Sustained release of 17β-estradiol from poly (lactide-co-glycolide) microspheres in vitro and in vivo

Abstract Poly (lactide- co -glycolide) microspheres containing four different concentrations (0.15, 0.3, 1.5, 2.25% (w/w)) of 17β-estradiol, all of which are monolithic devices, were prepared by a solvent evaporation method. In the preparation process, poly (lactide- co -glycolide) was dissolved in dichloromethane and estradiol was then dissolved or partly dispersed in the solution. The polymer solution containing drugs was emulsified in water to prepare o/w emulsion. Effects of surfactants and aqueous polymers added to the outer aqueous phase upon the emulsion stability were studied. It was found that polyvinylalcohol effectively stabilizes the dichloromethane in water emulsion. Effects of the estradiol concentration in the microspheres upon its release rate were studied. When the estradiol concentration in the microsphere is less than 0.3% (w/w), estradiol molecules can be dissolved in polymer matrices. When the estradiol concentrations in the microspheres are 1.5 and 2.25% (w/w), however, estradiol crystals exist in a microsphere as a dispersion in the polymer matrices together with estradiol molecules dissolved in the matrices. Sustained release of estradiol from poly (lactide- co -glycolide) microspheres containing 0.15 and 0.3% (w/w) was observed for 30 days in both systems, while that from poly (lactide- co -glycolide) microspheres containing 1.5 and 2.25% (w/w) was observed for 100 days in both systems. It was found that the release of estradiol from poly (lactide- co -glycolide) microspheres is affected by the following three mechanisms: (i) the release of estradiol molecules accompanied with the removal of degraded short polymer chains; (ii) the dissolution of estradiol crystals into polymer matrices and aqueous solution and (iii) pore formation in polymer matrices caused by the polymer degradation. In vivo study, estradiol was released with a constant rate from poly (lactide- co -glycolide) microspheres containing 0.3% estradiol and the plasma concentration of estradiol was kept constant at 1.5 ng ml −1 for 50 days.