CN113925952B - 一种中药组合物在制备防治消化道肿瘤药物中的应用 - Google Patents
一种中药组合物在制备防治消化道肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种中药组合物在制备防治消化道肿瘤药物中的应用，所述中药组合物的活性成分包括如下配方制成的成分，所述配方包括如下组分：黄连、炮姜、青黛、苦参、三七、煨木香、地榆炭、炙甘草。本发明利用清肠温中片开发出一种预防小肠肿瘤以及防治结直肠癌的疗效好而安全性高的一类中药新药，其可预防小肠肿瘤发生以及结直肠肿瘤的发生。这不仅为清肠温中片的应用提供了新的适应症，还为小肠肿瘤的预防以及结直肠癌的防治提供了一种新的治疗药物和治疗途径。
Description
技术领域
本发明属于预防肿瘤药物领域，具体涉及一种中药组合物在制备防治消化道肿瘤药物中的应用。
背景技术
消化道肿瘤，主要包括像食管肿瘤、胃部肿瘤、小肠肿瘤、大肠肿瘤等等，结直肠肿瘤都是属于大肠肿瘤的一种。消化道肿瘤继发出血是比较常见的，上消化道肿瘤是引起上消化道出血的常见病因之一，约占所有上消化道出血病因的2％-3％。良性肿瘤中以食管、胃及十二指肠息肉或息肉病最常见，此外，平滑肌瘤、腺瘤或神经纤维瘤等也可引起上消化道出血。恶性肿瘤主要有食道癌、胃癌、直结肠癌等。临床疾病出血时，可能需要根据病情状况进行治疗，如继发消化道大出血时，常常需要进行肿瘤切除手术，如果少量出血或者渗血时，一般需要根据病情选择药物控制治疗，但是多数药物效果欠佳。
结直肠癌是全球第三大常见恶性肿瘤，是癌症相关死亡的主要原因之一，约占全球新发癌症病例的10％。结直肠癌的发生发展过程受多种因素调控，包括遗传、环境、生活方式等因素。随着人口老龄化、生活方式、饮食习惯的改变，我国结直肠癌的发病率与病死率逐年攀升，严重威胁人民健康。结直肠癌的临床症状主要表现为大便习惯或大便性状的改变，并伴随有黏液脓血便、血便、腹胀和腹痛等。手术是结直肠癌最主要的治疗手段，但总体术后5年生存率约55％。目前，虽然抗肿瘤药物很多，但迄今为止发现的能够有效预防肿瘤发生的药物还很少见。最近有研究报道称长期服用阿司匹林的人群结肠癌发病率降低24％，胃肠道癌症死亡率整体下降35％，机制可能涉及对COX2和NF-κB的抑制作用，及DNA错配修复等方面。但因为阿司匹林是一种血液稀释剂，它容易损耗胃部的保护性黏膜导致消化道出血，甚至还会造成脑出血。所以阿司匹林在临床上被用于防止和阻断胃肠道癌方面的安全性还值得人们进一步研究和确定。由此可见，发现预防肿瘤发生的药物，周期长，难度大。因此，中医药预防肿瘤发生成为了我国的一大特色。
清肠温中片是扬子江药业的一个方剂，由黄连、炮姜、青黛、苦参、三七、煨木香、地榆炭、炙甘草按照7-11份、7-11份、4-1份、7-11份、4-8份、4-8份、7-11份、1-5份的重量份数制成，在轻度至中度UC患者中具有显著的临床疗效，能明显改善伴有粘液、脓液和血液的腹泻患者的活动性UC症状，减轻炎症，修复黏膜病变，但其对小肠肿瘤的预防作用以及结直肠癌的防治作用尚未见报道。
发明内容
发明目的：本发明所要解决的技术问题是针对现有技术的不足，提供一种中药组合物在制备防治消化道肿瘤药物中的应用。
