| The aim of this thesis was to incorporate flunarizine into submicro-emulsion by using high-pressure homogenization technology. In order to meet the clinical demand, different formulations and crafts were sieved to improve the solubility of flunarizine in aqueous media. Meanwhile, the detection of pharmacokinetics character in rats of FZ-SE was also undertaken, which will provide a reference for clinical dosage regimen.An HPLC method was used for the analysis of flunarizine in vitro according to Chinese Pharmacopoeia 2005 edition (vol. II). The solubility, stability and oil phase-water phase partition of flunarizine were closely related with the pH of mediums in some degree. By increasing the pH of mediums, the solubility decreased and oil phase-water phase partition turned higher.In this study, High pressure homogenization was adopted to prepare FZ-SE. The final formulation and preparing process of FZ-SE were as follows:Soybean lecithin 1.8%(w/v), LCT 5%(w/v), MCT 5%(w/v) and dl-a-tocopherol 0.1%(w/v) were mixed with stirring at 80℃in a water bath, and drug powder 0.1% was added when the lecithin was dissolved. While, F680.4% (w/v), Tween-800.2%(w/v), oleate sodium 0.03%(w/v), glycerol 2.5%(w/v), EDTA-Na 0.01% (w/v), Na2SO3 0.15%(w/v) and L-cysteine 0.05%(w/v) were dispersed in injectable water stirring at 80℃to obtain the aqueous phase. The oil phase was added to the aqueous phase gradually and mixed for 10 min, using a high-shear mixer at 8,000 r-min-1 to prepare a coarse emulsion. After adjusting the pH to 8.0 with 0.1 mol·L-1 HCl or NaOH solution, the primary emulsion was passed through a high pressure homogenizer at 70 MPa for eight cycles. The temperature of the entire homogenization process was controlled at 40℃using ice-water bath. Finally, the FZ-SE was transferred to vials under nitrogen gas condition and sterilized in a 100℃rotating water bath for 45 min.The particle size of the optimized flunarizine submicron emulsion was 136.0±60.4 nm,-31.70 mV in (?)- potential, and the entrapment efficiency was 96.16%. Shaking stability and light stability test showed flunarizine submicron emulsion was applicable to industrial production and transportation and in the process do not need protect from light. In addition, the results of long term stability test at (25±2)℃and (10±2)℃for 6 months showed that the characteristics of FZ-SE changed can be acceptable and can also met the demand of intravenous administration. Thus, FZ-SE owing the better physical-chemical stability will be very promising for industrial production and clinical application.A simple, rapid and sensitive UPLC/MS/MS method was established to determine flunarizine concentration in rat plasma samples after intravenous administration. The mean plasma concentration-time curves of flunarizine at three doses (0.5 mg-kg-1,1.0 mg-kg-1,2.0 mg-kg-1) were better fitted to three-compartment model and their pharmacokinetic curves were similar. Flunarizine hydrochloride submicron emulsion and flunarizine hydrochloride solution were injected to rats separately. There were three doses:0.5,1.0 and 2.0 mg-kg-1. For the submicron emulsion, AUC0-t followed by 504.94±259.38,1253.92±330.94,2907.58±408.80μg-h-L-1, MRT0-t were 3.65±1.68,7.31±2.23, and 6.23±0.54 h. While for the solution, AUC0-t were 656.73±306.00,1587.99±336.66,2135.75±463.75μg-h-L-1, MRT 0-t were 4.22±1.76, 7.96±2.65, and 6.23±1.81 h, respectively. Furthermore, AUCo-t of the three administrations were all linear correlation with doses range from 0.5 to 2.0 mg-kg-1, indicated that the pharmacokinetics of flunarizine submicro-emulsion and aqueous solution in rats body both fit linear dynamic feature in the dosage of 0.5-2.0 mg-kg-1. |
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