CN106265822A - 具有抗菌消炎生肌功能的阔叶十大功劳提取物、制备方法及其应用 - Google Patents
具有抗菌消炎生肌功能的阔叶十大功劳提取物、制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了阔叶十大功劳提取物作为唯一活性成分在制备治疗慢性炎症创伤药物中的应用,慢性炎症创伤包括慢性乳腺炎、糖尿病足、烧伤、慢性溃疡、克罗恩病任意之一引发的创伤。阔叶十大功劳提取物在医学上可接受载体或赋形剂制备成片剂、胶囊剂、注射剂、外用溶液剂、洗剂、搽剂、灌肠剂、软膏剂、糊剂、贴剂、缓释或控释制剂。阔叶十大功劳提取物的制备方法为:以植物阔叶十大功劳的茎、叶为原料,水、乙醇或含水醇类提取、过滤、浓缩至小体积,冷冻干燥后备用。本发明相对于现有技术的有益效果:(1)药物制备工艺简单、操作合理;(2)通过体内外抗炎药理实验,明确了阔叶十大功劳提取物在治疗慢性炎症伤口上的应用价值,为其临床开发提供了理论和实验基础;(3)阔叶十大功劳的经济价值研究尚属空白,开展药用及药效研究,在利用的基础上实现有效保护,可以起到迁地保护及可持续发展作用。
Description
技术领域
本发明涉及中药技术领域,特别涉及从天然植物阔叶十大功劳(土黄连)中提取有效部位的制备方法及其在慢性炎症创伤中的应用。
背景技术
全球范围内,慢性炎症伤口的患者大概有200多万人,并且每年以10-15%的速度递增。慢性难愈合创面是严重危害人民健康的常见多发病,如糖尿病足溃疡、克罗恩病、肠易激综合征以及小叶性肉芽肿性乳腺炎等。由于基础疾病复杂,患病部位伴有大量炎性细胞和因子浸润,组织损伤坏死严重,同时抗生素或激素治疗疗效有限,如何加速慢性炎症伤口愈合成为近年来亟待解决的临床难题。
中医药是世界解决难治性疾病的出路,对慢性炎症患者机体的免疫调节更是中医药的独特优势。近十年来,大量实验证明多种中药复方及单味药均可从抑制NF-κB信号通路、阻断活性氧自由基爆发、平衡紊乱细胞因子、抑制MAPK生长信号通路等多方面平衡患者的免疫功能,具有多环节、多靶点和整体调节的特点,如蒲公英、金银花、鱼腥草等,但同时具有抗菌、消炎和生肌功能的单味中药并不多见。
阔叶十大功劳又称土黄连,性味苦、寒、无毒,入药部位主要为其叶,目前对其药理活性研究较少,更无抗炎活性灭菌活性报道。化学成分分析显示此属植物以生物碱类化学成分为主,目前已分离鉴定出25种生物碱,除小檗碱、巴马亭、药根碱三种主要生物碱外,还有四氢药根、非洲防己碱、氧化小檗碱、小檗胺、黄连碱、尖刺碱、巴芦奇、黄树皮碱、阿莫灵、水叶碱、木兰花碱、木兰胺、黄小檗灵、异紫堇定、紫堇定、紫堇块茎碱、白蓬草坡、白蓬皱褶碱、海罂粟碱、异波尔定、异蒂巴和异粉防己碱等化学成分。但土黄连的活性药效成分及其药效作用目前尚无报道。在此基础上,本专利对阔叶十大功劳的化学成分、有效部位和生物学作用进行了全面研究。
发明内容
本发明的一个目的在于提供一种阔叶十大功劳提取物的制备方法;
本发明的另一个目的在于提供阔叶十大功劳在促进慢性炎症伤口愈合药物中的应用。
本发明具体采用如下技术方案:
阔叶十大功劳提取物在制备药物中的应用,其特征在于,阔叶十大功劳提取物作为唯一活性成分在制备治疗慢性炎症创伤药物中的应用。
所述的慢性炎症创伤包括慢性乳腺炎、糖尿病足、烧伤、慢性溃疡、克罗恩病任意之一引发的创伤。
所述的阔叶十大功劳提取物在医学上可接受载体或赋形剂制备成片剂、胶囊剂、注射剂、外用溶液剂、洗剂、搽剂、灌肠剂、软膏剂、糊剂、贴剂、缓释或控释制剂。
所述的阔叶十大功劳提取物的制备方法为:以植物阔叶十大功劳的茎、叶为原料,水、乙醇或含水醇类提取、过滤、浓缩至小体积,冷冻干燥后备用。
