In Vitro And In Vivo Evaluation Of Ibuprofen-paeonol Conjugate

Objective: A novel ibuprofen-paeonol conjugate (IPC) was synthesized by esterification method to improve the therapeutic efficacy and decrease the gastrointestinal (GI) tract irritation of ibuprofen. The systemic evaluations of IPC were carried out including pharmaceutical characterization, pharmacokinetics, pharmacodynamics and GI irritation of IPC.Method: (1) After the establishment of the HPLC analysis method of IPC, the solubi1ity, the partition coefficient, stabilities in different pH condition and plasma of IPC were investigated, respectively. (2) Rat single pass intestinal perfusion method was employed to characterize the absorption of IPC in various intestinal segments followed by the preparation and evaluation of its submicroemulsion. (3) The pharmacokinetic study was conducted after intravenous administration of IPC submicroemulsion into rats. (4) The anti-inflammation and analgesic activity of IPC were observed on the xylene-induced ear edema and acetic acid induced writhing model mice. (5) GI tract irritation test of IPC compared with ibuprofen were also performed by characterization of pathological section and the determination of inflammatory factors.Result: (1) IPC showed very high lipophilc characteristics, partly degraded in high temperature condition while not affected by high humidity and highlight. IPC displayed more stable in acidic environment, and degraded easily in rat plasma with short half life of 1.78min. (2) The average size of IPC submicroemulsion was 182±2 nm with narrow distribution, and the content of IPC was 9.228mg·mL^-1. The absorption rate constant (Ka) of IPC was influenced by perfused concentration and the Ka in jejunum were increased while compared with other parts of GI tract. (3) The results of pharmacokinetic study showed that the half life of ibuprofen solution, ibuprofen submicroemulsion and IPC submicroemulsion were 25.75±4.54, 27.88±5.90 and 29.04±7.86 min, respectily, while the AUC were 181.81,197.45 and 121.19 mg·mL^-1·min^-1. (4) IPC showed more potential anti-inflammation and analgesic activity in pharmacodynamic test, but similar effect in DPPH·scavenging test compared with Ibu. (5) The observation of pathological section and determination of MDA, PGE2 and NO in gastric tissue indicated that IPC could decrease adverse effectof ibuprofen.Conclusion: The results of previsous study suggest that: the water solubility of IPC is needed to be improved; the conjugate could be degraded immediately in plasma; the absorption of IPC was higher at the part of jejunum; the elimination half life of IPC was prolonged, more potential anti-inflammatory and analgesic activity of IPC were displayed compare with same dose of ibuprofen even the irritation of GI tract decreased.