Preparation Of Ursodeoxycholic Acid-phospholipid Complex In Vitro And In Vivo Characteristics

The phosphatide complex is a new drug delivery system, through the strength of the weak key such as Van De Waal's force, hydrogen key, drug combines with phospholipids. After combination, the solubility of drug is strengthened; its crystallization nature also changes, which leads to the improvement of absorption and the activity of pharmacology.UDCA is poorly soluble in water ,compares with Ursofalk (made in Folk), the civil marketable capsule performs bad in the clinical application, it is due to the difference in dosage forms .Therefore, this subject plans to take some relevant studies on the UDCA—phosphatide complex.Phospholipids are an important component of cell membrane, having the actions of keeping cell membrane fluidity and treating hepatic disorder. It is expected that UDCA combined with phospholipids might result in the increase of oral bioavailability and improvement of the biological effects. To take the advantages of phospholipids complex, we studied UDCA-phospholipids complex to improve oral bioavailability of UDCA. The results are as following:1. In this paper, the preparation was optimizated by Central Composite Designe Methodology.The effects of three independence variables, phospholipid/UDCA, temperature, concentration of principal agent were evaluated. Response variables selected in the research was Compound rate. The data were transformed into desirabilities. Overall desirability was calculated from the geometric mean of the four desirabilities of each formulation. The binomial and linear equations were fitted to the data of overall desirabilities, and the resulting eqution was used to produce 3-D response surface graphs, though which optimal formulation were predicted.2. X-ray diffraction spectra indicated that the complex exhibited an amorphous characteristic; The thermodynamic properties of UDCA-phospholipids complex were studied by DSC, the profiles showed that a new physical phase appeared after combination, the transformation temperature changed (became lower); IR curves showed that phospholipids complex structure didn't change remarkably, It was neither a new compound nor a mixture, It was some kind of complex. Morphologic observation showed that the complexes were spherical vesicle when dispersed in water.3. The solubility and oil/water apparent partitions of UDCA and its phospholipids complex were investigated in different pH waters and n-octylalcohol. The result showed that the dissolve capacities and coefficient of UDCA phospholipids complex were markedly different from free UDCA. The research on the stability of the complex showed that the drug should be kept under the condition of dry air.4. The pharmacokinetic research of UDCA-phospholipids complex and Ursofalk in vivo:Procedures for sample preparation and HPLC determination of UDCA in blood serum were developed and validated. Cholic acid was used as an internal standard (IS). The bile acids and IS were captured using solid phase extraction (C₁₈ cartridges). The carboxylic group of the analytes was derivatized using 2 -bromo -2%-acetonaphthone (a detection-oriented derivatization), and reaction mixtures were analyzed with HPLC. The absorption research of UDCA -phospholipids complex and Ursofalk in rats was conducted to determine the oral absolute bioavailability. There was significant difference in AUC between them, the area of complex is 1.3 times as that of Ursofalk, and the results approved the speculation that the bioavailability of UDCA could be improved by combined with phospholi -pids.