所述阔叶十大功劳水提取物优选60-120℃水提取1-8次,更优选提取2-5次。
所述阔叶十大功劳乙醇提取物,优选10-95%乙醇提取,更优选20-80%乙醇提取,更优选40-70%乙醇提取,提取方式可以选择采用渗漉、回流、浸渍或超声提取;优选提取1-8次,更优选提取2-5次。
阔叶十大功劳提取物可进一步优选上大孔树脂,先用水洗脱,后依次用浓度逐渐增大的乙醇洗脱,收集高浓度乙醇洗脱物即为阔叶十大功劳活性部位。
本发明所述阔叶十大功劳提取物进行体外抗炎实验筛选,利用脂蛋白(LPS)诱导的小鼠巨噬细胞RAW264.7建立体外抗炎模型,检测炎症因子环氧化酶-2(COX-2)、一氧化氮合酶(iNOS)、IL-1β、IL-6的生成,验证因子浓度越低,活性越高,实验结果显示本发明所述的阔叶十大功劳水提物及醇提物对炎症因子的表达均有抑制作用。
本发明所述阔叶十大功劳进行分子机制实验,各剂量组对NF-κB通路的激活均有不同程度的抑制作用,能显著阻断NF-κB向细胞核内转运,从而抑制其下游炎症因子的表达。
本发明所述阔叶十大功劳提取物进行抗菌实验,显示阔叶十大功劳提取物各剂量组对金黄色葡萄球菌、粪肠球菌、大肠埃希菌具有较好的抑菌活性,对绿脓杆菌、肺炎克雷伯菌、阴沟肠杆菌无抑制作用。
本发明所述阔叶十大功劳提取物进行血管新生实验,显示阔叶十大功劳提取物各剂量组能显著促进人血管内皮细胞增殖活性,促进其迁移和成管能力,并能促进成纤维细胞分泌I型和III型胶原,鸡主动脉环实验也表明其在体内也具有促进血管新生能力。
本发明所述阔叶十大功劳提取物进行体内临床个体实验,显示阔叶十大功劳提取物能够抑制乳腺炎性创面细菌生长、消除炎症、缓解炎症引起的红肿热痛现象,患者无任何不适,而且同时能够促进新生肉芽组织生长,促进炎症创口愈合。
综上,本发明相对于现有技术的有益效果:
(1)药物制备工艺简单、操作合理;
(2)通过体内外抗炎药理实验,明确了阔叶十大功劳提取物在治疗慢性炎症伤口上的应用价值,为其临床开发提供了理论和实验基础;
(3)阔叶十大功劳的经济价值研究尚属空白,开展药用及药效研究,在利用的基础上实现有效保护,可以起到迁地保护及可持续发展作用。阔叶十大功劳分布广泛,适应性强,一旦得到利用,可以规模化种植,其植物资源大大丰富,也可以增加农民的经济收益。
附图说明
图1:阔叶十大功劳提取物的体外抗炎活性实验。
图2:阔叶十大功劳提取物的体内外促血管新生实验。
具体实施方式
结合具体实施方式对本发明作进一步详细描述,但本发明的内容并不仅仅限于所列举的实施方式。
实施例1.阔叶十大功劳的制备
阔叶十大功劳茎叶100g,用十倍水(W/V)煎煮提取2次,每次1小时,合并两次提取液,减压浓缩,冷冻干燥后得粗提物12.3g。阔叶十大功劳茎叶100g,用10倍量60%(W/V)乙醇回流提取2次,每次1小时,合并两次提取液,减压浓缩,冷冻干燥后得粗提物13.7g。
采用HPLC技术对阔叶十大功劳提取物进行成分分析,分离柱为Ultimate AQ-C18(250mm×4.6mm,5μm),分离液由乙腈(A)和水(B)组成,分离方案为5%-8%A at 0-5min,8%-14%A at 5-30min,14%-50%A at 30-55min,50%-90%A at 55-60min,于250nm处观察化学指纹图谱。采用小檗碱作为标准品,其浓度在阔叶十大功劳中为0.014-0.018mg/ml。同时我们采用LC-MS技术鉴定了其中3个主峰的化学性质,经测定其分别为绿原酸、药根碱和木兰花碱。
实施例2阔叶十大功劳提取物细胞毒性实验
