CN116462659A - 一种伏诺拉生盐、其晶型及其制备方法与应用 - Google Patents
一种伏诺拉生盐、其晶型及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供了一种伏诺拉生与阿魏酸所成盐、其晶型及其制备方法与其在制备治疗胃酸疾病药物方面的应用。本发明提供的伏诺拉生阿魏酸盐与现有伏诺拉生的盐相比，不仅表现出更好的药效作用，而且有效的改善了溶解性和稳定性，有望开发成注射剂，提高临床用药顺应性。此外，伏诺拉生与阿魏酸成盐，能充分发挥药物的配伍作用，不仅可用于治疗和/或预防胃酸类疾病，协同增加药效，同时还能起到抗炎的效果。
Description
技术领域
本发明属于药物领域，涉及一种具有质子泵抑制作用的吡咯化合物的新盐，更具体的涉及伏诺拉生与阿魏酸所形成的盐，及其在制备方法与用途。
背景技术
胃酸相关疾病(Acid-relateddiseases，ARDs)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，如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(如伏诺拉生)的出现很好的解决了这一类问题，通过竞争性抑制剂质子泵(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。
伏诺拉生(Vonoprazan)，其化学名为1-[5-(2-氟苯基)-1-(吡咯-3-基磺酰基)-1氢-吡咯-3-基]-氮-甲基甲胺，结构式如式(Ⅰ)所示。伏诺拉生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，伏诺拉生在日本批准上市，上市盐型为富马酸盐，上市剂型为片剂。
体外实验研究表明伏诺拉生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。但现上市药物伏诺拉生富马酸盐的水溶性差，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疾病的作用，以及不易开发成其它制剂如注射剂等药物制剂。因此人们尝试合成伏诺拉生的各种盐，希望能有效改善水溶性及提高生物利用，以便更好的发挥该化合物的临床应用价值。
专利CN105693693A公开了伏诺拉生的各种有机酸或无机酸盐，如醋酸盐、甲磺酸盐、硫酸盐、磷酸盐、L-苹果酸盐、枸橼酸盐。专利CN107759568A公开了伏诺拉生的双盐酸盐、双磷酸盐、苯磺酸盐、1，4-丁二酸磺酸半盐、2-羟基乙磺酸盐和L-酒石酸盐等。上述专利申请对不同的伏诺拉生盐的溶解度和稳定性进行了考察，但并没有对各盐的生物活性及其生物利用度进行研究。由于化合物的生物活性及生物利用度将直接影响到药物剂型的开发和临床应用，因此开发一种伏诺拉生的新型盐以提高其生物利用度是十分必要的。
本发明提供了一种伏诺拉生与阿魏酸所成盐，其与现有伏诺拉生的盐相比，不仅表现出更好的药效作用，而且有效的改善了溶解性和稳定性，有望开发成注射剂，解决口服伏诺拉生富马酸片不适用病人用药的问题，提高临床用药顺应性。此外，阿魏酸有良好的药理作用和生物活性，在医药、保健品、化妆品原料方面有着较高的应用价值，结构式如式(Ⅱ)所示，其具有强大的抗氧化活性、清除自由基、消炎、止痛、抗紫外线辐射及其提高人体免疫力等作用，对人体健康有着极大的促进作用，以及还具有防止血脂被氧化，抗血小板凝集和血栓形成，改善心脑血管健康，预防骨质流失，改善妇女更年期综合征功效，恢复和改善老年人记忆等功能。因此伏诺拉生与阿魏酸成盐，能充分发挥药物的配伍作用，不仅可用于治疗和/或预防胃酸类疾病，协同增加药效，而且还能起到抗炎的效果。
发明内容
为解决现有技术存在的问题，本发明提供了一种新型的伏诺拉生盐，即伏诺拉生与阿魏酸所成伏诺拉生阿魏酸盐，其具有式(Ⅲ)所示结构：
进一步，本发明还提供了伏诺拉生阿魏酸盐的晶型，其X射线粉末衍射图在2θ值为5.941±0.2°、10.097±0.2°、13.259±0.2°、15.160±0.2°、17.781±0.2°、18.400±0.2°、19.919±0.2°、22.279±0.2°、24.601±0.2°、25.620±0.2°、27.080±0.2°处具有衍射峰。
