CN117085117B - 一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法 - Google Patents
一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了中药技术领域领域的一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,包括如下重量份的组分:洋甘菊混合菌液微凝胶20‑30份、牛乳蛋白5‑10份、菊粉5‑7份、花青素2‑5份;所述洋甘菊混合菌液微凝胶包括内芯和壁材两部分,内芯为洋甘菊混合菌液,壁材为改性壳聚糖涂层海藻酸钠。本发明提出通过将益生菌加入到中药提取物中,发酵制得洋甘菊混合菌液,用甲基唑接枝壳聚糖‑海藻酸钠复合材料包埋形成洋甘菊混合菌液微凝胶,一方面提高洋甘菊混合菌液中的益生菌在胃肠消化过程中的稳定性,另一方面,接枝甲基唑的壳聚糖具有抑制尿素酶活性的功能,降低对宿主细胞造成的损害,减弱幽门螺旋杆菌在胃黏膜上的粘附性,极大提高胃肠病治疗效果。
Description
技术领域
本发明属于中药技术领域,具体是指一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法。
背景技术
幽门螺旋杆菌是一种革兰氏阴性菌,定植于人体胃黏膜的粘液层和胃上皮细胞,是人类胃的病原体,与慢性型胃炎、消化性溃疡、淋巴瘤、胃癌等有密切关系;幽门螺旋杆菌的致病机理较为复杂,良好的粘附性使其能高密度定植于胃内,对胃的清除作用有抗性外,还能产生大量尿素酶,尿素酶能可分解尿素产生氨和二氧化碳,氨呈碱性,既保护细菌不受胃酶侵袭,又对胃黏膜上皮细胞具有细胞毒性作用。
对于幽门螺旋杆菌的治疗,目前医学上多采用大剂量多种抗生素同时服用杀灭幽门螺旋杆菌,此种方法会杀灭大量有益菌,导致菌群失调及耐药菌株的增加,进而降低治疗效果。
目前现有技术主要存在以下问题:目前,针对幽门螺旋杆菌引起的肠胃病的治疗多为服用抗生素,会杀灭胃肠道中大量有益菌,导致菌群失调及耐药菌株的增加,造成治疗效果不佳。
发明内容
针对上述情况,为克服现有技术的缺陷,本发明提供了一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,为了解决服用抗生素,会杀灭胃肠道中大量有益菌,导致菌群失调及耐药菌株的增加,治疗效果不佳的问题,本发明提出通过将益生菌加入到中药提取物中,发酵制得洋甘菊混合菌液,通过竞争作用,减少幽门螺旋杆菌定植,其代谢物破坏幽门螺旋杆菌周围碱性环境,抑制幽门螺旋杆菌生长繁殖,此外,用海藻酸钠包埋形成洋甘菊混合菌液微胶囊,再通过甲基唑接枝壳聚糖对洋甘菊混合菌液微胶囊的外部进行涂层形成保护膜,成膜材料一方面提高洋甘菊混合菌液中的益生菌在胃肠消化过程中的稳定性,降低微胶囊的渗透性,另一方面,接枝甲基唑的壳聚糖具有抑制尿素酶活性的功能,既降低对宿主细胞造成的损害,也能减弱幽门螺旋杆菌在胃黏膜上的粘附性,极大提高胃肠病治疗效果。
为了实现上述目的,本发明采取的技术方案如下:本发明提出了洋甘菊提取物的抗幽门螺旋杆菌组合物,具体包括如下重量份的组分:洋甘菊混合菌液微凝胶20-30份、牛乳蛋白5-10份、菊粉5-7份、花青素2-5份;所述洋甘菊混合菌液微凝胶包括内芯和壁材两部分,内芯为洋甘菊混合菌液,壁材为改性壳聚糖涂层海藻酸钠。
所述洋甘菊混合菌液微凝胶的制备方法包括如下步骤:
S1、取对甲苯磺酸氯和甲硝唑溶于无水CH2Cl2中,加入三乙胺,冰浴、搅拌反应4-5h,过滤,取滤液倒入冰水中,分离出有机相,水相加乙酸乙酯萃取,合并有机相,洗涤、干燥蒸馏,得到对甲苯磺酰基甲硝唑;
S2、取壳聚糖和S1制备的对甲苯磺酰基甲硝唑,溶解于N,N-二甲基甲酰胺中,加入无水碳酸钾,80℃搅拌18-20h,减压蒸去溶剂,层析得到甲硝唑接枝壳聚糖;
