Function And Evaluation Of TPGS In Simvastatin Microemulsion And Self-Microemulsifying Drug Delivery System

Alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of natural-source vitamin E, has been extensively applied at abroad as a pharmaceutical excipient, such as solubilizing agent, absorption enhancer, emulsifier, plasticizer and vehicle for controlled drug delivery application. With its suitable HLB and nontoxicity, TPGS could be used as a good surfactant in oil-in-water microemulsion safely and effectively. In this study, choosing poorly water-soluble simvastatin (SV) as a model drug, thermodynamically stable simvastatin microemulsion and self-microemulsifying drug delivery system had been prepared to enhance its absorption and to improve its bioavailability.Firstly, TPGS was synthesized withα-tocopherol succinate (VES) and polyethylene glycol 1000 (PEG 1000) by DCC/DMAP esterification. In order to improve the reaction yield, process parameters such as molar ratio of VES to PEG 1000, amount of catalyst, reaction time, amount of solvent and reaction temperature were investigated, synthesis process of TPGS was optimized by means of orthogonal design, and the average yield of 86.7% was achieved. Structure of TPGS was identified through analysis of TLC, HPLC, IR and ¹H-NMR.Then, physico-chemical properties of TPGS, such as solubility, acid value, HLB, CMC, cloud point and viscosity, was studied. HLB and CMC of TPGS at 25℃were determined to be 14.28 and 0.0225% (w/w) respectively. Antioxidation of TPGS was demonstrated in the study.HPLC method was developed for assay of SV and in vitro release of SV microemulsion. Stability of SV had been rudimentarily investigated. The results showed that SV exposed to air and exposed to 60℃were unstable, and SV would suck up moisture when it was exposed to high humidity.To identify the microemulsion region, pseudo-ternary phase diagrams were constructed to investigate the effects of oils, cosurfactants, mass ratio of TPGS to cosurfactants, additives and preparation temperature on SV microemulsion. Orthogonal experiment based on main influencing factors was carried out by taking area of microemulsion region in the diagram as main evaluating indexes. And the optimum formulation and preparation process of SV microemulsion were established. The in vitro release behavior of microemulsion was rudimenarily investigated by bulk-equilibrium reverse dialysis bag technique.Physico-chemical properties of SV microemulsion were investigated. The result showed that viscosity was 1.296×10^-2 Pa·s, interfacial tensions was 41.97×10^-3 N·m^-1, phase inversion temperature was 85℃, mean particle size was 22.8±3.2 nm. After storing 1 month at 4℃, 25℃and 30℃, the content of SV, appearance and mean particle size of SV microemulsion were studied and the results proved that SV microemulsion was very stable thermodynamically.To identify the SMEDDS region, pseudo-ternary phase diagrams were constructed to investigate the effects of oils, cosurfactants, mass ratio of TPGS to cosurfactants, additives on SV self-microemulsifying drug delivery system. Orthogonal experiment based on main influencing factors was carried out by taking area of microemulsion region in the diagram as main evaluating indexes. And the optimum formulation and preparation process of SV SMEDDS were established. The in vitro release behavior of SV self-microemulsifying drug delivery system was rudimenarily investigated by bulk-equilibrium reverse dialysis bag technique.Physico-chemical properties of SV self-microemulsifying drug delivery system were investigated. The result showed that interfacial tensions was 36.04×10^-3 N·m^-1, phase inversion temperature was 85℃, mean particle size was 23.8±4.2 nm. After storing 3 month at 4℃, 25℃and 60℃, the content of SV, appearance, the time of self-microemulsifying and mean particle size of SV self-microemulsifying drug delivery system were studied and the results proved that SV self-microemulsifying drug delivery system was very stable thermodynamically.Finally, the in vivo pharmacokinetics behavior of SV microemulsion in Beagle dogs was investigated and the results were compared with commercial SV conventional tablet. A RP-HPLC method was established to determine the concentration of SV and its active metabolite SVA in dog plasma, and results showed that the plasma concentration of SVA were higher than that of SV. According to SVA concentration, T_max of microemulsion, self-microemulsifying capsules and reference tablet were 1.41, 1.50 and 2.65 h, C_max were 60.60, 58.32 and 23.21 ng·mL^-1 respectively. Comparing with conventional tablet, the AUC_{0～∞} of SV microemulsion increase from 103.22 to 195.5 ng·mL^-1; the AUC_{0～∞} of SV self-microemulsifying capsules increase from 103.22 to 200.14 ng·mL^-1. Therefore SV microemulsion and self-microemulsifying drug delivery system could promote the absorption of SV and improve the bioavailability, which suggests that SV microemulsion and self-microemulsifying drug delivery system might be promising preparation.