Study On Simvastatin Self-microemulsifying Drug Delivery System

Simvastatin,an inhibitor of HMG-CoA deoxidization enzyme,has been used as a kind of highly effective therapeutic agent for hypercholesterolaemia.Now,domestic simvastatin is marketed in dosage forms of capsules,tablets and dripping pills.Due to its poor water solubility and poor absorption after p.o.adminstration,low bioavailability limits its clinical therapeutic effect.In recent years,much attention has been paid to self-microemulsifying drug delivery system(SMEDDS) to improve the bioavailability of poorly soluble drugs.In this study,simvastatin SMEDDS was prepared to improve its bioavailability.In the first part,pseudo-ternary phase diagrams were prepared by titrating the mixture of oil,surfactant and cosurfactant with distilled water in 37℃water bath., ethyl linoleate,median-chain glycerides and 2-monolinolein were used as oil phase, tween-80 as surfactant and ethanol,isopropanol,1,2-propanediol,glycerol, di(ethylene glycol) ethyl ether and PEG 400 as cosurfactants,respectively.The results showed that the self-emulsifying region area in the diagrams for the systems using ethyl linoleate as oil phase was bigger than those systems using mean-chain glyceride and 2-monolinolein as oil phase under same conditions.The self-emulsifying region aera and gel aera in the diagrams for the systems using PEG 400 or propanetriol as cosurfactants was bigger than those systems using other cosurfactants under same congditions.Both of them have infinite dilution area from Km of 1:6 to 6:1.The infinite dilution area for the systems using propanetriol was bigger than the systems using PEG 400 under same Kin.But when use glycerol as cosurfactants,there was a turbid area before adding water.In the second part,simvastatin SMEDDS formulation was screened and the basic characteristics were studied.The optimum SMEDDS formulation was composed of ethyl linoleate,tween80,PEG400 and vitamin E.The stability and self-microemulsified ability of SMEDDS was good after 90 days of storage at 37℃, room temperature and -4℃.Diluted by various solvents,the particle size change little.Usually the SMEDDS were designed as single dose capsules.In this study we make simvastatin into the soft capsule.The soft capsules have been stored under stress testing conditions:light illumination(4500±500 Lx),high humidity(RH75%, RH92.5%) and heat(40℃) for 5 days and 10 days.The results showed that the appearance and drug content of the capsules under strong light and high humidity did not change obviously.But for the capsules stored under 40℃,the content turned turbid and drug content decreased.The soft capsule was not stable under high temperature and it should be stored under low temperature.In the third part,the pharmacokinetics of self-microemulsifying drug delivery system of simvastatin(SV-SMEDDS) was evaluated in beagle dogs.Plasma simvastatin was determined by RP-HPLC with solid-phase extraction using Waters OASIS^? HLB cartridge.The pharmacokinetics of SV-SMEDDS was evaluated after a single oral dose of 40 mg of simvastain in a two-period crossover experiment design compared with simvastatin suspension(SV-Sus).The pharmacokinetics of both SV-SMEDDS and SV-Sus can be fitted to two-compartment model.SV-SMEDDS showed slightly shortened peak time and increased peak concentration of simvastatin with t_max of 0.84±0.26 h and C_max of 39.73±9.11 ng·mL^-1,while SV-Sus showed t_max of 0.99±0.32 h and C_max of 28.54±7.76 ng·mL^-1.AUC_{0→∞} of simvastatin SMSDDS was 184.84%that of simvastatin suspension.SMEDDS is able to increase the absorption and bioavailability of simvastatin.