Oral Site-specific Drug Delivery Systems Of Artemisinins For Anti-tumor

The purpose of this project was to develop oral site-specific drug delivery systems of artemisinin derivatives for treatment of gastrointestinal cancer.It was hoped to build foundation for the development of oral site-specific drug delivery systems of artemisinin derivatives.Artemisinin derivatives such as artemether and artesunate have the pharmacological effects of anti-gastric cancer and colon cancer.However,there are just ordinary dosage forms of artemisinin derivatives in market and it is difficult to achieve therapeutic concentration at the tumor site.Hence,this project developed artemisinins oral site-specific drug delivery systems which showed a promising approach for gastrointestinal cancer therapy by providing high local drug concentration.In this project,artemether and artesunate were choosed as the subjects.Based on the previous experimental results,artemether gastroretentive microemulsion-in situ gel was to design,formulate,and characterize.Besides,artesunate colon adhesive sustained release tablet was developed based on the research of the solubility,stability and intestinal absorption characteristics of artesunate.The major methods and results of this project are analysed and summarized as follows:(1)Artemether gastroretentive microemulsion-in situ gel was formulated and optimal formula was screened.The evaluation methods for fluidity,gelation,compatibility and adhesion were established to screen the optimal formula.The fluidity and gelation capacity of aqueous phase were studied.Composition of microemulsion-in situ gel was screened and optimized by solubility assay,compatibility,stability,pseudoternary phase diagram and adhesiveness test.The composition of optimized formulation was artemether(0.5%,w/w),glyceryl triacetate(4.5%,w/w),cremophor EL35(5%,w/w),transcutol HP(5%,w/w),and(0.3%Kell0.1%sodium alginate)(85%,w/w)as active pharmaceutical ingredient,oil,surfactant,cosurfactant,and aqueous phase respectively.(2)Artemether gastroretentive microemulsion-in situ gel was characterized in vitro and estimated in vivo.Based on the optimization of formula,artemether gastroretentive microemulsion-in situ gel was clear and transparent in appearance and spherical with a uniform particle size(20.90 nm).Its PDI,Zeta potential,viscosity,as well as concentration were 0.172,-19.5,15.32 mPa·s,5g·L-1 respectively and is stable at room temperature.In vitro drug release studies exhibited sustained and higher drug release from microemulsion-in situ gel compared with artemether API.Moreover,gastroretentive time and gastric mucosal irritation test of the optimized formula evaluated in rats was found retained in the stomach for 6 h and showed no stimulating effect on gastric mucosa.The present study indicates that artemether gastroretentive microemulsion-in situ gel can not only prolong the gastric retention time of artemether but also meet the requirement for topical medication and is suitable for oral administration.(3)Solubility,stability and intestinal absorption of artesunate in rats were investigated.Solubilities of artesunate in water at various pH values were determined by UPLC.The datas showed that solubility of artesunate was influenced by pH.As the pH was increased from 3 to 9,the apparent solubility of artesunate increased.Stability study indicated that artesunate was unstable in the conditions of acidic,alkaline or high temperature,in addition,drug concentration and intestinal enzymes had no influence on the stability of artesunate.For investigating the absorption of artesunate,a "four site perfusion model" was used.The results showed that absorption percentage of artesunate in the duodenum,jejunum,ileum,and colon was 15.16%,15.96%,6.98%,and 5.15%in order.The amount of drug absorbed increased when concentration of artesunate in perfusate was higher.Otherwise,pH of the perfusate had no effect on the absorption of artesunate.It was revealed that artesunate transported across intestinal epithelial cell membrane might occur by passive diffusion.(4)An oral drug delivery system with colon specific adhesive and sustained delivery of artesunate was developed and evaluated.For the mucoadhesive sustained-release core tablet,dissolution studies and adhesion test were utilized to simultaneously optimize the amount of lactose,microcrystalline cellulose,carbopol and hydroxypropyl methylcellulose.The artesunate colon adhesive sustained-release tablets were obtained by coating optimized core tablets with Eudragit S100 and characterized by dissolution studies.Mucoadhesion studies revealed there were strong adhesive forces between porcine colon mucosa and optimized core tablets.In vitro dissolution studies of artesunate colon adhesive sustained-release tablets exhibited that negligible release in simulated gastric and intestinal fluid,followed by sustained release in simulated colonic fluid within 12 h.It’s demonstrated that artesunate colon adhesive sustained-release tablet is a promising system for sustained drug delivery to colon and have the characteristic of adhesion.