CN105853419B - 一种用于胃溃疡治疗的药物组合物及其应用 - Google Patents
一种用于胃溃疡治疗的药物组合物及其应用 Download PDFInfo
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Abstract
本发明涉及一种用于胃溃疡治疗的药物组合物及其应用，属于医药技术领域。为了克服现有治疗胃溃疡药物的副作用较大，治疗效果欠佳的技术不足，本发明提供一种治疗胃溃疡药物组合物，其由埃索美拉唑锶和槲皮素组成。两种药物活性组分在治疗抑制胃溃疡方面具有显著的协同作用，从而对胃溃疡起到很好的治疗作用。
Description
技术领域
本发明涉及一种用于胃溃疡治疗的药物组合物及其应用，属于医药技术领域。
背景技术
消化道性溃疡 (peptic ulcer，PU)主要指发生在胃和十二指肠的慢性溃疡，即胃溃疡和十二指肠溃疡，也可发生于食管下端、胃十二指肠吻合口附近以及Meckel憩室。西医将其归纳为局限性组织缺损，能累及黏膜、黏膜下层和肌层的疾病，中医根据其临床症状将其归属于“胃脘痛”的范畴。该病病程较长，反复发作，临床表现复杂，是一种全球性常见的慢性胃肠病。有资料报道，消化性溃疡占国内胃镜检查人群的10.3%～2.6%。该病可见于任何年龄，以20～50岁居多，男性多于女性（2～5∶1），临床上十二指肠溃疡多于胃溃疡，两者之比约为3∶1。消化性溃疡由多种因素引起，通常认为消化性溃疡的发生是因胃黏膜的损害因素与防御因素之间失衡。当对胃黏膜的损害因素大于防御因素时，溃疡病就可能形成，此外，还有精神因素、遗传因素及其他一些因素的参与，构成了溃疡病发生的复杂致病机制。
临床上用于溃疡病的药物很多，抗酸剂、质子泵抑制剂、H2-受体拮抗剂以及胃黏膜保护剂是目前国内抗消化性溃疡的主要药物，但这些药物一般都存在不同程度的不良反应，并且愈后复发率高。在临床上，质子泵抑制剂(PPIs)已被广泛应用于ARDs的治疗，是此类疾病的主要治疗药物。但是PPIs仍有一些局限性需要进一步改进：①所有的PPIs都是酸不稳定性的，因此需要做成酸保护的剂型，如肠衣片等，它们的起效速度和药效受到胃排空的较大影响；②PPIs需要H+激活转化，起效较慢，通常需要3～5天时间且多次给药，才能达到稳定的最大疗效；③由于人群中肝脏CYP2C19代谢系统的基因多样性，PPIs在不同病人中疗效差异较大，而且有可能与其他药物存在药物代谢上的相互作用；④药效与给药剂量成线性关系，血浆中代谢较快，即使一天两次给药，PPIs也很难持续24小时控制胃酸分泌。因此，PPIs对于某些病人的夜间胃酸分泌的抑制作用是不足的，夜间酸突破现象普遍存在。
埃索美拉唑是奥美拉唑的S-旋光异构体，是全球首个异构体质子泵抑制剂（PPI）。由于具有代谢优势，埃索美拉唑较奥美拉唑具有更高的生物利用度和更一致的药代动力学性质，生物利用度和血药浓度比奥美拉唑或（R）-奥美拉唑高，半衰期延长至2小时以上，因此其药效比奥美拉唑高而持久，抑酸能力也强于兰索拉唑或雷贝拉唑，同时还具有夜间酸抑制能力强、药效呈现时间剂量依赖性的特点。
发明内容
为了克服现有治疗胃溃疡药物的副作用较大，治疗效果欠佳的技术不足，本发明提供一种治疗胃溃疡药物组合物，其由埃索美拉唑锶和槲皮素组成。所述的药物组合物在治疗抑制胃溃疡方面具有显著的协同作用，从而对胃溃疡起到很好的治疗作用。
为了实现上述目的，本发明采用了以下技术方案：
一种预防和治疗胃溃疡的药物组合物，其由如下活性成分组成：
1)埃索美拉唑锶；
2)槲皮素。
其中所述药物组合物中埃索美拉唑锶和槲皮素的重量比为1：0.1-10，更优选为1：5。
本发明还提供了一种治疗胃溃疡的药物制剂，它是由有效量的埃索美拉唑锶、有效量的槲皮素和药学上可接受的辅料或辅助性成分制备而成的制剂。其中，所述的药物制剂是口服制剂。所述的口服制剂优选为其胶囊剂、片剂、颗粒剂。
