CN115192645B - 一种中药组合物及其制备方法和应用 - Google Patents
一种中药组合物及其制备方法和应用 Download PDFInfo
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- CN115192645B CN115192645B CN202110385137.3A CN202110385137A CN115192645B CN 115192645 B CN115192645 B CN 115192645B CN 202110385137 A CN202110385137 A CN 202110385137A CN 115192645 B CN115192645 B CN 115192645B
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Abstract
本发明涉及一种中药组合物,包含青蒿、金银花、栀子提取纯化得到的活性成分,所述活性成分包括:新绿原酸2‰以上,绿原酸5‰以上,隐绿原酸2‰以上,咖啡酸0.07‰以上,异绿原酸B 0.35‰以上,异绿原酸A 0.17‰以上,异绿原酸C 0.19‰以上,栀子苷5.97‰以上,断氧化马钱子苷0.07‰以上,山栀苷0.17‰以上,京尼平苷酸0.22‰以上,京尼平龙胆双糖苷0.76‰以上,7‑羟基獐牙菜2.44‰以上;该组合物中,含总酸10.3‰以上,总苷21.58‰以上。基于本发明的实验内容,筛选出了具备特定活性成分含量特征的中药组合物具有稳定、优异的治疗效果,上述活性成分含量特征可用于该中药组合物的质量控制,从而保证中药制剂质量稳定以及疗效可靠。
Description
技术领域
本发明涉及中药技术领域,尤其涉及一种中药组合物及其制备方法和应用。
背景技术
外感风热证,是在人体卫外功能减弱,不能调节应变之时,病邪从口鼻、皮毛入侵,邪犯肺卫,卫表不和而致病。常见于上呼吸道感染、流感、急性支气管炎、肺炎等疾病,主要症状有高热不退、微恶风、鼻塞、流涕、头身痛、咳嗽、口渴、咽喉肿痛、舌边尖红、脉浮数等。据统计,由于发热引起的死亡,全世界每年至少有200万以上,尤其是上呼吸道感染和急性支气管炎起的高热,严重影响着人们的身体健康,每年用于治疗的费用高达几十亿元。
引起高热的原因有许多,如病毒性感染、细菌性感染、支原体感染、寄生虫感染等,其中常见的是病毒或细菌性感染引起的高热。发热本来是机体的一种防御反应。它可加快新陈代谢过程,抑制病原体的生长繁殖,促使白细胞增多,加强网状内皮系统的功能(吞噬细胞的活性、抗体生成及肝脏解毒能力等),有利于疾病的恢复。热型对疾病的诊断、判断治疗效果及预后都有重要的参考价值。另一方面发热也会使体力消耗,引起头痛、失眠甚至惊厥。超高热(41℃以上)或持久发热还可导致永久性脑损伤乃致死亡。因此,对中度以上发热适当应用退热药是必要的。西医对发热的治疗主要是应用解热镇痛药(如卡巴匹林钙、阿斯匹林赖氨酸、布洛芬、对乙酰氨基酚、萘普生等非甾体类药物)和抗病毒抗菌药物(如有阿昔洛韦、金刚脘胺、病毒唑、青霉素、红霉素等)。其退热虽快,但毒副作用大,主要表现为恶心,呕吐、腹泻、腹痛等胃肠道反应以及对血小板的影响,还偶见头晕、嗜唾、失眠、皮疹等症状。而中医在治疗该病上,有着疗效好、毒副作用小的特点,因此,开发新的高效抗病毒抗菌解热新中药有着广阔的前景。
申请号02114995.X的专利公开了一种用于清热解毒的药物,配方为青蒿6-25、金银花3-15、栀子3-12,对外感风热所致发热症有很好的治疗作用。然而,对于中药复方而言,原料大多来源于天然产物,受产地、生长时限、采收时节、种植加工技术等因素的影响,药材质量高度变异,即使在药材原料均符合药典规定的前提下,不同产地、批次的药材原料仍会由于有效成分的差异导致不同批次制剂成分不稳定、质量一致性差。可见,仅有药材重量的处方无法满足现代中成药的生产要求,严重制约中医药临床疗效的稳定可控,影响研究结果的可重复性和被认可度。同时,中药复方复杂体系中有效成分不明确,哪些主要成分对疗效有明显的影响作用,其合理的优选含量范围是多少,都需要对不同有效成分的范围进行合理控制,如何保证中药制剂质量稳定的同时还要保证其具有更好的疗效,是制约现代中药发展的一个关键问题。
发明内容
本发明旨在对青蒿、金银花、栀子3味中药组成的中药复方进行进一步研究,通过不同产地、不同批次药材组配中药复方进行成分分析和药效试验,关注该中药组方中含量差异波动较大的主要成分与药效试验效果的关系,寻找出能影响药效的具体活性成分及适宜含量,筛选出活性更强的中药组合物,进一步限定出活性成分的优选范围组合并完善制备工艺,保障中成药产品的质量稳定、疗效可靠。
经过前期大量的物质基础研究,已从该中药组合物中共分离101个化合物,其中包括32个有机酸类化合物(新绿原酸、绿原酸、异绿原酸A/B/C、隐绿原酸等)及29个环烯醚萜苷类化合物(栀子苷、京尼平龙胆双糖苷、京尼平苷酸、山栀苷、断氧化马钱子苷等)。文献报道了新绿原酸、绿原酸、异绿原酸A/B/C、隐绿原酸、均具有抗菌药理作用;咖啡酸具有抗呼吸道合胞病毒作用,断氧化马钱子苷具有抗炎药理作用抗病毒药理作用;栀子中大部分环烯醚萜苷类化合物具有抗炎镇痛、抗病毒作用,体外抗病毒活性试验证实,京尼平类化合物对H1N1流感病毒有抑制效果。
