Studies On The Self-Mcroemulsifying Drug Delivery System

The oral delivery of hydrophobic drugs presents a major challenge because of the low aqueous solubility of such compounds, which leads to poor oral bioavailability. Self-microemulsifying drug delivery systems(SMEDDS), which are isoreopic mixture of oils, surfactants and/or co-surfactants, can be used for the design of formulation in order to improve the oral absorption of lipophilic drug compounds. In our research, testosterone undecanoate(TU) and silymarin were chosen as the representatives, two different kinds of SMEDDS were prepared and evaluated both in vitro and in vivo.First,TU-SMEDDS was developed by combination of two nonionic surfactants as emulsifier. In the study of formulation, the equilibrium solubility of TU in different oils and surfactants was determined by reverse-phase HPLC;Emulsifying efficiency was used to select compatible oil and surfactant, Octulanddecylgycerate was chosen as oil phase;A fine SMEDDS could be obtained not by using single surfactant, but by Combing two nonionic surfactants, Tween 85 and Cremophor EL. With the amount of oil phase and Km(the weight ratio of two surfactants) as independent variables, the optimized formulation was determined by central composite design-response surface methodology. The response variables were emulsifying time, transparency of emulsion and drug content. The optimized formulation was quickly and conviently obtained as TU 11%, ODO 50%, Tween85/Cremophor EL=4.Diluted 100 times with H₂O, the average droplet size of blank and TU microemulsion were 53.0nm and 69.3nm, respectively. Different medium and drug content didn't have great effect on the droplet size, TU microemulsion was stable in 24 hours. The system was sensitive to light, and should be stored avoiding light.The pharmacokinetic prameters of TU-SMEDDS, Andriol(?) and raw material were investigated after oral administration to rats at a single dose of 200mg/kg. The results were as follows: C_max was 2.27±0.18,1.77±1.45,0.09 nmolml^-1, respectively;AUC_0-∞ was 8.79±1.96,9.12±5.76,0.15nmolml^-1*h,respectively.In the study of formulation of silymarin SMEDDS, the octanol-water partition coefficient and the equilibrium solubility of TU in H₂O, different oils,surfactants andco-surfactants were investigated by reverse-phase HPLC. The results indicated that silymarin was a middling lipophilic compound, which has high solubility in co-surfactants, thus a kind of SMEDDS with co-surfactants was chosen. Pseudo-ternary phase diagrams were construct to select co-surfactants and determined the region of microemulsion. An optimized formulation consisted ODO as oil phase, Cremophor RH40 as surfactant and Transcutol P as co-surfactant, concretely Silymarin 12.5 %, ODO 12.5 %, Cremophor RH40 45 %, Transcutol P 30 %.The average droplet size of silymarin microemulsion was 18.8nm. microemulsion kept stable in 8 hour. In vitro dissolution demonstrated the cumulative dissolution of SMEDDS was above 80% in 10 minutes, while it was just 10% in 60 minutes with tablet, indicating that SMEDDS can greatly improve the dissolution of silymarin. The system was sensitive to heat, it should be kept at room temperature or below.The pharmacokinetic prameters of Silymarin SMEDDS and raw material were investigated after oral administration to rats at a single dose of 80mg/kg. The results were as follows: Cmax was 14.62±2.42, 5.75±1.23 ug-mT1, respectively;AUQo-x) was 83.60±11.02, 36.00±5.90ug-mr1*h, respectively. The C^ and Ka of SMEDDS group was remarkably high than that of raw material group(P<0.05), the relative bioavailability was 232.2%. Thus SMEDDS could improve the rate and extent of drug absorption.