Novel High‐Donepezil Loaded One‐Month Release Microspheres for Alzheimer’s Disease Treatment

Abstract

AbstractBackgroundDonepezil is the most commonly prescribed medication for treating Alzheimer’s disease. However, the most commonly used once daily oral formulation or recently developed once or twice weekly patch formulations have side effects such as nausea, vomiting and weight loss or skin irritation, and the patient’s compliance with these medications is very low. One month release injectable of donepezil microspheres can be a good alternative to increase patient compliance and reduce these side effects. The biggest obstacle in the development of one month donepezil microspheres is that patients tend to feel pain at the injection site due to the large volume of dosage. We have developed novel donepezil microspheres with high drug contents which can improve patient compliance and medication convenience by lowering dosage volume at the injection site.MethodMono‐dispersed and spherical shaped donepezil microspheres with different drug contents were manufactured by membrane emulsification method. The morphology of the microspheres was observed by electron microscope, and the particle size distribution was measured by laser diffraction analysis. The donepezil contents in the microspheres were analyzed using HPLC. Pharmacokinetic studies were performed after a single injection in male SD rats. The concentration of donepezil in the plasma samples was determined by LC‐MS/MS.ResultDonepezil microspheres with three different drug contents (27%, 45% and 60%) were prepared successfully with high drug encapsulation efficiency. All the donepezil microspheres regardless of high drug content have a spherical shape and smooth surface with a narrow side distribution. Despite the high content of donepezil, the initial release was well controlled to less than 5% during the first 24 hours after injection. In rat PK studies of donepezil microspheres after a single injection, plasma donepezil concentration of all three formulations was kept within the therapeutic range for more than one month.ConclusionWe have developed novel donepezil microspheres with high drug contents and without initial burst release. These high donepezil‐loaded microspheres can improve patient compliance and medication convenience by lowering dosage volume at the injection site. Currently, this novel donepezil formulation is planned for commercialization after clinical trials.