Preparation And Quality Evalution Of Artesunate Self-microemulsions

Self-microemulsifying drug delivery system(SMEDDS)is a kind of solid or liquid dosage form composed of oil phase,surfactant and cosurfactant,which could spontaneously form microemulsion containing drugs with particle size in 10-100 nm in gastrointestinal tract or in the proper environmental conditions under moderate stirring(usually refers to the body temperature of 37 ℃).These small emulsion particles have large surface area to improve drug solubility,overcome absorption abst.acles of drugs through gastrointestinal epithelium cell membranes and finally effectively improve oral bioavailability of drugs.Artesunate(AS),developed independently by our country,it has a sesquiterpenes structure with antimalarial drug derivatives.Since the advent of artesunate,it has a good curative effect and low toxicity as an available antimalarrial,and is also effective in treatment to p.falciparum and cerebral malaria curative.Some scholars carried on the thorough research to artesunate and its derivatives in recent years,and found that Artesunate has the liver cancer resistance,anti live fibrosis,protecting live cells and immune regulating roles in many aspects,but due to its poor water soluble,obvious liver first pass effect and the microsomal drug metabolizing enzyme induction,its oral bioavailability is very low.So it is meaningful to study the oral Artesunate SMEDDS which could provide a new stratege to improve oral bioavailability of artesunate.The main research work is as follows:1.Foumula and preparation of Artesunate SMEDDS.The oil phase and surfactant were selected as ethyl oleate and Cremophor EL,respectively,according to the solubility test of Artesunate in materials and the interaction between Surfactant and oils.N-Butyl alcohol was chosen as the cosurfactant by the pseudo-ternary phase diagram;Artesunate SMEDDS formulation was optimized by drug loading and particle size as variables.The final formulation was consisting Cremophor EL(54%),n-Butyl alcohol(36%)and ethyl oleate(10%),and the drug concent was 50 mg/g.2.In vitro quality evaluation of Artesunate SMEDDS:(1)Quality assessment of Artesunate SMEDDS was evaluated by observation of the appearace,the morphology,particle size,Zata potential and the content.(2)To observe the release test in vitro of Artesunate SMEDDS and Artesunate API.The results showed drug release amounts of Artesunate SMEDDS was 80%above in 30 min while the Artesunate API was only about 27%,demonstrating that SMEDDS can greatly improve the drug dissolution of Artesunate.(3)Study the effect of different dispersion medium、temperature and the dilution ratio to Artesunate SMEDDS on the particle size and the time of self-emulsifying.The results showed that there was no significant difference.(4)Study the preliminary stability test:under the different conditions,compared to the zero days,the appearance,particle size and drug content has no obviously changed,showing that artesunate SMEDDS has a good stabilities.3.The vivo pharmacokinetic experiment of Artesunate SMEDDS on rats:With the male SD rats as the experimental animals to study the pharmacokinetic properties of Artesunate SMEDDS and Artesunate API,the pharmacokinetic parameters of Cmax,t1/2 and AUC0→t were(87.6±8.80)ng/mL and(421±41.6)ng/mL,(1.88±0.33)h and(1.48±0.17)h,(43.3±1.74)h · ng/mL and(282±17.7)h · ng/mL.Cma,and AUC0→t have significant differences(p<0.01),after gavage administration and compared to Artesunate Suspension,Artesunate SMEDDS could significantly enhance the drug bioavailability in rats.4.The pharmacodynamics study of Artesunate SMEDDS on non-alcoholic fatty liver disease(NAFLD)in rats:A model of the NAFLD was constructed by feeding rats with high fat diet for 10 weeks.Different doses of Artesunate SMEDDS were administrated by gavage,and the results showed that the model of serum ALT,AST,TC,TG and TNF-a were strikingly higher than the normal group while the IL-10 was significantly reduced with the remarkable differences(p<0.05 or p<0.01);Compared to the model group,the contents of ALT,AST,C and TNF-a were significantly reduced,while the level of IL-10 was increased,the differences have remarkable significane(p<0.05 or p<0.01);Liver biopsy showed that the Artesunate SMEDDS treatment groups ameliorated hepatic steatosis and inflammatory which confirmed the Artesunate SMEDDS has a better protetive effect on NAFLD induced by high fat diet.The mechanisms may be related to inhibiting lipid peroxide and reducing the level of inflammatory mediator in the liver.