Ye_2013_Pak.J.Pharm.Sci_26_315

Acetylcholinesterase inhibitors (AChEIs), including Huperzine A (HupA), have been the mainstay of treatment for Alzheimer's disease (AD). However, AChEIs can cause gastrointestinal side effects, which has been related to the high C and short tmax after oral administration. Clinical trials have verified that extended-release formulation with lower C and prolonged tmax, such as rivastigmine patch, could perform a similar efficacy with significantly improved tolerability compared with the oral formulations. In this study, we developed an extended-release microspheres formulation of HupA (called as HAM) with poly(lactide-co-glycolide) (PLGA) as drug carrier. HAM has showed the loading rate as 1.35% (w/w) and yielded 42% with mean particle size at 72.6 mum. In vitro and in vivo pharmacokinetics studies have showed that HAM produced a relatively smooth and continuous drug concentration in 14 days. Furthermore, in vivo pharmacokinetics data have demonstrated that the C was lower and the tmax was considerably later in single intramuscular administration of HAM (1,000 mug/kg) than the counterparts in single intragastric administration of HAT (75 mug/kg/d). Meanwhile, HAM has performed a continuous inhibition to brain AChE activity in normal rats and improvement of memory deficit in Abeta i.c.v. infused AD rat model for 14 days. The results have suggested that HAM has performed good extended-release properties and good prolonged pharmacological efficacy in vivo in the 2-week period, and could exert a similar efficacy with significantly lowered gastrointestinal side effects as compared with oral formulation.