The Studies On Pulsatile & Controlled Release Tablets Of Metoprolol Tartrate

Chronobiology and chrono-pharmacology showed that circadian rhythms existed in many diseases such as cardiovascular and respiratory diseases and the timing of medication regains can improve therapeutically effect. In this paper, metoprolol tartrate (MT) was chosen as the model drug, and MT pulsatile & controlled tablets (PCRT) were prepared successfully based on the osmotic pumping mechanism, meanwhile the in vitro/vivo release of the MT-PCRT were also studied.The precise and reliable methods to analysis in vitro and in vivo of MT-PCRT were established using UV, GC, HPLC and LC-MS/MS respectively which provided a basis for the further studies of pharmaceutics and pharmacokinetics in beagle dogs.Formulation effects of core on the release of MT-CRT were investigated using single factor test. On the base of single factor testing, orthogonal test was chosen to optimize the core formulation. The optimum formulation is as follows: MT 50mg, PEO WSR N750 50mg, PEO WSR N80 50mg, magnesium stearate 1.5mg in drug-layer, PEO WSR 303 80mg,Nacl 50mg,magnesium stearate 1.5mg, HPMC K15M 10mg, iron oxide red 1mg.Formulation effects of bi-layer film on in vivo release were invested using single factor test. According to these researches, the orthogonal test was chosen to optimize the formulations and the optimum formulation is as follows: the subcoat weight was 20% of tablet core, the pore-forming HPC proportion was 30% of CA, and the controlled film weight was 12% of tablet core.In vitro release showed that the lag time and release rate of the prepared MT-PCRT were 3.82h and 3.84mg/h, respectively, it indicated that well characteristic of pulsatile controlled-release. Furthermore, the drug release behavior in vitro was independent of pH, agitation and food effect.The spraying method was used to prepare the free controlled film and the properties of free film were investigated. The results showed that the eroded controlled film had uniform micropore and integrated appearance under SEM. And the eroded controlled film had good mechanical properties. The drug-release mechanism from MT-PCRT was osmotic pumping effect.In vivo release behavior of MT-PCRT (test formulation) and marketed MT conventional tablets (reference formulation) were evaluated in beagle dogs through a paralleled crossover oral administration. The pharmacokinetic parameters of the test and reference formulation are as below: T_max10.2±1.8 and 0.9±0.3h; C_max123.2±43.4 and 833.9±116.4ng/ml; MRT_0-t 2.3±0.3 and13.9±0.9h, respectively. The result showed that the prepared MT-PCRT with a lag time of about 4h and steady drug concentration, and it has well characteristic of pulsatile controlled-release behavior to better comply with the circadian rhythms of cardiovascular diseases.The in vitro-in vivo correlation of the test formulation was installed by using Wagner-Nelson equation technique at last. The results showed that we can predict the in vivo drug release behavior from the in vitro release characteristics well.