根据文献报道,结合药典中3味药材的含量控制成分以及热毒宁注射液成品中结构明确成分的量,综合确定选取了来自其中的新绿原酸,绿原酸,隐绿原酸,咖啡酸,异绿原酸B,异绿原酸A,异绿原酸C、7-羟基獐牙菜、栀子苷、断氧化马钱子苷、山栀苷、京尼平苷酸、京尼平龙胆双糖苷共13个成分作为指标成分组合,研究上述指标成分含量不同的组合情况发挥的药效作用,寻找能够更有效地发挥药效地含量范围及相互比例关系。
有鉴于此,本发明提出了一种中药组合物,其特征在于,所述组合物,以质量千分比计,包括新绿原酸2‰以上,绿原酸5‰以上,隐绿原酸2‰以上,咖啡酸0.07‰以上,异绿原酸B 0.35‰以上,异绿原酸A 0.17‰以上,异绿原酸C 0.19‰以上,栀子苷5.97‰以上,断氧化马钱子苷0.07‰以上,山栀苷0.17‰以上,京尼平苷酸0.22‰以上,京尼平龙胆双糖苷0.76‰以上,7-羟基獐牙菜2.44‰以上;该提取物中,总酸10.3‰以上,总苷21.58‰以上。
优选地,所述活性成分包括:新绿原酸2.5-5.14‰,绿原酸5.56-11.11‰,隐绿原酸2.36-5.00‰,咖啡酸0.14-0.26‰,异绿原酸B0.43-1.00‰,异绿原酸A 0.22-0.46‰,异绿原酸C 0.38-0.69‰,栀子苷9.53-17.71‰,断氧化马钱子苷0.35-3.43‰,山栀苷0.42-0.79‰,京尼平苷酸0.36-0.68‰,京尼平龙胆双糖苷1.00-1.88‰,7-羟基獐牙菜3.31-6.88‰;该提取物中,总酸13.89-27.78‰,总苷23.68-50.61‰。
上述活性成分的比例关系为:
新绿原酸2.5-5.14,绿原酸5.56-11.11,隐绿原酸2.36-5.00,咖啡酸0.14-0.26,异绿原酸B0.43-1.00,异绿原酸A 0.22-0.46,异绿原酸C 0.38-0.69,栀子苷9.53-17.71,断氧化马钱子苷0.35-3.43,山栀苷0.42-0.79,京尼平苷酸0.36-0.68,京尼平龙胆双糖苷1.00-1.88,7-羟基獐牙菜3.31-6.88;该提取物中,总酸13.89-27.78,总苷23.68-50.61。所述中药组合物可为任选的制剂形式,具体的制备方法如:
取金银花750重量份,加入9-16倍量的90-100℃的热水,提取1-3次,每次1-2小时,得金银花提取物;取青蒿1250重量份加3-6倍水浸润后水蒸气蒸馏5-8小时,提取青蒿挥发油,药渣加入3-9倍量水提取1-3小时,提取液浓缩到相对密度1.10-1.12(70-80℃)加入乙醇使含醇量达到60-80%,静置12小时,取醇沉上清液与金银花提取液合并60-80℃减压浓缩至相对密度1.05-1.15得青蒿金银花提取浓缩液,浓缩液加入乙醇,使含醇量达到70%-80%,醇沉静置24-48小时,取醇沉上清液,减压浓缩获得醇沉浓缩液,加浓盐酸调pH值到1.5-2.5,采用8-16倍乙酸乙酯萃取,获得萃取液,减压浓缩至无乙酸乙酯味,真空干燥,得金银花青蒿提取物;取栀子600重量份,粉碎成粗粉,加入6-10倍60-80%乙醇提取1-3次,每次1-3小时,提取液减压浓缩至相对密度1.10-1.20(60-70℃),得栀子提取浓缩液,加热至沸腾,盐酸调整pH值至2.5-3.5,加入栀子重量1%的固体石蜡,搅拌使完全溶解,冷至室温,冷藏24小时,滤过,采用5-10倍量正丁醇萃取,萃取浓缩液减压浓缩至无正丁醇味,真空干燥,得栀子提取物。将以上金银花青蒿提取物、栀子提取物以及青蒿挥发油,经过常规工序混合即得。
具体地,所述青蒿的指纹图谱与对照指纹图谱,以不少于15个如图1所标示的指纹峰为参照校正峰,相似度大于0.5。具体地,该对照指纹图谱峰面积及其保留时间如下:
Mark峰序号 | 保留时间[Min] | 峰面积 |
1 | 3.882885 | 731.039 |
2 | 9.348604 | 238.769 |
3 | 10.29601 | 271.04 |
4 | 12.74284 | 231.6808 |
5 | 15.21369 | 585.2557 |
6 | 16.36838 | 243.2447 |
7 | 19.64414 | 683.0679 |
8 | 25.43884 | 415.1487 |
9 | 26.61364 | 252.1879 |
10 | 28.55216 | 264.1007 |
11 | 32.46935 | 936.6907 |
12 | 33.13216 | 616.8419 |
13 | 34.28907 | 386.3651 |
14 | 36.97964 | 219.1915 |
15 | 38.53798 | 842.427 |
具体地,所述金银花中4个成分提取量:绿原酸应不得少于2.0%;新绿原酸应不得少于0.05%;隐绿原酸应不得少于0.05%;断氧化马钱子苷应不得少于0.2%;其与对照指纹图谱如图2相比,所标出的12个色谱峰显示,相似度大于0.95。具体地,该对照指纹图谱峰面积及其保留时间如下:
所述栀子的指纹图谱与对照指纹图谱如图3相比,所标出的4个色谱峰显示,相似度大于0.9。具体地,该对照指纹图谱峰面积及其保留时间如下:
具体地,所述中药组合物可包括提取物、汤剂、颗粒剂、胶囊剂、软胶囊剂、丸剂、口服液、酊剂、糖浆剂、栓剂、凝胶剂、喷雾剂、注射剂。
