CN115715196B - 包含三白草馏分的药物组合物及其制备方法 - Google Patents
包含三白草馏分的药物组合物及其制备方法 Download PDFInfo
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- CN115715196B CN115715196B CN202180043349.1A CN202180043349A CN115715196B CN 115715196 B CN115715196 B CN 115715196B CN 202180043349 A CN202180043349 A CN 202180043349A CN 115715196 B CN115715196 B CN 115715196B
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Abstract
本发明涉及包含利用三白草制备的特定馏分作为有效成分的用于预防、治疗或改善炎症性肠病的组合物及其制备方法。
Description
【技术领域】
本发明涉及三白草(Saururus chinensis)活性馏分的制备方法。本发明还涉及包含通过特定制备方法制备的三白草馏分的药物组合物。本发明还涉及通过特定制备方法制备的三白草馏分在治疗炎症性肠病中的医药用途。
本专利申请要求于2020年6月17日向韩国知识产权局提交的第10-2020-0073480号韩国专利申请的优先权,其公开内容在此引入本申请作为参考。
【背景技术】
炎症反应调节异常(dysregulation)或慢性炎症可引起风湿性关节炎、动脉粥样硬化及哮喘等多种疾病。结肠炎是结肠发炎的疾病,包括炎症性肠病(Inflammatory boweldisease;IBD)、肠易激综合征(irritable bowel syndrome,IBS)等。炎症性肠病(Inflammatory bowel disease,IBD)以溃疡性结肠炎(ulcerative colitis,UC)和克罗恩氏病(Crohn's disease,CD)为代表。在世界范围内,炎症性肠病的发病率呈增加趋势,在亚洲国家的增长率高于西欧国家。炎症性肠病是需要终身管理的慢性疾病。
炎症性肠病患者的黏膜活检显示促炎性细胞因子(pro-inflammatorycytokine)、趋化因子(chemokine)及细胞间黏附分子(ICAM-1(Intercellular AdhesionMolecule 1))的表达增加及粘液(mucous)损失、上皮细胞之间的紧密连接(tightjunction)的减少。目前用于治疗炎症性肠病的代表性药剂有5-氨基水杨酸(5-aminosalicyic acid)、皮质类固醇(corticosteroid)、免疫调节剂(immunomodulator)、肿瘤坏死因子抑制剂(anti-tumor necrosis factor-αagent,anti TNF-α)等。由于这些通过不同的作用机制产生效果,因此根据临床指南阶段性地使用,但很难看作是根本性治疗剂,而且已经报道了各种副作用。
最近作为炎症性肠病的治疗目标而备受关注的是黏膜愈合(mucosal healing)。炎症性肠病患者最大的特点是结肠的黏蛋白生成下降。黏膜层的缺失导致细菌直接到达肠上皮细胞,这些将引起严重的炎症反应(约翰逊(Johansson),M.E.(2014)炎症性肠病中的粘液层,炎症性肠病(Mucus layers in inflammatory bowel disease.Inflammatorybowel diseases 20,2124-2131))。为了从根本上改善肠道功能,必须恢复黏膜的生成,肠上皮细胞之间的紧密连接(tight junction)的牢固性也非常重要。因此,近年来,关于黏膜生成的研究正活跃地进行中。因此为了治疗炎症性肠病及维持健康的肠道功能,必须抑制炎症及恢复正常的黏液层、良好地恢复肠上皮细胞之间的紧密连接(tight junction)的牢固性。但目前还没有对炎症性肠病有效的治疗剂,实际上只能开出症状缓解剂的处方,由于患者日益增加,因此急需开发符合这种要求的治疗剂。
