Study On Combined-release Pellets Capsule Of Carbamazepine

Study on combined-release pellets capsule of carbamazepineCarbamazepine is used clinically to treat seizeure disorders, trigeminal neuralgia, and most recently, manic depressive illness. It's therapeutic range is very narrow (4～12μg·mL^-1). Many side effects would come if the plasma concentration fluctuated frequently. In this study, the aim was to reduce the fluctuation of the blood level of carbamazepine, and to improve the compliance of patients. The immediate-release (IR) pellets, the sustained-release (SR) pellets and the pulsatile pellets of carbamazepine were prepared. The mixture of the three kinds of pellets was to provide steady and consistent blood level of carbamazepine.Ultraviolet spectrophotometry was utilized to determine the content of carbamazepine in pellets, and to assay the dissolution of IR pellets and release of SR pellets and pulsatile pellets. The concentration of carbamazepine in the dog plasma was determined by high-performance liquid chromatography (HPLC).The IR pellets were prepared by centrifugal granulation technology. With low-sustituted hydropropyl cellulose (L-HPC) as diluents and hydropropyl methyl cellulose (HPMC) as adhesive, the formulation was optimized. The yield of the objective pellets (20～24 mesh cut) and the dissolution rate were investigating factors. The suitable process parameters were obtained by orthogonal design. The IR pellets of the optimized formulation and process parameters had much fast dissolution rate, less friability, better sphericity and higher yield.In fluid bed, the IR pellets were coated with Eudragit NE 30D to prepare the SR pellets. With the accumulative percentages of carbamazepine as index, central composite design was used to optimized these two screened factors, the coating level of Eudragit NE 30D and lactose. The release rate of the SR pellets made based on the optimizing coating formulation met the standard of the sustained release tablets of carbamazepine in USP 29.The pulsatile pellets were coated with an inner layer of the combination of L-HPC and sodium dodecyl sulphate (SDS), and an outer layer of Surelease. The coating levels of L-HPC, SDS and Surelease were studied, and achieved the optima formulation of coating.Consequently, the lag time of the pulsatile pellets was 6 hours, and release span was about 6 hours.The combined-release pellets should be packaged with protection from light, and be stored below 40℃, according to the study of influential factors.Pharmacokinetics studies of carbamazepine combined-release pellets capsule in dogs were performed by two-treatment, two periods, randomize, crossover design. The reference formulation was commercial common tablets. In this study, AUC_0-t of the test formulation and reference formulation were 25.76±9.9μg·h·mL^-1 and 22.12±4.8μg·h·mL^-1, and relative bioavailability was 101.8±9.2%. T_max and C_max of test formulation and reference formulation were 3.80±1.2h and 1.42±0.4h, 3.11±1.0μg·mL^-1 and 4.27±2.05μg·mL^-1, respectively. Thus, the test formulation and reference formulation had absorption level bioequivalence, and the test formulation had sustained release characteristic.