Synthesis, Characterization And Its Preliminary Pharmacodynamic Of PHI

Depressing the upper gastrointestinal (GI) of ibuprofen and paracetamol was considered as the focus in this study. Base on the considerations,4-(acetylamino) phenolic hydroxyl-ibuprofen (PHI) was synthesized. Meanwhile the physical-chemical properties, in vivo and in vitro’s stability, and the pharmacokinetics in mice of PHI were also investigated. Then the pharmacodynamics and toxicology of its toxicity tests was in a preliminary study.PHI was synthesized by ibuprofen and paracetamol as the raw material, the DCC /DMAP as catalyst. PHI was purified by recrystallization and its structure was identified by UV, HPLC, IR and HNMR. Its synthesis and crystallization conditions were optimized by orthogonal tests, and the optimal synthesis conditions was the ratio of paracetamol/ibuprofen as 1:1.5, reaction time as 8h, solvent volume as 70ml, and the average yield was 66.53%. Because the synthetic process was simple and reactants and the catalysts were cheap, PHI product by this method had good prospects. The industrialization parameters of PHI need further study.Results of the stability in vitro test showed that:degradation kinetics of PHI complied with first order kinetics in different pH buffer solutions at 37℃ and 60℃. Its degradation rate positively correlated with temperature that the higher the temperature was, the faster the degradation was; PHI was more stable pH 4.0 to 6.0. Therefore, we should fully consider and control the effect of pH, temperature for the stability in the study and use.Through the rat’s hot-plate test and auricle swelling test, the experimental data of pharmacodynamic was analysis by SPSS 19.0 and the results showed the effects of analgesic and anti-inflammatory of low-dose combination group was significantly lower than the other groups. The result showed the dose of low-dose combination group had not yet reached analgesic doses; the effects of analgesic and anti-inflammatory of PHI was no significant difference with PCM, IPF, mid-dose and high-dose combination group (P> 0.05) which showed the efficacy of PHI was equal with the original drugs and the physical mixture of equivalents. The effects of analgesic and anti-inflammatory were no significant difference between mid-dose and high-dose combination group (P>0.05). Therefore, the dose of PHI was determined as the equivalent of mid-dose physical mixture to save costs and reduce the dosage. The results of preliminary pharmacodynamic test showed PHI had the effects of significant analgesic and anti-inflammatory and there was no difference between PHI, PCM, IPF and the equivalent of physical mixture (mid-dose).The results of preliminary toxicology showed that the stimulation of the stomach of PHI was significantly lower than equivalent PCM, IPF and physical mixture. This proved that PCM and IPF were synthesized as PHI could shield their acidic groups, reduce the stimulation of the stomach and the side effects of drugs and increase the range of application of the drug.The study was based on prodrug design principles, and synthesized of PHI successfully. The method was simple, the yield was high, conditions were unrigorous and suitable for industrial production. Compares with PCM and IPF, the efficacy of PHI did not change significantly and the irritation of the stomach was significantly reduced. The experimental results had laid a solid foundation for PHI clinical application, and provided a new way for further development of the PCM and IPF.