Bifendate Saturated Since Microemulsion

Biphenyl dimethyl dicarboxylate (BDD) is an intermediate compound of schisandrin C synthesis discovered in China. Clinical experiences have shown that BDD possesses the therapeutically effect for Chronic hepatitis B by protecting the hepar and lowering the glutamic-pyruvic transaminase (GPT). In vitro the poor solubility of BDD (3.2μg·mL^-1, 37°C) leading to its lower dissolution and lower oral absorption in vivo. To improve its dissolution in vitro and bioavailability in vivo, we propose to develop a supersaturated self-microemulsifying drug delivery system (S-SMEDDS) for BDD. Firstly the optimum formulation was screened by drawing a pseudo-ternary phase diagram for the domain area of microemulsion and supersaturated additive was also selected to restrain the precipitation of BDD which was evaluated by self-emulsifying efficiency and dissolution. The dissolution in vitro and bioavailability in vivo were assessed comparing to the domestic reference (drop pills) and the abroad reference (SMEDDS sofgel). The stability of S-SMEDDS formulation was also investigated.The research concluded as follow.The HPLC method for BDD determination in vitro was established. It has good linear relation between the concentration of 1μg·mL^-1 and 50μg·mL^-1 that can be used for the BDD assaying of BDD-S-SMEDDS soft capsules. The HPLC method for related substance of BDD also was set up. The results showed that the method was sensitive, accuracy and reproducible to consistent with requirement of standard examination.The partition coefficient of BDD in 1-octanol/water, 1-octanol/0.1NHCl, 1-octanol/PBS was 3.21, 3.27 and 3.29 respectively, illustrated BDD had fairly strong liposolubililty. The solubility of BDD was measured in various materials such as surfactant, cosurfactant and oil phase. After screening the suitable ingredient, the optimum formulation was screening by drawing a pseudo-ternary phase diagram. Different kinds of supersaturated additives were selected as precipitation inhibitor. The optimum was assessed according to precipitation inhibiting, self-emulsifying time, particle size and Zeta potential. The BDD-S-SMEDDS spontaneously formed a stable microemulsion upon diluted with 50-fold water, whose particle size and Zeta potential is (38.40±0.28) nm and (-8.00±0.99) mV respectively.The HPLC method for BDD dissolution in vitro was established. It has good linear relation between the concentration of 0.05μg·mL^-1 and 10μg·mL^-1 that can be used for the dissolution assaying of BDD-S-SMEDDS. The dissolution curve was similar in water with the first method and second method of CHP. BDD released in 0.1NHCl was faster than that in water. So the second method of CHP and water was selected as dissolution method of BDD-S-SMEDDS products. BDD-S-SMEDDS and Korea SMEDDS products dissolved more than 80% within 30min, much faster than the market drop pills.The HPLC method for BDD plasma concentration in vivo was established. The plasma concentration in beagle dogs was used for the bioavailability assessment with the market drug pills and the Korea SMEDDS product as the reference. The pharmacokinetic data indicated BDD-S-SMEDDS had a 2.03-fold higher AUC_0-t than the market drug pills in the first trial, and achieved a similar absorption with the Korea SMEDDS product. In the second trial, the data indicated that BDD-S-SMEDDS had a 4.43-fold higher C_max (329.66±110.01μg·L^-1) and a 2.47-fold higher AUC_0-t (935.91±358.09μg?h·L^-1) compared to the market drug pills. The analysis of T test illustrated that there were significantly different C_max and AUC_0-t between the BDD-S-SMEDDS and drug pills. The T_max of above-mentioned preparations had no significant difference. BDD-S-SMEDDS can remarkably improve the bioavailability of BDD.Three batches of BDD-S-SMEDDS soft capsules were investigated for stability studies. The results of strong test indicated BDD-S-SMEDDS should be kept avoid high temperature, illumination and moisture. Products were stable after accelerated test for 6 months and long-term ambient temperature for 12 months. The appearance, particle size, content, dissolution and related substance did not have obviously distinction from the start month.In conclusion, a supersaturated self-microemulsifying drug delivery system (S-SMEDDS) for BDD was developed. The formulation significantly improved the dissolution and bioavailability of BDD and decreasing the amount of surfactant to some extent. It also promoted the stability of BDD-SMEDDS. The product had the feasible preparing technology, controlled quality and steady property. Also, it is easy to take and carry.