Preparation of Novel Donepezil Long‐Acting Injectable, IVL3003, and its Pharmacokinetic Study via Subcutaneous Injection in Dogs and Monkeys

Abstract Background Donepezil is a selective oral acetylcholinesterase inhibitor to treat Alzheimer’s disease (AD). Most patients with AD need help with taking oral donepezil for forgetfulness etc. Therefore, long acting injectables (LAIs) can improve patient’s compliance and quality of life. Because of narrow therapeutic window of donepezil, precisely size controlled microsphere technology is needed for drug release control. We have developed IVL3003 as a novel sustained release monodisperse subcutaneous (SC) LAI of donepezil for one month using IVL‐DrugFluidics ® technology. The purpose of this study is to evaluate the physicochemical characteristics of IVL3003 and investigate the inter‐species pharmacokinetic profile differences in beagle and monkey models. Method Various one month formulations of donepezil microspheres were prepared by IVL‐DrugFluidics ® . Characterization of IVL3003 was performed by scanning electron microscopy (SEM), and the size distribution was measured by laser particle size analyzer (PSA). The amount of donepezil and encapsulation efficiency (EE, %) was determined by HPLC. Size distributions were expressed as span value and CV(%). Non‐clinical models were used to optimize formulations and to evaluate their pharmacokinetic properties. IVL3003 was administered to male beagle dogs (n = 3/group, 11 months old, body weight 9∼11 kg) and male cynomolgus monkeys (n = 3/group, 30∼50 months old, body weight 2.6∼3.3 kg). Plasma concentrations were monitored for one month. Results The SEM images of the microspheres appeared spherical and smooth. Donepezil was well encapsulated and homogeneously. The EE(%) of microspheres was 97.5% and the residual solvent was 232.2 ppm. The span value was 0.25 and CV(%) was 10.01%. The plasma concentrations of donepezil were maintained for 28 days without any initial burst and had small individual variation. There was no big difference between species in plasma concentration and showed a similar PK profile in both. Conclusions As we postulated, narrow distribution of the particles was led to improvement of controlled‐release characteristics. These results proved the excellence of IVL‐DrugFluidics ® as an ideal microsphere fabrication method in manufacturing uniform and monodispersed microspheres. Long‐acting injectable, IVL3003 is expected to increase the compliance and the safety in the treatment of Alzheimer’s patients. We have filed Ph I for IVL3003 recently as the 1st donepezil containing LAI.