S3、向洋甘菊混合菌液中加入质量分数为1.5%的海藻酸钠溶液,混合均匀后,加入质量分数为1.6%的CaCl2溶液,搅拌均匀后,静止3-5h,得到海藻酸钙凝胶珠;
S4、取S2制备的甲硝唑改性壳聚糖,溶解于蒸馏水中,加入S3制备的海藻酸钙凝胶珠,搅拌30-40min,洗涤,得到洋甘菊混合菌液微凝胶。
优选地,在S1中,所述对甲苯磺酸氯和甲硝唑的质量比为1:1;
优选地,在S1中,所述对甲苯磺酸氯在无水CH2Cl2的质量分数为1.9%-2%;
优选地,在S1中,所述三乙胺与无水CH2Cl2的体积比为1:20-25;
优选地,在S2中,所述壳聚糖与对甲苯磺酰基甲硝唑的质量比为2-2.5:1;
优选地,在S2中,所述对甲苯磺酰基甲硝唑在N,N-二甲基甲酰胺中的质量分数为3%-3.5%;
优选地,在S2中,所述无水碳酸钾与对甲苯磺酰基甲硝唑的质量比为1.3-1.5:1;
优选地,在S3中,所述洋甘菊混合菌液与海藻酸钠溶液的体积比为1:1.5-2;
优选地,在S3中,所述CaCl2溶液与海藻酸钠溶液的体积比为1:1-1.5;
优选地,在S4中,所述甲硝唑改性壳聚糖在蒸馏水中的质量分数为1%-1.5%;
优选地,在S4中,所述海藻酸钙凝胶珠与甲硝唑改性壳聚糖的质量比为1:1.5-2。
所述洋甘菊混合菌液的制备方法包括如下步骤:
(1)、取植物原料进行筛选清洗,去除虫害病株及杂质,烘干后粉碎过80目筛,得到混合物粉末;
(2)、将步骤(1)制备的混合粉末按料液比1:3g/mL放入蒸馏水中,浸泡10-12h,用文火煎煮2-3h,过滤,收集滤液,滤渣重新煎煮2次,过滤,得滤液,合并2次滤液,旋蒸浓缩得植物浓缩液;
(3)、将嗜酸乳杆菌、类干酪乳杆菌菌、长双歧杆菌混合均匀,得到混合菌液;
(4)、将步骤(2)制备的植物浓缩液加入步骤(3)制备的混合菌液,按20-30g/L加入葡萄糖,调节pH至5-7,置于密封发酵罐中,37℃下发酵2-5天,得到洋甘菊混合菌液。
优选地,在步骤(1)中,所述植物原料包括如下,德国洋甘菊30-40份、茴香苗25-30份、吴茱萸20-25份、人参15-20份、鸦胆子10-15份、乳香2-10份;
优选地,在步骤(3)中,所述嗜酸乳杆菌接种量为1-1.5%;生物来源中国工业微生物菌种保藏管理中心,菌株编号为CICC6075;
优选地,在步骤(3)中,所述类干酪乳杆菌接种量为2-2.5%;生物来源中国工业微生物菌种保藏管理中心,菌株编号为CICC23494;
优选地,在步骤(3)中,所述长双歧杆菌接种量为1.5-2%;生物来源中国工业微生物菌种保藏管理中心,菌株编号为CICC25033;
本发明还提供了一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,具体包括如下步骤:
取洋甘菊混合菌液微凝胶、牛乳蛋白、菊粉、花青素,投入混料罐中,设置混合转速频率40-43Hz混合时间5-10min,得到洋甘菊提取物的抗幽门螺旋杆菌组合物。
本发明取得的有益效果如下:
本发明中加入的植物原料及组合物具有以下功效:德国洋甘菊花序中含有精油及黄酮类化合物,抗菌消炎活性非常显著,还含有比较丰富的多糖苷类物质,这类物质不但可以有效地改善睡眠,还可缓解胃部的一些慢性疾病;茴香苗主要成分是茴香油,能刺激胃肠神经血管,促进消化液分泌,增加胃肠蠕动;吴茱萸中存在多类型喹诺酮生物碱,如吴茱萸新碱、二氢吴茱萸新碱、1-甲基-α-十五烷基-4(1H)-喹诺酮等,具有显著的抗幽门螺旋杆菌活性;人参中含有丰富的人参皂苷,被人体吸收后,能抑制体内幽门螺杆菌的活性;鸦胆子含有主含鸦胆子油、苦木苦味素、苷、生物碱等成分,具有抗病原体及抑制幽门螺旋杆菌的作用;乳香含有乳香胶,主要成分是反式茴香烯,可以破坏幽门螺杆菌细胞膜的通透性,分解细胞结构,阻止幽门螺杆菌在