另一方面,三白草(Saururus chinensis)是属于三白草科(Saururaceae)的多年生草本植物,在民间众所周知全草或根、叶具有多种效果。
【发明内容】
【技术问题】
因此,本发明所要解决的问题在于,提供利用三白草的用于治疗、改善或预防炎症性肠病的药物组合物或保健功能食品组合物。
本发明所要解决的再一问题在于,提供炎症性肠病的治疗、改善或预防效果显著的三白草提取物或馏分的制备方法。
本发明所要解决的另一问题在于,提供通过特定制备方法制备的三白草馏分的医药用途。
本发明所要解决的还有一问题在于,提供炎症性肠病的治疗方法,其包括将利用上述三白草的用于治疗、改善或预防炎症性肠病的药物组合物向需要其的个体给药的步骤。
【解决问题的方案】
为了解决上述问题,本发明提供对炎症性肠病有用的三白草馏分(SCEP2)的制备方法(方法1),包括:
步骤(S1),用50体积百分比至90体积百分比的乙醇水溶液提取三白草;
步骤(S2),在上述提取后剩余的残渣中加入纯化水,并在70℃至100℃的温度,优选地,在80℃至100℃的温度,更优选地,在90℃至100℃的温度条件下加热;
步骤(S3),将上述步骤(S2)的产物进行酶处理;
步骤(S4),去除提取物中的残渣并过滤;
步骤(S5),在步骤(S4)的过滤液中添加乙醇,并形成沉淀物;以及
步骤(S6),回收沉淀物。
在本发明的上述方法1中,上述酶起到可分离存在于三白草中的活性多糖成分的作用,优选地,可通过将选自由果胶酶(果胶酶(pectinase)或多聚半乳糖醛酸酶(polygalacturonase))、果胶酯酶(pectinesterase)、果胶裂解酶(pectin lyase)、阿拉伯糖酶(arabinanase)、木聚糖酶(xylanase)、β-葡聚糖酶(beta-glucanase)、纤维素酶(cellulase)组成的组中的一种以上的酶单独或混合来进行。更优选地,上述酶可以是多聚半乳糖醛酸酶(polygalacturonase)、果胶裂解酶(pectin lyase)或它们的混合物,更加优选地,上述酶是多聚半乳糖醛酸酶(polygalacturonase)及果胶裂解酶(pectin lyase)的混合物。
例如,可通过将选自由作为商用酶的Ultra SP-L(多聚半乳糖醛酸酶(polygalacturonase))、/>Ultra MASH(果胶裂解酶(pectin lyase))、RapidaseC80Max(果胶酶(pectinase)、阿拉伯糖酶(arabinanase))、Viscozyme L(内切-1,3(4)-β-葡聚糖酶(endo-1,3(4)-beta-glucanase)、木聚糖酶(Xylanase)、纤维素酶(cellulase)、半纤维素酶(hemicellulase)、阿拉伯糖酶(arabinanase)、Pectinex 5XL(果胶裂解酶(pectin lyase)、多聚半乳糖醛酸酶(polygalacturonase)、果胶酯酶(pectinesterase))等组成的组中一种以上单独或混合来使用,更优选地,将/>Ultra SP-L及Ultra MASH单独或混合来使用。
当进行上述酶处理时,相对于三白草重量份,可添加0.05重量份至5重量份的酶,当上述酶小于0.05重量份时,由于酶量太少使得存在于三白草的活性多糖的回收率减少,当超过5重量份时,由于过度的酶作用有可能降低活性多糖的功效,因此不优选。
当进行上述酶处理时,优选地,反应时间为6小时至96小时,更优选地,为12小时至72小时。当进行酶处理时,优选地,温度及pH值可通过在不同酶的最佳条件下处理来获得最高回收率的活性多糖成分。当上述酶处理反应时间小于6小时时,由于酶处理时间过短导致回收率降低,当大于96小时时,由于过度的酶处理有可能降低活性多糖的功效。