为了解决上述第一个技术问题，本发明公开了一种中药组合物在制备防治消化道肿瘤药物中的应用，所述中药组合物的活性成分包括如下配方制成的成分，所述配方包括如下组分：黄连、炮姜、青黛、苦参、三七、煨木香、地榆炭、炙甘草。方中黄连、炮姜为君，二者均有良好的止泻功能，黄连清腹中湿热，炮姜温腹中寒湿，相互配伍，取平调寒热之义；黄连气味苦寒，清热祛湿止利，《神农本草经》主治“热气，肠澼，腹痛，下痢，妇人阴中肿痛”；炮姜辛热，温阳化湿止利，《神农本草经》曰“温中，止血，肠澼下利”，炮制后加强其止血功用。苦参、青黛、地榆炭为臣，三者为治疗肠炎的验药。苦参气味苦寒，清热燥湿，愈疮止利，《神农本草经》言其主治“心腹结气，疝瘕积聚，逐水，除痈肿”，《名医别录》记载“除伏热肠澼，疗恶疮下部疡”；青黛气味咸寒，清热泻火，解毒止利，《本经逢原》记载“散郁火，治温毒发斑及产后热痢下重”；地榆炭，气味苦酸涩微寒，凉血止血，解毒敛疮，《名医别录》曰“止脓血，恶疮”，《药性论》曰“止血痢蚀脓”，炒炭炮制加强其止血功用。三七、煨木香为佐，二者配伍，以达行气活血之效。三七，气味甘微苦温，《本草纲目》记载“止血散血定痛，下血血痢”；木香气味辛苦温，《日华子本草》称“心腹一切气，止泻，霍乱，痢疾，健脾消食”，两药合用，达到“调气则后重自除，行血则便脓自愈”。甘草为使，气味甘平，能调和寒热，调和诸药，缓急止痛止利，兼有补益作用。方中诸药，均有其针对的病机，相互配伍，能平调寒热，能除寒湿、湿热、滞气、瘀血和食积邪气，达到止利之效。
其中，所述配方中，各组分的重量份数为黄连4-14份、炮姜4-14份、青黛1-14份、苦参4-14份、三七1-11份、煨木香1-11份、地榆炭4-14份、炙甘草0.5-7份。
优选地，所述配方中，各组分的重量份数为黄连7-11份、炮姜7-11份、青黛4-11份、苦参7-11份、三七4-8份、煨木香4-8份、地榆炭7-11份、炙甘草1-5份。
进一步优选地，所述配方中，各组分的质量为黄连7-11g、炮姜7-11g、青黛4-11g、苦参7-11g、三七4-8g、煨木香4-8g、地榆炭7-11g、炙甘草1-5g。
其中，所述中药组合物的制备方法为根据配方取黄连、三七、青黛，加8-12倍量的50-80v％的乙醇回流提取，提取液经过滤、离心、浓缩、干燥，得干膏粉I；取苦参、煨木香、地榆炭、炮姜、甘草，加8-12倍量的水回流提取，将提取液过滤、浓缩，加乙醇至醇浓度达50-70v％，静置，过滤，滤液浓缩、干燥得干膏粉II；将干膏粉I与干膏粉II的混合物再进行低温干燥(60℃以下)，后用粉碎机粉碎成细粉，过100-150目筛，即得。
其中，所述中药组合物还包括药学上可接受的载体。
其中，所述药学上可接受的载体为稀释剂、湿润剂和润滑剂中的任意一种或几种的组合。
其中，所述稀释剂为乳糖、淀粉、糊精、糖粉、微晶纤维素和微粉硅胶中的任意一种或几种的组合；所述湿润剂为水和/或30v％～80v％乙醇；所述润滑剂为硬脂酸镁和/或滑石粉。
其中，所述中药组合物的制剂为适用于鼻腔黏膜、口腔黏膜、舌下给药、口服给药、皮肤给药、注射给药或肺部吸入的单位剂型形式。
其中，所述单位剂型为丸剂、胶囊剂、片剂、散剂、颗粒剂、口服液、灌肠液和煎煮剂中的任意一种。
