| Objective:Design and establish the stainless steel membrane emulsification system and use this system to prepare uniform-sized Silybin loaded poly (lactic-co-glycolic acid)(PLGA) microspheres, optimize its preparation. Study silybinPLGA microspheres’physicochemical properties, in vitro release behavior, and the performance of the stainless steel membrane emulsification system.Research silybin PLGA microspheres pharmacokinetic study of distribution in mice and provide methodological support for microsphere delivery system of other effective components of traditional Chinese medicine.Methods:Establish a HPLC method for the determination of Silybin.Use PLGA as the carrier material, prepare silybinPLGA microspheres by premix membrane emulsification-solvent extraction/evaporation method and stainless steel membrane emulsificationsystem. With an average particle size (DO.5) and span as index, use single factor experiment such as:concentration of the oil phase, concentration of the aqueous phase, membrane pressure, ratio of oil and water phase volume, etc. Combined with the results of single factortest, screen threemainfactors, ratio of drug andcarrier material, ratio of oil and water phase volume, aperture of membrane tube, the preparation conditions were optimizedby orthogonal experiment and then evaluate the physical and chemical properties of the microspheres from the dispersion of drug loading, encapsulation efficiency, DSC and so on. Under the research foundation earlier, immediate releasemethod was used to study the drug releaserule of silybin PLGA microspheres and examine the impact of additives on the release rate of microspheres.In pharmacokinetic study, mice were intravenously injected silybin PLGA microspheres and particles in10min,2h,6h,12h,24h,2d,4d,7d time point and sample, determine the drug concentration in the blood and tissues, Statistics conducted pharmacokinetic parameters, explore the body distribution ofSilybin PLGA microspheres and particles.Results:The final optimum conditions were as follows:membrane pore was size1μm, ratio of oil and water phase volume was3:7, ratio of drug andcarrier materialwas1:4, oil phase concentration was4%, PVA concentration of was3%, kind of Curing liquidwas saline solution, PLGA model was LA:GA=75:25, membrane pressure was1.0Mpa.Prepared microspheres were round and with a smooth surface. The mean diameter was(4.54±0.83)μm, the span was(1.68±0.18), the average drug loading was(23.16±1.71)%and entrapment efficiency was(55.00±4.05)%. In vitro release, PBS(PH=7.4) was chosen as the release medium. Two batches silybin PLGA microspheres which prepared with the optimum conditions release behaviors are almost same. After the early burst, release of the microspheres become gentle and release of agingis expected to reach more than40days.In vivo distribution studies showed thatsilybin microspheres and particles can rapidly enriched in the liver, spleen tissues after intravenous injection, but in the plasma and other organs were not distributed. Silybin microspheres have no significant differences in Cmax, Tmax,AUC, MRT and other pharmacokinetic parameters with particle groups.Conclusions:Evaluate the quality of silybin PLGA microspheres from their morphology, particle size and distribution, further dispersion, drug loading, encapsulation efficiency, stability, vitro release behavior and so on. The microspheres prepared with the optimal method had a uniform-sized, controlled particle size and stable quality. The premix membrane emulsification can be used to prepare the Silybin PLGA microspheres which was an insoluble extracted from Chinese medicine Silybin marianum Gaertn. In vitro release test, after the early burst, the drug transit to the smoothrelease. The experiment was only done25days, the cumulative release and recovery in total can reach70%-80%, is expected to be released over40days.Pharmacokinetic parameters of microspheres group and the particle group in the liver and spleenwere not statistically different, that is to say, there were no differencein vivo drug distribution and metabolism between silybinparticles and microspheres. There was no detection in plasma, drugs may achieve quickly homeostasis distribution. |
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