Studies On The Submicron Emulsions Of Ketoprofen Ester Prodrugs

Ketoprofen, a potent non-steroidal anti-inflammatory drug (NSAIDs), is a racemic proprionic acid derivative with well-recognized analgesic, anti-inflammatory and antipyretic properties. However, it is known that oral ketoprofen, like other NSAIDs, may cause gastrointestinal disturbances at a high incidence. In this study, two ester prodrugs of ketoprofen were synthesized. In vitro hydrolysis kinetics was investigated and the prodrug, which was suited to prepare the SE, was selected. Meanwhile the physical-chemical properties and stability were also investigated. KPI can be applied to the SE for intravenous administration. The pharmacokinetics, distribution and pharmacodynamics of the formulation were examined in order to explore the possibility of increasing the curative effect, decreasing the side effect and enlarging the clinical serviceable range by structure transform and formulation design.Ketoprofen vinyl acetate (KPA) and ketoprofen isopropyl ester (KPI) were synthesized by organic acid esterification method using ketoprofen as raw materials. The method was simple and reproducible. It can be applied to mass production. The structures of KPA and KPI were confirmed by UV,IR,¹H-NMR,¹³C-NMR and MS, respectively.HPLC method was developed for the assay of KPA and KPI. The in vitro hydrolysis kinectics of KPA and KPI were studied. KPA was sensitive to pH and temperature of the system and was easily hydrolyzed. So, KPI was selected to further investigation.The solubility and oil/water partition coefficient of KPI in different pH was determined. The solubility of KPI in water was very low, and was not affected by pH. The LogP was 4.26, showed that it was highly lipophilic. KPI shows its well stability by the results of the experiments in high temperature, humidity and light studies. The degradation of KPI in rat plasma and liver homogenate was belonged to enzymatic reaction, and KPI can be degraded to ketoprofen fastly.According to the results of pre-formulation study, high-pressure homogenization method was developed to prepared KPI intravenous SE. The homogenization temperature, pressure, times and the way of addition of lecithin was studied. The ratio of the emulsifiers and the dosage of sodium oleate were optimized, and the effect of pH was also detected. The result showed that the amount and composition hold the most distinct influence on the stability of KPI SE. The formula showed satisfactory stability character when the total amount of emulsifier was 1.2ï¼…with the lecithin-F68 (2:1). The formulation and preparation technology of emulsifier was: the oil phase was 10ï¼…soybean oil, the total amount of emulsifier was 1.2ï¼…with the lecithin-F68 (2:1), and the sodium oleate was 0.1ï¼…. pH was adjusted to 8.0 before homogenization, and the condition was 800bar, 6～10 times, sealed with nitrogen and sterilized. The mean particle size was 186.2nm,ζpotential was-30.34mv, drug content was 100.9ï¼…and the encapsulation efficiency was 98.8ï¼….Dilution test revealed that the sodium chloride injection (0.9ï¼…) diluted samples turned to unstable withζpotential changing markedly. The samples diluted with glucose injection (5.4ï¼…) showed good stability within 8 h. The influencing factor test showed that KPI SE has no significant change in 10 days under high temperature and illumination, and long-term stability study showed that KPI SE was stable after 6 months under 25±2℃and 6±2℃.The in vivo pharmacokinetic behavior of KPI SE was studied utilizing HPLC method. The pharmacokinetic study of KPI SE after intravenous administration in rats was performed. The pharmacokinetic parameters were studied according to non- compartment model. The result showed that the AUC value of KPI SE was (903.28+240.66)/μg·h/ml and 100.3ï¼…compared to ketoprofen solution. The concentration-time curves were alike and pharmacokinetic parameters showed no distinct difference. The distribution study after intravenous administration in rats of KPI SE indicated that no significant different of ketoprofen concentration in main tissues of rat compared to ketoprofen solution.Microdialysis technique was used to determine the concentration of free ketoprofen in rat plasma and CSF after intravenous administration of KPI SE and ketoprofen solution. The results showed that Ke and t_1/2 of free ketoprofen in rat plasma of KPI SE were (0.0042±0.0004) min^-1 and (166.36±15.72) min. Those of ketoprofen solution were (0.0039±0.0003)min^-1 and (180.83±16.26)min. The AUC value of free ketoprofen in CSF of solution was 2.19 times larger than that of KPI SE.Acute toxicity result suggested that the LD₅₀ of KPI SE for intravenous formulation were 201.2 mg/kg. The pharmaceutical safety test results indicated that haemolysis, stimulation and hypersensitiveness, none of these negative effects was found. The analgesic activity of KPI SE was better or the same as the ketoprofen in mice utilizing hot plate method and hot water method after intravenous administration in pharmacodynamics test. Inhibitory effect of KPI SE highly significant by using dimethylbenzene induced ear swelling in mice. And the effect was better than the same dosage of hydrocortisone and ketoprofen.