在本发明的上述方法1中,优选地,在上述步骤(S5)中,浓缩过滤液,添加多于浓缩液的乙醇(优选地,2-8倍体积比),搅拌后形成沉淀物。在本步骤中,沉淀物可通过静置反应液来形成。
在本发明的上述方法1中,回收沉淀物的上述步骤(S6)可通过离心分离来实现。回收的沉淀物可在浓缩并冷冻干燥后,用作医药品制备的原料。
本发明还提供对炎症性肠病有用的三白草馏分(SCESII-1)的制备方法(方法2),包括:
步骤(S1),用50体积百分比至90体积百分比的乙醇水溶液提取三白草;
步骤(S2),过滤上述提取液并浓缩;
步骤(S3),将浓缩液通过树脂填充柱,根据是否吸附在树脂来分离成分;以及步骤(S4),根据吸附在上述树脂上的成分中的水及乙醇浓度梯度来回收洗脱的成分。
更具体地,上述3种馏分可通过如下的方式获得。
馏分1(SCESII-1):用20体积百分比至40体积百分比(优选地,30体积百分比)的乙醇开始洗脱,当回收的洗脱液达到约1.5倍至2.5倍(优选地,2倍)的柱床体积时停止回收,将洗脱溶剂变更为60体积百分比至80体积百分比(优选地,70体积百分比)的乙醇。该馏分为将洗脱溶剂变更为60体积百分比至80体积百分比的乙醇之前的馏分。优选地,将洗脱液在室温条件下以每单位时间流动1倍柱床体积(bed volume,BV)的流速进行流动,并回收洗脱液。
馏分2(SCESII-2):用60体积百分比至80体积百分比(优选地,70体积百分比)的乙醇洗脱并回收。当洗脱液达到约1.5倍-2.5倍(优选地,2倍)的柱床体积(BV)时停止回收,将洗脱溶剂变更为100%的乙醇。
馏分3(SCESII-3):用100%的乙醇开始洗脱并回收。回收至洗脱液达到约2.5倍-3.5倍(优选地,3倍)的柱床体积(BV)。
本发明还提供对炎症性肠病有用的三白草馏分(SCESII-4)的制备方法(方法3),包括:
步骤(S1),用50体积百分比至90体积百分比的乙醇水溶液提取三白草;
步骤(S2),过滤上述提取液并浓缩;
步骤(S3),用树脂根据极性分离浓缩液;以及
步骤(S4),在分离上述树脂时,回收未吸附在柱上的成分。
众所周知,三白草提取物具有抗氧化、抗癌、抗炎症等多种效果,但本发明人确认的结果,常规的三白草提取物对炎症性肠病几乎没有效果。而特别地是通过特定制备方法获得的三白草馏分与常规的三白草提取物不同,对炎症性肠病的治疗或改善发挥了惊人的效果。本发明人确认了通过特定制备方法制备的三白草活性馏分示出用葡聚糖硫酸钠(DSS)诱导的小鼠的结肠炎治疗效果、抗炎症、增加黏蛋白生成能力、增强肠上皮细胞的紧密连接(tight junction)牢固性等效果,通过用葡聚糖硫酸钠诱导炎症性肠病的结肠组织的检查,确认了对炎症性肠病的治疗有用,从而完成了本发明。并且,确认了通过本发明的特定制备方法制备的三白草馏分抑制作为促炎性细胞因子的肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)等的活性,从而完成了本发明。
三白草可使用属于三白草科(Saururaceae)的三白草(Saururus chinensis)。
优选地,在本发明的上述方法1至3中,乙醇水溶液是60体积百分比至80体积百分比的乙醇水溶液。更优选地,在本发明的上述方法1至3中的乙醇水溶液是65体积百分比至75体积百分比的乙醇水溶液。
在本发明的上述方法2及3中,优选地,可通过与步骤(S1)的提取条件相同的条件提取在步骤(S1)中回收的残渣来回收提取液,并将该提取液与步骤(S1)中的提取液合并来利用。