上述所述的治疗胃溃疡的药物制剂中，每一制剂单位中槲皮素的含量为1-2000mg。
本发明还请求保护上述药物组合物在制备治疗胃溃疡药物中的用途。本发明实施例7显示，模型组大鼠溃疡指数较正常组显著增高，给药后埃索美拉唑锶单药组和槲皮素单药组均体现出一定的溃疡抑制效果，但效果并不理想，而复方各组则体现出显著的溃疡抑制效果，复方各组不论与埃索美拉唑锶单药组相比还是槲皮素组相比在抑制胃溃疡方面均有显著性或极显著性的差异，二者在抑制胃溃疡方面具有显著的协同作用。其中以复方3组效果更佳。
本发明与现有技术相比具有如下突出的预料不到的技术效果：
1）埃索美拉唑锶单药组和槲皮素单药组均体现出一定的溃疡抑制效果，但效果并不理想，而复方各组则体现出显著的溃疡抑制效果，复方各组不论与埃索美拉唑锶单药组相比还是槲皮素组相比在抑制胃溃疡方面均有显著性或极显著性的差异，二者在抑制胃溃疡方面具有显著的协同作用。
2）二者联合使用后在治疗效果增强的同时可以显著降低埃索美拉唑锶的用药剂量，从而降低了出血风险，提高了其用药安全性。
具体实施方式
以下通过实施例进一步描述本发明，但这些实施例仅是说明本发明，而不应理解为对本发明范围的任何限制。
实施例1 复方片剂的制备
| 槲皮素 | 1g |
| 埃索美拉唑锶 | 10g |
| 微晶纤维素 | 45g |
| 淀粉 | 30g |
| 15%淀粉浆 | 适量 |
| 硬脂酸镁 | 2.0g |
制备工艺：将槲皮素和埃索美拉唑锶与辅料微晶纤维素、淀粉混合均匀，加入适量的15%淀粉浆制软材，然后过16目筛制粒。湿颗粒在60℃干燥，干颗粒过16目筛整粒，筛出干粒中的细粉，与硬脂酸镁混匀，然后再与干颗粒混匀，压片，即得。
实施例2 复方片剂的制备
| 槲皮素 | 10g |
| 埃索美拉唑锶 | 1g |
| 可压性淀粉 | 90g |
| 乳糖 | 50g |
| 15%淀粉浆 | 适量 |
| 微粉硅胶 | 1.5g |
制备工艺：除组分不同外，制备工艺同实施例1所述工艺。
实施例3复方分散片的制备
| 槲皮素 | 10g |
| 埃索美拉唑锶 | 2g |
| 交联羧甲基纤维素钠 | 12g |
| 微晶纤维素 | 160g |
| 聚乙烯吡咯烷酮 | 6g |
| 5％PVP 60％乙醇溶液 | 适量 |
| 微粉硅胶 | 5g |
制备工艺：按处方量称取槲皮素、埃索美拉唑锶，以微晶纤维素为填充剂，交联羧甲基纤维素钠、聚乙烯吡咯烷酮为崩解剂，5％PVP 60％乙醇溶液为黏合剂，微粉硅胶为助流剂，用流化床一步制粒，然后压片，即得。
实施例4 复方片剂的制备
| 槲皮素 | 50g |
| 埃索美拉唑锶 | 5g |
| 可压性淀粉 | 90g |
| 乳糖 | 50g |
| 15%淀粉浆 | 适量 |
| 微粉硅胶 | 1.5g |
制备工艺：按实施例2所述工艺制备即得。
实施例5 复方颗粒剂的制备
| 槲皮素 | 40g |
| 埃索美拉唑锶 | 8g |
| 淀粉 | 180g |
| 糊精 | 50g |
| 蔗糖粉 | 60g |
| 80%乙醇 | 适量 |
制备工艺：称取处方量的槲皮素、埃索美拉唑锶、淀粉、糊精、蔗糖粉混合均匀。另将适量的80%乙醇加入于混合粉末中，混合均匀，制软材，通过18目尼龙筛制成湿粒，60℃左右干燥，20目筛整粒，分装，即得。
实施例6 复方颗粒剂的制备
| 槲皮素 | 50g |
| 埃索美拉唑锶 | 50g |
| 淀粉 | 180g |
| 糊精 | 50g |
| 蔗糖粉 | 60g |
| 80%乙醇 | 适量 |
制备工艺：称取处方量的槲皮素、淀粉、糊精、蔗糖粉混合均匀。另将适量的80%乙醇加入于混合粉末中，混合均匀，制软材，通过18目尼龙筛制成湿粒，60℃左右干燥，20目筛整粒，分装，即得。
实施例7 本发明复方制剂对大鼠水浸应激性胃溃疡的抑制作用
1、方法：
