CN109091478A - 尿囊素在制备抗高尿酸血症和抗痛风药物中的应用 - Google Patents
尿囊素在制备抗高尿酸血症和抗痛风药物中的应用 Download PDFInfo
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- CN109091478A CN109091478A CN201710467560.1A CN201710467560A CN109091478A CN 109091478 A CN109091478 A CN 109091478A CN 201710467560 A CN201710467560 A CN 201710467560A CN 109091478 A CN109091478 A CN 109091478A
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- hyperuricemia
- gout
- allantoin
- uric acid
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Abstract
本发明公开了尿囊素在抗高尿酸血症和/或抗痛风药物和/或保健品制备中的应用，高尿酸血症包括原发性与继发性高尿酸血症以及各种因素引起的血液中尿酸浓度高于(男)420μmol/L，(女)357μmol/L(磷钨酸还原法测定)，或尿酸酶‑过氧化物酶偶联法测定高于420μmol/L的成人，痛风包括原发性痛风与继发性痛风。本发明发现，尿囊素能显著降低小鼠血清尿酸水平，显著增加OAT1、OCTN1的mRNA表达。尿囊素可用于制备治疗抗高尿酸血症和/或抗痛风药物和/或保健品，减少不良反应，为疾病的治疗和预防提供一种安全、有效、经济的解决办法。
Description
技术领域
本发明涉及尿囊素在制备药物中的新应用，主要涉及尿囊素在制备抗痛风药物中的应用，特别涉及尿囊素在制备抗高尿酸血症药物和/或保健品中的应用，属于医药技术领域。
背景技术
痛风是单钠尿酸盐沉积形成晶体所导致的关节病，与嘌呤代谢紊乱及(或)尿酸***减少所引发的高尿酸血症直接相关。
最新观点认为痛风的临床病程包括：(1)高尿酸血症，无尿酸结晶，无痛风症状；(2)观察到尿酸结晶或结石存在，无痛风症状；(3)体内沉积尿酸结晶，痛风急性发作或有发作史；(4)严重痛风，有痛风石形成，造成慢性痛风性关节炎与痛风性肾病。
高尿酸血症是指成人血浆尿酸浓度≥7mg/dL(男性)或5.6mg/dL(女性)的状态,是由于人体内尿酸生成增加和(或)***减少所导致。
高尿酸血症的治疗可分为药物治疗和非药物治疗。临床研究报告显示，非药物治疗仅能降低约10～18％血浆尿酸水平，因此对高尿酸血症的药物治疗是必要的。
高尿酸血症的治疗药物可分为降尿酸药物与控制急性炎症发作的抗炎药物。降尿酸药按作用机制可分减少尿酸生成的黄嘌呤氧化酶抑制剂、增加尿酸***的促尿酸***药和分解尿酸的尿酸酶三类。但现有各药物均有不同程度的不良反应，如别嘌呤醇的超敏反应综合征，所以不够理想。
尿囊素(Allantoin)属咪唑类杂环化合物。化学名：N-(2,5-二氧代咪唑烷-4-基)脲，分子式为C4H6O3N4。能溶于水。纯品为无毒无味，无刺激性、无过敏性的白色晶体，在非水溶液、干燥空气、pH为4～9的溶液中均能保持稳定，在强碱溶液中呈两性。尿囊素广泛存在于哺乳动物的尿和动、植物的胚胎内，因其最早发现于牛的尿囊分泌液中，故名尿囊素。尿囊素具有促进细胞增长，软化角质层蛋白的生理功能；与干燥氢氧化铝凝胶混合，用于消化道溃疡的治疗；也可用来治疗皮肤干燥症和鳞屑性皮肤疾患；此外还可用于糖尿病、肝硬化、癌症、骨髓炎等的治疗。其化学结构如下：
近年来，对尿囊素的降压等药理作用有所报道，但对其在制备抗高尿酸血症和/或抗痛风药物和/或保健品中的作用尚未见报道。
发明内容
本发明解决的技术问题在于提供尿囊素在制备抗高尿酸血症和/或抗痛风药物和/或保健品中的应用，从而为降尿酸治疗提供一种不良反应轻微的解决办法。
为此，本发明提供了如下技术方案：
发明提供了尿囊素在制备抗高尿酸血症和/或抗痛风药物或/和保健品中的应用。
进一步，所述的高尿酸血症包括但不限于原发性与继发性以及各种因素引起的血液中尿酸浓度高于(男)420μmol/L，(女)357μmol/L(磷钨酸还原法测定)，或尿酸酶-过氧化物酶偶联法测定高于420μmol/L的成人。
进一步，所述的痛风包括但不限于原发性痛风与继发性痛风。
