The Study Of Osmotic Pump Controlled-release Tablets Of Bezafibrate With Poor Water Solubility And Large Dosage

In this paper, bezafibrate was selected as the model drug to prepare effervescent osmotic pump controlled-release tablets. Sodium bicarbonate, sodium alginate and lactose were used as the main vehicle in tablet core. The effects of many factors including composition of tablet core and coating membrane, the condition of drug release on the in vitro release behavior of bezafibrate effervescent osmotic pump tablets were investigated. Based on the single-factor experiments, central composite design-response surface methodology was used to optimize the formulation. The product prepared according to the optimized formulation was proved to have the excellent zero-order release character in 6 h and good reproducibility of different batches. In addition, the results of stability experiments showed that this product was sensitive to humidity but was stable on other conditions.A new type double-layered osmotic pump (DOP) tablets were developed as a combination of various osmotic pumps, such as push-pull osmotic pump, elementary osmotic pump and monolithic polymer osmotic pump. Alkaline substance was added to change the microenvironment and polymer was used as drug carrier. Two layers of the osmotic pump system were both drug-containing, The first layer of the DOP was designed using elementary osmotic pump theory which involved vehicle such as sodium carbonate, sodium lauryl sulphate and sodium chloride, and the second layer was designed using monolithic polymer osmotic pump theory which consisted of polyoxyethylene oxide and sodium chloride. Orifices with the same diameter were drilled on both side membrane surfaces and the release rate was constant in 12 hours. The single factor tests were carried out on the proportion of bezafibrate, sodium chloride in two layers, respectively, the kinds and the amount of polyoxyethylene oxide, coating materials, procedure as well as the in vitro release condition, which affect the release behavior. The formulation optimized according to orthogonal experiment design was proved to have the excellent zero-order release character (r=0.9963).With the conventional tablets, sustained-release tablets as the reference, the relative bioavailability and pharmacokinetic study of bezafibrate effervescent osmotic pump controlled-release tablets were performed in six Beagle dogs. With crossover design, an HPLC method was employed to detect the drug concentration in plasma of dogs after the administration of single dose. The AUC_0-∞, T_max and C_max of conventional tablets, sustained release tablets and effervescent osmotic pump controlled-release tablets were as follows: (334.50±26.14), (319.32±21.80) and (321.49±22.62)μg·h·mL^-1; (1.33±0.41), (3.50±0.45) and (3.58±0.49) h; (79.91±7.33), (51.24±5.47) and (51.01±6.08)μg·mL^-1. The relative bioavailability was 96.1% and 100.7%, respectively. Bioequivalent judgment indicated that osmotic pump controlled-release tablets were bioequivalent with these two commercial dosage forms. The correlation of drug release behavior was studied according to deconvolution integral method. The results indicated that test formulation had good vivo-vitro correlativity (r=0.9126).