Study On β-elemene Loaded Active Targeting Microemulsion Drug Delivery System Mediated By Folate Receptor

Folate receptor-mediated microemulsion formulation of active targeting in recent years is one of the keys. This selection ofβ-elemene as a model drug were prepared ofβ-elemene emulsion, and the pseudo-ternary phase diagram of the prescription, process inspection, and the best optimized microemulsion formulation. Final optimized microemulsion formulation whose diameter is 38.3±4.3nm is:β-elemene 1%, Labrafac cc 7%, SbPC8%, HS-15 8%,1,2-propanediol 16%, containing 0.1% sodium bisulfite and pH 7.4 PBS buffer solution 60%. Transmission electron microscope as spherical microemulsion particle size is slightly smaller than the results of dynamic light particle size measured by DLS results. Room temperature for one month, preparations are in good stability.Synthesis of novel PEG derivatives:1,2-oil acyl phosphatidylethanolamine-polyethylene glycol-folic acid (FA-PEG2000-DOPE), using IR,1H-NMR, MS, DSC, UV, X-ray, SEM and other preliminary for the purpose of identification of product. P-elemene in the microemulsion based on the study. By using FA-PEG2000-DOPE to prepare folate receptor-mediatedβ-elemene active targeting microemulsion (FRT ME). Using particle size as the index prescription and investigating the impact of technology on preparation size to determine the optimal formulation. Final prescribtion is P-elemene 1%, labrafac cc 7%, SbPC8%, FA-PEG2000-DOPE, phospholipid molar ratio for the 1%-2%, HS-15 8%,1,2-propanediol 16%, with 0.1% sodium bisulfite pH 7.4 PBS buffer 58%-59%. Diameter of folate receptor-mediatedβ-elemene microemulsion is 42.5±6.3nm. Transmission electron microscope used as spherical microemulsion particle size distribution.Analysis of the microemulsion electrical conductivity, viscosity, density, surface tension and different particle size and other physical and chemical properties of their quality.β-elemene on microemulsion and folate receptor-mediated P-elemene emulsion for active targeting in vitro release pharmaceutical. Containing 0.5% HS-15’s PBS7.4 buffer saline solution, the release is:Drug-loaded 1:7 ME:81.82%, Drug-loaded 1:4 ME:92.71%, FRT 1:7 ME:89.11%, FRT 1:4 ME:89.90% in 24h respectively. The microemulsion were not released completely, showing that the microemulsion has a sustained-release capability.Wistar rats were studied using the FRT ME ME and pharmacokinetic parameters in vivo. FA-PEG2000-DOPE P-elemene emulsion of the drug in rats in vivo pharmacokinetic parameters. Commercial P-elemene emulsion t1/2 is 0.131h, the t1/2 of 1:7 ME and 1:4 ME was 0.272 h and 0.219 h, respectively,2.08 and 1.69 folds compared to the commercial emulaion. The t1/2 of the FA-PEG2000-DOPE modified FRT 1:7 ME and FRT 1:4 ME was 0.344 h and 0.303 h,2.62 and 2.31 folds compared to the commercial emulaion..1:7 ME and 1:4 ME’s MRTO-t, MRTO-oo commercial emulsion group were 2.31 folds and 1.69 folds and 2.31 folds,1.56 folds; FA-PEG20oo-DOPE modified and FRT 1:7 ME and FRT1:4 ME’s MRT0-t, MRTO-∞were,3.355 folds,2.55 folds and 4.01 folds,3.81 folds compared to the commercial emulsion. That FA-PEG2000-DOPE modifiedβ-elemene microemulsion can significantly extend theβ-elemene elemene in vivo circulation time, proved to effectively reduce the P-elemene side effects on the human body to achieve the purpose of safe use.The distribution of tissue in Tumor-bear mice indicated that FRT 1:7 ME increased the amount ofβ-elemene in tumor. AUC0-2 shows that FRT 1:7 ME dramatically improved the AUCo-2 ofβ-elemene in tumor, which is 1.99 folds on 1:7 ME.Folate receptor-mediatedβ-elemene microemulsion in vitro targeting, the targeting mechanism was discussed. MTT method using the active targeting of different prescription and microemulsion on KB cells in vitro cytotoxicity in calculating IC50 values. The IC50 values of 1:7 ME,1:4 ME, FRT 1:7 ME, FRT 1:4 ME were:515.2μg·mL-1,564.8μg·mL/1,445.3μg·mL-1,472.5μg·mL-1. The results show that theβ-elemene microemulsion on the KB cell cytotoxicity than FA-PEG2ooo-DOPE-modified microemulsion small. Free solution by adding folic acid can reduce the folate receptor-mediatedβ-elemene emulsion cytotoxicity to prove that folic acid receptor-mediatedβ-elemene microemulsion mainly achieved through folate-mediated active targeting. Flow cytometry cell folate-mediated binding and internalization of microemulsion results show that, KB cells FA-PEG2ooo-DOPE-modified the drug combination and internalization of the microemulsion is greater thanβ-elemene microemulsion. Inferred FA-PEG2ooo-DOPE is mediated by folate internalization by endocytosis.