其中，所述防治消化道肿瘤药物为防治结直肠癌的药物，防治结直肠肿瘤的药物，防治小肠肿瘤的药物，抑制小肠肿瘤增殖的药物，抑制结直肠肿瘤增殖的药物，改善肠组织病变的药物和改善肠道屏障功能的药物中的任意一种或几种；优选地，所述防治消化道肿瘤药物为防治小肠肿瘤的药物和/或防治结直肠癌的药物。
有益效果：与现有技术相比，本发明具有如下优势：
本发明利用清肠温中片开发出一种预防小肠肿瘤以及防治结直肠癌的疗效好而安全性高的一类中药新药，其可预防小肠肿瘤发生以及结直肠肿瘤的发生。这不仅为清肠温中片的应用提供了新的适应症，还为小肠肿瘤的预防以及结直肠癌的防治提供了一种新的治疗药物和治疗途径。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明，本发明的上述和/或其他方面的优点将会变得更加清楚。
图1是动物分组。
图2是APCmin/+小鼠模型中清肠温中片对体重的影响。
图3是APCmin/+小鼠模型中清肠温中片对生存率的影响；其中，高剂量组和对照组重叠。
图4是清肠温中片对小肠形态学的影响，左图是完整的肠组织，右图是清除肠道内容物剖开后的肠组织。
图5是清肠温中片对小肠肿瘤数量的影响。
图6是清肠温中片对小肠肿瘤尺寸的影响。
图7是清肠温中片对小肠肿瘤负荷的影响。
图8是AOM/DSS模型的造模流程。
图9是清肠温中片对结直肠形态学的影响，左图是完整的肠组织，右图是清除肠道内容物剖开后的肠组织。
图10是清肠温中片对结直肠肿瘤数量的影响。
图11是清肠温中片对结直肠肿瘤尺寸的影响。
图12是清肠温中片对结直肠肿瘤负荷的影响。
图13是清肠温中片对肠组织病变的影响。
图14是清肠温中片对肠道屏障功能的影响。
具体实施方式
下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
本发明中所述倍量，如无特殊说明，均为质量倍数。
下面是本发明有关清肠温中片的部分药理试验及结果。
实施例1一种清肠温中片干膏粉的制备方法
配方：各组分的重量份数为黄连10份、炮姜7份、青黛5份、苦参10份、三七6份、煨木香4份、地榆炭10份、炙甘草3份。
按照配方比取黄连、三七、青黛，加10倍量的60v％的乙醇回流提取，提取2次，每次2h，合并提取液，提取液经过滤、离心(离心转速6000r/min，时间10min)、浓缩(60℃)至相对密度为1.30、干燥(50℃)，得干膏粉I；取苦参、煨木香、地榆炭、炮姜、甘草，加10倍量的水回流提取，提取2次，每次2h，合并提取液，将提取液过滤、浓缩(60℃)至相对密度为1.10，加乙醇至醇浓度达60v％，静置(温度8℃，时间12h)过滤，滤液浓缩(60℃)至相对密度为1.05、干燥(50℃)得干膏粉II；将干膏粉I与干膏粉II的混合物再进行低温干燥(60℃)，后用粉碎机粉碎成细粉，过100目筛，进行低温干燥得到清肠温中片干膏粉。
实施例2
配方：各组分的重量份数为黄连12份、炮姜2份、青黛3份、苦参12份、三七5份、煨木香5份、地榆炭6份、炙甘草4份。
