Preparation Of Venlafaxine Hydrochloride Osmotic Pump Release Tablets

Objectives: Venlafaxine Hydrochloride is a new type of phenylethylamine derivative antidepressant drug which has characteristic chemcial constitution and neuropharmacology effect. It educes antidepression effect by prohibiting reuptake of 5-hydroxytryptamine and norepinephrine. It refers to various kinds of depression, depression accompanying anxiety, catholic anxiety disorders and depression both accompanying psychomotor retardation and agitate behavior. But conventional capsule is usually administered two or three times a day, which would lead to large fluctuation in drug plasma concentration and side effect on human body. Controlled release preparation is often desirable. Among these, osmotic pump tablet is a typical example. It offers several advantages, such as releasing drug at the rate of approximate zero-order, reducing risk of adverse reactions, independing on pH and peristalsis of gastro-intestinal tract and gastric emptying, improving compliance of patients and exhibiting comparable in vitro/in vivo drug release.Methods: A method for preparation of venlafaxine hydrochloride osmotic pump release tablets was obtained by coating core tablet compressed by single punch tablet machine. Cellulose acetate, PEG 400, diethyl phthalate and acetone were respectively used as coating material, channeling agent, plasticizer and solvent. On the basis of pretesting and scientific literatures, the temperature of coating, rotary speed of coating pot and pressure of spraying were determined. The hardness and diameter of tablet, type and amount of osmotic agent, thickness of coating membrane were investigated and evaluated by similarity factor(?2). The orthogonal experiment was designed to optimize formula in which the amount of osmotic agent, PEG 400 and thickness of coating membrane were taken as three influential factors and three different levels were selected to part, each of them was selected refer to the L9(34) orthogonal design table. According to accumulative release percentage at 2h,6h,10h to select optimal formula with the colligation evaluation. The osmotic pump tablet with the optimal formula was prepared and its in vitro cumulative release profile was obtained.In vitro release test was performed in a dissolution apparatus using the first method according to CHP. The stirring rates in water was 75rpm. The temperature was maintained at (37±0.5)℃. At the predetermined intervals (1, 2, 4, 6, 8, 10, 12h), 5ml samples were withdrawn from each vessel, filtered with a 0.8μm membrane, and analyzed with HPLC method for venlafaxine hydrochloride. The same volume of fresh medium was replaced after sampling.Concentration of venlafaxine hydrochloride was determined using a HPLC system. Separation was achieved by using a Kromasil column(C8, 4.6mm×250mm, 5μm). The mobile phase consisted of acetonitrile and 0.1mol/ml ammonium dihydrogen phosphate aqueous solution at a ratio of 40:60(v/v). The flow rate was 1.0ml/min, and the injection volume was 20μl. All chromatographic separations were performed at 25℃. The wavelength of detectionwas set at 230nm.The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, strong illumination and accelerated condition (40℃/75% RH for 6 months). At the end of the study period, the formula was observed for change in physical appearance, drug content and drug release characteristics.Pharmacokinetics study in vivo: we selected the Beagle dogs as laboratory animal, which were divided into two groups in random. One group was given osmotic pump release tablets and the other was given market conventional capsules. Plasma samples were obtained at different times. Crossover experiment was taken after two weeks. HPLC with Ultraviolet detector was adopted in examining concentration of plasma. Then pharmacokinetics parameters were caculated by non-compartmental model analysis method.Results: The optimal technology and formula were defined through simple factor test and orthogonal experiments. The core tablet conditions were as follows: hardness of tablet, 8kg; diameter of tablet, 11mm; weight of tablet, 400mg. The coating conditions were as follows: coating temperature, 40℃; rotation rate of pot, 60rpm; spray pressure, 2kg/cm2. The optimal formula were as follows: the type of osmotic agent, mannitol and lactose a ratio of 1:1(g/g); osmotic agent in the drug of core tablet, 25%(g/g); PEG 400 in the cellulose acetate, 10%(g/g); coating membrane in core tablet, 3%(g/g). Total coating materials in the coating solution: 4.0%(w/v).The results of the system serve experiment of the HPLC method to determine the content of venlafaxine hydrochloride: the reserve time of venlafaxine hydrochloride were about 4.5min, the recoveries were 98.96~100.12%, the within-day precision was 0.25~0.43%, the between-day precision was 1.04~1.85%. Regression equation was C=21743A+ 5877.1(r=0.9999). The linearity range of venlafaxine hydrochloride was 5μg/ml~100μg/ml. Excipients had no interference with the results.Stability experiment: the result of high humidity test showed that 10 days after osmotic pump release tablets being placed in humidity(RH 92.5%), the weight highly increased. But in humidity(RH 75%), the weight hardly increased. There was no change in physical appearance, drug content and drug release characteristics after being stored at high humidity(RH 75%), high temperature(40℃) and strong illumination (4500±500 lx) for 10 days. The result of accelerated experiment showed that the data were not significantly different from before. Pharmacokinetic study: we took the experiment according to defined HPLC condition. The main pharmacokinetics parameters were respectively as following: Tmax(h), Cmax(μg/ml) and MRT of osmotic pump tablet were 6.333±0.816, 0.415±0.106 and 17.09±2.284 respectively. Tmax(h), Cmax(μg/ml) and MRT of conventional capsule were 3.833±0.408, 0.981±0.29 and 7.697±0.738 respectively.Compared with market conventional capsule, both peak time and MRT of osmotic pump tablet was extended and concentration of osmotic pump tablet was decreased.Conclusions: Venlafaxine hydrochloride osmotic pump tablets had good effect of controlled release property and repetition in vitro. The quality is independent on temperature, humidity and illumination. The methods of assay and dissolution for venlafaxine hydrochloride osmotic pump tablets were established, which provided a guideline with quality control. The experiment in vivo showed that both peak time and MRT of osmotic pump tablet was extended and plasma concentration of osmotic pump tablet was decreased.