胃上皮进行粘附,起到一定的预防作用;益生菌是一类对宿主有益的活性微生物,可以抑制幽门螺旋杆菌在体内外定植,调节细胞因子水平,避免机体过度炎症反应,同时促进幽门螺旋杆菌的清除,提高胃内菌群的多样性,加强胃粘膜屏障作用,从而降低了胃内幽门螺旋杆菌感染及定植密度;牛乳蛋白是一种多功能蛋白质,具有超强的活性、低铁饱和度的特性,具有参与体内转运的功能,牛乳铁蛋白进入胃部与幽门螺旋杆菌结合抢夺赖以生存的铁离子,破坏幽门螺旋杆菌的生存环境,达到抑制幽门螺旋杆菌生长的效果;菊粉是一种水溶性膳食纤维,不被肠道中内源性酶所消化,经口摄入直接到达结肠,随后被结肠内菌群选择性发酵,促进乳酸杆菌、长双歧杆菌等有益菌增殖;花青素是非常强效的抑菌剂,它的主要作用是防止细菌黏附在胃壁,抑制幽门螺杆菌生长,降低幽门螺杆菌的繁殖以及活性。
本发明提出通过将益生菌混合菌剂加入到中药提取物中,发酵制得洋甘菊混合菌液,通过竞争作用,减少幽门螺旋杆菌定植,其代谢物能破坏幽门螺旋杆菌周围碱性环境,抑制幽门螺旋杆菌生长繁殖,此外,用海藻酸钠包埋形成洋甘菊混合菌液微凝胶,海藻酸钠是一种安全、无毒、生物相容性良好的天然多糖,由β-D-甘露糖酸(M)和α-L-月桂酸(G)组成,在制备微胶囊过程中,G单元上的Na+与Ca2+交换,在海藻酸盐分子之间形成交联,构成网络结构,能在酸、胆盐、氧气和胃肠道条件等不利环境下保护保护洋甘菊混合菌液,但是单独的海藻酸钠微胶囊存在稳定性弱,在低酸环境下,其完整性易受离子和螯合剂的影响,存在生物分子渗漏等缺陷,通过甲基唑接枝壳聚糖对海藻酸钠微胶囊的外部进行涂层形成保护膜,一方面,海藻酸钠是一种聚阴离子物质,壳聚糖是一种聚阳离子物质,两者能形成聚合电解质络合物,离子凝胶中的钠离子在氯化钙中被钙离子取代,形成不溶于水的海藻酸钙,进而形成交联凝胶体系,通过钙离子交联作用,不仅降低微胶囊的孔隙率,可以很好的抵抗胃肠道恶劣条件,起到缓释和包封隔离等作用,此外,壳聚糖的质子化氨基基团(NH3+)和海藻酸钠的羧酸盐基团(COO-)之间的离子相互作用的形成导致更致密的膜,弥补了海藻酸钠微胶囊通透性大的缺点,显著增强对洋甘菊混合菌液中益生菌的保护作用,另一方面,接枝甲基唑的壳聚糖具有抑制尿素酶活性的功能,既降低对宿主细胞造成的损害,也能减弱幽门螺旋杆菌在胃黏膜上的粘附性,极大提高胃肠病治疗效果。
附图说明
图1为本发明实施例和对比例1、对比例2制备的组合物进行幽门螺旋杆菌抑菌效果测试结果图;
图2为本发明实施例和对比例1、对比例2制备的组合物进行幽门螺旋杆菌尿素酶抑制活性效果测试结果图;
图3为本发明实施例和对比例1、对比例2制备的组合物对大鼠胃部溃疡修复结果图;
图4为本发明实施例和对比例3和对比例4制备的组合物在人工模拟胃液中的存活率结果图。
附图用来提供对本发明的进一步理解,并且构成说明书的一部分,与本发明的实施例一起用于解释本发明,并不构成对本发明的限制。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,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;基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
除非另行定义,文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明中。文中所述的较佳实施方法与材料仅作示范之用,但不能限制本申请的内容。
下述实施例中的实验方法,如无特殊说明,均为常规方法;下述实施例中所用的试验材料及试验菌株,如无特殊说明,均为从商业渠道购买得到的。
二氯甲烷、石油醚、乙酸乙醋、甲醇、对甲基苯磺酚氯、N,N-二甲基甲酰胺均购于国药集团化学试剂有限公司;甲硝唑购于武汉合中生化有限公司;海藻酸钠、氯化钙、壳聚糖以及醋酸购自Aladdin公司。