进一步地,当所述中药组合物为注射剂,制备方法还包括:取注射用水800-1200体积份煮沸,投入上述方法制得的金银花青蒿提取物以及栀子提取物,搅拌使两种提取物溶解,保持沸腾3-7分钟,冷却至室温,冷藏20-36小时,滤过,滤液调pH值为2-3,取滤液加热至沸腾,加入1%活性炭,煮沸8-14分钟,冷藏20-36小时后过滤,取滤液,加热至沸腾,调pH为5.05,沸腾9-13分钟后冷却到室温,冷藏40-58小时,滤过,加入0.3-0.8重量份亚硫酸氢钠,定容1000体积份,搅拌取溶液50体积份,加热到65℃加入吐温803-5体积份,搅匀,加入青蒿挥发油,搅匀,滤过,将滤液用分子量为30000的中空纤维膜进行超滤,得超滤液;取30000超滤药液,用分子量为10000的板式膜进行超滤,得超滤液,过0.22μm的微孔滤膜,分装,流通蒸汽灭菌35-50min,即得。
本发明还提出了上述的中药组合物活性部位在制备解热药物中的应用和/或在制备抗炎药物中的应用。本发明利用鼠模型证实了上述活性成分在特定范围的中药组合物在解热和抗炎方面体现出优异的效果。
所述“应用”是指将上述提取物给予具有相应疾病或该疾病的倾向的受试者,其目的为赋予治疗效果,例如治愈、缓解、改变、影响、改善或预防上述疾病、其症状或其倾向。本领域技术人员,能根据所治疗的疾病的类型、给药途径、赋形剂的使用容易确定具体的有效剂量,该剂量可能会因为同时使用其它药物而有所差异。
上述成分含量关系同时为该中药组合物的质量控制提供依据,即本发明提出了上述中药组合物的质量控制方法,该中药组合物可选地为由青蒿、金银花、栀子提取纯化得到的活性成分提取物制得的注射剂,所述活性成分中:新绿原酸2‰以上,绿原酸5‰以上,隐绿原酸2‰以上,咖啡酸0.1‰以上,异绿原酸B 0.5‰以上,异绿原酸A 0.1‰以上,异绿原酸C 0.1‰以上,栀子苷10‰以上,断氧化马钱子苷1‰以上,断马钱子酸4‰以上,山栀苷0.1‰以上,京尼平苷酸0.1‰以上,京尼平龙胆双糖苷0.5‰以上,7-羟基獐牙菜2‰以上,总酸10‰以上,总苷15‰以上。
进一步地,所述活性成分的比例关系为:新绿原酸2.5-5.14,绿原酸5.56-11.11,隐绿原酸2.36-5.00,咖啡酸0.14-0.26,异绿原酸B0.43-1.00,异绿原酸A 0.22-0.46,异绿原酸C 0.38-0.69,栀子苷9.53-17.71,断氧化马钱子苷0.35-3.43,山栀苷0.42-0.79,京尼平苷酸0.36-0.68,京尼平龙胆双糖苷1.00-1.88,7-羟基獐牙菜3.31-6.88;该组合物中,含总酸13.89-27.78,总苷23.68-50.61。
本发明通过研究中药组合物活性成分对LPS致大鼠发热体温变化的影响以及对醋酸致小鼠腹腔毛细血管通透性的影响,实验结果表明,不同产地、批次的药材原料仍会由于有效成分的差异导致不同批次制剂成分不稳定、质量一致性差。但基于本发明的实验内容,筛选出了具备特定活性成分含量特征的中药组合物具有稳定、优异的治疗效果,是优选的中药组合物,上述活性成分含量特征可用于该中药组合物的质量控制,从而保证中药制剂质量稳定以及疗效可靠。
附图说明
图1为青蒿药材对照标准指纹图谱;
图2为金银花药材对照指纹图谱;
图3为栀子药材对照指纹图谱。
具体实施方式
如前所述,本发明旨在提供一种中药组合物及其制备方法和应用。以下将结合实验例的内容进行具体描述。
特别需要指出的是,针对本发明所做出的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。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。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
本发明如未注明具体条件者,均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,均为可以通过市购获得的常规产品。
实施例1:中药组合物的制备
选用不同产地、批次的药材组合,共制备多批次中药组合物。均采用如下方法:
取金银花750重量份,加入13倍量的100℃的热水,提取2次,每次2小时,得金银花提取物;取青蒿1250重量份,加5倍量水浸润后水蒸气蒸馏7小时,提取青蒿挥发油,药渣加入6倍量水提取2小时,提取液及金银花提取液60℃减压浓缩到相对密度为1.10,加入乙醇,使含醇量达到80%,静置30小时,取醇沉上清液,减压浓缩获得醇沉浓缩液,加浓盐酸调pH值到2.2,采用12倍乙酸乙酯萃取,获得萃取液,减压浓缩至无乙酸乙酯味,真空干燥,得金银花青蒿提取物。取栀子600重量份,粉碎成粗粉,用7倍量80%乙醇加热回流3次,每次2小时,提取液减压浓缩至相对密度1.15(65℃),得栀子提取浓缩液,加热至沸腾,盐酸调整pH值至3.0,加入栀子重量1%的固体石蜡,搅拌使完全溶解,冷至室温,冷藏24小时,滤过,采用5倍量正丁醇萃取,萃取浓缩液减压浓缩至无正丁醇味,真空干燥,得栀子提取物。
取注射用水900体积份煮沸,投入金银花青蒿提取物及栀子提取物,搅拌使两种提取物溶解,保持沸腾6分钟,冷却至室温,冷藏28小时,滤过,滤液调pH值为2.5,取滤液加热至沸腾,加入1%活性炭,煮沸12分钟,冷藏28小时后过滤,取滤液,加热至沸腾,调pH为5.05,沸腾12分钟后冷却到室温,冷藏50小时,滤过,加入0.5重量份亚硫酸氢钠,定容1000体积份,搅拌取溶液50体积份,加热到65℃加入吐温804体积份,搅匀,加入青蒿挥发油,搅匀,滤过,将滤液用分子量为30000的中空纤维膜进行超滤,得超滤液;取30000超滤药液,用分子量为10000的板式膜进行超滤,得超滤液,过0.22μm的微孔滤膜,分装,流通蒸汽灭菌50min,即得。
