CN112933091B - 一种抗胃酸类疾病的药物组合物及应用 - Google Patents
一种抗胃酸类疾病的药物组合物及应用 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract
一种抗胃酸类疾病的药物组合物，包括沃诺拉赞或其盐与铋盐，所述沃诺拉赞或其盐与铋盐的摩尔比为1：1～1：5，所述铋盐选自枸橼酸铋钾、酒石酸铋钾、酒石酸铋钠，在治疗抗胃酸类疾病时，具有协同作用，可以显著的增加治疗效果同时还能起到保护保护胃黏膜和胃肠道的双重作用。
Description
技术领域
本发明属于化学药物领域，具体涉及一种具有质子泵抑制作用的抗胃酸类疾病的药物组合物，更具体的涉及沃诺拉赞与铋盐所形成的组合物与应用。
背景技术
胃酸相关性疾病是一类由于胃酸分泌过多或对胃酸特别敏感而引起的疾病，如消化性溃疡、胃食管返流及非甾体类抗炎药物引起的消化系统病等。目前治疗胃酸分泌过多的最强药物是质子泵抑制剂(PPI)，例如奥美拉唑、兰索拉唑等。但该类药物存在着严重缺陷：夜间会发生酸反跳现象，影响治疗效果。钾离子竞争性酸阻滞剂(P-CAB)类药物(如沃诺拉赞)的出现很好的解决了这一类问题，通过竞争性抑制质子泵(H+，K+-ATPase)中K+而起作用，临床上可明显减少夜间酸反跳现象的发生。
沃诺拉赞，其化学名为1-[5-(2-氟苯基)-1-(吡咯-3-基磺酰基)-1H-吡咯-3-基]-N-甲基甲胺，结构式如式I所示。沃诺拉赞由武田制药公司研制，是全球第一个可逆的钾离子竞争性酸阻滞剂(P-CAB)。2015年2月，沃诺拉赞在日本批准上市，上市盐型为富马酸盐，上市剂型为片剂。
体外实验研究表明沃诺拉赞抑制质子泵的能力是常规质子泵抑制剂兰索拉唑的400倍，其相对于Na+、K+-ATPase的抑制选择性在1000倍以上，可有效地抑制胃酸分泌。沃诺拉赞具有抑制胃酸分泌强劲、持久、起效快等特点，是新一代的抗胃酸分泌药物。但现上市药物沃诺拉赞富马酸盐的动物口服生物利用度仅10％，限制了该化合物发挥其抑酸和治疗胃酸相关性疾病的作用。
枸橼酸铋钾或酒石酸铋钾或酒石酸铋钠均为含铋复合物的铋盐，可用于治疗胃肠疾病。枸橼酸铋钾又名次枸橼酸铋、三钾二枸橼酸铋等，为碱式枸橼酸铋的复盐。枸橼酸铋钾具有味咸、易溶于水和极微溶于乙醇的特点，其具有如下式Ⅱ结构式：
枸橼酸铋钾经定量热水解后口服，经胃液水解后，可生成有效成分为胶体次枸橼酸铋的沉淀，形成弥漫型的保护层覆盖在溃疡在溃疡面上，形成保护膜，防止胃酸和胃蛋白酶对溃疡粘膜的侵蚀，可促进溃疡粘膜再生和溃疡愈合。目前在治疗胃肠病的铋盐药物中，胶态次枸橼酸铋及果胶铋疗效较好，已经获得广泛应用。但是试验证明，许多铋盐对溃疡结肠炎无有效治疗作用。
发明内容
本发明的目的是提供一种药物组合物，包括沃诺拉赞或其盐与枸橼酸铋钾或酒石酸铋钾或酒石酸铋钠，此药物组合物配合使用时具有协同作用，可以提高治疗抗胃酸类疾病的效果。
进一步，沃诺拉赞盐为富马酸沃诺拉赞盐，具有如下式Ⅲ结构：
进一步，药物组合物包括富马酸沃诺拉赞盐和枸橼酸铋钾，所述富马酸沃诺拉赞盐和枸橼酸铋钾的摩尔比为1：2～1：4。优选摩尔比为1：2。
进一步，药物组合物包括富马酸沃诺拉赞盐和酒石酸铋钾或酒石酸铋钠，所述富马酸沃诺拉赞盐和酒石酸铋钾或酒石酸铋钠的摩尔比为1：2～1：4。优选富马酸沃诺拉赞盐和酒石酸铋钾，摩尔比为1：2。
进一步，药物组合物还包括增溶剂。优选增溶剂选自取代β-环糊精、卵磷脂。
进一步，药物组合物为注射剂或口服制剂。
所述口服制剂为片剂、丸剂、胶囊、粉剂、颗粒剂、软咀嚼剂或凝胶等。
本发明之抗胃酸类疾病的药物组合物，可以应用于制备用于预防或治疗胃酸类疾病的药物，如胃酸过多而引起的相关疾病，包括糜烂性食管炎、胃溃疡、十二指肠溃疡、幽门螺杆菌病等。
