Preparation And Pharmacokinetic Study Of Artesunate Enteric-coated Sustained-release Tablets

Objective:As a first-line antimalarial drug,artesunate has various pharmacological effects and broad development prospects.However,due to the poor water solubility of artesunate,short half-life in vivo and low bioavailability,its application is greatly limited.In this project,the water solubility of artesunate is improved by adding alkalizing agent,and the solubility and dissolution rate of the drug are further improved by solid dispersion technology.Finally,enteric-coated sustained-release tablets are prepared to prevent the drug from being destroyed in the gastric acid environment,so as to achieve the purpose of sustained release and improved the bioavailability of the drug.Methods:1.Artesunate was prepared into solid dispersion by solvent-spray（freeze）drying method,and the type of solid dispersion carrier and the ratio of carrier to drug were investigated by single factor test method and orthogonal design test method with dissolution rate as the inspection standard.Alkalizing agent（L-arginine）to drug ratio,preparation temperature,preparation time,stirring speed and other factors,jointly determine the best preparation recipe and process:artesunate:PEG4000:L-arginine ratio of 1:1:1,magnetic stirring at 500 rpm for 1 h at 30°C,and freeze-drying to prepare solid dispersions.2.According to the single factor test results,the star point design-response surface optimization method was used to investigate the effects of the type and the dosage of sustained-release materials,and the type and dosage of fillers on the release behavior of sustained-release tablets.The optimal formulation process was determined as follows:the dosage of solid dispersion was 150 mg per tablet;HPMC was used as sustained-release material,and the dosage was 126 mg per tablet;alpha lactose monohydrate was used as filler,and the dosage was 26 mg per tablet;lubricating The dosage was talcum powder,and the dosage was 3 mg per tablet.Sustained-release tablets were prepared by direct powder compression,and the enteric coating increased by 5%;3.The pharmacokinetic characteristics were investigated by single-dose intragastric administration on rats.Results:Artesunate solid dispersion could significantly improve the solubility and in vitro dissolution of artesunate.The prepared enteric-coated sustained-release tablet did not release in the simulated gastric juice for the first 2 hours,and had an obvious12-hour sustained-release effect in phosphate buffer with p H6.8.The pharmacokinetic parameters showed that AUC_0→12 was significantly related to the increase of C_max.T_maxwas delayed when compared with the original research,and the relative bioavailability（Fr）was 232.76%.Conclusion:The solid dispersion prepared in this subject can significantly improve the solubility and dissolution of the drug,and the enteric-coated sustained-release tablet prepared on this basis can improve the oral bioavailability of artesunate and has a sustained-release effect,delaying the drug in vivo.