所述体积份/重量份与ml/g相对应。
实施例2:13个组分检测方法
1.仪器与试剂
Agilent 1290高效液相色谱仪(美国安捷伦科技有限公司);ME204E电子分析天平(梅特勒-托利多上海有限公司);XS205电子分析天平(梅特勒-托利多上海有限公司);KH-300DB超声波清洗器(昆山禾创超声仪器有限公司);UV-2401PC紫外分光光度计(日本岛津公司);ST16R高速冷冻离心机(赛默飞世尔科技有限公司);HH-4数显恒温水浴锅(国华电器有限公司);电热恒温鼓风干燥箱(上海精宏实验设备有限公司)。13个组份对照品:京尼平苷酸、山栀苷、京尼平龙胆双糖苷、栀子苷、断氧化马钱子苷、7-羟基獐牙菜苷、新绿原酸、咖啡酸、绿原酸、隐绿原酸、异绿原酸B、异绿原酸A、异绿原酸C。
2.测定方法:采用UPLC方法进行13个组份含量的测定。
对照品溶液制备:分别称取山栀苷、京尼平苷酸、京尼平龙胆双糖苷、新绿原酸、绿原酸、隐绿原酸、咖啡酸、栀子苷、断氧化马钱子苷、异绿原酸B、异绿原酸A、异绿原酸C、7-羟基獐牙菜苷对照品各适量,精密称定,加25%甲醇溶解并定容,制成对照品储备液。混合对照品溶液制备:取上述对照品母液适量,配制成混合对照品溶液,分别取混标溶液1mL、2mL、4mL、6mL置10mL容量瓶中定容至刻度,再取4mL置5mL容量瓶中定容置刻度即得13个指标的对照品溶液。具体见表1。
表1 13个有机酸与环烯醚萜苷类化合物的浓度信息
供试品溶液制备:精密吸取实施例1制备的注射液1.0mL,置于25mL量瓶中,加25%甲醇稀释近刻度,超声处理20min,放冷,用25%甲醇定容至刻度,摇匀,12000r/min离心10min,取上清液,作为供试品溶液。
色谱条件:色谱柱为Agilent Eclipise Plus C18(2.1mm×50mm,1.8μm);流动相:A相为0.1%磷酸溶液,B相为乙腈:甲醇(3:97);洗脱梯度为0~6min:4%B,6~8min:4~5%B,8~14min:5~12%B,14~22min:12~16%B,22~30min:16~24%B,30~38min:24~38%B,38~40min:38~95%B,40~42min:95~4%B;检测波长:237nm、324nm(环烯醚萜苷类成分的检测波长为237nm,有机酸类成分的检测波长为324nm);流速:0.3ml/min;柱温:30℃。精密吸取上述溶液1μL,注入液相色谱仪,测定。取实施例1中注射液,采用上述方法进行13个组分的含量测定,结果见表2。
实施例3:总酸的含量测定
绿原酸作为主要的有机酸类成分,最为廉价易得。故实验采用紫外分光光度法、以绿原酸为对照品,对实施例1制备的注射液中的总酸进行含量测定。
1.仪器与试剂
UV-2401PC紫外分光光度计(日本岛津公司);ST16R高速冷冻离心机(赛默飞世尔科技有限公司);万分之一电子分析天平(AL104,梅特勒-托利多上海仪器有限公司);十万分之一电子天平(XS205,梅特勒-托利多上海有限公司);KH2200B型超声波清洗器(昆山禾创超声仪器有限公司);HH-4数显恒温水浴锅(国华电器有限公司);电热恒温鼓风干燥箱(上海精宏实验设备有限公司)。绿原酸对照品。
2.检测方法
在波长200~600nm范围内,通过对绿原酸对照品、成品、及缺三味药材(辅料亚硫酸氢钠、吐温-80等)的空白样品进行扫描,结果:绿原酸对照品和成品在324nm下均有最大吸收,在400nm无明显吸收;缺三味药材的空白样品在324nm和400nm下均无明显吸收,故确定测定波长为324nm,参比波长为400nm。
对照品溶液的制备:精密称取绿原酸对照品11.04mg,置于100mL的容量瓶中,加水溶解并稀释至刻度,摇匀,即得(每1mL中含绿原酸110.4μg)。
供试品溶液的制备:精密量取本品1mL,置于100mL容量瓶中,加水稀释至刻度,摇匀,再精密量取2mL置于25mL容量瓶中,加水稀释至刻度,摇匀,即得。检测结果见表2。
实施例4:总苷的含量测定
1.仪器
UV-2401PC紫外分光光度计和UV-2550紫外分光光度计(日本岛津公司);ST16R高速冷冻离心机(赛默飞世尔科技有限公司);万分之一电子分析天平(AL104,梅特勒-托利多上海仪器有限公司);十万分之一电子天平(XS205,梅特勒-托利多上海有限公司);KH2200B型超声波清洗器(昆山禾创超声仪器有限公司);HH-4数显恒温水浴锅(国华电器有限公司);电热恒温鼓风干燥箱(上海精宏实验设备有限公司)。栀子苷对照品,香草醛对照品,冰乙酸。
2.检测方法
标准溶液的配制:精密称取干燥至恒重的栀子苷对照品适量,置于10mL的容量瓶中,加50%甲醇溶解并稀释至刻度,摇匀,即得(每1mL中含栀子苷1891μg)。
供试品溶液的制备:精密吸取实施例1制备的注射液1.0mL,置于25mL量瓶中,加50%甲醇稀释近刻度,超声处理30min,放冷,用50%甲醇定容至刻度,摇匀,12000r/min离心10min,取上清液,作为供试品溶液。
