| Curcumin, a polyphenol of turmeric, is derived from the rhizomes of curcuma longa, which can suppress the tumorigenic activity of various cancers such as the colon, duodenum, esophagus, forestomach, stomach, liver, breast, leukemia, oral cavity and prostate cancer. Phase I clinical trial completed showed the safety and tolerability of curcumin in colorectal cancer patients. In spite of this huge potential of curcumin as an effective chemotherapy agent against colon cancer, it has poor systemic availability due to its low aqueous solubility, efficient first-pass effect and some degree of intestinal metabolism when administered via the oral route. In the present study, an attempt was made to improve the solubility and the target to colon of curcumin by formulating it in folate-modified self-microemulsifying drug delivery system (FSMEDDS) and filling the formulation into colon targeted capsules. Under conditions of colon fluid, curcumin loaded SMEDDS containing folate conjucted material can form a microemulsion, and then it can bind with folate receptor (FR) at the surface of colorectal tissues or colon cancer cells to increase the absorption in the colon or induce the endocytosis of curcumin FSMEDDS.The solubilities of curcumin in various vehicles (oil, surfactant and co-surfactant) were determined, and the excipients had high solubility for curcumin were used to construct the ternary phase diagrams. The formulation of curcumin-loaded SMEDDS (CUR-SMEDDS) was optimized with a simplex lattice experiment design. Based on the consideration of solubility for curcumin and mean particle size of formed microemulsion, the composition of optimized formulation was chosen as follows:57.5%surfactant (Cremophor EL),32.5%co-surfactant (Transcutol HP) and10%oil (Capryol90).Then, three lipophilic folate derivatives, folate-polythylene glycol-distearoyl-phosphatidylethanolamine (F-PEG-DSPE), folate-polythylene glycol-cholesteryl hemisuccinate (F-PEG-CHEMS) and folate-polythylene glycol-cholesterol (F-PEG-Chol) used as one of the surfactants was added to CUR-SMEDDS formulations, respectively. The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of57.5%Cremophor EL,32.5%Transcutol HP,10%Capryol90and a little amount of F-PEG-CHEMS (the weight ratio of folate materials to Cremophor EL was1:100).CUR-FSMEDDS can be turned into microemulsion when diluted with distilled water and the droplets were spherical under transmission electron microscope (TEM), the average particle size was31.1±0.99nm and zeta potential was-6.56±0.49mV. CUR-FSMEDDS was filled into colon targeted capsules and the in vitro release results indicated the obtained formulation of CUR could reach colon efficiently and release drug immediately.Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the FR on the surface of HT-29and Hela cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. All of the results showed that FSMEDDS filled in a colon targeted capsule was a potential carrier for colon delivery of curcumin.In the pharmacokinetic studies of curcumin, HPLC was used to determine the concention of curcumin in the plasma. Pharmacokinetic parameters were obtained using the DAS2.0software, including area under the curve (AUC), mean residence time (MRT) and plasma half-lives (t1/2) for the elimination phase. The t1/2of CUR-FSMEDDS after oral administrating in rats exhibited much longer plasma half-lives (8.3h) compared to the CUR-SMEDDS formulation (6.2h). The relative bioavailability of CUR-FSMEDDS to CUR-SMEDDS formulations was149.2%, indicating the oral absorption of the formulation was enhanced by the addition of folate derivatives. |
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