在本发明的上述方法2及3中,优选地,树脂可使用苯乙烯(Styrene)与二乙烯苯(DVB,Divinyl benzene)的共聚物的多孔性(High Porous Type)合成吸附剂(例如,安伯来特(Amberlite)XAD-2、Amberlite XAD-4、Amberlite XAD-16N、Amberlite XAD-1180N、三养GSH-20、TRILITE GSP-25TRILITE GSP-50、TRILITE GSP-07、三菱(DIAION)HP20),非离子性脂肪族丙烯酸聚合物的多孔性合成吸附剂(例如,Amberlite XAD-7HP)等。优选地,在本发明的上述方法2及3中,上述树脂利用三菱(DIAION)公司的HP20。
本发明的三白草馏分为了去除以适合用作医药品原料的方式残存的低级醇类和有机溶剂,可通过利用减压干燥、喷雾干燥或冷冻干燥等常规的干燥方法来制备粉末状态。具体地,上述三白草馏分可以是浓缩的液体形式,也可以是冷冻干燥的粉末形式。根据本发明的一实施方式,本发明的三白草馏分可以是浓缩的液体形式的软提取剂。
本发明还提供包含三白草馏分的药物组合物或保健功能食品组合物,通过本发明的上述方法1至3中任一种方法获得。
本发明还提供包含三白草馏分的用于预防、治疗或改善炎症性肠病的药物组合物或保健功能食品组合物,通过本发明的上述方法1至3中任一种方法获得。
在本发明中,术语“炎症性肠病”是作为在肠道中引起炎症的疾病的总称的术语,具体地,可以是在小肠和/或结肠中因免疫系统调节异常引起的慢性复发性炎症疾病。上述炎症性肠病包括溃疡性结肠炎、克罗恩氏病及肠易激综合征(irritable bowel syndrome,IBS)等。
本发明的药物组合物或保健功能食品组合物可根据用于预防或治疗炎症性肠病的常规方法,例如通过用片剂、含片剂(troches)、锭剂(lozenge)、水溶性或油性悬浮液、粉末或颗粒、乳液、硬或软胶囊、糖浆或酏剂(elixirs)等口服用剂型来制剂化。
为了制剂化成片剂及胶囊等剂型,可含有如乳糖、蔗糖、山梨糖醇、甘露醇、淀粉、乳糖、微晶纤维素等赋形剂,如聚乙烯吡咯烷酮、羟丙基甲基纤维素等粘合剂,如磷酸二钙、交联聚维酮等崩解剂,如硬脂酸镁、硬脂酸钙、硬脂富马酸钠、聚乙二醇蜡等润滑剂。在胶囊剂型的情况下,除上述提及的物质外,还可含有脂肪油等液体载体。
并且,本发明的组合物可通过肠胃外给药方式给药,肠胃外给药可通过皮下注射、静脉注射、肌肉注射或胸腔注射方式进行。为了制剂化成肠胃外给药用剂型,可将上述组合物与稳定剂或缓冲剂一起在水中混合制成溶液,并将其制剂化成安瓿或小瓶的单位剂型。
本发明的药物组合物或保健功能食品组合物的给药量应为用于在治疗或预防学上示出充分效果的有效剂量。“有效剂量”意味着以可适用于医学治疗的合理受益/风险比足以预防或治疗疾病的量,有效剂量水平可由本领域普通技术人员根据制剂化方法、患者的状态及体重、患者性别、年龄、疾病的严重程度、给药形式、给药途径及持续时间、排泄率、反应灵敏性等因素进行多种选择。如本领域普通技术人员公认的,有效剂量可随着处理的途径、赋形剂的使用以及与其他药剂一起使用的可能性而变化。
本发明的三白草馏分的给药量或服用量可根据患者的年龄、身体条件、体重等多样化,但优选地,通常在每天10mg/kg(体重)至100mg/kg(体重)范围内给药。而且,可在每天有效给药量范围内,一天一次或一天多次分次给药。
本发明的保健功能食品组合物可包含在多种食品中被摄取。例如,通过包含在肉类、香肠、面包、巧克力、糖果类、快餐类、饼干类、披萨、拉面、其他面类、口香糖类、包括冰淇淋类在内的酪农产品、各种汤、饮用水、茶、饮料、酒精饮料及复合维生素等被摄取。
本发明还提供炎症性肠病的治疗、预防或改善方法,包括:将通过本发明的特定制备方法制备的三白草馏分的药学或预防学上需要的有效剂量向需要炎症性肠病的治疗、预防或改善的个体给药的步骤。优选地,上述个体为人类。
【发明的效果】
本发明提供对炎症性肠病的治疗、预防或改善有用的三白草馏分的制备方法。本发明还提供包含根据本发明的制备方法制备的三白草馏分作为有效成分的用于治疗、改善或预防炎症性肠病的药物组合物或保健功能食品组合物。
【附图说明】
在本说明书中的以下附图用于例示本发明的优选实施例,与上述的发明的内容一起用于进一步理解本发明的技术思想,因此本发明不应解释为仅限定于这些附图中记载的内容。
