Proeparation And Study Of Probucol Solid Dispersion

Objective: the effect of reducing serum lipids ofprobucol has received increased attention, but its practical use is limited because of poor wettability and low bioavailability. We attempted to use solid dispersion technique to enhance its dissolution rate and bioavailability.Methods: solid dispersions(SD) of probucol in such carriers as PEG6000, PEG 12000 and PVP were prepared by the solvent-melting method and the solvent method and stabilizing agent was added in. The dissolution rate and stability were used as parameters to select the optimum carrier, ratio and ratio of stabilizing agent. Padded method was used in dissolution experiment, probucol can be determined by using ultraviolet spectrometry instrument at a wave-length of 242nm. The materials were characterized by differenttial scanning calorimetery(DSC). The bioavailability and pharmacokinetic behavior of probucol solid dispersion was determined after oral administration to rabbits. Plasma concentration of probucol can be assayed by high pressure liquid chromatography(HPLC). hi situ recirculating of intestinal segments of the rats is used to study the intestinalabsorption of probucol. The sample was analysed by using HPLC equipped with a YMG ODS column. The mobile phase consisting of 94 volume of acetonitrile and 6 volume of water and 0.1 volume of 10% glacial acetic acid and 0.1 volume of 10% n-butylamine. The detection wavelength was at 241 nm.Results : the result of in-vitro release of solid dispersion prepared with PEG and PVP as carriers showd that the PEG was not appropriate carriers for the dissolution of probucol-PEG SD was slow and incomplete, Whereas, the probucol-PVP SD dissolved out fast and completely and the optimum proportion of probucol and PVP is 1:5. But SD was instable if PVP was used as single carrier, in- vitro dissolution rate of probucol dropped 20% after one month. The stability was increased after stabilizing agent was added in, in-vitro dissolution rate of probucol only dropped 15% after 5 months. The DSC demonstrated that coprecipitates was formed in probucol-PVP solid dispersion . The in-vivo release of probucol complied with the first order kinetics, two-compartment model. The parameters were: the team given probucol SD: Ka=0.2765+0.031/h ; Lag time- 1.4999+0.18h; t1/2 a =7.75+1.45h; t1/2 3 = 54.92+3.38h; t1/2Ka= 2.5506 + 0.41h; AUC=656.7685+62.8(ug/ml)*h ; CL(s)=0.1533 +0.02 mg/h/ (ug/ml); T (peak) =9.93+0.53h; C (max) =9.3685+0.27 ug/mL The control: Ka=0.1573+0.03 l/h;Lagtirne=1.4847+0.06h;t1/2a=9.15+1.83h;t1/2 P =85.78+7.44h; t1/2Ka=4.7806+0.55h; AUC=117.6174+36.6(ug/ml)*h; CL (s) =0.9038?.23mg/h/ (ug/ml); T(peak)=11.25+1.05h; C (max) =1.7770+0.23ug/mlThe result of t-test showed that there was significantdifference between two groups (P<0.01). Comparing with pure probucol, probucol in SD was absorbed more quickly, Cmax was much larger, AUC was much greater. The relative bioavailability of SD vs the control was 558.39 % The result of intestinal absorption of probucol of rats showed that absorbed dose of probucol in SD was more than that of the control, whereas the absorbed dose of duodenum was more than that of colon. The difference between two groups was statistically significant (P<0. 05).Conclusion: the solid dispersion of probucol-PVP-10% stabilizing agent not only could increase in vitro dissolution rate and stability, but enhance bioavailability. Probucol solid dispersion was a promising preparation.