Improved physical stability and injectability of non-aqueous in situ PLGA microparticle forming emulsions

The goal of this study was to obtain physically stable non-aqueous in situ forming microparticle (ISM) emulsions capable of forming biodegradable microparticles upon injection. ISM emulsions consist of a biocompatible organic PLGA solution dispersed in a continuous oil phase prepared in a two-syringe/connector system prior to administration. A variety of parenteral approved excipients were tested for a stability-enhancing effect and possible stabilization mechanisms evaluated. Glycerol monostearate (GMS) showed superior stabilizing potential prolonging the emulsion stability from a few minutes to more than 12h. Flow behavior analysis, differential scanning calorimetry, polarized light- and Cryo-electron microscopy revealed, that the stabilization was caused by an immediate, more than 5-fold viscosity increase in the continuous phase after emulsification and by a stabilized interface through a liquid crystalline GMS layer around the polymer solution droplets. Despite the viscosity increase the injectability of the stabilized ISM emulsion was improved by about 30% compared to the corresponding highly viscous PLGA solution (in situ implant) due to a pronounced shear thinning of the GMS containing oil phase. The injectability improvement allows a faster administration or enables the use of thinner needles and hence reduced patient discomfort.