Research And Development Of Metoprolol Tartrate Pulsatile Pellets

With the development of chrono-pharmacology and chrono-therapeutics, controlled release formulation with a zero- or first-order drug release was not always desired to treat such diseases which show circadian rhythms in their pathophysiology. Pharmaceutical scientists and technicians have progressively interests in developing oral dosage forms with pulsed-release kinetics which emerges chrono-therapeutic requirements. The occurrence of angina pectoris attacks demonstrates a significant circadian variation with a morning peak from 6:00 to 10:00. It is essential to develop a pulsed-release system to achieve an effective drug level only at the required time.Metoprolol Tartrate was used as model drug to develop a novel pulsatile release delivery system meeting the specific therapeutic needs of angina pectoris. Because of the early morning symptoms, the assumption in the evening of a dosage form by starting release the dose some hours after ingestion could be a suitable therapeutic regimen.Ultraviolet spectrophotometer method was developed for assay during of content and drug release. The microcrystalline cellulose (MCC) pellet cores were spay-coated with MT containing layer, alkaline layer and polymeric outer-layer which contains the component Eudragit? S100 subsequently by MINI-Glatt fluid-bed sprayer. To investigate the mechanism of drug release from the pulsatile release system, several release behaviors were examined under the conditions of various influential factor levels. Lag time was mainly determined by the property of outer-layer like thickness or component; release rate was dependent on swellable core, alkaline layer and the mechanical strength of outer-layer. Different rotation speeds and different pH values factually seldom affect the MT release behavior in vitro. The simple preparation process makes it easy to practical manufacture.The release profiles of MT pulsatile pellets were fitted and compared employing different mathematic models. The Logistic was optimal to fit the pulsatile release profiles. From the information derived from Logistic curve we obtained the key-points: t1 =– ( ln c2 + 1.317) / c3, t2 = (1.317– ln c2) / c3. And using two yielding points of the velocity function from the growth process of Logistic model, the release profile was divided into time-delayed release period (0～t1), rapid release period (t1～t2), decelerating platform period (t2～∞). Release properties from different formulations were evaluated and the whole release process of MT pellet simulated by regression and prediction. The optimization of the formulation as well as conduct the further research could be guided by the comparing results.