Long-acting injectable donepezil microspheres: Formulation development and evaluation.

Area of Science:

• Pharmaceutical Sciences
• Biomaterials Engineering
• Drug Delivery Systems

Background:

• Alzheimer's disease treatment often involves frequent dosing of donepezil (DNP), leading to adherence issues.
• Developing long-acting DNP formulations can improve patient compliance and reduce side effects.

Purpose of the Study:

• To develop novel, biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres for DNP with a one-month duration.
• To optimize DNP-loaded microsphere formulations using various polymers and drug/polymer ratios (DPR).
• To predict human pharmacokinetics (PK) for DNP-loaded microspheres through animal studies and PK modeling.

Main Methods:

• Fabrication of DNP-loaded microspheres using the Inventage Lab Precision Particle Fabrication method (IVL-PPFM®).
• Characterization using laser-light particle size analysis and scanning electron microscopy.
• Pharmacokinetic evaluation in beagle dogs and subsequent PK modeling and simulation for human extrapolation.

Main Results:

• The drug/polymer ratio (DPR) and lactide ratio of PLGA significantly influenced DNP release kinetics.
• PK modeling and simulation successfully addressed inter-species variations between dogs and humans.
• A specific formulation (PLGA 7525A, DPR 1/9) was predicted to maintain therapeutic DNP concentrations for one month in humans with controlled initial release.

Conclusions:

• Biodegradable PLGA microspheres offer a promising approach for long-acting DNP delivery.
• The IVL-PPFM® technology enables precise fabrication of DNP-loaded microspheres.
• The developed PK model provides a basis for future human formulation development and clinical translation.