CN101675924B - 驱蛔素在制备抗幽门螺杆菌及其引起的疾病的药物中的应用 - Google Patents
驱蛔素在制备抗幽门螺杆菌及其引起的疾病的药物中的应用 Download PDFInfo
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- CN101675924B CN101675924B CN 200810151482 CN200810151482A CN101675924B CN 101675924 B CN101675924 B CN 101675924B CN 200810151482 CN200810151482 CN 200810151482 CN 200810151482 A CN200810151482 A CN 200810151482A CN 101675924 B CN101675924 B CN 101675924B
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Abstract
本发明涉及驱蛔素在制备抗幽门螺杆菌的药物中的应用。
Description
技术领域
本发明涉及驱蛔素的在在制备抗幽门螺杆菌的药物中的应用。
背景技术
幽门螺杆菌(Helicobacterpylori)是一种单极、多鞭毛、末端钝圆、螺旋形弯曲的革兰染色阴性菌。幽门螺杆菌通常寄生于人胃小凹的黏液层内，依靠其尿素酶分解产生的氨来中和胃酸，从而在胃内定植。幽门螺杆菌分泌的两种毒素CagA和VacA，CagA能够使与细胞增殖有关的蛋白质NFAT活性化，促使细胞异常增殖，并引起一系列炎症反应，导致胃粘膜的慢性炎症和溃疡。1982年Warren和Marshall从胃黏膜活检样本中成功分离和培养出了这种细菌，证实该菌是导致胃炎的罪魁祸首(Marshell et al.，Letters，1984，25：83)。随后大量研究证实，幽门螺杆菌是十二指肠溃疡、十二指肠炎、十二指肠癌、胃溃疡、慢性胃炎或残胃炎的重要致病因素，与胃癌发生有密切关系。目前，国内外应用于治疗消化性溃疡疾病的药物有增强胃粘膜保护作用的药物(如，铋制剂)、降低胃酸的药物(如，ATP酶(质子泵)抑制剂(PPI)或H2受体阻断剂)、抗菌素(如，阿莫西林、克拉霉素、甲硝唑、庆大霉素等)这三大类药物。
驱蛔素(Ascaridole)，别名土荆芥油精，又称驱蛔脑(Ascarisin)，化学名称为1-methyl-4-(1-methylethyl)-2，3-dioxabicyclo[2.2.2]oct-5-ene，分子式：C10H16O2，结构式如下式(I)，分子量168.23g/mol。驱蛔素是土荆芥油杀肠虫的主要成分，可用于驱除蛔虫、钩虫，动物实验表明还具有一定的抗疟作用。但对于驱蛔素在抑制幽门螺杆菌作用和治疗消化性溃疡，慢性胃炎等疾病方面，国内外尚无报道。
发明内容
本发明提供了驱蛔素在制备抗幽门螺杆菌的药物中的应用。
驱蛔素是一种驱虫药，本发明的发明人却意外地发现，驱蛔素具有很强的抗抗幽门螺杆菌的作用。因此，可以用于预防和治疗幽门螺旋杆菌引起的疾病，这些疾病包括但不限于十二指肠溃疡、十二指肠炎、十二指肠癌、胃溃疡、慢性胃炎、残胃炎或胃癌。驱蛔素可以缩小溃疡面积，降低十二指肠蠕动速度，故而可以减轻痉挛性疼痛。
另外，发明人还惊奇地发现，对于无幽门螺旋杆菌感染的溃疡，如高胃酸分泌型溃疡，驱蛔素也能缩小溃疡面积，降低十二指肠蠕动速度，故而可以减轻痉挛性疼痛。
