Preparation And Quality Assessment Of Indapamide Micro-porous Osmotic Pump Tablet

Indapamide (INDP) is a non-thiazide sulphonamide diuretic drug marketed by Servier, generally used in the treatment of hypertension, as well as decompensated cardiac failure. So far there are only conventional tablets,sustained release tablets and capsules in domestic and foreign markets. Osmotic pump tablets have a constant release rate and the release rate is pH-independent and agitation-independent which lead to comparable in vitro/in vivo correlation. But they are usually applieable for soluble drugs. In this study, micro-porous osmotic pump (MPOP) tablets were prepared using INDP as the model of indissoluble drugs.Based on the comprehensive pre-formulation research, single-factor tests were carried out to inspect the influence of formulation and manufacture process on the release of indapamide. The results suggested that osmotic pressure promoting agent, pore former, plasticizer and coating weight had marked effect on the drug release. By orthogonal experimental design, optimal formulation modified to release drug over 16h was obtained. Meanwhile, the parameters of coating technique were determined. Microcrystalline cellulose(MCC), amylum pregelatinisatum, lactose, sodium chloride and hypromellose(HPMC) were used to make the tablet core. Cellulose acetate (CA), PEG-400, diethyl phthalate (DEP) and acetone were selected as the coating solution. Tablets were coated by pan-spray method, and the coating process was described as the spray speed of 5 ml·min-1, coating temperature 30℃. Cumulative drug release of the best formulation at 16 h exceeded 90% and the linear correlation coefficient exceeded 0.99.Investigation about the drug release mechanism proved that the release kinetics derives from the difference of the osmotic pressure across the membrance. The release behavior in vitro of the INDP MPOP complied with zero order release rule. The type of dissolution medium, dissolution method and rotation speed had less effect. According to literatures, UV spectrophotometer and high-performance liquid chromatography(HPLC) were developed for in vitro assay during the studies of content, related substance and release. The stability test results showed that INDP MPOP is a little wet under high humidity, whereas good stability was found under light, high temperature, the accelerating test and room temperature.High-performance liquid chromatography-mass spectrometry (HPLC-MS) method was preformed to detect the concentration of INDP in Plasma of dogs, using sustained release tablets as the reference and by the two Periods cross-over design for determining the pharmacokinetics and bioavailability in six healthy dogs. By comparing the pharmacokinetic parameters of the test and refrence tablets, such as AUC, Cmax, Tpeak and T1/2, the results of analysis of varianee and the two one-sided test showed they were bio-equivalent. The relative bioavailability was 106%. Obvious correlation was observed between absorption percentage in vivo and release rate in vitro.