进一步，所述尿囊素可与药学上可接受的辅料按常规制剂方法制成各种剂型的抗高尿酸血症和/或抗痛风药物。
进一步，所述尿囊素可与保健品包括保健食品和功能食品可接受的辅料按常规制剂方法制成各种抗高尿酸血症和/或抗痛风的保健品。
本发明因此还涉及以本发明化合物作为活性成分的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过发明所述尿囊素与一种或多种药学上可接受的固体或液体赋形剂和/或辅料组合，制成与人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-99％。
进一步，本发明还涉及以本发明化合物作为活性成分的保健品组合物。该组合物可根据本领域公知的方法制备。可通过发明所述尿囊素与一种或多种保健品和食品上可接受的固体或液体赋形剂和/或辅料组合，制成与人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-99％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可以为胃肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、***、直肠等。
所述的药物组合剂型包括口服制剂，注射给药剂型，皮肤黏膜途径给药剂型。
根据权利要求7的应用，其特征在于：所属的口服制剂包括片剂、缓释剂、胶囊剂、控释剂、滴丸剂、液体制剂，所述的注射给药剂型包括肌肉注射、静脉注射、静脉滴注。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药***。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、***胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羧丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、酷酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-400mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明的有益效果在于：本发明采用高尿酸血症小鼠模型，对尿囊素抗高尿酸血症和/或抗痛风药物，尤其是降低血尿酸水平作用进行了考察，结果显示，通过口服给药尿囊素可显著降低小鼠血清尿酸水平，可显著增加OAT1、OCTN1的mRNA表达水平，所以为高尿酸血症和/或痛风的治疗预防与治疗提供了一种安全、有效、经济的解决办法。
附图说明
图1.尿囊素对高尿酸血症模型小鼠血清尿酸(UA)水平影响。n＝10。
图2.尿囊素对高尿酸血症模型小鼠有机阴离子转运体1(OAT1)的mRNA表达水平影响。n＝3。
图3.尿囊素对高尿酸血症模型小鼠有机阳离子转运体1(OCTN1)的mRNA表达水平影响。n＝3。
具体实施方式
为使本发明的目的、技术方案、优点更加清楚，下面将结合附图对本发明作进一步的详细描述。
实验例1.尿囊素降低高尿酸血症模型小鼠血清尿酸(UA)水平。
实验材料：昆明小鼠购自北京市华阜康生物科技股份有限公司。氧嗪酸钾，尿囊素，别嘌呤醇，苯溴马隆购自西格玛奥德里奇(Sigma-Aldrich，Germany)。羧甲基纤维素钠购自国药集团化学试剂有限公司。尿酸试剂盒购自中生北控生物科技股份有限公司。
溶液配制：将1％羧甲基纤维素钠溶解，煮沸，冷却后作为溶媒，将尿囊素、氧嗪酸钾、别嘌呤醇、苯溴马隆分别溶解配置成混悬液。
实验分组：18-20g小鼠随机分为正常对照组，模型组，苯溴马隆组(25mg·kg-1，阳性对照)，尿囊素低、高剂量组(100，400mg·kg-1)，每组10只。
除对照组外每日腹腔注射氧嗪酸钾300mg·kg-1，正常对照组每日注射等量1％羧甲基纤维素钠溶液，连续造模8天，随后按分组给药，给药14天后处死小鼠，眼后静脉丛取血，静置2h，5000rpm，4℃离心10min取血清，用尿酸试剂盒测定血清尿酸水平。
结果：模型动物口服尿囊素(100,400mg/kg)后，血清尿酸水平均能一定程度的降低，提示口服尿囊素可以发挥抗高尿酸血症和/或抗痛风作用。
表1.尿囊素对高尿酸血症模型小鼠血清尿酸水平影响(n＝10)。
与对照组比较，a：P<0.01，与模型组相比，b:P<0.05，c：P<0.01。
实验例2.尿囊素对高尿酸血症模型小鼠有机阴离子转运体1(OAT1)的mRNA表达水平影响。n＝3。