MTT法是一种检测细胞存活和生长的方法。其检测原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶甲瓒并沉积在细胞中,而死细胞无此功能。二甲基亚砜(DMSO)能溶解细胞中的甲瓒,用酶联免疫检测仪在540-720nm处测定其光吸收值,可间接反映活细胞数量。在一定细胞数范围内,MTT结晶形成的量与细胞数成正比。该方法已广泛应用于一些生物活性因子的活性检测、大规模的抗肿瘤药物筛选、细胞毒性实验以及肿瘤放射敏感性测定等。它的特点是灵敏度高、经济。而巨噬细胞是重要的炎症因子分泌细胞、其细胞功能与炎症密切相关。
实验样品为阔叶十大功劳的水提物及60%乙醇提取物,阳性对照药为脂蛋白(LPS),按照浓度梯度依次添加。
取对数生长期状态良好的小鼠巨噬细胞Raw264.7接种于96孔板中,加入受试药物,分别培养48小时。将5mg/mlMTT加入96孔板中,每孔10μl,培养箱中反应4小时,吸去上清液,加入DMSO,每孔100μl,振摇5min,用酶标仪测定每孔吸光度值,测定波长570m,计算下拨抑制率。
实验结果显示阳性药物LPS可显著促进Raw264.7细胞增殖,而阔叶十大功劳水提取及醇提物在浓度范围1-500ug/ml范围内对细胞增殖均无显著抑制作用,证明阔叶十大功劳提取物无显著细胞毒性。
实施例3阔叶十大功劳提取物体外抗炎活性实验
COX-2、iNOS、IL-1β、IL-6是极为重要的炎症因子产物,在调节炎性创口疼痛、红肿等方面发挥重要作用,其表达含量越高,炎性反应越严重。相反,其表达水平下降,炎症反应的程度也相应降低,所以其表达水平是衡量炎性反应程度的重要指标。利用脂蛋白(LPS)诱导的小鼠巨噬细胞Raw264.7建立体外抗炎模型,Real-time PCR法检测四种指标在添加阔叶十大功劳提取物后的变化。
实验结果表明四种因子表达含量在添加阔叶十大功劳水提和醇提物后,均呈现剂量依赖性降低,表明阔叶十大功劳提取物具有抗炎活性。
实施例4阔叶十大功劳提取物体外抗菌活性实验
以革兰氏染色阳性菌金黄色葡萄球菌、粪肠球菌和革兰氏染色阴性菌绿脓杆菌、大肠埃希菌、肺炎克雷伯菌、阴沟肠杆菌为研究对象,采用LB培养基琼脂块法测定阔叶十大功劳提取物各浓度对细菌的生长抑制活性。将被测的菌株制成悬液,均匀的涂布在LB培养板上,倒置于37℃培养箱中培养。待LB培养板干燥后,用无菌打孔器将无菌滤纸打成直径0.5cm的圆形纸片,将其浸入各个浓度的阔叶十大功劳提取液中,随后将圆形滤纸小片按照浓度梯度放入LB细菌培养板,于37℃培养过夜,第二天测定抑菌圈直径,评价阔叶十大功劳抑菌活性。
实验结果显示阔叶十大功劳提取物各剂量组对金黄色葡萄球菌、粪肠球菌、大肠埃希菌具有较好的抑菌活性,呈剂量依赖性;而对绿脓杆菌、肺炎克雷伯菌、阴沟肠杆菌无抑制作用。
实施例5阔叶十大功劳提取物体内外促血管新生实验
血管新生是肉芽组织形成的必要条件。本发明以人脐静脉血管内皮细胞(HUVEC)为研究对象,采用MTT法研究阔叶十大功劳提取液能否促进HUVEC增殖,同时采用划痕实验评价阔叶十大功劳提取物对HUVEC的迁移促进作用。在此基础上,利用Matrigel诱导HUVEC形成管型,评价阔叶十大功劳提取物能否加速成管过程。最后采用鸡主动脉环实验确定阔叶十大功劳提取物对鸡胚新生血管的促进作用。将鸡胚解剖,取其主动脉并切成环状,放置于铺备有Matrigel的12孔板中,随后加入不同浓度的阔叶十大功劳提取物,观察主动脉周围血管内皮细胞的增殖速度和生长长度。
