PLGA-Phospholipid Hybrid Oleogel In Situ Forming Implant for Sustained 30-Day Co-Delivery of Dosnepezil and Memantine.

The management of Alzheimer's disease requires continuous therapeutic intervention due to its progressive nature. Currently, the FDA has approved acetylcholinesterase inhibitors, NMDA receptor antagonists, and disease-modifying monoclonal antibodies for the treatment of Alzheimer's disease. This study aimed to develop a long-acting injectable formulation for symptomatic therapy. An in-situ gel formulation, DM00PG-M13, comprising Lipoid, PLGA (50:50), and sesame oil, was developed and loaded with memantine and donepezil for combination therapy. The optimized gel formulation demonstrated good uniformity with a pH of 7.80 ± 0.015. Rheological and syringeability studies showed a consistent viscosity in the range of 0.20-0.22 Pa·s and an injection force of 9.97 ± 0.29 N using a 22-G needle. In vitro drug release studies performed in phosphate-buffered saline (pH 7.4) demonstrated sustained drug release over one month, with cumulative releases of 82.58% for donepezil and 87.61% for memantine after 30 days. Furthermore, the release kinetics were best described by the Peppas-Sahlin model for donepezil and the Weibull-lag model for memantine. Ex vivo studies evaluating the optimized formulation injected into pig muscle tissue showed release profiles comparable to the in vitro release pattern, with approximately 20% release of donepezil and 26% release of memantine over 7 days, indicating sustained release behavior. Cytotoxicity studies using NIH/3T3 fibroblast cells confirmed the formulation's safety profile. Overall, these results suggest that the drug-loaded DM00PG-M13 formulation can be administered intramuscularly as a depot system for sustained drug release, potentially improving patient compliance.