在一些实施例中，本发明所述伏诺拉生阿魏酸盐的晶型，其X射线粉末衍射图还在2θ角为9.860±0.2°、11.821±0.2°、15.936±0.2°、16.579±0.2°、17.338±0.2°、18.783±0.2°、20.623±0.2°、20.778±0.2°、23.818±0.2°、25.201±0.2°、27.877±0.2°、28.357±0.2°、31.181±0.2°中的一处或多处具有衍射峰。
在另一些实施例中，本发明所述伏诺拉生阿魏酸盐的晶型，其X射线粉末衍射图还在2θ值为11.097±0.2°、16.280±0.2°、19.339±0.2°、20.195±0.2°、21.269±0.2°、29.140±0.2°、29.779±0.2°、30.518±0.2°、31.603±0.2°、32.280±0.2°、33.739±0.2°、34.241±0.2°、35.318±0.2°、36.261±0.2°、36.997±0.2°、38.060±0.2°、39.117±0.2°、39.796±0.2°、40.495±0.2°、41.879±0.2°、43.323±0.2°、45.112±0.2°中的一处或多处具有衍射峰。
还在一些实施例中，本发明所述伏诺拉生与阿魏酸组成的药物复合物晶型具有如图1所示的X射线粉末衍射图。
本发明的另一方面提供了伏诺拉生阿魏酸盐制备方法，所述制备方法包括以下步骤：
步骤一：分别将伏诺拉生、阿魏酸于室温下搅拌溶于有机溶剂中得溶液A和溶液B；
步骤二：将溶液B缓慢滴加到溶液A中，室温继续搅拌，慢慢析出固体，得伏诺拉生阿魏酸盐。
在一些实施例中，本发明所述有机溶剂选自甲基叔丁基醚、异丙醚、乙二醇二甲醚、乙二醇单甲醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、异丙醇、丙酮中的一种或其混合体系。
本发明还提供了一种药物组合物，该药物组合物含有本发明所述的伏诺拉生阿魏酸盐，及其药学上可接受的载体。
本发明所述的伏诺拉生阿魏酸盐，可应用于制备用于治疗和/或预防胃酸类疾病的药物，如胃酸过多引起的相关疾病，包括糜烂性食管炎、胃溃疡、十二指肠溃疡、幽门螺杆菌病等。
本发明提供了一种伏诺拉生与阿魏酸所成盐，其与现有伏诺拉生的盐相比，不仅表现出更好的药效作用，而且有效的改善了溶解性和稳定性，有望开发成注射剂，解决口服伏诺拉生富马酸片不适用病人用药的问题，提高临床用药顺应性。此外，阿魏酸有良好的药理作用和生物活性，在医药、保健品、化妆品原料方面有着较高的应用价值，其具有强大的抗氧化活性、清除自由基、消炎、止痛、抗紫外线辐射及其提高人体免疫力等作用，对人体健康有着极大的促进作用，以及还具有防止血脂被氧化，抗血小板凝集和血栓形成，改善心脑血管健康，预防骨质流失，改善妇女更年期综合征功效，恢复和改善老年人记忆等功能。因此伏诺拉生与阿魏酸成盐，能充分发挥药物的配伍作用，不仅可用于治疗和/或预防胃酸类疾病，协同增加药效，而且还能同时起到抗炎的效果，有望开发成一种具有更好的治疗和/或预防胃酸类疾病的同时具有抗炎效果的药物。
附图说明
图1为本发明伏诺拉生阿魏盐的X射线粉末衍射图谱。
具体实施方式
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制，本发明所用伏诺拉生、阿魏酸均采用现在技术制备获得或购买自商业。
实施例1
伏诺拉生阿魏酸盐的制备
将伏诺拉生(30mg，0.087mmol，1.0eq)和甲基叔丁基醚(2mL)置于反应瓶中，室温下搅拌至溶清，阿魏酸(18mg，0.096mmol，1.1eq)溶于甲基叔丁基醚(1mL)后缓慢滴加到反应瓶中，室温下继续搅拌28h，过滤，得白色固体32mg，收率64％。
核磁共振光谱数据：1H NMR(400MHz,Chloroform-d)δ8.75(dd,J＝4.8,1.6Hz,1H),8.59(d,J＝2.4Hz,1H),7.75-7.72(m,1H),7.64(d,J＝1.9Hz,1H),7.50(d,J＝15.8Hz,1H),7.43–7.36(m,3H),7.327.29(m,2H),7.14-7.07(m,2H),7.06–7.03(m,1H),7.02-6.98(m,2H),6.89(d,J＝8.2Hz,1H),6.42(d,J＝1.9Hz,1H),6.36(d,J＝15.8Hz,1H),3.89(s,5H),2.56(s,3H).
