發(fā)布時(shí)間：2018-03-04 19:00

  本文選題：撲熱息痛　切入點(diǎn)：布洛芬　出處：《四川農(nóng)業(yè)大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：布洛芬(Ibuprofen,IPF)化學(xué)名為2-(4-異丁基苯基)丙酸,具有抗炎、鎮(zhèn)痛、解熱作用,適用于治療風(fēng)濕性關(guān)節(jié)炎、類風(fēng)濕性關(guān)節(jié)炎、骨關(guān)節(jié)炎、強(qiáng)直性脊椎炎和神經(jīng)炎等。撲熱息痛(Paracetamol,PCM)也稱之為撲熱息痛,是目前臨床常用的解熱鎮(zhèn)痛藥,因其能夠有效緩解疼痛和退熱,而被廣泛應(yīng)用于感冒的輔助治療,是治療感冒及鎮(zhèn)痛類藥物中最常用的成分。本文以減小非甾體抗炎藥布洛芬和撲熱息痛對(duì)胃腸道刺激為設(shè)計(jì)思路,將撲熱息痛和布洛芬通過(guò)酯化反應(yīng)合成了前體藥物撲熱息痛-布洛芬孿藥(4-(乙�；被�)酚性羥基-異丁苯丙酸,PHI),并對(duì)其結(jié)構(gòu)、理化性質(zhì)、體外穩(wěn)定性、藥效學(xué)和毒理學(xué)進(jìn)行了初步研究。本研究以DCC/DMAP為催化劑合成撲熱息痛-布洛芬孿藥,并通過(guò)重結(jié)晶的方法進(jìn)行純化,通過(guò)UV、HPLC、R、HNMR對(duì)其結(jié)構(gòu)進(jìn)行鑒定。通過(guò)正交試驗(yàn)對(duì)其合成工藝和結(jié)晶條件進(jìn)行優(yōu)化,最終合成條件為：撲熱息痛／布洛芬配比為1：1.5,反應(yīng)時(shí)間為8h,溶媒體積為70ml,平均收率達(dá)66.53%。體外穩(wěn)定性試驗(yàn)結(jié)果表明：PHI在37℃和60℃條件下,在不同pH值緩沖溶液中的降解動(dòng)力學(xué)過(guò)程符合一級(jí)動(dòng)力學(xué)特征,其降解速率與溫度正相關(guān),溫度越高,降解越快：PHI在pH值為4.0～6.0之間最穩(wěn)定。通過(guò)小鼠熱板試驗(yàn)和耳郭腫脹試驗(yàn)考察孿藥的鎮(zhèn)痛和抗炎效果,并通過(guò)SPSS19.0分析其差異,結(jié)果顯示：低復(fù)方組的鎮(zhèn)痛和抗炎效果明顯低于其他組,說(shuō)明低復(fù)方的藥物劑量還沒(méi)有達(dá)到治療所需的劑量：PHI的鎮(zhèn)痛和抗炎效果與PCM、IPF、中復(fù)方組和高復(fù)方組沒(méi)有明顯差異(P0.05),可以說(shuō)明PHI的藥效與原藥和當(dāng)量的物理混合藥物相當(dāng)；中復(fù)方組和高復(fù)方組的鎮(zhèn)痛和抗炎效果也沒(méi)有明顯差異,所以為了節(jié)約成本,減少藥物使用劑量,以中復(fù)方當(dāng)量的劑量為孿藥的使用劑量。初步藥效學(xué)試驗(yàn)結(jié)果表明合成的PHI有明顯的鎮(zhèn)痛和抗炎效果,并且與原藥和當(dāng)量的(中劑量)物理混合物沒(méi)有差異。初步毒理學(xué)試驗(yàn)結(jié)果表明：PHI對(duì)胃部的刺激明顯低于當(dāng)量的PCM、IPF和物理混合物,證明了將PCM和IPF合成為孿藥能夠屏蔽他們的酸性集團(tuán),減小對(duì)胃部的刺激,從而降低藥物的毒副作用,增加藥物的應(yīng)用范圍。本研究根據(jù)前體藥物設(shè)計(jì)原理,成功合成了撲熱息痛=布洛芬孿藥,其合成方法操作簡(jiǎn)單,產(chǎn)物收率和純度較高,反應(yīng)要求較低,適合工業(yè)化生產(chǎn)。與撲熱息痛和布洛芬相比,撲熱息痛-布洛芬孿藥藥效沒(méi)有明顯變化,并且明顯降低了對(duì)胃部的刺激。本實(shí)驗(yàn)研究結(jié)果為撲熱息痛-布洛芬孿藥的臨床應(yīng)用奠定了堅(jiān)實(shí)的基礎(chǔ),為更好地發(fā)揮撲熱息痛和布洛芬解熱鎮(zhèn)痛抗炎的性能和進(jìn)一步開(kāi)發(fā)撲熱息痛和布洛芬新藥提供了新的思路。
[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，

本文編號(hào)：1566890