图1简要示出制备三白草(Saururus chinensis)馏分的过程。
图2a及图2b为将三白草馏分给药后在进行肠炎症模型评价的第10天评价小鼠的结肠长度的结果(n=8)。
图3为三白草馏分给药后观察结肠的组织学变化的结果。
图4为三白草馏分给药后结肠组织内肿瘤坏死因子α的评价结果。
图5为三白草馏分给药后评价肠炎症模型的派伊尔结细胞(Peyer's patchescell)引起的分泌型免疫球蛋白A(sIgA)分泌能力及相关细胞因子(cytokine)诱导能力的结果。
图6为评价三白草活性成分馏分影响肠内粘液分泌细胞(结肠腺癌细胞(LS174T),人肠道杯状细胞系(a human intestinal goblet cell line))的效果的结果。
【具体实施方式】
以下,为了帮助理解本发明,将举出实施例等详细说明。但是,本发明的实施例可变形为多种不同形式,本发明的范围不应解释为限定于如下实施例。本发明的实施例为了向本发明所属技术领域的普通技术人员更完整地说明本发明而提供。
【三白草馏分的制备】
如图1所示,制备了多种馏分。
【实施例1:三白草热水提取物(SCW)的制备】
在干燥粉碎的三白草中混合20倍体积的纯化水,并在100℃的温度条件下提取2小时。在提取后利用提取布去除残渣后,用沃特曼2号滤纸(Whatman No.2filter paper)过滤提取液。利用减压浓缩机浓缩过滤液后,通过进行冷冻干燥来制备三白草热水提取物(SCW)。
【实施例2:多种三白草有机溶剂提取物(SCE、SCESII-1、SCESII-2、SCESII-3及SCESII-4)的制备】
在干燥粉碎的三白草中混合10倍体积的70%(v/v)的乙醇水溶液,并在70℃的温度条件下提取2小时。用提取布过滤后,将过滤的残渣在相同条件下再提取一次。用沃特曼2号滤纸(Whatman No.2filter paper)过滤提取液后,利用减压浓缩机进行浓缩。将其命名为70%乙醇提取物浓缩液SCE。将SCE提取物通过填充有合成树脂HP20的柱。利用纯化水回收所有未吸附在树脂上的成分,并将该成分命名为SCESII-4。下一步,将吸附在树脂上的成分按纯化水至30体积百分比的乙醇、30体积百分比至70体积百分比的乙醇、70体积百分比至100体积百分比的乙醇的顺序洗脱,根据洗脱溶剂的极性进行回收。按先洗脱的顺序将其命名为SCESII-1、SCESII-2及SCESII-3。
【实施例3:三白草粗多糖SCEP1、活性多糖SCEP2及低分子糖SCES馏分的制备】
用70%的乙醇水溶液提取三白草,在剩余残渣中再次混合20倍体积的纯化水,并在100℃的温度条件下搅拌2小时。添加酶(Ultra SP-L与/>UltraMASH的重量比为1∶1),并在55℃的温度条件下搅拌并反应72小时。将酶反应液在100℃的温度条件下灭活30分钟。在利用提取布去除残渣后,用沃特曼2号滤纸(Whatman No.2filterpaper)过滤提取液。将该过滤液命名为粗多糖SCEP1。在浓缩该过滤液后,添加浓缩液的4倍体积的乙醇搅拌30分钟后,在常温条件下静置24小时形成沉淀物。将沉淀液进行离心分离分别回收沉淀物及上清液。在浓缩回收的沉淀物后,通过进行冷冻干燥来制备三白草SCEP2活性多糖馏分,在浓缩上清液后,通过进行冷冻干燥来制备三白草SCES低分子糖馏分。
【实验例1:肠炎模型中的炎症抑制效果评价】
对三白草活性成分馏分抑制肠炎发生及治疗效果进行了研究。用葡聚糖硫酸钠(DSS,dextran sodium sulfate)对白变种实验室(BALB/c)小鼠模型诱导炎症性肠病。为了进行实验,购入100只8周龄雄性BALB/c小鼠,随机分为9组。为了诱发小鼠急性结肠炎,在饮用水中以5%的浓度溶解葡聚糖硫酸钠,使BALB/c小鼠自由饮水7天,使正常对照组(NT:Nottreated)自由饮用饮用水。在供水葡聚糖硫酸钠1天后,向正常对照组及单独摄取5%的葡聚糖硫酸钠的阴性对照组(NC:Negative Control)给药蒸馏水,将各试样以在下述表1中记载的剂量溶解在蒸馏水中并向试样组给药,每天口服给药一次,共给药9天。