实施例2
伏诺拉生与阿魏酸盐的制备
将伏诺拉生(100mg，0.29mmol，1.0eq)和乙酸乙酯(3mL)置于反应瓶中，室温下搅拌至溶清，阿魏酸(62mg，0.32mmol，1.1eq)溶于乙酸乙酯(1mL)后缓慢滴加到反应瓶中，室温下继续搅拌3h，过滤干燥，得白色固体120mg，收率76％。
本发明实施例制得的伏诺拉生阿魏酸盐的粉X射线粉末衍射图见图1，其晶型数据如下表1所示：
表1
实施例3
溶解度考察
为了测定伏诺拉生阿魏酸盐在水中的溶解性，取约25mg样品加入到2ml超纯水中，参考《中国药典》四部凡例中溶解度测定方法，配制成过饱和溶液，取饱和溶液在3000rpm/min条件下离心20min，取上清液用稀释剂(V甲醇：V水＝1:1)以1:20的比例稀释以获得样品，平行制备两份。以同法制备两份伏诺拉生富马酸盐的溶解度溶液。采用高效液相色谱法测定各化合物在水中的溶解度，具体测定结果数据如下表2所示，测定方法如下：
色谱柱：YMC-Triart C18150×4.6mm，3um；
流速：1ml/min；柱温：40℃；波长：230nm；进样量：5ul；
流动相A:称取磷酸二氢钾约1.36g、无水高氯酸钠约6.12g于1L流动相瓶中，加入1000ml水，溶解，摇匀，用磷酸调节pH至3.0，水系滤膜过滤，超声脱气，即得；
流动相B：乙腈；
流动相C：甲醇；
洗脱梯度：
表2伏诺拉生盐的溶解度实验结果
备注：伏诺拉生阿魏酸换算因子为0.6401，伏诺拉生富马酸盐的换算因子为0.7484。
实验结果：从上述表2中可以看出，伏诺拉生阿魏酸盐在水中的溶解度明显高于伏诺拉生富马酸盐。
实施例4
本发明伏诺拉生阿魏酸盐的药代动力学研究
大鼠药代动力学研究
实验方法：雄性SD大鼠(200-300g)20只，随机分成2组(n＝10)：伏诺拉生富马酸盐、伏诺拉生阿魏酸盐。分别静脉注射伏诺拉生富马酸盐(8.4mg/kg)，伏诺拉生阿魏酸盐(9.8mg/kg)，其中以上各组为等摩尔伏诺拉生给药，各组给药体积为5ml·kg-1。分别于给药前和给药后5min，15min，30min，45min，1h，1.5h，2h，4h，8h取血，离心取血浆，检测血浆中伏诺拉生浓度。实验结果见表3；
表3大鼠静脉给药后血浆中伏诺拉生药代动力学参数(Mean±SD)
实验结论：伏诺拉生富马酸盐、伏诺拉生阿魏酸盐血浆中伏诺拉生的AUC0-t(h*ng/mL)分别为1342.0和1215.0，两者相比AUC0-t无显著差异。此外，伏诺拉生富马酸盐、伏诺拉生阿魏酸盐血浆中伏诺拉生的半衰期、药峰浓度、平均驻留时间均无显著差异，药时曲线走势一致，说明两者给药后血浆中伏诺拉生在体内吸收代谢较一致，伏诺拉生阿魏酸盐能发挥较好的预防和/或治疗胃酸类疾病的药效。
实施例5本发明伏诺拉生阿魏酸盐的药效研究
抗胃溃疡药效研究
实验方法：雄性SD大鼠，根据体重随机分组，每组8只，分为6组(Sham组、Vehicle组、伏诺拉生富马酸盐2.67mg/kg组、伏诺拉生阿魏酸盐0.31mg/kg组、伏诺拉生阿魏酸盐1.00mg/kg组、伏诺拉生阿魏酸盐3.12mg/kg组)，其中伏诺拉生富马酸盐2.67mg/kg组与伏诺拉生阿魏酸盐3.12mg/kg组为等摩尔剂量给药(以伏诺拉生计，相当于推荐的人临床给药剂量20mg)，溶媒为5％DMSO+10％Solutol(HS-15)+85％saline，其中伏诺拉生富马酸盐2.67mg/kg组为口服给药，其他组均为静脉注射给药。动物禁食24小时后，给溶媒或化合物，给药后1小时，动物进行胃幽门结扎手术，结扎后，禁食禁水9小时。在禁食禁水9小时后，动物安乐死，取胃部铺平，测量胃溃疡长和宽，计算溃疡面积，评价溃疡指数；同时取血静置1h，离心取血清检测相关炎症因子。溃疡评分标准和实验结果见表4、表5，炎性因子指标结果见表6：
表4Okabe法溃疡评分标准
表5大鼠Okabe法溃疡评分结果
数据标*表示与vehicle相比有显著差异，*P<0.05，**P<0.01，***P<0.001。
实验结论：各组与Vehicle组相比溃疡指数均显著降低，其中口服给药伏诺拉生富马酸盐2.67mg/kg组和低剂量静脉注射给药伏诺拉生阿魏酸盐0.31mg/kg组抗胃溃疡作用效果一致，都有显著的抗胃溃疡作用。且伏诺拉生阿魏酸盐随着剂量增加，抗胃溃疡作用效果增强，呈剂量依赖性。说明静脉注射给药伏诺拉生阿魏酸盐具有抗胃溃疡作用效果，且随着剂量增加，抗胃溃疡作用效果增强，静脉注射给药伏诺拉生阿魏酸盐的同等效应剂量是口服给药伏诺拉生富马酸盐的十分之一左右(以伏诺拉生摩尔剂量比)。因此有望将本发明提供的新型伏诺拉生阿魏酸盐开发成静脉给药的注射剂，从而实现减低药物使用量，提高用药顺应。