1.1 溃疡模型的复制及溃疡程度的指标：取SD大鼠90只，体重为200～250g，雄性，随机分为9组。实验前禁食24h，自由饮水。实验组于浸水应激前30min，分别通过胃肠给药方式给予下述药物：
对照组、模型组给与等量生理盐水。
埃索美拉唑锶低组：灌胃给予埃索美拉唑锶0.5mg/kg;
埃索美拉唑锶高组：灌胃给予埃索美拉唑锶5mg/kg;
槲皮素低组：灌胃给予槲皮素0.5mg/kg；
槲皮素高组：灌胃给予槲皮素5mg/kg；
复方1组：灌胃给予埃索美拉唑锶0.5mg/kg+槲皮素5mg/kg；
复方2组：灌胃给予埃索美拉唑锶5mg/kg+槲皮素0.5mg/kg；
复方3组：灌胃给予埃索美拉唑锶0.5mg/kg+槲皮素2.5mg/kg。
以上药物用前均以5g/l羧甲基纤维素溶液配成所需浓度。水浸条件为水温（23±1）℃，浸水应激5h，处死动物，观察溃疡情况。按Cuth的方法计算溃疡指数，点状出血为1分；线状出血，长度<1mm为2分，1～2mm为3分，2～4mm为4分，>4mm为5分，宽度>1mm时分值×2。
1.2 数据处理：数据以均数±标准差（x±S）表示。根据所得每组溃疡指数，按溃疡抑制率的计算公式：溃疡抑制率=[(对照组指数-给药组指数)/对照组指数] ×100%；算出溃疡抑制率。各组间差异的比较采用t检验。
2.结果：
实验结果采用SPSS10.0 软件进行ONE-ANOVA 分析， 结果用(x±s)表示。实验结果如表1所示。
表1 各给药组对大鼠水浸应激性胃溃疡的作用
| 组别 | n | 溃疡指数 | 溃疡抑制率（%） |
| 对照组 | 10 | 0.56±1.13 | - |
| 模型组 | 10 | 49.65±9.38 | - |
| 埃索美拉唑锶低组 | 10 | 40.25±6.58* | 18.9* |
| 埃索美拉唑锶高组 | 10 | 37.62±5.64* | 24.2* |
| 槲皮素低组 | 10 | 43.71±6.95 | 11.9 |
| 槲皮素高组 | 10 | 39.52±4.63* | 20.4* |
| 复方1组 | 10 | 25.11±4.34**#▼ | 49.43**#▼ |
| 复方2组 | 10 | 17.52±7.63**##▼▼ | 64.71**##▼▼ |
| 复方3组 | 10 | 11.53±6.01**##▼▼ | 76.78**##▼▼ |
注:与模型组相比*P <0 .05，**P <0 .01 ;与埃索美拉唑锶单药组相比，#P <0.05，##P<0.01；与槲皮素单药组相比，▼P<0 .05，▼▼P <0 .01；
根据表1 的结果显示，模型组大鼠溃疡指数较正常组显著增高，给药后埃索美拉唑锶单药组和槲皮素单药组均体现出一定的溃疡抑制效果，但效果并不理想，而复方各组则体现出显著的溃疡抑制效果，复方各组不论与埃索美拉唑锶单药组相比还是槲皮素组相比在抑制胃溃疡方面均有显著性或极显著性的差异，二者在抑制胃溃疡方面具有显著的协同作用。其中以复方3组效果更佳。
Claims (6)
1.一种用于胃溃疡治疗的药物组合物，其由如下活性成分组成：
1)埃索美拉唑锶；
2)槲皮素；所述药物组合物中埃索美拉唑锶和槲皮素的重量比为1：0.1‐10。
2.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物中埃索美拉唑锶和槲皮素的重量比为1：5。
3.根据权利要求1或2所述的药物组合物，其特征在于，所述药物组合物为其口服制剂。
4.根据权利要求3所述的药物组合物，其特征在于，所述的药物组合物的口服制剂为其胶囊剂、片剂或颗粒剂。
5.根据权利要求3所述的药物组合物，其特征在于，每一制剂单位中槲皮素的含量为1‐2000mg。
6.权利要求1所述的药物组合物在制备治疗胃溃疡药物中的用途。
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