Research On Optimization And Pharmacokintics Of Donepezil Formulation

Donepezil (DPB) is a reversible acetylcholinesterase inhibitor. Currently DPB is the most described pharmacological agent for the treatment of mild to moderate to severe Alzheimer's disease (AD). It also can improve the patients'mental state and keeping their brains active. Now the drug dosage forms of DPB are mainly through oral administration, like Tabts and capsules. Researches have showed that AD is the most common cause of dementia in people over 65 years old and it needs long time for treatment. And for elderly alzheimer's patients, they have difficulty in swallowing, so administrating orally may lead to poor compliance. In addition, the violent fluctuation of plasma concentration may lead to adverse events, so a transdermal drug delivery system (TDDS) could be considered as an alternative dosage form for donepezil. TDDS can guarantee constant effective drug input, reduce or eliminate the liver first pass effect, relieve the side effects and improve compliance. It is an ideal mode of drug delivery for patients who can not take medicines independently.The aim of the present study was based on the previous study, to optimize the novel drug-in-adhesive transdermal patch system for DPB by evaluating drug-loading capability, drug stability, permeation and release characteristics, and eventually to get prolonged once-weekly transdermal donepezil patch. In this research, ester 1,ester 2 and various organic alcohols were chose to evaluate their influences on donepezil through in vitro skin permeation tests and stability tests, and eventually selecting the most beneficial one. The ratio of different pressure-sensitive adhesives was investigated through in vitro release and skin permeation tests and drug-loading capability to estimate its effect on donepezil solubility, release characteristics and stability and obtain the best ratio. Also animal experiments were took to evaluate pharmacokinetics of DPB transdermal formulation and oral administration by using SD rats.The results showed that ester 1 and ester 2 were equivalent in promotion, ester 1 was more stable over the longterm. Ester 1 was chose to add in patch. Organic alcohol 6 obviously promoted the permeation ability of donepezil, but it showed adverse influence on stability and persistent adhesivity. Organic alcohol 6 was not considered in the successive experiments. The mixed adhesives of DT 87-A and DT 87-B with the ratio of 1/2 (w/w) could bear more than 20%(w/w) DPB without crystallization, and had less related substances and the high in vitro permeation rate. The in vitro accumulative permeation percent achieve 60% to the labelled amount.According to pharmacokinetic experiments, the ransdermal delivery system showed prolonged t1/2 (for intragastric administration t1/2=2.44±0.49h and t1/22=3.59±1.80h respectively, for transdermal t1/2=15.78±8.67h) and AUC0-t (41.50±8.74?g·h/mL and 65.62±26.30?g-h/mL for intragastric administration respectively,190.13±79.20?g-h/mL for transdrmal) compared to intragastric administration. The results showed that the transdermal path for donepezil was feasible.