Preparation Of Donepezil Hydrochloride Freeze-dried Orally Disintegrating Tablets And Study On Its Taste Maskin

Objective:Donepezil hydrochloride is used as a second-generation long-acting acetylcholinesterase inhibitor to increase the amount of neurotransmitters in the brain by non-competitive inhibition of acetylcholinesterase.Because of its high selectivity,it has the advantages of long half-life,low hepatotoxicity and few adverse effects,and is often used as the drug of choice for patients with mild to moderate cognitive impairment.The currently available dosage forms of donepezil hydrochloride are all oral formulations.Traditional tablets and capsules need to be delivered with water,which requires a high level of patient autonomy.Due to the bitter taste of donepezil hydrochloride,it is necessary to find a suitable taste correction method to prepare it as an orally disintegrating tablets with high taste and texture requirements.Lyophilised orally disintegrating tablets prepared using freeze-drying technology have the advantages of being water-free,loose and porous,and disintegrating rapidly.Therefore,this study aims to prepare lyophilised orally disintegrating tablets by correcting the flavor of donepezil hydrochloride,which can not only effectively improve the problem of swallowing difficulty caused by the shape and taste of the drug,but also help to solve the phenomenon of drug omission and refusal caused by memory loss and mental abnormality in AD patients,which can effectively improve patients’ compliance with taking the drug and lay the foundation for industrial production.Methods:To explore the correlation between concentration and bitterness of donepezil hydrochloride by combining oral tasting method and electronic tongue method,to further compare the taste correction effect of different correction agents,and to optimize the way of correction agent compounding;The basic matrix and composition of the prescription of donepezil hydrochloride lyophilised orally disintegrating tablets were investigated with the comprehensive score as the index,and the pre-freezing time,inlet time,sublimation drying and resolution drying time in the freeze-drying curve were optimized;The lyophilized orally disintegrating tablets were evaluated in terms of appearance,microstructure,disintegration time,weight difference and content uniformity;The in vitro dissolution assay was established to simulate the dissolution of drugs in human body more realistically.Results:(1)Study on the taste masking process of donepezil hydrochloride:①Establish a linear correlation model between the oral taste bitterness value of the drug and the signal value of the electronic tongue sensor,and the electronic tongue can quickly and accurately quantify the bitterness of donepezil hydrochloride solution;② Optimize the taste correction agent compounding method as follows:AMP 4 mg/tablet,β-CD 20 mg/tablet,sucralose 0.4 mg/tablet and neotame 0.3 mg/tablet.(2)Study on the preparation process of lyophilised orally disintegrating tablets of Donepezil hydrochloride:①The prescription optimization process is:prululan polysaccharide 9.5 mg/tablet,mannitol 4.9 mg/tablet,xanthan gum 0.2 mg/tablet,AMP 4 mg/tablet,β-CD 20 mg/tablet,sucralose 0.4 mg/tablet,neotame 0.3 mg/tablet;②The optimized freeze-drying curve is:the drug solution in the low temperature refrigerator at-60℃ pre-freezing for 10 min;-40℃ into the box,maintenance time of 60 min;sublimation drying stage,warming to-15℃,maintenance of 45 min,warming again to-5℃,maintenance of 45 min;resolution drying stage warming to 25℃,maintenance of 45 min,warming rate are 1℃/min,lyophilization curve time of 260 min in total.(3)Quality evaluation of lyophilised orally disintegrating tablets of donepezil hydrochloride:The surface of the prepared orally disintegrating tablets is full and smooth,white and uniform,disintegrating rapidly,with good formability,and the microstructure pores are closely arranged and orderly,and the results are in accordance with the relevant provisions of the Pharmacopoeia through the determination of their water content,disintegration time limit and content uniformity.(4)In vitro dissolution behavior of lyophilized orally disintegrating tablets of donepezil hydrochloride:By simulating the dissolution process of real drugs in human,the dissolution degree measurement results showed that the dissolution rate of orally disintegrating tablets could reach more than 90%after completing 5 min in the simulated oral cavity,and its dissolution rate was higher than that of the reference tablets under the conditions of simulating different gastric dynamics and the way of taking drugs,exhibits the advantage of rapid predisintegration and dissolution.Conclusion:In this study,the taste improvement of donepezil hydrochloride was successfully achieved by combining the oral tasting method and electronic tongue method to mask the taste correction of donepezil hydrochloride,which has a very bitter taste and a severe numbing sensation,and by studying the bitterness pattern of the drug and the taste correction agent compounding.We also optimized the preparation process and the freeze-drying curve of donepezil hydrochloride lyophilised orally disintegrating tablets,which are prepared by freeze-drying method and have the advantages of being taken without water,disintegrating rapidly in the mouth,tasting good,improving the compliance of patients to take the drug and reducing the gastrointestinal adverse reactions,which are in line with the drug "three small,three effective and five convenient "formulation principles,providing reference for industrial production.