表6大鼠血清中TNF-a、IL-6的含量影响结果
| 组别 | TNF-a(ng/L) | IL-6(ng/L) |
| Sham | 65.371±12.459*** | 112.547±32.918*** |
| Vehicle | 215.259±25.336 | 435.219±43.989 |
| 伏诺拉生富马酸盐2.67mg/kg | 181.629±20.045* | 351.719±32.967* |
| 伏诺拉生阿魏酸盐0.31mg/kg | 172.863±16.936* | 314.763±39.797* |
| 伏诺拉生阿魏酸盐1.00mg/kg | 145.367±17.319*** | 276..216±26.024*** |
| 伏诺拉生阿魏酸盐3.12mg/kg | 138.756±13.549*** | 216.878±31.523*** |
数据标*表示与vehicle相比有显著差异，*P<0.05，**P<0.01，***P<0.001。
实验结论：从表6的数据结果可看出，各组与Vehicle组相比血清中炎症因子TNF-a、IL-6的含量均具有一定程度的降低，其中各静脉注射给药伏诺拉生阿魏酸盐组血清中炎症因子TNF-a、IL-6的含量降低显著，表现出较强的抗炎作用。且伏诺拉生阿魏酸盐随着剂量增加，抗炎作用效果增强，呈剂量依赖性。说明静脉注射给药伏诺拉生阿魏酸盐同时具有抗炎作用效果，随着剂量增加，抗炎作用效果增强。
综上所述，伏诺拉生与阿魏酸成盐，能充分发挥药物的配伍作用，不仅可用于预防和/或治疗胃酸类疾病，协同增加药效，而且还能同时起到抗炎的效果，有望开发成一种具有更好的预防和/或治疗胃酸类疾病的同时具有抗炎效果的药物。
Claims (6)
1.一种伏诺拉生盐，其特征在于，为伏诺拉生与阿魏酸所形成的盐，其具有式(Ⅲ)所示结构：
2.根据权利要求1所述的伏诺拉生盐，其特征在于，所述盐的晶型的X射线粉末衍射图在2θ值为5.941±0.2°、10.097±0.2°、13.259±0.2°、15.160±0.2°、17.781±0.2°、18.400±0.2°、19.919±0.2°、22.279±0.2°、24.601±0.2°、25.620±0.2°、27.080±0.2°处具有衍射峰。
3.根据权利要求3所述的伏诺拉生盐，其特征在于，所述盐的晶型的X射线粉末衍射图还在2θ值为9.860±0.2°、11.821±0.2°、15.936±0.2°、16.579±0.2°、17.338±0.2°、18.783±0.2°、20.623±0.2°、20.778±0.2°、23.818±0.2°、25.201±0.2°、27.877±0.2°、28.357±0.2°、31.181±0.2°中的一处或多处具有的衍射峰。
4.根据权利要求2或3所述的伏诺拉生盐，其特征在于，所述盐的晶型具有基本上如图1所示的X射线粉末衍射图。
5.一种药物组合物，其包含权利要求1-4任一项所述的药物伏诺拉生盐及其药学上可接受的载体。
6.权利要求1-4任一项所述的伏诺拉生盐或权利要求5所述的药物组合物在制备用于治疗和/或预防胃酸类疾病药物中的用途。
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| WO2014003199A1 (en) * | 2012-06-27 | 2014-01-03 | Takeda Pharmaceutical Company Limited | Liquid preparations of amines and organic acids stabilized by salts |
| CN109942545A (zh) * | 2019-04-15 | 2019-06-28 | 中国药科大学 | 含吲哚结构的钾离子竞争性酸阻滞剂及其制备方法与用途 |
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