ft1对二甲苯致小鼠耳肿胀的影响
与对照组相比,*/**P<0.05/0.01
(2)对角叉菜胶致小鼠足肿胀的影响
选19~21g雄性ICR小鼠,按体重随机分为7组:对照组;阳性对照吲哚美辛片10mg/kg;20(R)-三七皂苷Ft1 200、100、40mg/kg组(ig);20(R)-三七皂苷Ft1 10、20mg/kg(ip)每组12只。除吲哚美辛片仅于实验当天灌胃给药一次外,其余各组动物均每日按剂量灌胃给药一次,连续7天,对照组给予20mL/kg.bw的纯水。末次给药后30分钟,于各组小鼠右后足跖皮下注射1%角叉菜胶0.05mL/足。致炎后4h脱颈椎处死动物,用利剪于踝关节处取下双足称重,以两足重量之差作为肿胀度。为减小系统误差,试验采用平行操作。结果见表2。
由表2可见,所有给药组均能不同程度抑制角叉菜胶所致小鼠的足肿胀,与溶媒对照组相比,以20(R)-三七皂苷Ft1 200mg/kg、40mg/kg灌胃给药;20(R)-三七皂苷Ft110mg/kg、20mg/kg腹腔注射给药作用显著(P<0.05,P<0.01)。差异均具有统计学意义。
表2 20(R)-三七皂苷Ft1对角叉菜胶致小鼠足肿胀的影响
与对照组相比,*/**P<0.05/0.01
实施例3:
将20(R)-三七皂苷Ft1溶于无菌注射用水,使溶解,再经无菌漏斗抽滤,精滤,灌封,灭菌,制成注射液。
实施例4:
将20(R)-三七皂苷Ft1按其与赋形剂重量比1:15的比例混合均匀,制粒,压片。
实施例5:
将20(R)-三七皂苷Ft1按其与赋形剂重量比1:8的比例混合均匀,制粒,压片。
实施例6:
将20(R)-三七皂苷Ft1按其与赋形剂重量比1:12的比例混合均匀,制粒,制成胶囊剂。
实施例7:
将20(R)-三七皂苷Ft1按其与赋形剂重量比1:5的比例混合均匀,制粒,制成胶囊剂。
实施例8:
将20(R)-三七皂苷Ft1按常规口服液的制法制成口服液。
实施例9:
20(R)-三七皂苷Ft1干粉100g,糊精30000g,8%淀粉浆。将上述原辅料按照常规制备颗粒剂的工艺制备,即先对原辅料进行检验称重-制软材-制粒-燥-粒-品分装-灭菌。颗粒剂规格:10g/袋。
实施例10:
20(R)-三七皂苷Ft1以1∶10000的比例添加到果酱、牛奶、蜂蜜等固体和液体食品中,发挥其保健功能。
实施例11:
取实施例1所得20(R)-三七皂苷Ft1 50克,加入石蜡150克,加热溶解,置冷;另取50克20(R)-三七皂苷Ft1干粉,研细,倒入大豆油2680g,搅拌,加入大豆磷脂(70克),混匀。将上述配好的药液过胶体磨(混匀),过40目筛,最后灌装软胶囊(规格:内容物0.5-1克),干燥3天,灭菌,包装即得。
Claims (10)
1.化合物20(R)-三七皂苷Ft1在制备治疗炎症的药物中的应用。
2.根据权利要求1所述的化合物20(R)-三七皂苷Ft1在制备治疗炎症的药物中的应用,其特征在于所述的炎症为急性或亚急性或慢性炎症。
3.化合物20(R)-三七皂苷Ft1在制备治疗关节炎、风湿性关节炎的药物中的应用。
4.根据权利要求1或3所述的化合物20(R)-三七皂苷Ft1在制备治疗炎症或治疗关节炎、风湿性关节炎的药物中的应用,其特征在于化合物20(R)-三七皂苷Ft1是通过抑制二甲苯所致机体耳肿胀且呈剂量依赖性,实现抗炎作用。
5.根据权利要求1或3所述的化合物20(R)-三七皂苷Ft1在制备治疗炎症或治疗关节炎、风湿性关节炎的药物中的应用,其特征在于化合物20(R)-三七皂苷Ft1是通过抑制角叉菜胶所致机体足肿胀且呈剂量依赖性,实现抗炎作用,抗炎作用优于阳性药吲哚美辛。
6.化合物20(R)-三七皂苷Ft1在制备抗炎功能性食品中的应用。
7.一种抗炎的药物组合物,含有式(A)所示的化合物20-(R)-三七皂苷Ft1及可药用载体或赋形剂,
8.权利要求7所述的药物组合物在制备治疗炎症的药物中的应用。
9.根据权利要求8所述的药物组合物在制备治疗炎症的药物中的应用,其中所述的炎症指急性或亚急性或慢性炎症。
10.权利要求7所述的药物组合物在制备治疗关节炎、风湿性关节炎药物中的应用。
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