含量测定方法:精密量取对照品溶液0.05mL、0.10mL、0.15mL、0.20mL、0.30mL,分别置于10mL量瓶中,挥干溶剂,各加5%香草醛冰醋酸溶液0.4mL,混匀,迅速加入高氯酸1.6mL,至60℃水浴加热15min,再移至冰水浴中,放置3min,取出,加冰醋酸8.0mL,摇匀;以不加对照品溶液为空白,在530nm处测定吸光度A,以A为纵坐标,含量(mg)为横坐标,绘制标准曲线。精密量取供试品溶液0.40mL,置10mL具塞试管中,挥干溶剂,自“加5%香草醛冰醋酸溶液0.4mL,混匀”起依法操作,根据标准曲线计算供试品溶液中总苷的含量。试验结果见表2。
实施例5.药效试验
1.不同批次中药组合物对LPS致大鼠发热体温变化的影响
1.1试剂与供试品
LPS:大肠杆菌O55:B5提炼;布洛芬缓释胶囊,规格:每粒含主要成分布洛芬0.3克;本发明中药组合物A-O共计15个批次由江苏康缘药业股份有限公司自制;
1.2实验动物:
wistar大鼠300只,雄性,体重150-170g,SPF级。
1.3主要仪器:
电子体温计。
1.4实验方法
大鼠前处理:
大鼠在实验环境(温度20-22℃)中适应3天,自由进食、饮水。实验前两天每日用体温计测肛门温度1次(体温计插入肛门2cm),每日2次,选取体温在不超过38.5℃,两次测量体温变化不超过0.5℃的大鼠作为实验对象。实验当日连续测体温2次,每隔30min测1次,以2次测定体温的平均值定为造模前大鼠的基础体温。
大鼠发热模型制备及实验动物分组:
取基础体温筛选出的230只大鼠,分别腹腔注射LPS生理盐水溶液(40μg/kg,5ml/kg按大鼠重量计),造模后4h测温,将升温幅度在0.8-1.6℃范围内的大鼠随机分成17组,分别为模型组,布洛芬组(54.4mg/kg),中药组合物A-O组(4.68g生药/kg),每组10只。分组完毕立即给药,给药组大鼠按体重4mL/kg尾静脉注射给药,模型组和阳性灌胃给药。给药后持续观察大鼠的体温变化,以给药开始计时,连续观察4h,测定0.5h/1h/2h/3h/4h的大鼠体温,计算升温及降温幅度。
1.5实验结果及结论
实验结果见表3,可见,在给药前各组体温之间无显差,给药后各组体温升高较模型组降低,其中布洛芬胶囊在给药后0.5h开始就迅速起效,能明显降低LPS导致的体温升高现象,与模型组比较,0.5、1、2、3、4h均有显著性差异(p<0.05;p<0.01);组合物A,B,F,G,H,J,M,N在给药后1h开始有降低体温的趋势,与模型组比较,2、3、4h均有显著性差异(p<0.05;p<0.01);而组合物C,E,I,L,O,与模型组比较,仅4h有显著性差异(p<0.05;p<0.01),组合物D与模型组比较,仅3h均有显著性差异(p<0.05;p<0.01),组合物K降温效果和模型组比无明显差异。
表3不同批次中药组合物对LPS致大鼠发热体温变化的影响
与模型组相比有统计学差异,*P<0.05,**P<0.01
2.不同批次中药组合物对醋酸致小鼠腹腔毛细血管通透性的影响2.1试剂与供试品
依文思蓝,冰醋酸,布洛芬缓释胶囊,每粒含主要成分布洛芬0.3克;本发明中药组合物A-O共计15个批次由江苏康缘药业股份有限公司自制;
2.2实验动物:
ICR小鼠170只,雌雄各半,体重15-17g,SPF级。
2.3主要仪器:
酶标仪、注射器。
2.4实验方法
选取健康ICR小鼠,SPF级,体重16-18g,按体重随机分为17组,分别为模型组,布洛芬组(78.07mg/kg),中药组合物A-O组(6.76g生药/kg),每组10只,雌雄各半。组合物组分别尾静脉给药(0.1ml/10g体重),模型对照组和阳性药组灌胃给予(0.1ml/10g体重),每天给药1次,连续7天。末次药后1小时,尾静脉注射0.5%伊文思兰液0.1ml/10g,随后立即腹腔注射0.8%醋酸0.1ml/10g,再30分钟后处死小鼠,腹腔注射5ml生理盐水注射液,轻揉腹部50次,剪开皮肤,用吸管吸取腹腔液,离心,取上清在波长590nm下测吸光度,以t检验进行组间比较,并计算抑制率。
2.5试验结果
实验结果见表4,组合物A,B,C,E,F,G,H,I,K,L,M,N和阳性对照药布洛芬组均可明显地抑制醋酸致小鼠腹腔毛细血管通透性增高,与模型组相比具有显著性差异(p<0.01,p<0.05);而组合物D,J,O和模型组比无明显差异。
表4不同批次中药组合物对醋酸致小鼠腹腔毛细血管通透性的影响
与模型组相比有统计学差异,*P<0.05,**P<0.01
组合物对LPS致大鼠发热体温变化的影响试验结果显示:组合物A,B,F,G,H,J,M,N在给药后1h开始有降低体温的趋势,与模型组比较,2、3、4h均有显著性差异(p<0.05;p<0.01);而组合物C,E,I,L,O,与模型组比较,仅4h有显著性差异(p<0.05;p<0.01),组合物D与模型组比较,仅3h均有显著性差异(p<0.05;p<0.01)。另外在组合物对醋酸致小鼠腹腔毛细血管通透性的影响试验结果显示:组合物A,B,C,E,F,G,H,I,K,L,M,N组均可明显地抑制醋酸致小鼠腹腔毛细血管通透性增高,与模型组相比具有显著性差异(p<0.01,p<0.05)。综合两个试验结果显示:组合物A,B,F,G,H,M,N有明显的解热抗炎作用。
根据以上指标均与模型组相比具有显著性差异(p<0.01)的批次A,B,F,G,H,M,N对应的活性成分含量,可以得到优选的活性成分含量范围,即:
新绿原酸2.5-5.14‰,绿原酸5.56-11.11‰,隐绿原酸2.36-5.00‰,咖啡酸0.14-0.26‰,异绿原酸B0.43-1.00‰,异绿原酸A 0.22-0.46‰,异绿原酸C 0.38-0.69‰,栀子苷9.53-17.71‰,断氧化马钱子苷0.35-3.43‰,山栀苷0.42-0.79‰,京尼平苷酸0.36-0.68‰,京尼平龙胆双糖苷1.00-1.88‰,7-羟基獐牙菜3.31-6.88‰,总酸13.89-27.78‰,总苷含23.68-50.61‰。
上述活性成分的比例关系为:
新绿原酸2.5-5.14,绿原酸5.56-11.11,隐绿原酸2.36-5.00,咖啡酸0.14-0.26,异绿原酸B0.43-1.00,异绿原酸A 0.22-0.46,异绿原酸C 0.38-0.69,栀子苷9.53-17.71,断氧化马钱子苷0.35-3.43,山栀苷0.42-0.79,京尼平苷酸0.36-0.68,京尼平龙胆双糖苷1.00-1.88,7-羟基獐牙菜3.31-6.88;该提取物中,总酸13.89-27.78,总苷23.68-50.61。根据动物试验可知,具备上述活性成分含量特征的中药组合物具有稳定、优异的治疗效果,是优选的中药组合物;上述活性成分含量特征并可用于该中药组合物的质量控制。
实施例6.制定内控标准和优化制备工艺
根据上述药效优选样品,我们回溯药材原料的成分含量特征,建立相关的药材指纹图谱作为内控标准,并完善制备工艺,保障了产品质量提升、均一稳定。
1、建立青蒿药材内控标准:在药典基础上增加液相指纹图谱控制项
液相指纹图谱检测方法:供试品指纹图谱与对照指纹图谱1,以不少于15个如对照指纹图谱图所标示的指纹峰为参照校正峰,经计算软件计算,相似度应大于0.5。
本实施例中对照指纹图谱峰面积及其保留时间如下:
Mark峰序号 | 保留时间[Min] | 峰面积 |
1 | 3.882885 | 731.039 |
2 | 9.348604 | 238.769 |
3 | 10.29601 | 271.04 |
4 | 12.74284 | 231.6808 |
5 | 15.21369 | 585.2557 |
6 | 16.36838 | 243.2447 |
7 | 19.64414 | 683.0679 |
8 | 25.43884 | 415.1487 |
9 | 26.61364 | 252.1879 |
10 | 28.55216 | 264.1007 |
11 | 32.46935 | 936.6907 |
12 | 33.13216 | 616.8419 |
13 | 34.28907 | 386.3651 |
14 | 36.97964 | 219.1915 |
15 | 38.53798 | 842.427 |
色谱条件与系统适应性试验用十八烷基硅烷键合硅胶为填充剂:甲醇-0.1%磷酸水溶液系统为流动相;洗脱程序为:
流速为0.8ml/min;检测波长为225nm。理论板数按参照物(槲皮素)峰计算,应不低于6000。
对照品溶液的制备:取槲皮素标准品适量,精密称定,加甲醇制成每1ml含50μg的溶液,即得。
供试品溶液的制备:取青蒿药材,粉碎,取粉末约1.0g,精密称定,置100ml烧瓶中,加水50ml,回流提取1小时,过滤,取续滤液,即得。
测定法:精密吸取对照品溶液与供试品溶液各10μl,分别注入液相色谱仪,测定。
2、建立金银花药材内控标准:在药典标准基础上增加绿原酸、新绿原酸、隐绿原酸、断氧化马钱子苷提取量及药材液相指纹图谱。
(1)金银花药材中4个成分提取量:绿原酸应不得少于2.0%;新绿原酸应不得少于0.05%;隐绿原酸应不得少于0.05%;断氧化马钱子苷应不得少于0.2%。即,本实施例中,以绿原酸为例,每100g金银花经水提取得到的绿原酸不少于2g。
色谱条件与系统适用性试验:用十八烷基硅烷键合硅胶为填充剂,以甲醇-0.1%磷酸水溶液系统为流动相,按下表进行梯度洗脱;流速为0.8ml/min;绿原酸、新绿原酸和隐绿原酸的检测波长为324nm,栀子苷和断氧化马钱子苷的检测波长为237nm;理论塔板数按绿原酸峰计算,应不低于10000。
对照品溶液的制备:取绿原酸对照品和栀子苷对照品各适量,加50%甲醇制成每1ml约含绿原酸0.3mg、栀子苷0.5mg的溶液,摇匀,即得。
供试品溶液的制备:量取水1800ml,置烧瓶中,煮沸,投入本品100g,使水液没过药材,回流提取1小时,滤过,药渣中再加入1800ml水,煮沸,回流提取1小时,趁热滤过,合并滤液,放冷,精密量取续滤液1~10ml,置50ml量瓶中,加50%甲醇至刻度。摇匀,即得。
测定法:分别精密量取对照品溶液和供试品溶液各10μl,注入液相色谱仪,测定。以绿原酸对照品为对照,按外标法计算本品中绿原酸的含量;以本品中的绿原酸为内参物,根据相对校正因子计算本品中新绿原酸和隐绿原酸的含量;以对照溶液中的栀子苷为内参物,根据相对校正因子计算本品中断氧化马钱子苷的浓度;以相对保留时间确定各成分峰位。
新绿原酸、隐绿原酸、断氧化马钱子苷的相对校正因子和相对保留时间见下表:
注:相对保留时间为待测成分与其内参物的保留时间之比。
技术参数(参考):色谱柱phenomenex Luna C18(4.6×250mm,5μm)或KromasilC18(4.6×250mm,5μm)。
按下式进行计算:
式中:f平均——校正因子的平均值;
A样——供试品溶液中绿原酸的峰面积(2针平均值);
10-3——单位换算系数;
