Timing Pulse Drug Delivery Systems Based On Diffusion, Swelling, And Osmotic Pump Mechanism

Terbutaline pulsatile tablets were prepared in this research. Release behaviors and mechanism were investigated deeply. Furthermore, other three drugs were applied to prepare pulsatile tablets based on the same mechanism.Bronchial asthma is a disease with proven chronopathological rhythms. Since asthma attack is much more common during the night, especially 2:00-8:00 a.m., chronotherapeutical treatment of asthma is necessary. Terbutaline, a β2-agonist known to exhibit chronopharmacokinetic and chronopharmadynamic rhythms, was adopted as the model drug, and multi-layered pulsatile tablets were prepared. Effects of many factors on the release behavior of terbutaline pulsatile tablets were investigated. These factors include ingredients of core tablets, the amount of NaCl in the core tablets, coating level of swelling agent, etc. the results of stability tests indicated that terbutaline pulsatile tablets were stable under strong light, high temperature and accelerated conditions. However, pulsatile tablets were sensitive to humidity.The mechanism of drug release from this pulsatile system was investigated in virtue of the dynamics of swelling and water uptake. No significant difference in drug release behavior was observed for release study in media with different pH of under different rotation speed. With the increase of osmotic pressure of the dissolution medium, the lag time was prolonged and the drug release rate decreased. The diffusion coefficient of water in the outer coat was calculated. The increase oftablets volume and the change of outer membrane during the release study were examined. Logical explanations for drug release behavior and the lag time were given based on above results. It was indicated that diffusion, swelling and osmotic pumping mechanism were involved in drug release from pulsatile tablets, but the latter was more dominant.Pharmacokinetic study was carried out in six dogs. The dogs were administered, in a crossover design, either the immediate-release tablets containing terbutaline sulphate 30 mg (control group) or the pulsatile tablets with different lag-times (test group). A pharmacokinetic model for double sites GI absorption was built on the basis of multiple sites discontinuous GI absorption. The pharmacokinetic parameters of test group and control group were as follows: AUCo-m were (3275±431) h ? ng/ml and (1691±377) h ? ng/ml; and MRT were (14.6±0.6) h, and (5.2±0.6)h; Cmax of test group were (237.0 + 41.1) ng/ml and (219.8 + 55.0)ng/ml, while Cmax of control group was(332.2 + 126.4)ng/ml; Tmax of test group were (5.00±0.55) and (12.3 ±0.5)h, while Tmax of control group was (1.9±0.60) h; Tiagoftest group were (2.38±0.4) and (9.93 ± 1.1 )h, while Tiag of control group was( 0.21 +0.04 )h. results of ANOVA and two one-sided tests showed that they were bioequivalent, but significant difference was observed in Cmix. Also, significant difference was observed in Tmax, Tiag and MRT based on the results of paired t-test.Pulsatile tablets of other three drugs, including water soluble salbutamol, water insoluble ibuprofen and nifidipine, were prepared. The results of in-vitro release study showed that rotation speed and pH value of dissolution media have no effect on drug release behavior of the threekinds of pulsatile tablets. With the increase of osmotic pressure of the dissolution medium, the lag time was prolonged and the drug release rate decreased. The in-vitro release behaviors of the three kinds of pulsatile tablets were similar to terbtalline pulsatile tablets, indicating that combination of swelling, diffusion and osmotic pumping mechanism can be generally applicable to prepare pulsatile tablets. However, it should be paid attention to that the lag time of water soluble drug was longer than that of water insoluble drug at the same coating level, and steady released rate of water soluble drug was smaller that that of water insoluble drug.