Study On The Preparation And Release Mechanism Of Donepezil- PLGA Microspheres

Donepezil is a second-generation acetylcholinesterase inhibitor that improves cognitive function in patients with Alzheimer's disease by reducing the rate of elimination of acetylcholine in the synaptic cleft.Currently available on the market is donepezil hydrochloride(DP·HCl)tablets that need to be taken daily.However,it is very difficult for patients with Alzheimer's disease to take the drug on time every day.Oral administration of DP·HCl tablets may cause gastrointestinal adverse reactions.Therefore,in this study,a degradable biomaterial poly(lactic-co-glycolic acid)(PLGA)was used to prepare donepezil-PLGA microspheres with long-term sustained release.The use of donepezil-PLGA microspheres not only reduce the frequency of dosing but also avoids gastrointestinal adverse reactions.In this study,donepezil-PLGA microspheres were prepared by oil-water emulsion solvent extraction technique.The drug loading,encapsulation efficiency,particle size and particle size distribution were used as microsphere quality evaluation indicators,and the formulation was optimized by single factor method and central composite design-response surface method.The donepezil microspheres prepared by optimal formulation had an average particle size of 71.75±0.95 ?m,particle size distribution of 0.819 ± 0.027,encapsulation efficiency of 78.11±1.2% and drug loading of 14.80± 0.41%.The release studies were carried out on microspheres prepared by PLGA with different molecular weights and different LA/GA ratios and microspheres prepared by different solvent evaporation rate.The results show that when the LA content of PLGA was 75%,the molecular weight increased from 12000 to 47000,and the time of lag release increased from 0 days to 6-7 days,while the sustained release time increased from 8 days to 26 days.Determine the molecular weight of PLGA is about 47000,the content of LA increases from 50% to 75%,he time of lag release increased from 2 days to 6-7 days,and the sustained release time increased from 17 days to 26 days.When the LA content of PLGA is 75% and the molecular weight is 53000,the temperature of the aqueous phase increases from 20°C to 28°C during the preparation of the microspheres.The solvent volatilization rate increases,and the burst release of the drug in one day increases from 1.99 to 5.59.%,the time of lag release reduced from 12 days to 6 days.In order to predict the release behavior of drugs in vitro in a short time,accelerated release studies of different microsphere were carried out by elevated the release temperature.It was found that the accelerated release method can describe the overall release tendency of different microsphere at 37°C,and has an accurate predictive ability for the in vitro release behavior of microspheres with the time of lag release less than 3days.To investigate the differences in the release mechanisms of donepezil-PLGA microspheres in vitro and in vivo,the microspheres of different release stages were recovered from the mice and the release kinetics of the drug,as well as the mechanistic indicators of the release,such as glass transition temperature,mass loss,water uptake,and microsphere swelling,were directly measured and analyzed in vitro and in vivo.The results showed that the drug was released in vitro for 42 days and released in vivo for about 21 days.The glass transition temperature of PLGA is reduced from 48.4°C to 30°C for more than 42 days in vitro and only take 20 days in vivo.When the drug is completely released,the mass loss of the microspheres in vitro is 50.75%,and the mass loss of microspheres in vivo is 64.12%.The water absorption and particle size expansion speed of the microspheres are accelerated in vivo.In one day,the microspheres absorb water is 9.14% in vitro,the particle size increases 6.65%,the water absorption in vivo is 19.52%,and the particle size increases 12.37%.The mass loss data indicated that the microsphere exhibits diffusion and erosion via jointly controlled release both in vivo and in vitro,but the control of erosion on release is enhanced in vivo.The study showed that there are some unknown substances or biochemical reactions in in vivo environment that cause the microspheres to absorb water quickly and accelerate the degradation of the polymer.