Facile Technology for Extemporaneous Preparation of Long-Acting Injectable Microparticulate Suspensions at the Patient Side

Abstract

In this study, we present an innovative and facile in situ approach for extemporaneous preparation of sterile microparticles. An amazingly simple approach, in situ technology circumvents the stability, and scale up challenges as well as sterilization issues associated with long-acting particulate systems. Monophasic preconcentrates of donepezil base (DPZ), a model drug with a biodegradable polymer poly (DL-lactide-co-glycolide) (PLGA), with stabilizer were prepared by simple solution and sterilized by filtration (0.22 micron). The sterile preconcentrates when added to aqueous dextrose solution (total volume < 3mL) generated ready-to-inject DPZ PLGA microparticles (DPZ-PLGA-MP) with high reproducibility, entrapment efficiency (> 80%), and size ~ 80 micron. DPZ micro suspension(DPZ-MS) with high precipitation efficiency (> 90%) and size ~ 80 micron was obtained in a similar manner omitting PLGA. XRD and DSC study confirmed decreased crystallinity in the presence of PLGA. No interaction between PLGA and DPZ was evident in the FTIR study. The microparticulate dispersions exhibited good in vitro injectability when tested using the texture analyzer (force < 5 N). When evaluated using the dialysis bag method (Himedia 12-14kDa molecular weight cutoff), both microparticulate formulations exhibited controlled release up to 1week in vitro. Further, low burst release of ~ 10% at the end of 6h in the ex vivo chicken muscle study proposes great promise. Our data propose the facile extemporaneous generation of microparticles as a practical and promising approach for development of long-acting injectables. This facile approach could serve as platform technology for other drug candidates.