Venlafaxine Hydrochloride Porosity Osmotic Pump Tablets

Venlafaxine hydrochloride is one of new structure phenylethylamine class anti-despondent medicine,which through blocks 5-hydroxy tryptamine and goes to the armor adrenalin dually to absorb again plays the role.In this paper,micro-porous osmotic pumps(MPOP)controlled release tablets are prepared,taking VH as the model drug.Based on the comprehensive pre-formulation research,MCC,lactose,sodium chloride and HPMCK_4Mare used to make the tablet core.Take cellulose acetate(CA),Polyethylene glycol400(PEG-400),Dibutyl phthalate(DBP)and acetone as the coating solution.Tablets are coated by pan-spray method,and the coating process is described as the spray speed is 5mL·min^-1,coating temperature 30℃and the coating pan rotational speed 30 rpm.In this paper,physics-chemistry characteristic of VH and dissociation membrane nature were studied.Equilibrium solubility of VH in water was 558.64 mg·mL^-1under 37℃;Apparent n-octanol/water partition coefficient was 0.1198.Acetonl,DBP and PEG-400 were good solvent,good plasticizer and good pore forme for CA by investigating solubility parameter(δ),T_g,water permeability and canning electronic micrographs.To investigate the absorption characters of VH in the intestine,the absorption kinetics and the absorption sites were studied by utilizing the rat intestinal absorption single pass perfusion model in situ.The results of perfused rat intestinal model showed that VH could be well absorbed at all segments of intestine in rats,where there was no special absorption site and was a good candidate for a sustained-release system.The concentration of drug had no evident influence on the absorption rate constants.Increasing perfusion flow rate produced increased values of K_a and P_app.It was showed that the absorption of VH was the passive diffusion mechanism.Studies were made about the various effect factors on the drug release of VH MPOP. The release behavior in vitro of the VH MPOP complied with zero order release rule.The results suggested that osmotic pressure promoting agent,pore former and coating weight had marked effect on the drug release,whereas the type of dissolution medium,dissolution method,rotation speed and pressure of the tablet core had less effect.Meanwhile,the effect of coating technique on the drug release was studied.By orthogonal experimental design, the best coating material were optimized.Investigation about the drug release mechanism proved that the release kinetic derives from the difference of the osmotic pressure across the membrance.The stability test results showed that VH MPOP is unstable under high humidity,whereas good stability was found under light,high temperature,the accelerating test and room temperature.HPLC with UV method was preformed to detect the concentration of VH in plasma of dogs.using commercial conventional capsules as the reference and by the two periods cross-over design for determining the pharmacokinetics and bioavailability in six healthy dogs.For controlled-release tablets and capsules,AUC_0-twas(142±3.58)and(153±8.20)μg·h·mL^-1;T_maxwas 11.7h and 6h;C_maxwas10.2μg·mL^-1and 15.9μg·mL^-1;t_1/2was (5.55±0.261)and(5.44±0.839)h respectively.MRT was 14.1h and 10.6h.The relative bioavailability was 92.6.%.MPOP tablets had the controlled-release characteristics of delayed T_max,lower C_maxand smoother plasma concentration.Obvious correlation was observed between absorption percentage in vivo and release rate in vitro.