实施例
本发明提出了一种洋甘菊提取物的抗幽门螺旋杆菌组合物,具体包括如下重量份的组分:洋甘菊混合菌液微凝胶20份、牛乳蛋白5份、菊粉5份、花青素2份;所述洋甘菊混合菌液微凝胶包括内芯和壁材两部分,内芯为洋甘菊混合菌液,壁材为改性壳聚糖涂层海藻酸钠。
所述洋甘菊混合菌液微凝胶的制备方法包括如下步骤:
S1、取对甲苯磺酸氯按质量分数为1.9%溶于无水CH2Cl2中,加入等质量的甲硝唑,混合均匀后,按三乙胺与无水CH2Cl2的体积比1:20加入三乙胺,冰浴、搅拌反应4h,过滤,取滤液倒入冰水中,分离出有机相,水相加乙酸乙酯萃取,合并有机相,用饱和碳酸氢钠和水分别洗涤有机相,用无水干燥有机相,减压蒸去溶剂,得到对甲苯磺酰基甲硝唑;
S2、取壳聚糖,按质量比为2:1加入S1制备的对甲苯磺酰基甲硝唑,按对甲苯磺酰基甲硝唑在N,N-二甲基甲酰胺中的质量分数为3%,加入N,N-二甲基甲酰胺,按无水碳酸钾与对甲苯磺酰基甲硝唑的质量比为1.3:1加入无水碳酸钾,80℃搅拌18h,减压蒸去溶剂,层析得到甲硝唑接枝壳聚糖;
S3、取洋甘菊混合菌液,按体积比为1:1.5加入1.5%的海藻酸钠溶液,混合均匀后,按体积比为1:1加入1.6%的CaCl2溶液,搅拌均匀后,静止3h,得到海藻酸钙凝胶珠;
S4、取S2制备的甲硝唑改性壳聚糖,按质量分数为1%溶解于蒸馏水中,按质量比为1:1.5加入S3制备的海藻酸钙凝胶珠,搅拌30-40min,洗涤,得到益生菌组合物微凝胶。
所述洋甘菊混合菌液的制备方法包括如下步骤:
(1)、取德国洋甘菊30份、茴香苗25份、吴茱萸20份、人参15份、鸦胆子10份、乳香2份进行筛选清洗,去除虫害病株及杂质,烘干后粉碎过80目筛,得到混合物粉末;
(2)、将步骤(1)制备的混合粉末按料液比1:3g/mL放入蒸馏水中,浸泡10h,用文火煎煮2h,过滤,收集滤液,滤渣重新煎煮2次,过滤,得滤液,合并2次滤液,转蒸浓缩得植物浓缩液;
(3)、将接种量为1%的嗜酸乳杆菌、2%的类干酪乳杆菌、1.5%的长双歧杆菌混合均匀,得到混合菌液;
(4)、将步骤(2)制备的植物浓缩液加入步骤(3)制备的混合菌液,按20g/L加入葡萄糖,调节pH至5,置于密封发酵罐中,37℃下进行发酵2天,得到洋甘菊混合菌液。
本发明还提供了一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,具体包括如下步骤:
取洋甘菊混合菌液微凝胶、牛乳蛋白、菊粉、花青素,投入混料罐中,设置混合转速频率40Hz混合时间5min,得到洋甘菊提取物的抗幽门螺旋杆菌组合物。
实施例
本发明提出了一种洋甘菊提取物的抗幽门螺旋杆菌组合物,具体包括如下重量份的组分:洋甘菊混合菌液微凝胶25份、牛乳蛋白7份、菊粉6份、花青素4份;所述洋甘菊混合菌液微凝胶包括内芯和壁材两部分,内芯为洋甘菊混合菌液,壁材为改性壳聚糖涂层海藻酸钠。
所述洋甘菊混合菌液微凝胶的制备方法包括如下步骤:
S1、取对甲苯磺酸氯按质量分数为1.9%溶于无水CH2Cl2中,加入等质量的甲硝唑,混合均匀后,按三乙胺与无水CH2Cl2的体积比1:23加入三乙胺,冰浴、搅拌反应4h,过滤,取滤液倒入冰水中,分离出有机相,水相加乙酸乙酯萃取,合并有机相,用饱和碳酸氢钠和水分别洗涤有机相,用无水干燥有机相,减压蒸去溶剂,得到对甲苯磺酰基甲硝唑;
S2、取壳聚糖,按质量比为2.3:1加入S1制备的对甲苯磺酰基甲硝唑,按对甲苯磺酰基甲硝唑在N,N-二甲基甲酰胺中的质量分数为3.5%,加入N,N-二甲基甲酰胺,按无水碳酸钾与对甲苯磺酰基甲硝唑的质量比为1.4:1加入无水碳酸钾,80℃搅拌18h,减压蒸去溶剂,层析得到甲硝唑接枝壳聚糖;
S3、取洋甘菊混合菌液,按体积比为1:1.5加入1.5%的海藻酸钠溶液,混合均匀后,按体积比为1:1.5加入1.6%的CaCl2溶液,搅拌均匀后,静止4h,得到海藻酸钙凝胶珠;