实验分组：18-20g小鼠随机分为正常对照组，模型组，苯溴马隆组(25mg·kg-1，阳性对照)，尿囊素低、高剂量组(100，400mg·kg-1)，每组10只。相关溶液准备与实验方案同实施例1。逆转录试剂盒、SYBR green染料购自宝日医生物技术有限公司(TAKARA，Japan)。引物购自生工生物工程股份有限公司，纯化方式为HAP。
表2.OAT1引物及内参引物序列。
小鼠处死后，取小鼠肾脏，使用Trizol法提取肾脏中总RNA，用紫外分光光度计进行RNA定量，再用逆转录试剂盒进行逆转录得到对应cDNA，利用SYBRGreen染料进行实时荧光定量PCR，观察mRNA表达变化情况。
结果：模型动物口服尿囊素(400mg/kg)能够显著增加OAT1的表达，如表3所示，尿囊素可能通过增加离子转运体的表达，起到增加尿酸转运***而降低血浆尿酸浓度的效果。
表3.尿囊素对高尿酸血症模型小鼠OAT1的mRNA表达水平影响。n＝3。
与对照组相比，a：P<0.05，与模型组相比，b:P<0.05，c：P<0.01。
实验例3.尿囊素对高尿酸血症模型小鼠有机阳离子转运体1(OCTN1)的mRNA表达水平影响。(n＝3)。
实验分组：18-20g小鼠随机分为正常对照组，模型组，苯溴马隆组(25mg·kg-1，阳性对照)，尿囊素低、高剂量组(100，400mg·kg-1)，每组10只。相关溶液配制与实验方案同实施例2。逆转录试剂盒、SYBR green染料购自宝日医生物技术有限公司(TAKARA，Japan)。引物购自生工生物工程股份有限公司，纯化方式为HAP。
表4.OCTN1引物与内参引物序列。
小鼠处死后，取小鼠肾脏，使用Trizol法提取肾脏中总RNA，用紫外分光光度计进行RNA定量，再用逆转录试剂盒进行逆转录得到对应cDNA，利用SYBRGreen染料进行实时荧光定量PCR，观察mRNA表达变化情况。
结果：模型动物口服尿囊素(100mg/kg)能显著增加OCTN1的表达，如表5所示，尿囊素可能通过增加离子转运体的表达，起到增加尿酸转运体***而降低血浆尿酸浓度的效果。
表5.尿囊素对高尿酸血症模型小鼠OCTN1的mRNA表达水平影响。(n＝3)。
与对照组相比，a：P<0.05，与模型组相比，b:P<0.05，c：P<0.01。
综上所述，本发明采用高尿酸血症小鼠模型对尿囊素抗高尿酸血症和/或抗痛风药物和/或保健品，尤其是降低血尿酸水平作用进行了考察，结果显示，通过灌胃给药尿囊素可显著降低小鼠血清尿酸水平，可显著增加OAT1、OCTN1的mRNA表达水平。因此，尿囊素有抗高尿酸血症和/或抗痛风作用。以尿囊素为活性物质，单独使用或/与其他具有药理学活性的化合物和/或提取物组成复方使用，按照药学领域的常规制剂方法制成各种剂型的抗高尿酸血症和/或抗痛风药物和/或保健品，或与其他促尿酸***药物和/或黄嘌呤氧化酶抑制剂等制成复方制剂，用于在保持疗效的情况下减少药物作用中的不良反应，可为高尿酸血症和/或痛风的治疗预防与治疗提供了一种安全、有效、经济的解决办法。
最后说明的是，以上实施例仅用于说明本发明的技术方案而非限制，尽管通过参照本非发明的优选实施例已对本发明进行了描述，但本领域普通技术人员应当理解，可以在实行上和细节上对其做出各种各样的改变，而不偏离所附权利要求说明书所限定的本发明的精神和范围。
Claims (7)
1.如式Ⅰ所示的N-(2,5-二氧代-4-咪唑啉啶基)尿素及其药学上可接受的盐在制备抗高尿酸血症和/或抗痛风产品中的应用
2.根据权利要求1的应用，所述高尿酸血症为原发性与继发性以及各种因素引起的通过磷钨酸还原法测定男性血液中尿酸浓度高于420μmol/L，女性血液中尿酸浓度高于357μmol/L，或通过尿酸酶-过氧化物酶偶联法测定成人血液中尿酸浓度高于420μmol/L。
3.根据权利要求1的应用，所述痛风为原发性痛风与继发性痛风。
4.一种药物组合物在制备抗高尿酸血症和/或抗痛风产品中的应用，其特征在于，含有权利要求1的N-(2,5-二氧代-4-咪唑啉啶基)尿素及其药学上可接受的盐、及药学上可接受的载体。
5.根据权利要求1的应用，其特征在于，所述的产品选自药物或保健品。
6.根据权利要求4的应用，其特征在于，所述的药物组合物选自口服制剂，注射给药剂型，皮肤黏膜途径给药剂型。
7.根据权利要求6的应用，其特征在口服制剂选自片剂、缓释剂、胶囊剂、控释剂、滴丸剂、液体制剂，所述的注射给药剂型选自肌肉注射、静脉注射、静脉滴注。
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