The Studies Of 3-n-Butylphthalide Submicron Emulsion For Intravenous Administration

3-n-Butylphthalide（NBP）, a novel cerebral antiischemic agent, was isolated and identified from several plants including celery oil. The main objective of this research was to study an intravenous formulation of NBP- NBP submicron emulsion for intravenous administration. We determined the uptake of NBP into the brain to investigate whether the NBP submicron emulsion can cross the blood-brain-barrier with the method of brain microdialysis. We also determined NBP concentration in serum to study the correlation of NBP content both in brain and blood.A method for determining NBP submicron emulsion in vitro was developed. The effect of pH and temperature on NBP was investigated. The constituent and content of NBP submicron emulsion formulation was studied by one-factor experiment. Processing parameters were studied and optimized., and then the optimized formulation was selected through orthogonal experimental design. The stability of the optimized formulation was also inspected. The methods for detecting NBP both in brain dialysate and serum were established. Pharmacokinetics in brain and blood were studied by intracerebral microdialysis and serum content determination., and the correlation of both was also investigated.A specified HPLC method was developed for the determination of NBP in vitro. NBP was stable under heating within the pH range from 5 to 11. The content of NBP in the formulation was 5％, and the emulsifier（E-80）, coemulsifier（COE2）, stabilizer（ST）had obviously effect on the stability of NBP submicron emulsion. The best formulation was selected by orthogonal experimental design. A fine and stable NBP submicron emulsion was acquired under good processing control. The average particle size was 128.0±3.4 nm（n=3）and the zeta potential was -34.3±5.3 mv（n=3）. NBP submicron emulsion was stable after sterilization. All the property parameters of NBP submicron emulsion were almost the same under the condition of 4, 25, 40℃except that the colour of the NBP submicron emulsion under 40℃was a little yellow and the average size under all conditions was slightly increased.The intracerebral NBP content in rats was determined using brain microdialysis technique. The recovery of probes was calculated by the way of recovery by gain. Two preparations and two doses of NBP were compared in brain. For NBP submicron emulsion, the concentrain of NBP in brain increased when the rats administered more drugs. For NBP ethanol solution and NBP submicron emulsion, the former reached the maximum concentration faster than the latter and also eliminated more quickly than the latter.It indicated from the serum NBP concentration that both the NBP submicron emulsion and NBP ethanol solution exhibited two-compartment distribution. T_1/2α values were 17.2007±2.6308 min and 17.0438±4.5502 min, respectively. T_1/2β values were 233.38±134.43 min and 382.11±206.82 min, respectively. NBP ethanol solution eliminated more rapidly than NBP submicron emulsion.When correlated the NBP concentration both in brain and serum, we fotmd that the concentration of NBP in brain decreased with the NBP concentration in serum for NBP ethanol solution; the concentration of NBP in brain increased first and then decreased with the NBP concentration in serum for NBP submicron emulsion.The self-made NBP submicron emulsion for intravenous administration with small size and narrow size distribution was stable and can be used for intravenous administration. The in vivo study proved that NBP submicron emulsion can distributed into brain and acted on it.