【表1】
组 | 饮食方法 |
正常组Not treated(NT) | 葡聚糖硫酸钠及试样均未给药的组 |
阴性对照组(NC) | 用葡聚糖硫酸钠诱导炎症性肠病的组 |
实验组三白草酒精提取物SCE | 用SCE 2.0mg/小鼠+葡聚糖硫酸钠处理 |
实验组三白草水提取物SCW | 用SCW 2.0mg/小鼠+葡聚糖硫酸钠处理 |
实验组低分子非极性SCESII-1 | 用SCESII-1 2.0mg/小鼠+葡聚糖硫酸钠处理 |
实验组低分子非极性SCESII-2 | 用SCESII-2 2.0mg/小鼠+葡聚糖硫酸钠处理 |
实验组低分子非极性SCESII-3 | 用SCESII-3 2.0mg/小鼠+葡聚糖硫酸钠处理 |
实验组低分子极性SCESII-4 | 用SCESII-4 2.0mg/小鼠+葡聚糖硫酸钠处理 |
实验组低分子糖SCES | 用SCES2.0mg/小鼠+葡聚糖硫酸钠处理 |
实验组粗多糖SCEP1 | 用SCEP1 2.0mg/小鼠+葡聚糖硫酸钠处理 |
实验组活性多糖SCEP2 | 用SCEP2 2.0mg/小鼠+葡聚糖硫酸钠处理 |
通过每隔2天用肉眼确认体重减轻、粪便稠度、血便程度及肛门上有无血液来确认结肠炎的诱发程度(疾病活动指数(Disease Activity Index,DAI)),并基于在下述表2中记载的分数计算。
计算公式:
疾病活动指数=(体重减轻分数(weight loss score))+(粪便稠度分数(stoolconsistency score))+(血便分数(blood in stool score))+(肛门出血分数(blood inanus score))
疾病活动指数评分系统(Disease activity index(DAI)scoring system)
【表2】
分数 | 体重 | 粪便稠度 | 血便 | 肛门出血 |
0 | 0 | 正常 | 正常 | 正常 |
1 | 1~5% | - | 微量 | 微量 |
2 | 5~10% | 稀粪 | 潜血+ | 潜血+ |
3 | 10~20% | - | 潜血++ | 潜血++ |
4 | >20% | 腹泻 | 出血严重 | 出血严重 |
在下述表3中示出评价结果。
【表3】
测定各个给药组的疾病活动指数变化的结果,除了正常对照组以外的所有组从第二天开始疾病活动指数增加,但低分子活性物质馏分SCESII-1、活性多糖馏分SCEP2则在第8天示出疾病活动指数分数显著低于阴性对照组(NC),确认了具有结肠炎抑制效果。反之,其他馏分与三白草水提取物几乎没有效果。
由于疾病活动指数是以体重、粪便状况、血痕程度等作为因子进行测定的,因此疾病活动指数可成为更重要的评价因素。
在实验第10天牺牲小鼠,通过测量结肠及小肠的长度以及脾脏的重量来评价。在图2中汇总示出其结果。
通过牺牲小鼠来测量结肠长度的结果,单独摄取5%的葡聚糖硫酸钠的阴性对照组与未摄取葡聚糖硫酸钠的阴性对照组相比,结肠的长度减少约32%,但低分子活性馏分SCESII-1、SCESII-4及活性多糖馏分SCEP2与作为正常组的正常对照组相比时恢复为几乎相似的长度。这表示结肠炎与阴性对照组相比有显著好转。尤其,来源于三白草的活性多糖馏分SCEP2及低分子活性馏分SCESII-1是由于小鼠之间的结肠长度非常相似,因此认为实验可信度高。与此相反,包含三白草水提取物、酒精提取物等的其他提取物或馏分实验组示出了与阴性对照组相似的结肠长度或细微的恢复,因此确认为没有效果。
尤其,5%的葡聚糖硫酸钠单独摄取组(正常对照组)在所有小鼠中观察到粪便的稠度增加、出现血便,而活性多糖馏分SCEP2是粪便的稠度低于正常对照组,在3只小鼠中仅观察到潜血。这结果表明来源于三白草的活性多糖对结肠炎的治疗效果显著。综合上述结果,活性多糖馏分SCEP2及低分子活性馏分SCESII-1与单独摄取5%的葡聚糖硫酸钠的阴性对照组(NC)不同,疾病活动指数分数恢复为正常水平,由于结肠长度相对变长,因此确认了具有结肠炎抑制活性。