S4、取S2制备的甲硝唑改性壳聚糖,按质量分数为1.5%溶解于蒸馏水中,按质量比为1:2加入S3制备的海藻酸钙凝胶珠,搅拌35min,洗涤,得到益生菌组合物微凝胶。
所述洋甘菊混合菌液的制备方法包括如下步骤:
(1)、取德国洋甘菊35份、茴香苗25份、吴茱萸25份、人参15份、鸦胆子15份、乳香7份进行筛选清洗,去除虫害病株及杂质,烘干后粉碎过80目筛,得到混合物粉末;
(2)、将步骤(1)制备的混合粉末按料液比1:3g/mL放入蒸馏水中,浸泡10h,用文火煎煮2h,过滤,收集滤液,滤渣重新煎煮2次,过滤,得滤液,合并2次滤液,转蒸浓缩得植物浓缩液;
(3)、将接种量为1.5%的嗜酸乳杆菌、2%的类干酪乳杆菌、2%的长双歧杆菌混合均匀,得到混合菌液;
(4)、将步骤(2)制备的植物浓缩液加入步骤(3)制备的混合菌液,按25g/L加入葡萄糖,调节pH至6,置于密封发酵罐中,37℃下进行发酵3天,得到洋甘菊混合菌液。
本发明还提供了一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,具体包括如下步骤:
取洋甘菊混合菌液微凝胶、牛乳蛋白、菊粉、花青素,投入混料罐中,设置混合转速频率42Hz混合时间8min,得到洋甘菊提取物的抗幽门螺旋杆菌组合物。
实例例3
本发明提出了一种洋甘菊提取物的抗幽门螺旋杆菌组合物,具体包括如下重量份的组分:洋甘菊混合菌液微凝胶30份、牛乳蛋白10份、菊粉7份、花青素5份;所述洋甘菊混合菌液微凝胶包括内芯和壁材两部分,内芯为洋甘菊混合菌液,壁材为改性壳聚糖涂层海藻酸钠。
所述洋甘菊混合菌液微凝胶的制备方法包括如下步骤:
S1、取对甲苯磺酸氯按质量分数为2%溶于无水CH2Cl2中,加入等质量的甲硝唑,混合均匀后,按三乙胺与无水CH2Cl2的体积比1:25加入三乙胺,冰浴、搅拌反应5h,过滤,取滤液倒入冰水中,分离出有机相,水相加乙酸乙酯萃取,合并有机相,用饱和碳酸氢钠和水分别洗涤有机相,用无水干燥有机相,减压蒸去溶剂,得到对甲苯磺酰基甲硝唑;
S2、取壳聚糖,按质量比为2.5:1加入S1制备的对甲苯磺酰基甲硝唑,按对甲苯磺酰基甲硝唑在N,N-二甲基甲酰胺中的质量分数为3.5%,加入N,N-二甲基甲酰胺,按无水碳酸钾与对甲苯磺酰基甲硝唑的质量比为1.5:1加入无水碳酸钾,80℃搅拌20h,减压蒸去溶剂,层析得到甲硝唑接枝壳聚糖;
S3、取洋甘菊混合菌液,按体积比为1:2加入1.5%的海藻酸钠溶液,混合均匀后,按体积比为1:1.3加入1.6%的CaCl2溶液,搅拌均匀后,静止5h,得到海藻酸钙凝胶珠;
S4、取S2制备的甲硝唑改性壳聚糖,按质量分数为1.5%溶解于蒸馏水中,按质量比为1:1.8加入S3制备的海藻酸钙凝胶珠,搅拌40min,洗涤,得到益生菌组合物微凝胶。
所述洋甘菊混合菌液的制备方法包括如下步骤:
(1)、取德国洋甘菊40份、茴香苗30份、吴茱萸25份、人参20份、鸦胆子15份、乳香10份进行筛选清洗,去除虫害病株及杂质,烘干后粉碎过80目筛,得到混合物粉末;
(2)、将步骤(1)制备的混合粉末按料液比1:3g/mL放入蒸馏水中,浸泡12h,用文火煎煮3h,过滤,收集滤液,滤渣重新煎煮2次,过滤,得滤液,合并2次滤液,转蒸浓缩得植物浓缩液;
(3)、将接种量为1.5%的嗜酸乳杆菌、2.5%的类干酪乳杆菌、2%的长双歧杆菌混合均匀,得到混合菌液;
(4)、将步骤(2)制备的植物浓缩液加入步骤(3)制备的混合菌液,按30g/L加入葡萄糖,调节pH至7,置于密封发酵罐中,37℃下进行发酵5天,得到洋甘菊混合菌液。
本发明还提供了一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,具体包括如下步骤:
取洋甘菊混合菌液微凝胶、牛乳蛋白、菊粉、花青素,投入混料罐中,设置混合转速频率43Hz混合时间10min,得到洋甘菊提取物的抗幽门螺旋杆菌组合物。
对比例1
本对比例提供一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,其与实施例1的区别仅在于不对植物浓缩液进行益生菌发酵处理,即不包括步骤(3)、步骤(4)。
对比例2
本对比例提供一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,其与实施例1的区别仅在于不对壳聚糖进行甲基唑接枝处理,即不包括S1、S2。
对比例3
本对比例提供一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,其与实施例1的区别仅在于不进行壳聚糖包膜处理,即不包括S4。
对比例4
本对比例提供一种洋甘菊提取物的抗幽门螺旋杆菌组合物及其制备方法,其与实施例1的区别仅在于不对于洋甘菊混合菌液进行包膜处理,即不包括洋甘菊混合菌液微凝胶的制备。
实验例1
幽门螺旋杆菌的培养:在布氏肉汤中加入10%的经过灭活的马血清作为培养幽门螺旋杆菌(ATCC43504)的培养液,在微氧条件下(5%O2,10%CO2,85%N2)培养至对数期。
幽门螺旋杆菌尿素酶的提取:取培养好的50mL菌液置于离心管中离心分离(5000G,4℃)收集幽门螺旋杆菌,用磷酸盐缓冲液(pH=7.4)洗涤两次,将沉淀下来幽门螺旋杆菌储存在-80℃,然后升温至室温,加入3mL蒸馏水和蛋白酶抑制剂,超声波振荡1min,离心(15000G,4℃)上层清夜通过SephadexG-25柱除盐,所得到的尿素酶的溶液加入等量的丙三醇后于4℃储存。
1)、幽门螺旋杆菌的抑制实验
取5mL培养到对数期的幽门螺旋杆菌培养液,5000g离心5min,用TSB培养基重悬菌体,并调整菌液浓度为1.5×106CFU/mL,无菌环境下,分别称取5mg实施例1-3和对比例1、对比例2制备的组合物溶于50ml无菌水中,搅拌溶解,取96孔板,每孔加入100μL的上述菌液,95μL的TSB培养基,并分别加入5μL上述实施例1-3、对比例1-2的组合物,空白对照则为加入5μL的DMSO溶液,将96孔板置于37℃,150rpm震荡培养48h,以OD600的值反映菌液浓度,抑菌率(%)按照如下公式计算:
抑菌率(%)=(OD空白对照菌液-OD处理菌液)/OD空白对照菌液×100%。
2)、幽门螺旋杆菌尿素酶抑制活性实验
将本发明实施例1-3和对比例1、对比例2制备的组合物分别溶于50ml无菌水中,向96孔板上分别加入25μL上述溶液及25μL(4U)幽门螺旋杆菌尿素酶溶液,在室温下预培养3h,加入55μL含有100mM尿素的磷酸盐缓冲溶液(36MmK2HPO4·3H2O,3.6mM EDTA,36mMLiCl),pH约为7.5,在30℃共培养20min,向每个孔中分别加入45μL的A液(5g苯酚溶液与25mg亚硝基铁氰化钠加蒸馏水定容至500mL),70μL的B液(2.5g的NaOH和4.2mL含有效氯5%的次氯酸钠溶液,加水定容至500mL),50min后,用酶标仪在630nm下测定OD值,乙酞羟氨酸作为尿素酶抑制剂的阳性对照,测定组合物对幽门螺旋杆菌尿素酶的抑制率,按下式计算;
抑制率(%)=100-(OD实验组/OD对照组)×100
结果分析