发明人经过大量实验发现，本发明所提供的药物组合物，包括沃诺拉赞或其盐与铋盐，在治疗抗胃酸类疾病时，具有协同作用，优选富马酸沃诺拉赞盐和枸橼酸铋钾或酒石酸铋钾药物组合物，可以显著的增加治疗效果，同时还能起到保护保护胃黏膜和胃肠道的双重作用。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂或物料均可以从市场上购得或者可以通过现有技术所公开的方法制备而得。
实施例1
| 物料名称 | 用量(mg) |
| 富马酸沃诺拉赞(A) | 10 |
| 枸橼酸铋钾(B) | 30 |
| 结晶纤维素 | 20 |
| 甘露糖醇 | 32 |
| 硬脂酸镁 | 2 |
| 羟丙纤维素 | 6 |
| 柠檬酸 | 20 |
| 卵磷脂 | 10 |
在必要时，使用干露糖醇作为组分来更改含量，本发明提供该片剂形式的药物组合物的制备方法，其包括如下步骤：按照配方量称取好各组分，混合均匀，然后采用湿法制粒，干燥，压片，即得。
实施例2
| 物料名称 | 用量(mg) |
| 富马酸沃诺拉赞(A) | 10 |
| 枸橼酸铋钾(B) | 60 |
| 结晶纤维素 | 20 |
| 甘露糖醇 | 22 |
| 硬脂酸镁 | 2 |
| 羟丙纤维素 | 6 |
| 柠檬酸 | 20 |
| 卵磷脂 | 10 |
在必要时，使用干露糖醇作为组分来更改含量，本发明提供该片剂形式的药物组合物的制备方法，其包括如下步骤：按照配方量称取好各组分，混合均匀，然后采用湿法制粒，干燥，压片，即得。
实施例3
| 物料名称 | 用量(mg) |
| 富马酸沃诺拉赞(A) | 10 |
| 酒石酸铋钾(C) | 33 |
| 结晶纤维素 | 20 |
| 甘露糖醇 | 49 |
| 硬脂酸镁 | 2 |
| 羟丙纤维素 | 6 |
| 柠檬酸 | 20 |
| 卵磷脂 | 10 |
在必要时，使用干露糖醇作为组分来更改含量，本发明提供该片剂形式的药物组合物的制备方法，其包括如下步骤：按照配方量称取好各组分，混合均匀，然后采用湿法制粒，干燥，压片，即得。
实施例4
| 物料名称 | 用量(mg) |
| 富马酸沃诺拉赞 | 10 |
| 酒石酸铋钾 | 66 |
| 结晶纤维素 | 20 |
| 甘露糖醇 | 16 |
| 硬脂酸镁 | 2 |
| 羟丙纤维素 | 6 |
| 柠檬酸 | 20 |
| 卵磷脂 | 10 |
在必要时，使用干露糖醇作为组分来更改含量，本发明提供该片剂形式的药物组合物的制备方法，其包括如下步骤：按照配方量称取好各组分，混合均匀，然后采用湿法制粒，干燥，压片，即得。
实施例5
| 物料名称 | 用量(mg) |
| 富马酸沃诺拉赞 | 10 |
| 酒石酸铋钠 | 31 |
| 结晶纤维素 | 20 |
| 甘露糖醇 | 51 |
| 硬脂酸镁 | 2 |
| 羟丙纤维素 | 6 |
| 柠檬酸 | 20 |
| 卵磷脂 | 10 |
在必要时，使用干露糖醇作为组分来更改含量，本明提供该片剂形式的药物组合物的制备方法，其包括如下步骤：按照配方量称取好各组分，混合均匀，然后采用湿法制粒，干燥，压片，即得。
实施例6
在必要时，使用干露糖醇作为组分来更改含量，本明提供该片剂形式的药物组合物的制备方法，其包括如下步骤：按照配方量称取好各组分，混合均匀，然后采用湿法制粒，干燥，压片，即得。
实施例7：药效实验
富马酸沃诺拉赞与含铋盐复方对胃溃疡的抑制作用
实验材料：SD大鼠，SPF级，雄性，体重(250-280g)，北京维通利华实验动物技术有限公司提供。
实验药物：对比例1(富马酸沃诺拉赞)，对比例2(枸橼酸铋钾)，对比例3(酒石酸铋钾)，对比例4(酒石酸铋钠)，实施例1，实施例2，实施例3，实施例4，实施例5，实施例6，溶媒5％DMSO+10％Solutol+85％Saline。
