Research Of Casein Solid Self-emulsifying Drug Delivery Systems (SEDDS) For Improving Oral Bioavailability

The casein is a kind of natural surfactant which is non-toxic and nonirritant compared with normal surfactant. The solid self-emusifying drug delivery system(SSEDDS) is more stability and portability than liquid self-emusifying drug delivery system(LSEDDS). SSEDDS can increase the solubility of the drug and improve the bioavailability. Simvastatin can control the content of cholesterol and prevent cardiovascular disease efficiently. Simvastatin is a kind of poorly water soluble drug, the oral bioavailabilty is less than 5 %.In this paper, we use casein as surfactant, select the proper oil, prepared simvastatin SSEDDS which is stability and good solubility successfully. We have finished the research work as follow:(1) We have established the HPLC method for the detection of simvastatin and simvastatin acid simultaneously. Simvastatin and simvastatin acid had a good linear relationship in the scope of 0.3-50μg·mL^-1, the solution is stability. This method is accurate and can satisfy the requirements for the analysis of pharmaceutical process.(2) We have selected the oil phase, the concentration and pH of casein solution, the water solubility carrier and the drying processing. The combination of Capryol 90 and Maisine 35^-1 (1:1 proportions) was used as oily phase. The concentration of casein is 50mg?mL^-1, pH is 6.0. We prepare liquid microemulsion by microjet technology, then we transform LSEDDS to SSEDDS by Spray-drying technology. The solid self-emulsifying power is stability and have good redissolved ability.(3) We have researched the in vitro release of SSEDDS. The dissolution experiment indicate that the release amount and speed of SSEDDS is improved significantly than tablet. The experiment of everted intestine indicate that the water soluble carrier is bad for the absorb of the drug.(4) We have established the LC-MS/MS method for the detection of simvastatin and simvastatin acid simultaneously. Simvastatin and simvastatin acid had a good linear relationship in the scope of 0.1 ng·mL^-1-50 ng·mL^-1. The recovery of simvastatin is 70-80 %; the recovery of simvastatin acid is 65-75 %. The coefficient of variation of inter-day and intra-day samples of high, medium and low concentration of simvastatin and simvastatin acid are less than 10 % respectively, the accurate and stability are both well, this method can meet the requirement of the biological samples.(5) We have researched the pharmacokinetic of different formulation. We detected the concentration of drug of in the plasma at the different time point after intragastric infusion to rats, the tablet is the reference formulation. We find that the bioavailability of raw material drug is the lowest, the bioavailability of casein SSEDDS with water soluble carrier is almost the same as tablet. The bioavailability of casein SSEDDS without water soluble carrier is the highest. The relative bioavailability of simvastatin is 184.08 %, simvastatin acid is 284.53 %. The casein SSEDDS can promote absorption of simvastatin, improved the bioavailability of simvastatin.