图1为本发明实施例和对比例制备的组合物进行幽门螺旋杆菌抑菌效果测试结果图,图2为本发明实施例和对比例制备的组合物进行幽门螺旋杆菌尿素酶抑制活性效果测试结果图,如图1,实施例对幽门螺旋杆菌抑菌率在81%左右,对比例1抑菌率在51%左右,对比例2抑菌率在56%左右;如图2,实施例对幽门螺旋杆菌尿素酶抑制率在85%左右,对比例1抑制率在61%左右,对比例2抑制率在53%左右;本发明实施例制备的组合物,相较于对比例1,对于提取的植物浓缩液进行益生菌发酵,发酵过程通过产生和富集具有药用价值的次级代谢物,提高了草药的生物利用度,同时,微生物还释放生长因子、色素、酶和抗生素等其他化合物,增强了抗菌性;对比例1与对比例2相比,对洋甘菊混合菌液进行包埋处理,其包埋的外膜壳聚糖上接枝了甲硝唑基团,使其加强酶抑制活性,因此,本发明实施例制备的组合物能显著提高对幽门螺旋杆菌的抑制作用。
实验例2
对本发明实施例1-3和对比例1、对比例2制备的组合物进行胃部溃疡和胃黏膜损伤的修复实验测定,具体实验如下:
实验鼠处理:取实验鼠90只,实验前禁食24h,腹腔注射3%戊巴比妥钠进行麻醉,用酒精棉签消毒皮肤后剖开腹腔,暴露全胃,将于冰醋酸中浸透的直径5mm的圆形纸片贴于胃部浆膜面上,重复3次,关腹,缝合创口,术后正常饮食2d,第3d将大鼠分为6组,每组15只。
分别称取5g本发明实施例1-3和对比例1、对比例2的组合物溶于100ml无菌水中,试验组大鼠每天分别以10mL本发明实施例1-3制备的药液进行灌胃,对照组大鼠每天分别以10mL本发明实施例1-3制备的药液进行灌胃,空白组每天灌胃给予等量清水,连续10d,最后一次灌胃12h后脱颈椎处死,剖腹取胃,用生理盐水洗涤胃内容物,然后将胃固定于10%甲醛中,15min后将胃平展于玻璃表面皿上,量取溃疡面积作为溃疡指数。
结果分析
图3为本发明实施例和对比例制备的组合物对大鼠胃部溃疡修复结果图,如图3,与空白组相比,本发明实施例和对比例对大鼠胃部溃疡均具有一定的修复能力,其中本发明实施例制备的组合物效果最好,溃疡指数为1.4左右,是空白组的0.35倍;可见,通过对药草有效成分的提取,通过益生菌进行发酵处理,既活化了有效成分,又能够与益生菌协同作用,强化功能,提高胃粘膜的修复效果,减轻胃部炎症。
实验例3
将实施例1-3和对比例3、对比例4制得的组合物在人工模拟胃液(pH=2.4)中的存活情况进行试验测定,具体步骤为:将本发明实施例1-3和对比例1、对比例2制备的组合物分散于20mL在37℃下预热的人工模拟胃液中,温育10h,分别取1g样品加入100mL生理盐水,在20℃、150rpm下震荡1h,采用稀释平板计数法测定菌数,测得菌数与初始菌数的比值即为菌体存活率,按下列公式计算存活率:
存活率(%)=N1/N0×100%;
N1为在体外人工模拟胃液中孵育一定时间后存活的益生菌浓度(cfu/g);
N0为人工模拟胃液中添加的益生菌原始浓度(cfu/g);
结果分析
图4为本发明实施例和对比例3和对比例4制备的组合物在人工模拟胃液中的存活率结果图,如图,实施例制备的组合物中,复合菌的存活率为70%左右,对比例3的存活率为50%左右,对比例4的存活率为15%左右,与对比例相比,本发明实施例对益生菌进行包埋处理,能较好的保护益生菌,避免其在胃中低pH值和近端肠内高浓度胆盐环境下失活,此外,本发明实施例与对比例3相比,对海藻酸钠包埋后的益生菌进行壳聚糖二次包埋,能降低微胶囊的孔隙率,可以很好的抵抗胃肠道恶劣条件,使微胶囊中的益生菌稳定性得到明显改善。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
以上对本发明及其实施方式进行了描述,这种描述没有限制性,附图中所示的也只是本发明的实施方式之一,实际的应用并不局限于此。总而言之如果本领域的普通技术人员受其启示,在不脱离本发明创造宗旨的情况下,不经创造性的设计出与该技术方案相似的方式及实施例,均应属于本发明的保护范围。
Claims (8)
1.一种洋甘菊提取物的抗幽门螺旋杆菌组合物,其特征在于:所述洋甘菊提取物的抗幽门螺旋杆菌组合物具体包括如下重量份的组分:洋甘菊混合菌液微凝胶20-30份、牛乳蛋白5-10份、菊粉5-7份、花青素2-5份;所述洋甘菊混合菌液微凝胶包括内芯和壁材两部分,内芯为洋甘菊混合菌液,壁材为改性壳聚糖涂层海藻酸钠;
