Monopotassium phosphate-reinforced in situ forming injectable hyaluronic acid hydrogels for subcutaneous injection.

Monopotassium phosphate and pH modulation-reinforced hydrogel based on hyaluronic acid (HA) grafted with dopamine (dopa) was fabricated as one of subcutaneous injection formulations of donepezil (DPZ). Both incorporation of KHPO and pH adjustment finally attributed to tuning viscoelastic and biodegradable properties of hydrogel system. Appropriate gelation time for in situ gel formation, single syringe injectability, self-healing capability, and viscoelastic features were accomplished with the optimization of KHPO concentration in hydrogel systems. DPZ base (as a poorly water soluble drug) was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) and it was further embedded in the hydrogel structure for sustained drug release. Biodegradability of designed KHPO-incorporated HA-dopa/DPZ MS hydrogel system was assessed by optical imaging and the remained gel weight of crosslinked HA-dopa hydrogel group was 3.4-fold higher than that of unmodified HA-dopa mixture group on day 14 (p < 0.05). Subcutaneous injection of KHPO-incorporated HA-dopa/DPZ MS hydrogel did not induce any severe systemic toxicities. All these data suggest that designed HA-dopa/DPZ MS hydrogel structure crosslinked by KHPO incorporation and pH adjustment can be one of promising subcutaneous injection formulations for sustained drug delivery.