实验结果显示显示阔叶十大功劳提取物各剂量组能显著促进人血管内皮细胞增殖活性,促进其迁移和成管能力,同时鸡主动脉环实验也表明其可促进体内血管新生。另一方面,用阔叶十大功劳提取物处理人乳腺成纤维细胞HMF7630,发现阔叶十大功劳提取物能够显著促进HMF7630增殖,同时细胞内I型和III型胶原分泌增多,证明阔叶十大功劳提取物能够促进伤口愈合,增块肉芽组织生长速度。
实施例6阔叶十大功劳提取物分子机制实验
NF-κB通路激活是炎症反应过程中主要激活通路,作为上游水平控制着炎症因子COX-2、iNOS、IL-1β、IL-6的表达。在此发明中,我们采用蛋白免疫印迹技术及激光共聚焦技术检测阔叶十大功劳提取物对NF-κB通路的影响。
实验结果表明阔叶十大功劳提取物能够剂量依赖性抑制NF-κB的激活,抑制其磷酸化程度,同时对其上游分子IKKα/β和IKBα的磷酸化均有抑制作用。激光共聚焦实验表明阔叶十大功劳提取物能够抑制NF-κB向细胞核内转移,从而阻断其激活下游基因的转录。
实施例7阔叶十大功劳临床效果实验
纳入慢性小叶性肉芽肿性乳腺炎患者138例,以阔叶十大功劳提取物为主的中医治疗71例,西医手术治疗67例,均为女性,两组平均年龄33.29±7.47岁,最小年龄16岁,最大年龄69岁,两组的年龄构成、临床症状、病程、临床分期等方面均无统计学差异,比较基线一致。手术治疗以乳腺区段切除、肿块扩大切除、单纯乳房切除术构成。中医治疗组以炎性创口清创术后以阔叶十大功劳液清洗、引流及湿敷为主。
(1)疗效判定标准:
治愈:
好转:
未愈:
(2)乳房外形变化判定标准:
优秀:
良好:
尚可:
差:
治疗结果见表1和表2。
表1阔叶十大功劳临床疗效
表2阔叶十大功劳治疗组乳房外形变化
经过统计发现两组在治疗疗效上无显著差异,但中医治疗组乳房外形评价优良,明显好于手术治疗组(P<0.05),而且治疗过程中均未见明显毒副反应及不良事件发生,皮肤无过敏现象。
Claims (9)
1.阔叶十大功劳提取物在制备药物中的应用,其特征在于,阔叶十大功劳提取物作为唯一活性成分在制备治疗慢性炎症创伤药物中的应用。
2.根据权利要求1所述的阔叶十大功劳提取物在制备药物中的应用,其特征在于,慢性炎症创伤包括慢性乳腺炎、糖尿病足、烧伤、慢性溃疡、克罗恩病任意之一引发的创伤。
3.根据权利要求1或2所述的阔叶十大功劳提取物在制备药物中的应用,其特征在于,阔叶十大功劳提取物在医学上可接受载体或赋形剂制备成片剂、胶囊剂、注射剂、外用溶液剂、洗剂、搽剂、灌肠剂、软膏剂、糊剂、贴剂、缓释或控释制剂。
4.根据权利要求1所述的阔叶十大功劳提取物在制备药物中的应用,其特征在于,阔叶十大功劳提取物的制备方法为:以植物阔叶十大功劳的茎、叶为原料,水、乙醇或含水醇类提取、过滤、浓缩至小体积,冷冻干燥后备用。
5.根据权利要求4所述的阔叶十大功劳提取物在制备药物中的应用,其特征在于,用60-120℃的水提取1-8次。
6.根据权利要求5所述的阔叶十大功劳提取物在制备药物中的应用,其特征在于,用60-120℃的水提取2-5次。
7.根据权利要求4所述的阔叶十大功劳提取物在制备药物中的应用,其特征在于,用体积浓度为10-95%的乙醇提取1-8次,提取方式采用渗漉、回流、浸渍或超声提取1-8次。
8.根据权利要求7所述的阔叶十大功劳提取物在制备药物中的应用,其特征在于,用体积浓度为40-70%的乙醇提取2-5次,提取方式采用渗漉、回流、浸渍或超声提取2-5次。
9.根据权利要求4~8任一所述的阔叶十大功劳提取物在制备药物中的应用,其特征在于,阔叶十大功劳提取物上大孔树脂,先用水洗脱,后依次用浓度逐渐增大的乙醇洗脱,收集高浓度乙醇洗脱物即为阔叶十大功劳活性部位。
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