Preclinical Studies On Sustained Release Capsule Of Paroxetine Hydrochloride

Selective serotonin reuptake inhibitors (SSRIs) are a kind of the safe and effective medicine for depression treatment at present. paroxetine hydrochloride as the representative medicine of SSRIs , which is the best-selling antidepressants for its fast and clear effect at present. The most common adverse reaction of the immediate release preparations of paroxetine hydrochloride is nausea. Researches were reported that higher concentration of paroxetine hydrochloride in the stomach and the upper small intestine was the reason of gastrointestinal side effects , and the incidence of adverse effects could up to 25 percent~[1,2]. To further reduce the incidence of side effects of paroxetine hydrochloride and improve patient compliance, the paroxetine controlled release tablets that developed by GlaxoSmithKline was approved and listed by U.S. FDA. The randomized comparative study of paroxetine enteric-coated sustained-release tablets, rapid release tablets and placebo showed that paroxetine enteric-coated sustained-release tablets had improved tolerance and lower incidence of side effects , which was more suitable for clinical treatment of depression[3,4].In This study paroxetine hydrochloride pellets with skeleton structure were prepared by extrusion-spheronization, and the pellets were coated with sustained-release layer and the enteric layer by the fluidized bed coating technology to obtain a 12-hour intestinal dissolving sustained-release effect.The high performance liquid chromatography(HPLC) method was established for enteric release pellets vitro release and determination, and the physical and chemical properties of Paroxetine Hemihydrochloride was studied with HPLC. Solubility experiments showed that the solubility of Paroxetine Hemihydrochloride was more than 1mg/ml in water, 0.l mol/L HCl and pH7.5 TRIS-NaCl buffer; apparent partition coefficients with the increase of pH.The effects of forming pellets of sustained-release materials were investigated, and microcrystalline cellulose was chosen for skeleton material ultimately, lactose as a release rate regulator, HPMC E5 as the binder, water as wetting agent, and Paroxetine hydrochloride pellets was prepared with these materials, and the factors of properties of powders and pellets release rate were investigated. The process parameters were optimized by orthogonal test, Pellets prepared with optimized parameters showed an effect of sustained-release, but pre-release was over limitation.Pellets having a 12-hour effect of intestinal dissolving sustained-release were prepared using Eudragit RS, Eudragit RL as a sustained-release coating material, Eudragit L100 for the enteric material, by fluidized bed coating method. The influence factors of release were investigated to determine the best solution coating process and coating formulation.Mechanism study of drug release showed that the drug release behavior fitted the first order release model better.The quality of enteric-coated sustained-release capsules of PAX showed that content does not exceed the limits of capsules, the release uniformity was well, and the cumulative release at 12h was over 80%.Influence factors test of enteric-coated sustained-release capsule showed that the in vitro release behavior of pellets did not changed in the light, high temperature, high humidity and accelerated conditions ,but the appearance of pellets changed from white to yellow under conditions of high humidity and accelerated , and after three Months under accelerated conditions the drug content decreased.