按照配方比取黄连、三七、青黛，加10倍量的60v％的乙醇回流提取2次，每次2h，合并提取液，过滤，于6000r/min下离心10min，离心液减压浓缩至60℃下相对密度为1.30的浸膏，而后于50℃干燥，得干膏粉Ⅰ；取苦参、煨木香、地榆炭、炮姜、甘草，加10倍量的水回流提取2次，每次2h，合并提取液，过滤，于60℃浓缩得60℃下相对密度为1.10的药液，加乙醇至醇浓度达60v％，而后于4℃下静置12h，过滤，滤液于60℃浓缩至相对密度为1.05、50℃干燥后得干膏粉Ⅱ；S3：将干膏粉Ⅰ和干膏粉Ⅱ的混合物与糊精按质量比2:1混合均匀，加入95v％的乙醇制软材，过筛制粒，将颗粒置于50℃下干燥，整粒，即得。
实施例3
1.试验方法
(1)药物配置：①AOM溶液：将AOM溶于无菌蒸馏水中，配成10mg/mL的储备液，置于-20℃储存。使用当日，将储备液用无菌生理盐水稀释10倍，得到1mg/mL的工作液(注：储备液应避免反复冻融；腹腔注射的剂量为10mg/kg，即每10g小鼠注射0.1mL的AOM工作液)。②DSS溶液：称取20g DSS粉末，溶解于1L无菌蒸馏水中，配制成2％的DSS溶液。③清肠温中溶液：称取适量实施例1所制备的清肠温中干膏粉溶于水中，配成0.175g/ml以及0.0875g/ml的溶液；其中，0.0175g和0.0875g指的是清肠温中片干膏粉的重量。
(2)模型建立：①APCmin/+小鼠模型：用高脂饲料喂养，自发形成消化道肿瘤肿瘤，多见于小肠。②AOM/DSS模型：腹腔注射致癌剂AOM与饮水给药致炎剂DSS联合建立小鼠结直肠癌模型，具体步骤如下(图8)：清肠温中片干预组饮水给药一周后，模型组和药物组一次性腹腔注射10mg/kg AOM，而对照组注射生理盐水作为空白对照，次周给予2％DSS水饲喂1周，后正常饮水2周，此为一个周期，循环3次，造模后第15周处死小鼠。
(3)如图1所示，动物分组：①APCmin/+小鼠模型：雄性APCmin/+小鼠，6周龄，每组6只，分别设立正常对照组、模型组、清肠温中片低剂量组(0.7g/kg/天，隔天灌胃给药14周)、清肠温中片高剂量组(1.4g/kg/天，隔天灌胃给药14周)。②AOM/DSS模型：雄性SPF级近交系C57BL/6J小鼠，6-8周龄，体重18-20g，按体重随机分为4组，每组20只，分别设立正常对照组、模型组、清肠温中片低剂量组(0.7g/kg/天，隔天灌胃给药14周)、清肠温中片高剂量组(1.4g/kg/天，隔天灌胃给药14周)；其中，0.7g和1.4g指的是清肠温中片干膏粉的重量。
(4)指标的测定与评价：
A.样本采集及结直肠形态学的记录：
血清：用摘除眼球法取血，将获得的新鲜血液静置1-2h后，及时用高速离心机(12000g，4℃)离心15min，取得上清即为血清，后放于-80℃冰箱中保存。
肠组织：通过脱颈椎处死小鼠，打开小鼠腹腔，剥离回盲部至肛门的整段肠组织，放入预冷的PBS中清洗，去除外壁上粘附的脂肪组织和肠系膜。将肠段置于预冷的玻璃板上平铺，使用直尺测量小肠、结直肠长度，记录并拍照。使用手术剪刀和镊子小心取出小肠、结肠内容物。剪下约1cm的小肠、结直肠末端迅速放入1mL多聚甲醛固定液中，用于后期病理检查。沿肠管纵向剖开剩余肠段，并于PBS中洗净粘附的结肠内容物。将小肠、结直肠内侧面朝上再次置于预冷的玻璃板上平铺，拍照并记录肿瘤大小和数目。将剩余肠段放入Ep管中，置于-80℃保存，用于后续的分子生物学检测。
B.H&E染色：
