Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin

Abstract

The daily oral administration of acetylcholinesterase (AChE) inhibitors for Alzheimer's disease features low patient compliance and can lead to low efficacy or high toxicity owing to irregular intake. Herein, we developed a subcutaneously injectable hyaluronic acid hydrogel (MLC/HSA hydrogel) hybridized with microstructured lipid carriers (MLCs) and human serum albumin (HSA) for the sustained release of donepezil (DNP) with reduced initial burst release. The lipid carrier was designed to have a microsized mean diameter (32.6 +/- 12.8 mu m) to be well-localized in the hydrogel. The hybridization of MLCs and HSA enhanced the structural integrity of the HA hydrogel, as demonstrated by the measurements of storage modulus (G '), loss modulus (G ''), and viscosity. In the pharmacokinetic study, subcutaneous administration of MLC/HSA hydrogel in rats prolonged the release of DNP for up to seven days and reduced the initial plasma concentration, where the C-max value was 0.3-fold lower than that of the control hydrogel without a significant change in the AUC(last) value. Histological analyses of the hydrogels supported their biocompatibility for subcutaneous injection. These results suggest that a new hybrid MLC/HSA hydrogel could be promising as a subcutaneously injectable controlled drug delivery system for the treatment of Alzheimer's disease.