Synthesis And Application In Simvastatin Microemulsion Of α-tocopherol Polyethylene Glycol 1000 Succinate

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 high 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 had been prepared to enhance its absorption and to improve its bioavailability.Firstly, TPGS was synthesized with α-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 °C were determined to be 14.28 and 0.0225% (w /w) respectively. Antioxidation of TPGS was demonstrated in the study.A 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°C 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...