正是由于驱蛔素同时具有抗幽门螺旋杆菌、缩小溃疡面积，降低十二指肠蠕动速度等作用，因此特别适合治疗幽门螺旋杆菌引起的疾病，既能治标，又能治本，实现标本兼治。
所述的驱蛔素用于治疗上述疾病时，其用量由医生根据疾病种类、病情或者病人的一般状况很容易确定。
为了本发明目的的驱蛔素，可以从商业途径购买。也可以按照现有技术的方法制备，如可采用化学方法制备，例如光氧化反应法(袁履冰.单态氧及其在有机合成中的应用.辽宁化工，1985年第4期：2-9，沈玉全，曹怡.光氧化反应的工业应用前景.感光科学与光化学，第3期1985年8月：58-64.，江致勤.有机光化学的应用前景.有机化学，1984年8月第4期：252-258.)、吸附法(刘和，孙忠贵.我国化学领域天然植物挥发性成分研究的进展.江西农业大学学报，第20卷第1期1998年3月：75-81.)或者植物生长激素处理法(李树殿.栽培技术对药用植物有效成分含量的影响)来制备。本发明所用的驱蛔素，还可以是按照现有技术教导的方法从土荆芥(Chenopodium ambrosioides L.)或波尔多(Boldo，Peumus boldus Molina)等植物中提取而来。
本发明涉及的驱蛔素可制成任何一种药剂学上所述的药物制剂，包括但不限于胶囊剂、硬胶囊剂、软胶囊剂、注射剂、滴注剂、粉针剂、颗粒剂、片剂、冲剂、散剂、口服液、糖衣片剂、薄膜衣片剂、肠溶衣片剂、口含剂、丸剂、膏剂、丹剂、喷雾剂、滴丸剂、口崩剂、微丸、气雾剂等。
为了本发明的目的，驱蛔素优选制成口服剂型，如：胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等，更优选软胶囊剂。
驱蛔素的口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
驱蛔素制剂，在制备成药剂时可选择性的加入适合的药物可接受的载体，所述药物可接受的载体选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β—环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
为了进一步阐释本发明，申请人提供了以下实验：驱蛔素体外抗幽门螺杆菌实验、体外抗其他细菌实验、抗乙酸烧灼慢性胃溃疡实验和对小鼠小肠墨汁推进的抑制作用实验。这些实验表明驱蛔素有很强的抗幽门螺旋杆菌的作用，但对其它肠道细菌的抑制作用很弱，表明驱蛔素胃肠道用药而不致对肠道的正常菌群造成影响。另外，驱蛔素对于缩小溃疡面积，抑制小肠蠕动都有很好的作用，这对于溃疡的治疗也是非常重要和有益的。
驱蛔素体外抗幽门螺杆菌实验
幽门螺杆菌菌株采用的是国际标准株ATCC43504购于上海仁济医院消化内科。幽门螺杆菌生长在改良的Skirrow选择性培养基(即在改良Skirrow琼脂基础中加入抗生素混合液，使终浓度为TMP5mg/L，万古霉素10mg/L，多粘菌素B2500IU/L，(加入以上物质目的何在？细菌的培养方法)并加入100ml脱纤维羊血)，置37℃微需氧环境(5％O2，10％CO2，85％N2)培养72h。称取20mg样品油溶于12mg/ml聚山梨醇酯80水溶液1ml中，混合均匀，超声5分钟。用灭菌蒸馏水进行等比稀释。
采用打孔琼脂扩散法。取直径9cm、培养基厚度约4mm的改良Skirrow选择性培养基的平板，每块平板加入100μl1×108CFU/ml的幽门螺杆菌菌液，立即用涂布棒涂布均匀。之后，每个培养皿挖4个杯状小孔，呈均匀分布，每孔直径4mm。每孔中加入10μl的驱蛔素样液，微需氧37℃培养72h，观察抑菌圈，测量直径。每个样品浓度重复三次。结果见表1。
