Development Of Curcumin Phospholipid Complex/Tween Mixed Micelles

Curcumin is a hydrophobic polyphenol and derived from the rhizome of Curcuma longa,which has long been used as pharmaceutical/food resource in China,India and other countries.It has found that curcumin possesses diverse pharmacologic effects,including anti-inflammatory,antioxidant,anti-infection etc.It is able to prevention and treatment various chronic diseases such as hyperglycaemia,and high blood pressure.It has concluded that curcumin is safe even at high dosages in humans.However,the pharmacological potential of curcumin is hampered by its low solubility,stability and bioavailability.In this study,the curcumin phospholipid complex was prepared by the solvent evaporation method and the physical and chemical properties of curcumin was remoulded.The reaction conditions were investigated by single factor method with recombination rate as indicator,the optimal prescription was with anhydrous ethanol-chloroform mixed solvent(volume ratio was 3:4)as reaction solvent,the ratio of curcumin to phospholipids was 1:5(W/W),drug reaction concentration was 1.5 mg/mL,reaction temperature was 55?,reaction time is 3 h,the curcumin phospholipid complex recombination rate was 96.4% eventually.The curcumin phospholipid complex could dissolved in hexane,indicated that the physical and chemical properties of curcumin had changed;the complex was characterized by Fourier transform infrared Spectrum(FT-IR),Ultraviolet spectroscopy(UV)and fluorescence detection,the results showed that curcumin and phospholipids did not form a new compound,but connected by hydrogen bonds or molecular inter-atomic forces;Differential scanning calorimetry(DSC)spectrum showed that curcumin exists in amorphous form in the phospholipid complex.The curcumin phospholipid complex and Tween 80 were utlized to prepare curcumin phospholipid complex/Tween 80 mixed micelles by the thin film hydration method.With drug solubilization and drug loadings as the examining index,mixed micelles preparation conditions was investigated by single factor method,and different kinds and concentrations precipitation inhibitors were added in hydration liquid at the same time.The optimal prescription was the ratio of curcumin phospholipid complex(curcumin 10 mg,phospholipid 50mg)to Tween 80 was 1:1,thehydration volume was 2.5mL,the hydration time was 1h,the temperature was 37 ? and the concentration of precipitation inhibitors(HPMC E15)in the aqueous solution was 3mg/m L.Studying on the physicochemical properties of mixed micelles,micelles were spherical,particle size was 144.6 nm and PDI 0.147,and the zeta potential was-41.6 mVDSC.showed that the drug exists in amorphous form in the mixed micelles;with change Tween 80 amount and determine the micelle structure through fluorescence spectrum,the non-polar end of Tween 80 and phospholipids were linked together forming a bilayer structure,curcumin was connected with polar end of phospholipid forming the hydrophobic core,the polarity around curcumin was decreases and the fluorescence intensity was enhanced,the strongest absorption wavelength was blue shift.The mixed micelles was diluted different times in different p H,ionic strength solution,the particle size can still remain unchanged;with the pH,light and temperature conditions change,the UV spectrum form of drug in micelles was unchanged and the stability of drug improved significantly than active drug.The in vitro release of liquid micelle was studied and the results showed that the release content of curcumin was significantly increased than the original drug.The solid state mixed micelle was prepared by the decompression drying method.The types of curing agent,curing morphology,drug recovery,micelle particles dispersion were examined and the A200 was chosen as the optimized curing agent.The solid preparation was powder,the drug had less amount adsorption on curing agent,and the particle size dispersion was good after hydration,which was favorable for long time preservation and divided dose use.The accelerated test results showed that the stability of solid micelles was good.The in vitro dissolution test indicated that with the pH increase the drug dissolution speed was accelerated and can sustain release in solid micelle containing HPMC E15,when without HPMC E15 the dissolution rate was decreased at higher p H.The result indicated that the HPMC E15 could maintain the drug saturation state and prolong the stable time of preparation.In vitro cell experiments were use the HepG-2 cell lines as cancer cell model,L-02 as normal cell model to test the cell toxic effects of drug and carriers by MTT experiment.The results showed that the drug had an inhibitory effect on the growth of cancer cells and normal cells,and there was a dose and time dependence.Drug preparation into mixed micelles cannot specific recognition of cells.It was conclued that the sensitivity of curcumin on cells is HepG-2 cells > L-02 cells.Phospholipids could provide nutrients for cell growth;the carrier material containingTween 80 had a toxic effect on cancer cells and no toxicity to normal cells.The cell uptake was studied by using the fluorescence properties of curcumin,and the uptake ability of different cells was determined by intracellular fluorescence intensity;With extended time,the intracellular drug fluorescence intensity gradually increased,observed that more drugs amount of cell uptake in Hep G-2 cells than in L-02 cells;the capability of different drug formed into cells was mixed micelles > phospholipid complex >free curcumin,indicated that curcumin in mixed micelles was conducive to the drug absorption into cell.The HPLC methodology was established to determinate the curcumin concentration in rat plasma.With curcumin suspension as control,examines the rats lavage with Tween 80 in curcumin suspension,curcumin phospholipid complex,curcumin solid mixed micelle(with and without HPMC).Pharmacokinetics results showed that Tween 80 can promote the absorption of drugs;the drug maximum concentration increased significantly and removed rapidly of curcumin phospholipid complex,indicated that phospholipid complex can promote drug absorption,but the effect to prolong the drug residence time within the body was not obvious;the mixed micelle containing HPMC could increase the peak concentration and residence time of the drug in vivo significantly than that without HPMC,oral bioavailability was 32.78 times of curcumin suspension.The results showed that the mixed micelle system could improve the pharmacokinetics of curcumin and increase the drug absorption and utilization.