【实验例2:三白草馏分给药后结肠的组织学变化观察】
在尸检后,将为了进行组织检查而摘除的结肠固定在10%的福尔马林(formaldehyde)溶液中后,经过常规组织处理过程用石蜡包埋。包埋的各组织用显微镜用薄片切片机(microtome)(徕卡(Leica),韦茨拉尔(Wetzlar),德国(Germany))切成5.0μm的薄片后,进行阿利新蓝染色(alcian blue staining),用加拿大香脂(canadian balsam)处理各薄片,用光学显微镜(奥林巴斯BX53显微镜(Olympus BX53 microscope),(奥林巴斯公司,东京,日本(Olympus Corp.,Tokyo,Japan))观察。在图3中示出其结果。
如图3所示,在用葡聚糖硫酸钠处理的组中炎症引起的组织损伤严重,炎症直达黏膜,整个肠腺和上皮细胞损伤严重。但是,在活性多糖馏分SCEP2、低分子活性馏分SCESII-1及低分子活性馏分SCESII-4给药组中,可发现组织显着恢复。
【实验例3:三白草馏分给药后结肠组织内髓过氧化物酶及肿瘤坏死因子α的评价】
在结肠炎诱发结肠组织中进行了肿瘤坏死因子α及髓过氧化物酶(myeloperoxidase,MPO)的分析。将结肠组织样品放入裂解液(lysis buffer)(Intron,首尔(Seoul),韩国(Korea))中,使用均质机(homogenizer)(西洛盖克斯(Scilogex),洛基山(Rocky hill),CT,美国(USA))磨碎。将其在10000rpm条件下,离心分离4分钟至20分钟,回收上清液,并根据制造商的指南使用酶联免疫吸附剂测定(ELISA)试剂盒测量肿瘤坏死因子α及髓过氧化物酶含量。在图4中示出其结果。
其结果,活性多糖馏分SCEP2及低分子活性馏分SCESII-1非常显著地减少生成作为主要促炎因子的肿瘤坏死因子α。不仅如此,确认了多糖馏分SCEP2及低分子活性馏分SCESII-1、SCESII-3显著抑制参与巨噬细胞活性化的髓过氧化物酶的生成。
【实验例4:肠炎症模型的派伊尔结细胞(Peyer's patches cell)引起的分泌型免疫球蛋白(sIgA)分泌能力及相关细胞因子(cytokine)诱导能力评价】
将62-1周龄的C3H/HeN小鼠分成每6只为一组后,将三白草馏分口服给药20天,共给药10次(1次/2天)。在回收小鼠的派伊尔结细胞后,在96孔板(96well plate)中培养3天,通过酶联免疫吸附剂测定法分析由口服给药被活性化的派伊尔结细胞所生产的分泌型免疫球蛋白。摘除口服给药结束的小鼠的小肠并回收粪便(feces),通过酶联免疫吸附剂测定法分析分泌型免疫球蛋白的生产能力。在图5中示出其结果。
通过评价结果确认到分泌型免疫球蛋白的生成在活性多糖馏分SCEP2、粗多糖SCEP1、低分子活性馏分SCESII-1及低分子活性馏分SCESII-4中增加。
【实验例5:由于口服给药三白草活性馏分而在粪便中诱导的短链脂肪酸(SCFA)生产能力的评价】
回收口服给药结束的小鼠的盲肠,用80%的甲醇(methanol)稀释至最终浓度为1g/mL之后,用0.45μm的注射器式滤器(syringe filter)过滤,通过安装有气相色谱毛细管柱(DBFFAP capillary column)的气相色谱仪(gas chromatography,GC)确认了5种短链脂肪酸(乙酸(acetic acid)、丙酸(propionic acid)、丁酸(butyric acid)、戊酸(valericacid)及庚酸(heptanoic acid))的生产能力。在下述表4中示出其结果。
在粪便中,确认了活性多糖馏分SCEP2及低分子活性馏分SCESII-1浓度依赖性地增加短链脂肪酸(SCFA)的生成量。作为阳性对照组的柳氮磺吡啶反而减少了短链脂肪酸的生成。