m样——供试品的取样量(g)
(2)液相指纹图谱:供试品指纹图谱与对照指纹图谱应相似,所标出的12个色谱峰应显示,经计算软件计算,相似度应大于0.95。
本实施例中对照指纹图谱峰面积及其保留时间如下:
色谱条件与系统适用性试验:用十八烷基硅烷键合硅胶为填充剂(色谱柱:phenomenex luna C18,4.6×250mm,5μm);甲醇-0.1%磷酸水溶液系统为流动相;检测波长为225nm。理论塔板数按参照物(绿原酸)峰计算为应不低于6000。洗脱程序为:
参照物溶液的制备:取绿原酸对照品适量,精密称定,加50%甲醇制成每1ml含50μg的溶液,即得。
供试品溶液的制备:取绿原酸提取量项下的溶液,过滤,取续滤液,即得。
测定法分别精密吸取参照物溶液与供试品溶液各5μl,注入液相色谱仪,测定。
3、建立栀子药材内控标准:在药典基础上增加液相指纹图谱控制项
液相指纹图谱检测方法:供试品指纹图谱与对照指纹图谱应相似,所标出的4个色谱峰应显示,经计算软件计算,相似度应大于0.9。
本实施例中对照指纹图谱峰面积及其保留时间如下:
色谱条件与系统适用性试验:以十八烷基硅烷键合硅胶为填充剂(色谱柱:phenomenex luna C18,4.6×250mm,5μm);甲醇-0.1%磷酸水溶液系统为流动相,洗脱程序为:
时间(分钟) | 甲醇(%) | 0.1%磷酸水溶液(%) |
0 | 20 | 80 |
50 | 60 | 40 |
60 | 60 | 40 |
流速为0.8ml/min;检测波长为225nm。理论板数按参照物(栀子苷)峰计算,应不低于6000。
参照物溶液的制备:取栀子苷对照品适量,精密称定,加甲醇制成每1ml含50μg的溶液,即得。
供试品溶液的制备:取栀子药材,粉碎,取粉末约0.1g,精密称定,置50ml锥形瓶中,精密加入甲醇25ml,超声30分钟,过滤,取续滤液,即得。
测定法:分别精密吸取参照物溶液与供试品溶液各10μl,注入液相色谱仪,测定。
4.优化制备工艺
在研究分析制备工艺影响产品成分稳定性的过程中,我们发现青蒿的鞣质对产品的成分影响较大,在实施例1的工艺中,青蒿提取液与金银花提取液合并醇沉,而青蒿的鞣质在醇沉过程中不容易沉淀完全,且容易与金银花的有效成分形成沉淀造成损失,是造成成品成分含量不稳定的一个重要因素。通过比较实施例1的青蒿提取液与金银花提取液合并醇沉一次工艺、青蒿提取液与金银花提取液单独醇沉一次工艺、青蒿提取液单独醇沉两次金银花单独醇沉一次工艺、青蒿提取液单独醇沉一次后合并金银花提取液醇沉一次工艺,发现去除青蒿的鞣质干扰,需要两次醇沉才能完全,且第二次醇沉可与金银花合并醇沉,并不会对金银花的有效成分造成较大损失。因此在实施例1工艺中得到青蒿提取液后增加一步醇沉再与金银花提取液合并醇沉的步骤,即:青蒿提取液浓缩到相对密度1.10-1.12(70-80℃)加入乙醇使含醇量达到60-80%,静置12小时,取醇沉上清液与金银花提取液合并。
5.验证试验
选用不同产地、批次的药材,经检验符合上述内控标准,组合按上述优化工艺制备出10批次中药组合物,检测相关成分含量。
由此可见,上述药材内控标准结合优化的制备工艺,可以保障产品主要活性成分含量均落入优选范围,实现了产品的质量提升、均一稳定。
以上仅是本发明的实施方式示范性说明,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 (7)
1.一种解热抗炎的中药组合物,其特征在于,是由青蒿、金银花、栀子提取纯化得到的活性成分,以质量千分比计,所述活性成分包括:新绿原酸2.5-5.14‰,绿原酸5.56-11.11‰,隐绿原酸2.36-5.00‰,咖啡酸0.14-0.26‰,异绿原酸B 0.43-1.00‰,异绿原酸A0.22-0.46‰,异绿原酸C 0.38-0.69‰,栀子苷9.53-17.71‰,断氧化马钱子苷0.35-3.43‰,山栀苷0.42-0.79‰,京尼平苷酸0.36-0.68‰,京尼平龙胆双糖苷1.00-1.88‰,7-羟基獐牙菜3.31-6.88‰;该组合物中,含总酸13.89-27.78‰,总苷23.68-50.61‰;其中,
所述中药组合物的制备包括以下步骤:取金银花750重量份,以9-16倍量的90-100℃的水,提取1-3次,每次1-2小时,得金银花提取物;取青蒿1250重量份加3-6倍水浸润后水蒸气蒸馏5-8小时,提取青蒿挥发油,药渣加入3-9倍量水提取1-3小时,提取液在70-80℃下浓缩到相对密度1.10-1.12后加入乙醇使含醇量达到60-80%,静置12小时,取醇沉上清液与金银花提取液合并60-80℃减压浓缩至相对密度1.05-1.15,得青蒿金银花提取浓缩液,浓缩液加入乙醇,使含醇量达到70%-80%,醇沉静置24-48小时,取醇沉上清液,减压浓缩获得醇沉浓缩液,加浓盐酸调pH值到1.5-2.5,采用8-16倍乙酸乙酯萃取,获得萃取液,减压浓缩至无乙酸乙酯味,真空干燥,得金银花青蒿提取物;取栀子600重量份,粉碎成粗粉,加入6-10倍60-80%乙醇提取1-3次,每次1-3小时,提取液在60-70℃下减压浓缩至相对密度1.10-1.20,得栀子提取浓缩液,加热至沸腾,盐酸调整pH值至2.5-3.5,加入栀子重量1%的固体石蜡,搅拌使完全溶解,冷至室温,冷藏24小时,滤过,采用5-10倍量正丁醇萃取,萃取浓缩液减压浓缩至无正丁醇味,真空干燥,得栀子提取物;将金银花青蒿提取物、栀子提取物以及青蒿挥发油,经过常规工序混合。
