Studies On Oral Delayed Onset Drug Delivery System Of Metoprolol Fumarate

Chronobiology and chrono-pharmacology are developed with the continual advancement of medical science and it has been well realized that circadian rhythms exist in many physiological phenomena such as blood pressure, heart-beat rate, gastric acid secretion, hormone secretion and the occurrence of some diseases such as angina, hypertension, asthma, rheumatoid arthritis and so on. Therefore, recent research activities have increasingly focused on the exploration of novel oral chrono-pharmacological drug delivery systems for the conventional first-order release or zero-order release drug delivery system can't meet clinical needs in these cases. Successful treatment strategies such as pulsatile controlled releae dosage forms is used to prevent and cure the disease attacked at early dawn such as angina pectoris and hypertension. In our studies, Metoprolol Fumarate(MF) was selected as the model drug and two kinds of were prepared by film coating technology: MF delayed-pulsatile quickly release tablet (MF-DPQT) and MF delayed-pulsatile sustained release tablet (MF-DPST)Firstly, the method to determine the drug concentration in MF raw material, MF-DPQT and MF-DPST in vitro was established; The MF-DPQT containing MF 50mg was prepared by the film-coated methods using lactose and MCC as loading agents while CMS-Na and L-HPC as disintegrants. The effect of varieties and amounts of disintegrant and plasticize, the amounts of lactose, the composition and thickness of the coating films and the varieties of binder to lag time and release character was investigated. The optimal formulation was screened based on the studies of single factor experimentations and related literatures; The MF-DPST containing quickly and sustained release layers was prepared by the film-coated methods. The sustained release layer consisted of MF (75mg) and HPMC, and the quickly release layer was composed of MF (25mg), lactose and MCC as loading agents, CMS-Na and L-HPC as disintegrants. The effect of the viscosities and amounts of HPMC and the varieties and amounts of block agent on the release characteristics was investigated. The optimal formulation was screened by central composite design-response surface methodology; the release mechanism of the two kinds of preparation was proved by the model fitting of drug release, water uptake experiments, scanning electron microscope experiments and Power Law equation. The results of these experiments indicated that the UV method which was developed in our studies as a determination method was a convenient, accurate, specific and sensitive method for assay the drug content and the release percent of MF from the raw material, MF-DPQT and MF-DPST. The results of the single factor experiment indicated that the lag time and release characteritics of the MF-DPQT were affected by the varieties and amounts of disintegrant and plasticize, the composition and thickness of the coating films and the amounts of lactose, while the varieties of binder had unconspicuous influence. The optimal formulation of core and coating solution of MF-DPQT was MF 50mg, lactose 30mg, MCC 80mg, L-HPC 20mg, CMS-Na 20mg and Eudragit L100 7.8g, EC 4.2g, PEG6000 1.8g in 95% ethanol (200ml), respectively; The results of the single factor experiment indicated that the release characteristics of the MF-DPST were affected/influenced by the viscosities and amounts of HPMC as well as the addition of block agent. Few influence were observed on the release rate of MF with different viscosity of HPMC K_15M and K_100M, but a slight high release rate was detected when low viscosity of HPMC K_4M were used. The release rate of MF decreased accordingly with the increase of HPMC content in tablets. The release rate of MF decreased if hydrophobic materials such as EC and Eudragit RSPO were used in matrix. The optimal formulation of core and coating solution of MF-DPST was MF 50mg, lactose 30mg, MCC 80mg, L-HPC 15mg, CMS-Na 15mg in quickly releae layer , MF 75mg, EC 25mg, HPMC 112.5mg in sustained release layer and Eudragit L100 8.0g, EC 4.0g, PEG6000 1.7g in 95% ethanol (200ml), respectively. The results of model fitting of two kinds of preparation indicated that the dissolution kinetics was fitted to the diffusion/erosion model. The results of water uptake experiments indicated that the coating time of the hydrone penetrating coating layer was the principal rate-limiting step for lag time. The results of scanning electron microscope experiments indicated that porous appeared on the film after release might owe to the solubility of Eudragit L100 above pH 6, the solvent penetrated into the interior core through the porous, the core tablet dissolves or swells, breaking the outer shell and resulting in drug release. The result of the experiment according to the Power Law equation indicated that the release properties of the two kinds of preparations were fitted to diffusion and erosion mechanism.Secondly, the determination method of plasma concentrations in dogs of MF was established; which had been oral administrated of MF conventional tablets, MF-DPQT, MF conventional sustained tablets and MF-DPST, respectively. The parameters of pharmacokinetics were obtained by DAS2.0 program. The AUC was calculated by ladder-shaped method. The results indicated that the HPLC- fluorescence detector method was a convenient, accurate, specific and sensitive method for determining plasma concentrations of metoprolol. The concentration-time curve of four kinds of preparation fitted to one-compatment model. The statistics analysis results showed that there were remarkable differences of T_max, MRT ,T_lag (p < 0.01) and no obviously differences of C_max, AUC , t_1/2(p>0.05) between MF conventional tablets, MF conventional sustained tablets and MF-DPQT, MF-DPST, respectively. The relative bioavailability of MF-DPQT and MF-DPST were 92.71% and 106.8% comparing to conventional tablets and conventional sustained tablets, respectively.Finally, the correlation between in vitro and in vivo of MF-DPQT and MF-DPST was investigated. The Fa% was calculated by Wagner-Nelson method. The results indicated that there was a remarkable relativity between the absorption fraction in vivo and the release rate in vitro of MF-DPQT and MF-DPST (r =0.9710, 0.9929) . The in vivo parameters of 5.0h, 4.9h of T_lag were in good agreement with the in vitro parameters of 5.0h, 5.0h of T₁₀ for MF-DPQT and MF-DPST.