扑热息痛与布洛芬孪药的合成、表征及初步药效学研究

发布时间：2018-03-04 19:00

  本文选题：扑热息痛　切入点：布洛芬　出处：《四川农业大学》2014年硕士论文　论文类型：学位论文

【摘要】：布洛芬(Ibuprofen,IPF)化学名为2-(4-异丁基苯基)丙酸,具有抗炎、镇痛、解热作用,适用于治疗风湿性关节炎、类风湿性关节炎、骨关节炎、强直性脊椎炎和神经炎等。扑热息痛(Paracetamol,PCM)也称之为扑热息痛,是目前临床常用的解热镇痛药,因其能够有效缓解疼痛和退热,而被广泛应用于感冒的辅助治疗,是治疗感冒及镇痛类药物中最常用的成分。本文以减小非甾体抗炎药布洛芬和扑热息痛对胃肠道刺激为设计思路,将扑热息痛和布洛芬通过酯化反应合成了前体药物扑热息痛-布洛芬孪药(4-(乙酰基氨基)酚性羟基-异丁苯丙酸,PHI),并对其结构、理化性质、体外稳定性、药效学和毒理学进行了初步研究。本研究以DCC/DMAP为催化剂合成扑热息痛-布洛芬孪药,并通过重结晶的方法进行纯化,通过UV、HPLC、R、HNMR对其结构进行鉴定。通过正交试验对其合成工艺和结晶条件进行优化,最终合成条件为：扑热息痛／布洛芬配比为1：1.5,反应时间为8h,溶媒体积为70ml,平均收率达66.53%。体外稳定性试验结果表明：PHI在37℃和60℃条件下,在不同pH值缓冲溶液中的降解动力学过程符合一级动力学特征,其降解速率与温度正相关,温度越高,降解越快：PHI在pH值为4.0～6.0之间最稳定。通过小鼠热板试验和耳郭肿胀试验考察孪药的镇痛和抗炎效果,并通过SPSS19.0分析其差异,结果显示：低复方组的镇痛和抗炎效果明显低于其他组,说明低复方的药物剂量还没有达到治疗所需的剂量：PHI的镇痛和抗炎效果与PCM、IPF、中复方组和高复方组没有明显差异(P0.05),可以说明PHI的药效与原药和当量的物理混合药物相当；中复方组和高复方组的镇痛和抗炎效果也没有明显差异,所以为了节约成本,减少药物使用剂量,以中复方当量的剂量为孪药的使用剂量。初步药效学试验结果表明合成的PHI有明显的镇痛和抗炎效果,并且与原药和当量的(中剂量)物理混合物没有差异。初步毒理学试验结果表明：PHI对胃部的刺激明显低于当量的PCM、IPF和物理混合物,证明了将PCM和IPF合成为孪药能够屏蔽他们的酸性集团,减小对胃部的刺激,从而降低药物的毒副作用,增加药物的应用范围。本研究根据前体药物设计原理,成功合成了扑热息痛=布洛芬孪药,其合成方法操作简单,产物收率和纯度较高,反应要求较低,适合工业化生产。与扑热息痛和布洛芬相比,扑热息痛-布洛芬孪药药效没有明显变化,并且明显降低了对胃部的刺激。本实验研究结果为扑热息痛-布洛芬孪药的临床应用奠定了坚实的基础,为更好地发挥扑热息痛和布洛芬解热镇痛抗炎的性能和进一步开发扑热息痛和布洛芬新药提供了新的思路。
[Abstract]:Ibuprofen (Ibuprofen) Ibuprofen (Ibuprofen) (Ibuprofen) (IPF) is an anti-inflammatory, analgesic and antipyretic acid, and is suitable for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, and osteoarthritis. Paracetamol paracetamol (PCM), also known as paracetamol, is a commonly used antipyretic and analgesics drug, which is widely used in the adjuvant treatment of colds because it can effectively relieve pain and fever. Ibuprofen and paracetamol are the most commonly used components in the treatment of colds and analgesic drugs. The design idea is to reduce the stimulation of non-steroidal anti-inflammatory drugs ibuprofen and paracetamol to the gastrointestinal tract. Paracetamol and ibuprofen were synthesized from paracetamol and ibuprofen by esterification reaction. The pharmacodynamics and toxicology of paracetamol ibuprofen twins were synthesized using DCC/DMAP as catalyst and purified by recrystallization. Its structure was identified by RHNMR, and the synthesis process and crystallization conditions were optimized by orthogonal test. The final synthesis conditions were as follows: the ratio of paracetamol / ibuprofen was 1: 1.5, the reaction time was 8 h, the volume of solvent was 70 ml, the average yield was 66.53. The stability test in vitro showed that the stability of the solution was at 37 鈩，

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