所述洋甘菊混合菌液微凝胶的制备方法包括如下步骤:
S1、取对甲苯磺酸氯和甲硝唑溶于无水CH2Cl2中,加入三乙胺,冰浴、搅拌反应4-5h,过滤,取滤液倒入冰水中,分离出有机相,水相加乙酸乙酯萃取,合并有机相,洗涤、干燥蒸馏,得到对甲苯磺酰基甲硝唑;
S2、取壳聚糖和S1制备的对甲苯磺酰基甲硝唑,溶解于N,N-二甲基甲酰胺中,加入无水碳酸钾,80℃搅拌18-20h,减压蒸去溶剂,层析得到甲硝唑接枝壳聚糖;
S3、向洋甘菊混合菌液中加入质量分数为1.5%的海藻酸钠溶液,混合均匀后,加入质量分数为1.6%的CaCl2溶液,搅拌均匀后,静止3-5h,得到海藻酸钙凝胶珠;
S4、取S2制备的甲硝唑改性壳聚糖,溶解于蒸馏水中,加入S3制备的海藻酸钙凝胶珠,搅拌30-40min,洗涤,得到洋甘菊混合菌液微凝胶;
所述洋甘菊混合菌液的制备方法包括如下步骤:
(1)、取植物原料进行筛选清洗,去除虫害病株及杂质,烘干后粉碎过80目筛,得到混合物粉末;
(2)、将步骤(1)制备的混合粉末按料液比1:3g/mL放入蒸馏水中,浸泡10-12h,用文火煎煮2-3h,过滤,收集滤液,滤渣重新煎煮2次,过滤,得滤液,合并2次滤液,旋蒸浓缩得植物浓缩液;
(3)、将嗜酸乳杆菌、类干酪乳杆菌、长双歧杆菌混合均匀,得到混合菌液;
(4)、将步骤(2)制备的植物浓缩液加入步骤(3)制备的混合菌液,加入葡萄糖,调节pH至5-7,置于密封发酵罐中进行发酵,得到洋甘菊混合菌液。
2.根据权利要求1所述的一种洋甘菊提取物的抗幽门螺旋杆菌组合物,其特征在于:在S1中,所述对甲苯磺酸氯和甲硝唑的质量比为1:1;所述对甲苯磺酸氯在无水CH2Cl2的质量分数为1.9%-2%;所述三乙胺与无水CH2Cl2的体积比为1:20-25。
3.根据权利要求2所述的一种洋甘菊提取物的抗幽门螺旋杆菌组合物,其特征在于:在S2中,所述壳聚糖与对甲苯磺酰基甲硝唑的质量比为2-2.5:1;所述对甲苯磺酰基甲硝唑在N,N-二甲基甲酰胺中的质量分数为3%-3.5%;所述无水碳酸钾与对甲苯磺酰基甲硝唑的质量比为1.3-1.5:1。
4.根据权利要求3所述的一种洋甘菊提取物的抗幽门螺旋杆菌组合物,其特征在于:在S3中,所述洋甘菊混合菌液与海藻酸钠溶液的体积比为1:1.5-2;所述CaCl2溶液与海藻酸钠溶液的体积比为1:1-1.5。
5.根据权利要求4所述的一种洋甘菊提取物的抗幽门螺旋杆菌组合物,其特征在于:在S4中,所述甲硝唑改性壳聚糖在蒸馏水中的质量分数为1%-1.5%;所述海藻酸钙凝胶珠与甲硝唑改性壳聚糖的质量比为1:1.5-2。
6.根据权利要求5所述的一种洋甘菊提取物的抗幽门螺旋杆菌组合物,其特征在于:在步骤(1)中,所述植物原料包括如下重量组分,洋甘菊30-40份、茴香苗25-30份、吴茱萸20-25份、人参15-20份、鸦胆子10-15份、乳香2-10份。
7.根据权利要求6所述的一种洋甘菊提取物的抗幽门螺旋杆菌组合物,其特征在于:在步骤(3)中,所述嗜酸乳杆菌接种量为1-1.5%;生物来源中国工业微生物菌种保藏管理中心,菌株编号为CICC6075;所述类干酪乳杆菌接种量2-2.5%;生物来源中国工业微生物菌种保藏管理中心,菌株编号为CICC23494;所述长双歧杆菌接种量为1.5-2%;生物来源中国工业微生物菌种保藏管理中心,菌株编号为CICC25033。
8.根据权利要求1-7任一项所述的一种洋甘菊提取物的抗幽门螺旋杆菌组合物的制备方法,其特征在于:取洋甘菊混合菌液微凝胶、牛乳蛋白、菊粉、花青素,投入混料罐中,设置混合转速频率41-43Hz混合时间5-10min,得到洋甘菊提取物的抗幽门螺旋杆菌组合物。
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