Study On Compound Pseudoephedrine Hydrochloride Sustained-release Pellets

Naproxen sodium (NPS) is a non-steroidal anti-inflammatory drug (NSAID), pseudoephedrine hydrochloride (PSE·HCl) is an adrenergic agent (vasoconstrictor) for the relief of nasal congestion. The combination of these two agents is used in clinic to temporarily relieve cold, sinus and flu symptoms. The fixed dose combination of the rapid-release pellets of NPS and combined pellets of PSE·HCl was prepared. The latter Consist of rapid-release and sustained-release pellets.High performance liquid chromatography and ultraviolet spectrophotometry (UV) were developed for the measurement of drug physicochemical properties,accumulative release and the content of NPS and PSE·HCl in preparations.The NPS rapid-release pellets were prepared by extrusion-spheronization. The effects of independent process parameters on yield, roundness and friability of pellets were studied. Orthogonal design was used to optimize the technology of preparing. The NPS pellets presented perfect sphericity and friability and the accumulative release of NPS in 10 minutes was above 90%.The same method as that of NPS rapid-release pellets was used to prepare PSE·HCl rapid-release pellets. Eudragit^? RS30D was used as coating material to prepare PSE·HCl sustained-release pellets in a fluid-bed equipment. The effect of coating level, talc level and curing time on the release of PSE·HCl from the sustained-release pellets was studied. With the accumulative release percentages as indices, central composite design was used to optimize coating solution formulation. Linear regression equation and predicted response surface and contour plot were given by SAS programme. Combined pellets in different ratio of rapid-release pellets to sustained-release pellets. Similarity factors (f₂) between drug release profile of combined pellets and reference preparation were used as the evaluation standard to optimize the combining scheme. The result exhibited that when the ratio was 6:4, the release profile was most satisfied.The results of preliminary stability experiments indicated that light, temperature, humidity and air had little effect on compound sustained-release pellets. But high temperature and moisture might cause some changes in capsule shell, so the preparation should be stored in dry condition and should avoid high temperature. Accumulative release of PSE·HCl from sustained-release pellets was in accordance with zero-order equation.The plasma concentration in six healthy dogs was tested after a single oral administration of commercial and test formulation. The pharmacokinetic parameters were analyzed by non-compartment model theory. Compared with commercial tablets, the relative bioavailabilities of NPS and PSE·HCl in self-made preparations were 106.5% and 92.8%, respectively. The result of statistic analysis showed that NPS and PSE·HCl were bioequivalent with reference preparation. The pharmacokinetics results verified that the desired purpose was achieved, which proved this formulation was successful.