Preparation And Evaluation Of Self-nanoemulsifying Drug Delivery System Of Curcumin

Curcumin（Cur）is a natural polyphenol extracted from the rhizomes of Zingiberaceae,which exhibits various pharmacological effects such as anti-inflammatory,anti-tumor,antioxidant,and immune regulation.However,curcumin has poor aqueous solubility and stability,resulting in low bioavailability and efficacy.In this study,self-nanoemulsifying drug delivery system of curcumin（Cur-SNEDDS）was prepared to solve the problems above,and its pharmacokinetics and pharmacodynamics in vivo and in vitro was studied.Firstly,by examining the solubility of curcumin in different oil phases,surfactants and cosurfactants,and the emulsification efficiency of different surfactants and cosurfactants,Capryol 90,Labrasol and PEG 400 were selected as the oil phase,surfactant and cosurfactant,respectively.By comparing the size of emulsifying region of pseudo-terpolymer phase diagram under different mass ratios of surfactant and cosurfactant（Smix）,Smix was preliminarily accounted for 50-70%of the prescription,and the ratio was 1:2.Finally,with the emulsification efficiency and average particle size as indicators,the formulation was optimized as Capryol 90:Labrasol:PEG 400=0.4:0.2:0.4（mass ratio）by the response surface optimization experiment.The optimal formulation was evaluated:the average particle size was 12.43±0.29 nm,the polydispersity index（PDI）was 0.069±0.025,the potential was-10.52±0.29 m V,and the encapsulation efficiency and drug loading were 99.82±0.13%and 39.80±0.12 mg/g,respectively.The different dilution ratios and dispersion media had little effect on the stability of Cur-SNEDDS,and the stability was good within 6 months.The in vitro dissolution test showed that curcumin of Cur-SNEDDS could be released almost completely in the buffer salt solution of p H 6.8 and HCl solution of p H 1.2 in about 40minutes,which indicated of Cur-SNEDDS could significantly improve the solubility of curcumin.The pharmacokinetics of Cur-SNEDDS in rabbits was studied.According to the drug-time curve and pharmacokinetic parameters,the pharmacokinetic process of Cur-SNEDDS in rabbits was conformed to a two-compartment model with a weight coefficient of 1/C~2.Compared with pure curcumin,the peak concentration(C_max)of Cur-SNEDDS was significantly increased（from 25.15±0.92μg/L to 51.64±0.90μg/L）,the mean drug residence time(MRT_0-t)was significantly prolonged（from 3.93±0.03 h to7.11±0.30 h）,and the relative bioavailability(AUC_0-t)was significantly improved（from106.47±0.79μg/（L·h）to 378.97±0.85μg/（L·h）,which was 3.5 times of pure curcumin）.The results showed that Cur-SNEDDS improved bioavailability by promoting drug absorption and prolonging drug residence time in vivo.A mouse model of intestinal mucosal immunosuppression and injury was established to study the pharmacodynamics of Cur-SNEDDS in vivo.Mice were randomly divided into normal control group,cyclophosphamide model group,levamisole hydrochloride positive control group,pure curcumin control group and low,medium and high doses（50mg/kg,100 mg/kg,200 mg/kg）of Cur-SNEDDS groups.Except for the normal control group,the other mice were injected intraperitoneally with cyclophosphamide（ATX）at 80mg/kg for three consecutive days.The mice were treated with levamisole hydrochloride,pure curcumin and different doses of Cur-SNEDDS for 14 days.The organ index,the number of Peyer’s nodes,MDA,SOD,SIg A,IL-2,IL-4 and IFN-γlevel and the pathological changes of spleen and small intestine were compared in different groups.The results showed that different dose groups of Cur-SNEDDS could improve the intestinal mucosal immunosuppression and injury of mice,the middle dose group exhibited the best effect,which was significantly better than that of the pure curcumin group,and exhibited no significant difference compared with the positive control group.The cellular inflammation model was established by Macrophage RAW264.7 cell which was stimulated by lipopolysaccharide（LPS）,the pharmacodynamics of Cur-SNEDDS in vitro was studied.The cells were divided into blank control group,LPS model group,dexamethasone positive control group,pure curcumin control group and Cur-SNEDDS（12.5,25,50,100μmol/L）experimental groups.The cytotoxicity was determined by MTT method,which proved that Cur-SNEDDS had no influence on cell viability.Then,the levels of pro-inflammatory factors（NO,TNF-αand IL-1β）in the cell supernatants of different groups were determined and compared.The results showed that compared with the model group,the level of pro-inflammatory factors in Cur-SNEDDS groups decreased,which was correlated with the concentration of Cur-SNEDDS.When the concentration of Cur-SNEDDS was 100μmol/L,the effect was significantly better than that of pure curcumin group,and equivalent to that of the positive control group.In conclusion,Cur-SNEDDS could significantly improve the bioavailability of curcumin,and exhibited better anti-inflammatory and therapeutic effects on intestinal mucosal immune suppression and injury,which could extend the clinical application of curcumin.