干燥后的组织切片需要脱蜡及水化才能在水溶性染料中进行染色。使用二甲苯脱蜡，再依次使用纯乙醇、95％乙醇、80％乙醇、70％乙醇洗，最后用蒸馏水洗。甩干后置于苏木精染液中染色5-10min。经水洗等操作后，再将切片用伊红染色1-3min。然后将切片依次放入95％乙醇、纯乙醇中梯度脱水，二甲苯中透化。最后使用中性树胶封片。利用数字病理切片扫描仪对制成的切片进行扫描。
C.免疫组化检测：
脱蜡至水步骤同H&E染色。接着进行抗原修复和阻断内源性过氧化物酶的过程。PBS洗涤5min/2次，使用3％的BSA室温封闭30min。PBS洗涤5min/2次，在切片上滴加适量特异性一抗，4℃孵育过夜。PBS洗涤5min/2次，再滴加适量与一抗相应种属的二抗，室温避光孵育1-2h。PBS洗涤5min/2次，滴加DAB染色液。自来水充分冲洗后，进行细胞核复染，脱水，透化，封片。利用数字病理切片扫描仪对制成的切片进行扫描。检测的蛋白指标为CLDN3、Occludin、ZO-1。
(5)统计学分析：
数据使用GraphPad Prism 8软件进行统计学分析，采用mean±SEM表示。两组独立样本的均值比较使用Student′s-t检验，两组以上分析利用单因素方差分析。设α＝0.05，*P＜0.05表示具有显著性差异，**P＜0.01表示差异极显著。
2.试验结果
(1)清肠温中片对小鼠体重、生存率的影响
实验期间记录小鼠的体重变化并统计小鼠的生存率，由图2见，与对照组相比，模型组小鼠的体重显著降低，但高剂量的清肠温中片可以缓解体重减轻；由图3可见，与模型组相比，高剂量的清肠温中片可以显著提高小鼠的生存率。
(2)清肠温中片对小鼠小肠、结直肠及肿瘤形态学的影响
造模结束后，测量各组小鼠小肠结直肠长度，拍照记录其大体形态并剖开小肠、结直肠段，观察肿瘤形成情况并拍照记录表面观。由图4和图9可见，对照组小鼠的小肠、结直肠肠壁光滑透亮，无凸起和异常增生的情况，肠腔内粪便成型。而模型组小鼠小肠、结直肠肠壁增厚变硬，剖开后可见成型肿瘤。而与模型组相比，清肠温中片干预组小肠、结直肠肠壁增厚减轻。
(3)清肠温中片对小鼠小肠、结直肠肿瘤的影响
造模结束后，沿肠管纵向剖开剩余肠段，拍照并记录肿瘤大小和数目。由图4可见，对照组小肠形态正常，而模型组小肠有肿瘤形成。由图5可见，与模型组相比，给药组小肠肿瘤数目减少。由图6和图7可见，清肠温中片亦使小鼠的小肠平均肿瘤尺寸、小肠肿瘤负荷降低，且在小肠肿瘤负荷上具有显著差异。由图9可见，对照组结肠形态正常，而模型组有大量肿瘤形成。由图10可见，与模型组相比，给药组结肠肿瘤数目减少，且高剂量组有显著差异。由图11和图12可见，高剂量的清肠温中片亦使小鼠的结肠平均肿瘤尺寸、结肠肿瘤负荷显著降低。以上结果显示清肠温中片可预防小肠以及结直肠肿瘤的形成。
(4)清肠温中片对肠组织病变的影响
造模结束后，取小鼠肠组织末端进行H&E染色。如图13的切片照片显示，对照组小鼠肠组织上皮细胞排列紧密，隐窝正常，肠壁粘膜层、粘膜下层完整，无炎症细胞浸润。模型组小鼠H&E染色可见肠黏膜层上皮细胞局部坏死脱落；黏膜层局部可见炎性细胞灶性浸润；黏膜层局部可见纤维组织增生，部分肠腺消失；黏膜下层可见纤维结缔组织增生，组织间隙增大。经QCWZ片治疗后，炎症细胞浸润程度降低，呈现较多正常隐窝细胞。上述结果说明，清肠温中片干预治疗可以明显改善肠组织的病变程度。
(5)清肠温中片对肠道屏障功能的影响
