Preparation And Evaluation Of Dihydroartemisinin Solid Dispersions Tablets

Dihydroartemisinin（DHA）,a new antimalarial drug developed by China,is the derivative of artemisinin,which is reduced by sodium borohydride and has a unique peroxide bridge structure.Studies have shown that DHA has many pharmacological activities such as anti-tumor,anti-parasite,anti-inflammation,and anti-fibrosis,confirming that it has broad prospects in clinical application.DHA belongs to BCS-II drugs,which are characterized by poor solubility and low oral bioavailability.These characteristics lead to the restriction of its application.Thus,increasing its solubility and dissolution rate is one of the most effective approaches to improve its bioavailability.Solid dispersion（SD）technology mixes the drugs and the carrier into a highly dispersed solid dispersion,and the drug is present in the carrier material in a molecular,colloidal,microcrystalline,or amorphous state.Therefore,SD can improve the solubility and dissolution of hydrophobic drugs effectively.Otherwise,it can also improve their oral bioavailability.This study,for the first time,prepared dihydroartemisinin solid dispersions（DHA-SD）using hydroxypropyl-β-cyclodextrin（H-β-CD）and soybean phospholipid as carrier materials.The prepared DHA-SD was then characterized and evaluated.Afterward,this study further prepared DHA-SD tablets and compared the relative bioavailability of tablets and APIs by studying the pharmacokinetic characteristics of DHA tablets in rats.1.Pre-prescription research.In this chapter,the equilibrium solubility of DHA API and the stability of DHA API in different solution media were determined.Then,the compatibility of DHA API with different excipients was studied,and the HPLC analysis method for the determination of DHA content was established.The experiments showed that the equilibrium solubility of DHA in pure water at 25℃for 24 h was 0.140 mg/m L.DHA API has poor stability in an alkaline and strongly acidic environment,and good stability in a weakly acidic environment.The results of the methodological investigation indicated that linearity,precision,repeatability,reproducibility,and recovery all met the requirements of content determination.The compatibility of API and excipients showed that H-β-CD,Ethylenediaminetetraacetic acid disodium salt（EDTA-2Na）,and citric acid could enhance the stability of DHA at high temperatures.2.Preparation and evaluation of DHA-SD.This chapter introduces the preparation of DHA-SD by the solvent method.Through screening and investigating carrier materials,H-β-CD,soybean phospholipid,and citric acid were selected as carrier materials.The dissolution degree in vitro was taken as the evaluation index,and an orthogonal test was used to optimize the formula of DHA-SD.Eventually,the formula of DHA-SD was determined as follows:DHA20%,H-β-Cd 66.12%,soy phospholipid 13.22%,citric acid 0.66%.By using this formula,its dissolution rate in pure water for 30 min has reached 94.51%.The prepared DHA-SD was characterized.The XRD results showed that DHA still exists in crystal form,while the SEM results showed that DHA and the carrier material were polymerized to form massive and uniform particles,and their morphology changed significantly,indicating that several compounds generated a physical form different from any one of the raw materials,so it was DHA and all carrier materials that generated SD.The DSC results showed that the endothermic peak of DHA was not detected in DHA-SD,possibly because the drug had been dispersed in SD.The IR results showed that a hydrogen bond was formed between DHA and the carrier material,and the 1,2,4-trioxane pharmacophore of DHA was not affected in the preparation process.3.Preparation and evaluation of DHA-SD tablets.DHA-SD tablets were prepared by direct powder pressing method.Taking the in vitro dissolution,hardness,and disintegration time of DHA-SD tablets as the main indexes,the types and dosages of tablet excipients were screened.The tablets were prescribed as follows:DHA-SD 55.54%,crosslinked povidone 20%,microcrystalline cellulose 22%,EDTA-2Na 0.56%,and magnesium stearate 1.67%.After comparing samples from three batches,it was found that the optimized formulation process had fine stability and reproducibility.Otherwise,the hardness,friability,weight difference,and dissolution of tablets can all meet the requirements.4.Bioavailability study of DHA-SD tablets in rats.The pharmacokinetic characteristics of DHA in rats were analyzed by the LC-MS/MS method,and the relative bioavailability of tablets and APIs were compared.Then,the main pharmacokinetic parameters of DHA were calculated by the Win Nonlin 8.3.1 software non-compartmental model statistical moment method.The results showed that,after intragastric administration of DHA tablets to SD rats,C_max and AUC_0-t was 4.44 times and 2.94 times that of the crude drug,respectively.This experiment indicated that DHA-SD can significantly improve the in vitro dissolution and oral bioavailability of the drug.