表1驱蛔素体外对幽门螺杆菌的抑制作用
“+”表示有菌生长；“-”表示无菌生长。
实验结果表明：驱蛔素在体外能抑制幽门螺杆菌。
驱蛔素体外抗其他细菌实验
枯草芽孢杆菌(CMCC63501)、铜绿假单胞菌(CMCC10104)、大肠埃希菌(CMCC44102)和金黄色葡萄球菌(CMCC26003)购置于中国医学微生物菌种保藏管理中心。将菌株接种于普通琼脂平板上，置于35℃恒温箱中培养20～24h，用无菌肉汤调整菌液浊度相当于0.5麦氏标准。取100ul菌液均匀涂布于营养琼脂培养基上，之后，每个培养皿挖4个杯状小孔，呈均匀分布，每孔直径4mm。每孔中加入20μl的样液。样品初始浓度为200mg/ml。
表2驱蛔素和荆花胃康市售油体外抑菌试验
实验结果显示：和荆花胃康市售油类似，驱蛔素对大肠埃希菌、枯草芽孢杆菌、铜绿假单胞菌和金黄色葡萄球菌抑制作用很弱。
抗乙酸烧灼慢性胃溃疡实验
选用SD大鼠、雌雄各半，随机分为4组，每组10只。按体重灌胃给药，连续10天，每日一次，在第2天给药后2小时，进行手术造模，造模前禁食24小时。动物麻醉，剑突下切口，取胃于近幽门腺胃部浆膜下注射20％冰醋酸溶液，送回腹腔，洒青霉素粉，缝合伤口。手术后继续给药。最后一次给药后，禁食24小时。处死大鼠，取胃，用游标卡尺测量胃溃疡的长短径，计算溃疡面积。结果见下表：
表2大鼠醋酸烧灼慢性胃溃疡模型
实验结果表明：驱蛔素有降低大鼠醋酸引起的胃溃疡面积的作用，和模型组相比较，都有显著性差异。
对小鼠小肠墨汁推进的抑制作用实验
CD-1小鼠，随机分为4组，每组10只。灌胃给药三天。末次灌胃前禁食24小时，灌胃后2小时，灌胃给予50％碳素墨汁(生理盐水配制)0.3ml/10g。准确计时20分钟，将小鼠脱颈椎处死。打开腹腔，取出肠(从幽门开始，至回盲部)，测量肠道全长以及墨汁推进距离，计算推进百分比。结果见表3.
表3小鼠小肠墨汁推进实验。
结论：5mg/kg和10mg/kg的驱蛔素有明显抑制小肠推进的作用，和模型组比较都有显著性差异。
附图说明
图1实施例1制备的驱蛔素在CDCl3中的1H NMR(请在实施例中具体描述该图)
图2实施例1制备的驱蛔素HPLC谱图(请在实施例中具体描述该图)
具体实施方式
本发明通过以下实施例进一步阐述，但不以任何形式对本发明构成限制。
实施例1驱蛔素的制备
取土荆芥挥发油，采用正相硅胶(≤100um)柱色谱分离，硅胶用量为挥发油重量的5～50倍。以正己烷为起始溶剂洗脱约3～5倍的保留体积，得流分I。再以正己烷/乙酸乙酯梯度洗脱，分步收集。顺序为正己烷/乙酸乙酯(100:1)洗脱约3～5倍保留体积，得流分II；正己烷/乙酸乙酯(80:1)洗脱约3～5倍保留体积，得流分III。流分III中驱蛔素含量达90％以上。图1显示了提取的驱蛔素的在CDCl3中的1H NMR，从谱图分析提取驱蛔素结构正确。图2显示了驱蛔素提取样品的HPLC谱图。图2显示了驱蛔素提取样品的HPLC谱图，该图表明保留时间28.592处是驱蛔素的峰，纯度为91.1％。
实施例2驱蛔素的制备
取土荆芥挥发油，采用正相硅胶(≤100um)柱色谱分离，硅胶用量为挥发油重量的5～50倍。以石油醚(沸程30～60℃)为起始溶剂洗脱约5倍的保留体积，得流分I。再以石油醚/乙酸乙酯梯度洗脱，分步收集。顺序为石油醚/乙酸乙酯(100:1)洗脱约5倍保留体积，得流分II；石油醚/乙酸乙酯(80:1)洗脱约5倍保留体积，得流分III。流分III中驱蛔素含量达90％以上。