肠道屏障功能由机械屏障、化学屏障、微生物屏障以及免疫屏障共同组成的，完整的肠道屏障系统能降低机体因肠道渗透性升高而诱导的炎症性肠疾病、结直肠癌等肠道系统疾病的发生风险，对维持肠道及机体健康具有重要作用。其中，机械屏障主要由肠道上皮细胞以及肠道上皮细胞间紧密连接(Tight junction)和黏附连接(Adherens junction)蛋白组成。CLDN3、Occludin、ZO-1都是与肠道屏障功能相关的紧密连接蛋白。图14的免疫组化检测结果显示，清肠温中片改善了AOM/DSS小鼠的肠道屏障功能。
综上，本发明利用APCmin/+小鼠模型和AOM/DSS小鼠模型，评价了清肠温中片预防小肠肿瘤发生以及防治结直肠癌的作用。实验设计时采取提前给药干预，使用C57BL/6J小鼠，AOM/DSS诱导法构建模型以及APCmin/+小鼠自发形成肿瘤的模型。结果表明，高剂量的清肠温中片可以使小鼠的结肠平均肿瘤数目显著减少，结肠平均肿瘤尺寸以及结肠肿瘤负荷亦显著降低。通过HE染色可以发现，与模型组相比，给药组的结肠组织病变程度降低。同时研究发现，清肠温中片能明显改善肠道屏障功能。此外，清肠温中片在防治结直肠癌的同时也可以预防小肠肿瘤发生，高剂量的清肠温中片可明显减少小肠平均肿瘤数量，小肠平均肿瘤尺寸以及小肠肿瘤负荷亦显著降低。即清肠温中片能够抑制小肠以及结肠肿瘤形成，减轻肠组织病变，改善肠道屏障功能。
本发明提供了一种中药组合物在制备防治消化道肿瘤药物中的应用的思路及方法，具体实现该技术方案的方法和途径很多，以上所述仅是本发明的优选实施方式，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。本实施例中未明确的各组成部分均可用现有技术加以实现。
Claims (6)
1.一种中药组合物在制备防治小肠肿瘤药物中的应用，其特征在于，所述中药组合物的活性成分 由如下组分制备：黄连、炮姜、青黛、苦参、三七、煨木香、地榆炭、炙甘草；所述各组分的重量份数为黄连7-11份、炮姜7-11份、青黛 4-11份、苦参7-11份、三七4-8份、煨木香4-8份、地榆炭7-11份、炙甘草1-5份。
2.根据权利要求1所述中药组合物在制备防治小肠肿瘤药物中的应用，其特征在于，所述中药组合物还包括药学上可接受的载体。
3.根据权利要求2所述中药组合物在制备防治小肠肿瘤药物中的应用，其特征在于，所述药学上可接受的载体为稀释剂、湿润剂和润滑剂中的任意一种或几种的组合。
4.根据权利要求3所述中药组合物在制备防治小肠肿瘤药物中的应用，其特征在于，所述稀释剂为乳糖、淀粉、糊精、糖粉、微晶纤维素和微粉硅胶中的任意一种或几种的组合；所述湿润剂为水和/或30v%~80v%乙醇；所述润滑剂为硬脂酸镁和/或滑石粉。
5.根据权利要求1所述中药组合物在制备防治小肠肿瘤药物中的应用，其特征在于，所述中药组合物的制剂为适用于鼻腔黏膜、口腔黏膜、舌下给药、口服给药、皮肤给药、注射给药或肺部吸入的单位剂型形式。
6.根据权利要求5所述中药组合物在制备防治小肠肿瘤药物中的应用，其特征在于，所述单位剂型为丸剂、胶囊剂、片剂、散剂、颗粒剂、口服液、灌肠液和煎煮剂中的任意一种。
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