实验分组及给药剂量：假手术组(溶媒)，模型组(溶媒)，对比例1(富马酸沃诺拉赞2.67mg/kg)，对比例2(枸橼酸铋钾8.01mg/kg)，对比例3(酒石酸铋钾8.81mg/kg)，对比例4(酒石酸铋钠8.28mg/kg)，实施例1(富马酸沃诺拉赞2.67mg/kg+枸橼酸铋钾8.01mg/kg)，实施例2(富马酸沃诺拉赞2.67mg/kg+枸橼酸铋钾16.02mg/kg)，实施例3(富马酸沃诺拉赞2.67mg/kg+酒石酸铋钾8.81mg/kg)，实施例4(富马酸沃诺拉赞2.67mg/kg+酒石酸铋钾17.62mg/kg)，实施例5(富马酸沃诺拉赞2.67mg/kg+酒石酸铋钠8.28mg/kg)，实施例6(富马酸沃诺拉赞2.67mg/kg+酒石酸铋钠16.56mg/kg)。
实验方法：雄性SD大鼠120只，根据体重随机分成十二组，禁食不禁水24小时后，动物给溶媒或化合物，给药后1小时，动物进行胃幽门结扎手术。手术前，动物异氟烷麻醉，剃毛后，动物腹部朝上，固定在手术板上。在箭突下1厘米偏右处，剪出1厘米左右伤口。用棉签沾湿生理盐水，伸入腹腔，勾出胃周脂肪，暴露胃和十二指肠。将胃与十二指肠连接处，即幽门处剥离脂肪，进行双线结扎。并在胃幽门前庭部再次进行双线结扎。动物结扎后，禁食禁水9小时。在禁食禁水9小时后，动物安乐死，解剖，将胃贲门结扎，小心取出整个胃，沿胃大弯剪开，测量胃溃疡长和宽，计算溃疡面积，Okabe法评价溃疡指数以及溃疡抑制率，实验结果见表1。
表1大鼠口服实施例及对比例药物的溃疡指数以及溃疡抑制率(Mean±SD)
| 组别 | 溃疡评分(Okabe法) | 溃疡抑制率 |
| 假手术组 | 0 | — |
| 模型组 | 2.46±0.730 | — |
| 对比例1 | 2.19±0.626 | 10.97％ |
| 对比例2 | 2.20±0.892 | 10.57％ |
| 对比例3 | 2.17±0.957 | 11.79％ |
| 对比例4 | 2.15±0.829 | 12.60％ |
| 实施例1 | 0.95±0.799 | 61.38％ |
| 实施例2 | 1.07±0.624 | 56.5％ |
| 实施例3 | 0.84±0.552 | 65.85％ |
| 实施例4 | 0.96±0.498 | 60.97％ |
| 实施例5 | 0.87±0.691 | 64.63％ |
| 实施例6 | 0.99±0.701 | 59.75％ |
结果表明：各组大鼠除了假手术组外均出现胃溃疡，大鼠口服实施例及对比例药物后，实施例组及对比例组的胃溃疡出现不同程度的抑制，各实施例组均出现显著的溃疡抑制作用(P<0.05)，其中实施例组比对比例组胃溃疡抑制作用更强。说明富马酸沃诺拉赞与枸橼酸铋钾或酒石酸铋钾或酒石酸铋钠复方比单方有更强的抗胃溃疡作用，富马酸沃诺拉赞与铋盐(枸橼酸铋钾或酒石酸铋钾或酒石酸铋钠)两者联用能起到协同增强抗胃溃疡的作用。
Claims (6)
1.一种抗胃酸类疾病的药物组合物，其特征在于，所述药物组合物由沃诺拉赞或其盐与铋盐组成，所述沃诺拉赞或其盐与铋盐的摩尔比为1:2～1:4，所述铋盐选自枸橼酸铋钾、酒石酸铋钾、酒石酸铋钠。
2.根据权利要求1所述的药物组合物，其特征在于，所述沃诺拉赞盐为富马酸沃诺拉赞盐，具有如下式Ⅲ结构：
3.根据权利要求2所述的药物组合物，其特征在于，所述富马酸沃诺拉赞盐和枸橼酸铋钾的摩尔比为1:2。
4.根据权利要求2所述的药物组合物，特征在于，所述富马酸沃诺拉赞盐和酒石酸铋钾或酒石酸铋钠的摩尔比为1:2。
5.根据权利要求4所述的药物组合物，特征在于，所述药物组合物为富马酸沃诺拉赞盐和酒石酸铋钾。
6.一种根据权利要求1～5任一项所述的药物组合在制备治疗抗胃酸类疾病的药物中的应用。
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