实施例3驱蛔素的制备
先将正相硅胶(≤100um)用2％～2.5％的硝酸银溶液充分浸泡后，避光阴干，备用。取土荆芥挥发油，采用上述硝酸银硅胶进行柱色谱分离，硅胶用量为挥发油重量的5～50倍。以正己烷为起始溶剂洗脱约3～5倍的保留体积后，再以正己烷/乙酸乙酯梯度洗脱，分步收集。顺序为正己烷/乙酸乙酯(100:1)洗脱约3～5倍保留体积，得流分I；正己烷/乙酸乙酯(80:1)洗脱约3～5倍保留体积，得流分II。流分II中驱蛔素含量达90％以上。
实施例6驱蛔素的制备方法
先将正相硅胶(≤100um)用2％～2.5％的硝酸银溶液充分浸泡后，避光阴干，备用。取土荆芥挥发油，采用上述硝酸银硅胶进行柱色谱分离，硅胶用量为挥发油重量的5～50倍。以石油醚(沸程30～60℃)为起始溶剂洗脱约3～5倍的保留体积，得流分I。再以石油醚/乙酸乙酯梯度洗脱，分步收集。顺序为石油醚/乙酸乙酯(100:1)洗脱约3～5倍保留体积，得流分II；石油醚/乙酸乙酯(80:1)洗脱约3～5倍保留体积，得流分III。流分III中驱蛔素含量达90％以上。
实施例5驱蛔素的制备
取土荆芥挥发油，采用反相C18硅胶(≤100um)柱色谱分离，反相C18硅胶用量为挥发油重量的20～500倍。以甲醇/水为洗脱溶剂梯度洗脱，分布收集。顺序为甲醇/水(30:70)洗脱约3～5倍保留体积，得流分I；甲醇/水(40:60)洗脱约3～5倍保留体积，得流分II；甲醇/水(50:50)洗脱约3～5倍保留体积，得流分III；甲醇/水(60:40)洗脱约3～5倍保留体积，得流分IV；甲醇/水(70:30)洗脱约3～5倍保留体积，得流分V；甲醇/水(80:20)洗脱约3～5倍保留体积，得流分VI；甲醇/水(90:10)洗脱约3～5倍保留体积，得流分VII。流分V中驱蛔素含量达90％以上。
实施例6驱蛔素胶丸的制备
取明胶100份加入120份水中，使其吸水膨胀，另将30份甘油加热至60℃，将膨胀的明胶加入，搅拌、熔融、保温待用。称取实施例3中驱蛔素油6g，加入4g菜籽色拉油，搅均，得到原料油。将明胶液和原料油装入自动旋转轧囊机，压制成内含油状液体60mg/粒的胶丸，胶丸定型、干燥、洗涤、消毒，包装即得。
实施例7驱蛔素滴丸的制备
取300g聚乙二醇4000加热至75℃，熔融后加入实施例3中得驱蛔素50g，搅拌均匀，移至滴丸机中，保持熔融液温度75℃，由上往下，滴速适中滴入5℃液体石蜡中，制成滴丸剂。
Claims (10)
1.驱蛔素作为唯一活性成分在制备抗幽门螺杆菌的药物中的应用。
2.如权利要求1的应用，其特征在于所述的药物用于预防和治疗幽门螺旋杆菌引起的疾病。
3.如权利要求2的应用，其特征在于所述的疾病选自十二指肠溃疡、十二指肠炎、十二指肠癌、胃溃疡、慢性胃炎、残胃炎或胃癌。
4.如权利要求3的应用，其特征在于所述的药物用于缩小溃疡面积。
5.如权利要求3的应用，其特征在于所述的药物用于减轻痉挛性疼痛。
6.驱蛔素作为唯一活性成分在制备治疗高胃酸分泌型溃疡的药物中的应用。
7.如权利要求6的应用，其特征在于所述的药物用于缩小溃疡面积。
8.如权利要求6的应用，其特征在于所述的药物用于减轻痉挛性疼痛。
9.如权利要求1～8的任一权利要求的应用，其特征在于所述的驱蛔素制成口服制剂。
10.如权利要求1～8的任一权利要求的应用，其特征在于所述的驱蛔素制成软胶囊剂。
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