2.一种解热抗炎的中药组合物,其特征在于,是由青蒿、金银花、栀子提取得到的活性成分,所述活性成分中各成分的比例关系为:新绿原酸2.5-5.14,绿原酸5.56-11.11,隐绿原酸2.36-5.00,咖啡酸0.14-0.26,异绿原酸B0.43-1.00,异绿原酸A 0.22-0.46,异绿原酸C0.38-0.69,栀子苷9.53-17.71,断氧化马钱子苷0.35-3.43,山栀苷0.42-0.79,京尼平苷酸0.36-0.68,京尼平龙胆双糖苷1.00-1.88,7-羟基獐牙菜3.31-6.88;该组合物中,含总酸13.89-27.78,总苷23.68-50.61;其中,所述中药组合物的制备包括以下步骤:取金银花750重量份,以9-16倍量的90-100℃的水,提取1-3次,每次1-2小时,得金银花提取物;取青蒿1250重量份加3-6倍水浸润后水蒸气蒸馏5-8小时,提取青蒿挥发油,药渣加入3-9倍量水提取1-3小时,提取液在70-80℃下浓缩到相对密度1.10-1.12后加入乙醇使含醇量达到60-80%,静置12小时,取醇沉上清液与金银花提取液合并60-80℃减压浓缩至相对密度1.05-1.15,得青蒿金银花提取浓缩液,浓缩液加入乙醇,使含醇量达到70%-80%,醇沉静置24-48小时,取醇沉上清液,减压浓缩获得醇沉浓缩液,加浓盐酸调pH值到1.5-2.5,采用8-16倍乙酸乙酯萃取,获得萃取液,减压浓缩至无乙酸乙酯味,真空干燥,得金银花青蒿提取物;取栀子600重量份,粉碎成粗粉,加入6-10倍60-80%乙醇提取1-3次,每次1-3小时,提取液在60-70℃下减压浓缩至相对密度1.10-1.20,得栀子提取浓缩液,加热至沸腾,盐酸调整pH值至2.5-3.5,加入栀子重量1%的固体石蜡,搅拌使完全溶解,冷至室温,冷藏24小时,滤过,采用5-10倍量正丁醇萃取,萃取浓缩液减压浓缩至无正丁醇味,真空干燥,得栀子提取物;将金银花青蒿提取物、栀子提取物以及青蒿挥发油,经过常规工序混合。
3.根据权利要求1或2所述的中药组合物,其特征在于,该中药组合物为任选的制剂形式。
4.根据权利要求3所述的中药组合物,其特征在于,所述制剂形式包括汤剂、颗粒剂、胶囊剂、丸剂、口服液、酊剂、糖浆剂、栓剂、凝胶剂、喷雾剂、注射剂。
5.一种如权利要求3或4所述中药组合物的制备方法,其特征在于,包括以下步骤:取金银花750重量份,以9-16倍量的90-100℃的水,提取1-3次,每次1-2小时,得金银花提取物;取青蒿1250重量份加3-6倍水浸润后水蒸气蒸馏5-8小时,提取青蒿挥发油,药渣加入3-9倍量水提取1-3小时,提取液在70-80℃下浓缩到相对密度1.10-1.12后加入乙醇使含醇量达到60-80%,静置12小时,取醇沉上清液与金银花提取液合并60-80℃减压浓缩至相对密度1.05-1.15,得青蒿金银花提取浓缩液,浓缩液加入乙醇,使含醇量达到70%-80%,醇沉静置24-48小时,取醇沉上清液,减压浓缩获得醇沉浓缩液,加浓盐酸调pH值到1.5-2.5,采用8-16倍乙酸乙酯萃取,获得萃取液,减压浓缩至无乙酸乙酯味,真空干燥,得金银花青蒿提取物;取栀子600重量份,粉碎成粗粉,加入6-10倍60-80%乙醇提取1-3次,每次1-3小时,提取液在60-70℃下减压浓缩至相对密度1.10-1.20,得栀子提取浓缩液,加热至沸腾,盐酸调整pH值至2.5-3.5,加入栀子重量1%的固体石蜡,搅拌使完全溶解,冷至室温,冷藏24小时,滤过,采用5-10倍量正丁醇萃取,萃取浓缩液减压浓缩至无正丁醇味,真空干燥,得栀子提取物;将金银花青蒿提取物、栀子提取物以及青蒿挥发油,经过常规工序混合。
6.根据权利要求5所述的制备方法,其特征在于,所述中药组合物为注射剂,制备方法还包括:取注射用水800-1200体积份煮沸,投入权利要求5所得的金银花青蒿提取物以及栀子提取物,搅拌使两种提取物溶解,保持沸腾3-7分钟,冷却至室温,冷藏20-36小时,滤过,滤液调pH值为2-3,取滤液加热至沸腾,加入1%活性炭,煮沸8-14分钟,冷藏20-36小时后过滤,取滤液,加热至沸腾,调pH为5.05,沸腾9-13分钟后冷却到室温,冷藏40-58小时,滤过,加入0.3-0.8重量份亚硫酸氢钠,定容1000体积份,搅拌取溶液50体积份,加热到65℃加入吐温80 3-5体积份,搅匀,加入青蒿挥发油,搅匀,滤过,将滤液用分子量为30000的中空纤维膜进行超滤,得超滤液;取30000超滤药液,用分子量为10000的板式膜进行超滤,得超滤液,过0.22μm的微孔滤膜,分装,流通蒸汽灭菌35-50min,即得。
7.权利要求1或2所述的中药组合物在制备解热、抗炎药物中的应用。
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CN110390422A (zh) * | 2019-06-13 | 2019-10-29 | 江苏康缘药业股份有限公司 | 一种数据驱动的热毒宁注射液绿原酸转移率预测方法 |
CN111896637B (zh) * | 2020-06-05 | 2021-07-23 | 江苏康缘药业股份有限公司 | 一种金青中间体的检测方法及其指纹图谱构建方法 |
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