Studies On Pulsatile & Controlled Release Tablets Of Verapamil Hydrochloride Based On The Osmotic Pumping Mechanism

Chronobiology and chrono-pharmacology were developed with the continual advancement of medical science and it had been well realized that eircadian thythms existed in many physiological phenomena and occurrence of some diseases. Therefore, recent research activities had increasingly focused on the exploration of novel oral pulsatile release drug delivery systems that depended on the circadian thythms ,because the conventional drug delivery system couldn’t meet clinical needs in these cases. In the paper, verapamil hydrochloride（VP） were chosen as the model drug , and VP pulsatile & controlled tablets（PCRT） were prepared successfully based on the osmotic pumping mechanism . It had been designed for bedtime dosing and initiated the release of drug in the early morning at a constant rate, which was used to prevent and cure the disease attacked at early dawn such as angina pectoris and hypertension.The precise and reliable UV and HPLC method were established for analysis of VP in vitro and in vivo, which provided a basis for the further studies of pharmaceutics and pharmacokinetics in beagle dogs .The physicochemical properties showed that solubility and apparent partition coefficients were significantly pH-dependent, but VP had a well absorption in the whole gastrointestinal tract ,which was suitable for the long-effective controlled release preparation.The VP-PCRT which was on the basis of the conventional two-layer osmotic pump was prepared by using HPMC as the subcoat and cellulose acetate（CA） and pore-forming as the controlled release membrane on the condition of the preparation process. The effect of coating formulation and the mount of orifice on the release of VP-PCRT were investigated. The results indicated that there was positive linear correlation between subcoat weight and lag time （r=0.9959）, but subcoat did not affect on drug release rate Pore-making agent and the level of controlled-release membrane affected drug release to a certain extent. Although the number of delivery orifice had rarely influence on drug release, less would result in the expansion of tablets.According to these researches , the central composite design was chosen to optimize the formulations and the optimum formulation is as follows: the range of pore-forming HPC-L proportion （X₁） was 26～30%,the range of subcoat weight（X₂） was 108～122mg.The prepared tablets released the drug after a lag time about 3⁴h and the release rate was 22～26mg/h. Furthermore, drug release was independent of pH, agitation and food effect.At last, the properties of free membrane were investigated and the erosion and water-uptake rate, permeability, surface morphology and mechanical performance tests of free films were set up as assessment index. Then the release mechanism of VP-PCRT were discussed in the two aspects of lag time and release rate.The behavior in vivo of the tablets was evaluated in beagle dogs after a parallel oral administration of VP-PCRT （test formulation） and the marketed Covera-HS （reference formulation）. The pharmacokinetic parameters of the test and reference formulation are as below: T_lag 3.09±0.09 and 3.31±0.20h; C_max 110.17±13.46 and 108.02±112.91ng/ml; AUC_0-24 are 1256.44±166.08 and 1260.01±148.03 ng·h/ml, repectively. The relative bioavailability is 99.72% and were proved to be bioequivalent. At last, the in vitro-in vivo correlations of the test and reference formulations are installed by using Wagner-Nelson equation technique, which appeared to be significant.