| Curcumin is a yellow polyphenol compound extracted from the rhizomes of Curcuma longa and has been studied for its activities such as anti-inflammatory, anti-oxidation and anti-infection effect. Curcumin as anti-cancer drug can treat breast cancer, colon cancer and cervical cancer by a series of biological functions, such as inducing the apoptosis of turner cells, surpressing the expression of oncogenes and inhibiting the tumor angiogenesis. However, curcumin is insoluble in water and unstable in strong acid or alkaline environment, furthermore it can occur biotransformation upon intestinal absorption.The methoxy poly(ethylene glycol)-poly(lactide) (mPEG2ooo-PLA2ooo) and D-a-tocopherol polyethylene glycol 1000 succinate (TPGS) were used to prepare curcumin-loaded mPEG2ooo-PLA.2000/TPGS mixed micelles by thin film diffusion method. To get the optimal prescription of high drug-loading and stability, single-factor experiments such as dosage of curcumin, mass ratio between mPEG2ooo-PLA2ooo and TPGS, volume of hydration medium and hydration temperature were studied with drug-loading, entrapment efficiency and precipitated drug as indicators. The uniform experimental design and response surface method were also performed to further optimize the preparation technology. Then the micromophology, particle size, zeta potential, critical micelle concentration and dilution stability were investigated to evaluate the characteristics of micelles. The in vitro release behavior of curcumin-loaded micelles was determined using dialysis bag method. The intestine absorption properties of cucumin-loaded micelles was studied by in situ perfusion experiments, moreover, the mechanism of absorption and main absorption site were obtained. The quantitative methodology of curcumin in animal plasma and tissues were established in this study. After oral administration, the in vivo pharmacokinetics and distribution of curcumin in tissues were measured.The optimal presription was received that curcumin was 6mg, the mass ratio between mPEG2000-PLA2000 and TPGS was 4:1, the volume of hydration medium was 5ml and the hydration temperature was 25 ℃. The optimized curcumin-loaded mPEG2000-PLA2000/TPGS mixed micelles showed high drug-loading (16.1%), low precipitated drug (4.0%), spherical shape, small size (46.0 nm), weak positive electricity (+0.613 mV) and low critical micelle concentration (0.0054 g/L). The micelles displayed small change of drug content in 6h after dilution by artificial gastric fluid within 500-times and artificial intestinal fluid within 1000-times. The curcumin-loaded micelles showed a slow release behavior in artificial gastrointestinal fluid, which was benificial to the sustained drug release in intestinal tract.The intestine absorption was studied using in situ perfusion experiments. At low, middle and high doses, the absorption of curcumin-loaded mPEG2000-PLA2000/TPGS mixed micelles all showed first order kinetics properties. The relevant absorption rate constants (Ka) were 0.1310 h-1,0.1198 h-1 and 0.1357 h-1 separately. The result of T test indicated that Ka values had no significant difference (P>0.05), meaning that curcumin-loaded micelles were absorbed via passive diffusion method. The absorption percentages of curcumin-loaded micelles in duodenum, jejunal, ileum and colon were (21.45±2.13)%, (8.07±2.85)%, (14.89±8.75)%and (9.70±5.65)%. respectively, and duodenum was the main absorption segment.The HPLC methodology was established to determine the curcumin concentration in plasma. With curcumin suspension as control, the in vivo pharmacokinetics of curcumin-loaded mPEG2000-PLA2000/TPGS mixed micelles was investigated in rats. The results showed that the peak concentration and mean retention time of curcumin-loaded micelles were 7.7 fold and 2.1 fold these of control group, and the relative bioavailability of micelles was 927.3%. The micelle system improved the in vivo pharmacokinetics of curcumin and promoted the drug absorption in gastrointestinal tract.With curcumin suspension as control, the distribution of curcumin-loaded mPEG2ooo-PLA2ooo/TPGS mixed micelles in tissues was studied in mice. After oral administration with curcumin-loaded micelles, drug was mainly distributed in spleen, lung and kidney tissues. The drug concentration in liver, spleen, lung, kidney were all higher than these of control group, moreover, the micelle solution decreased the drug accumulation in heart and reduced the side effects towards heart. |
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