Preparation and in vitro and in vivo evaluation of HupA PLGA Microsphere

ABSTRACT

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[max] and short t[max] after oral administration. Clinical trials have verified that extended-release formulation with lower C[max] and prolonged t[max], 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 micro m. 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[max] was lower and the t[max] was considerably later in single intramuscular administration of HAM [1,000 micro g/kg] than the counterparts in single intragastric administration of HAT [75 micro g/kg/d]. Meanwhile, HAM has performed a continuous inhibition to brain AChE activity in normal rats and improvement of memory deficit in A beta 1-40 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