盲肠提取物中短链脂肪酸的产生(The production of short chain fatty acidin cecal extracts)((盲肠中短链脂肪酸的产生)(Short chain fatty acid productionin cecum(μm)))
【表4】
【实验例6:三白草活性成分馏分影响肠内粘液分泌细胞(结肠腺癌细胞(LS174T),人肠道杯状细胞系(a human intestinal goblet cell line))的效果】
向BALB/c小鼠提供包含5%的葡聚糖硫酸钠的水,共7天,并口服给药实验样品,共8天。在牺牲实验动物后进行组织分析。将结肠切片用10%的福尔马林溶液(formalin)固定后,填充石蜡。准备厚度为5μm的薄片后,用阿尔新蓝(alcian blue,AB)染色剂染色。然后用加拿大香脂(canada balsam)处理。使用光学显微镜观察各载玻片。(40放大率(40×magnification)),使用显微镜自动化及图像分析软件(MetaMorph software)(美谷分子(Molecular Devices),桑尼维尔(Sunnyvale),加利福尼亚州(CA),美国(USA))分析图像。在图6中示出其结果。
通过结果确认到,在活性多糖馏分SCEP2、低分子活性馏分SCESII-1及低分子活性馏分SCESII-4的与未处理葡聚糖硫酸钠的正常组相比,在杯状(Goblet)细胞中分泌的黏蛋白(Mucin)(被阿尔新蓝染成蓝色)生成量恢复成与正常组相似。
【产业上的可利用性】
本发明涉及包含利用三白草制备的特定馏分作为有效成分的用于预防、治疗或改善炎症性肠病的组合物及其制备方法。
Claims (10)
1.一种对炎症性肠病有用的三白草馏分的制备方法,其包括:
步骤(S1),用50体积百分比至90体积百分比的乙醇水溶液提取三白草;
步骤(S2),在所述提取后剩余的残渣中加入纯化水,并加热到70℃至100℃;
步骤(S3),将所述步骤(S2)的产物进行酶处理;
步骤(S4),去除提取物中的残渣并对所述提取物进行过滤;
步骤(S5),在步骤(S4)的过滤液中添加乙醇,并形成沉淀物;以及
步骤(S6),回收沉淀物。
2.根据权利要求1所述的制备方法,其中所述酶是多聚半乳糖醛酸酶、果胶裂解酶或它们的混合物。
3.根据权利要求1所述的制备方法,其中所述步骤(S1)的乙醇水溶液为60体积百分比至80体积百分比的乙醇水溶液。
4.根据权利要求1所述的制备方法,其中在所述步骤(S5)中,浓缩过滤液,添加多于浓缩液的乙醇搅拌后形成沉淀物。
5.根据权利要求1所述的制备方法,其中所述制备方法还包括在步骤(S6)之后浓缩沉淀物并冷冻干燥的步骤。
6.一种对炎症性肠病有用的三白草馏分的制备方法,其包括:
步骤(S1),用50体积百分比至90体积百分比的乙醇水溶液提取三白草;
步骤(S2),过滤所述提取液并浓缩;
步骤(S3),将浓缩液通过树脂填充柱,根据是否吸附在树脂来分离成分;以及
步骤(S4),在吸附在所述树脂上的成分中,根据水及乙醇浓度梯度来回收在20体积百分比至40体积百分比的乙醇水溶液区间中洗脱的成分,
其中所述树脂是苯乙烯与二乙烯苯的共聚物的多孔性合成吸附剂或非离子性脂肪族丙烯酸聚合物的多孔性合成吸附剂。
7.根据权利要求6所述的制备方法,其中所述步骤(S1)的乙醇水溶液为60体积百分比至80体积百分比的乙醇水溶液。
8.一种用于改善或治疗炎症性肠病的药物组合物,其包含根据权利要求1~7之任一项所述的方法得到的三白草馏分。
9.根据权利要求1~7之任一项所述的方法得到的三白草馏分在制造用于改善或治疗炎症性肠病的药物组合物中的用途。
10.根据权利要求1~7之任一项所述的方法得到的三白草馏分作为活性成分在制造用于预防或缓解炎症性肠病的组合物中的用途。
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