Study Of Sustained-release Epirnomectin Loaded PLGA Microspheres

Eprinomectin(EPR), a highly effective and broad spectrum antiparasite drug, is theonly avermectin drug approved by the FDA for treatment of parasitic infections inlactating cows because of its lower residue levels in cattle milk. The low water solubilityof EPR results in poor bioavailability in its oral dosage forms. Hence, the mainformulations of EPR are pour-on dosage forms and injection dosage forms. Nevertheless,its repeated and indiscriminate application has led to treatment failures and appearance ofresistance in some animal species. Besides, pour-on dosage form is easily influenced bythe environment. In this paper, EPR is combined with a microspheres parenteral deliverysystem which can prolong the action of EPR to50days as well as maintaining constanttherapeutic levels and improving bioavailability. The major content and the results arelisted below.EPR microspheres were prepared with DCM as oil phase by using O/Wsimple emulsion solvent evaporation method. In the process of preparation, the concept ofuniform infusing and vortex dispersing was utilized to obtain spherical microspheres withnarrower diameter distribution. Mannitol was added in the washing process to prevent theaggregation of microspheres. Characteristics of microspheres such as morphology, particlesize, encapsulation efficiency(EE), the vitro release and vivo release were also developed.The influence of various processing variables(PLGA concentration, PVA concentration,drug loading et al) on morphology, particle size and drug EE was systematically assessed.The best values for parameters were determined and those were70mg/mL for PLGAconcentration,1.0%for PVA concentration,1000rpm for stiring,20%for theoretical drugloading and1/35for O/W. The microspheres were spherical with microvoid and deepindentations, diameter of75μm, drug loading of18.5%and EE of above90%. The resultsof DSC illustrated that EPR existed in an amorphous state as a componentof solid solution in the polymeric matrix.Dynamic dialysis method was applied for the in vitro release study. EPR is a verylipophilic drug, so a certain amount of anhydrous alcohol was added in the pH7.4PBS.Through the experiment an accelerated method with good correlation with real-timerelease was groped. The resulting vitro release conditions were the volume ratio ofanhydrous alcohol to pH7.4PBS of4:6, stiring of50rpm, temperature at37℃. Theeffects of PLGA concentration, microspheres size and theoretical drug loading on EPRreleasing profiles were also revealed, and experimental data demonstrated that the microspheres had good sustained-release capacity. The results of Ritger-Peppas equationfitting showed EPR release from microspheres occured by a combined mechanism of drugdiffusion and polymer degradation.A sensitive HPLC with fluorometric detection for the determination of EPR in plasmawas developed. The limit of quantitation of EPR in plasma was0.3ng/ml. EPRconcentration in plasma was steady from the second day to the fiftieth day which wereexpected. The pharmacokinetics parameters determined following injection at a dose rateof0.3mg/kg. The kinetics of plasma concentrations were analysed using aone-compartment model. The maximum plasma concentration(Cmax) was18.9ng/ml, andthe mean residence time(MRT) was575h, and the area under the concentration-time curvewas6.18μg h/mL.