Paroxetine Hydrochloride Controlled Release Pellets

Paroxetine is an antidepressant agent with a structure totally unrelated to other antidepressant agent such as serotonin reuptake inhibitors or tricyclic or tetracyclic agents. Its action is believed to be linked to the inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamin,5-HT)in the central nervous system(CNS).Commercial tablets of paroxetine has a serious gastroenteric side-effect,which is caused by the locally high concentration in stomach and duodenum.The purpose of the present study was to develop a kind of paroxetine enteric controlled release pellets,which would avoid the gastroenteric side-effect,and which enhance applying safety and the convenience for patients to use.In the preformulation study,HPLC method and UV method for assay was developed. UV method was utilized to determine the paroxetine content and release of controlled release pellets,HPLC method for enteric capsules.The solubilities of paroxetine in three different kinds of dissolution media were determined.Paroxetine pellets were prepared by a fluid bed spray processor,and the coating process variables were determined and controlled. A suitable pH-independent sustained release pellets system was produced by coating with Ethocel and Pore formerⅠ/Ⅱ.In this research,filtration of a series of EC concentration, Pore formerⅠ/Ⅱand coating level were studied.The diffusion rate of paroxetine during release depends on the permeabilityof the coating and its thickness.The content of pore former had a positive effect on drug release rate,while coating level decreased the released amount.The description of dissolution profiles suggested that the release profiles follow the zero-order equation more fitly as the coating level increased.This study used an artificial neural network(ANN)to predict drug release from controlled release pellets of paroxetine hydrochloride.The amount of Pore formerⅠand coating level were selected as casual factors,and the accumulative drug release in each sampling time was used as response variables.A set of release parameters and causal factors were used as tutorial data.The predictive ability of the ANN was assessed by comparing the linear regression equations,similarity factors and AIC values of predicted against observed property values.The results showed a fairly good agreement between the observed values of release parameters and the ANN predicted values.Therefore,ANN provides a feasible way of optimizing and estimating drug release from controlled release pellets of paroxetine hydrochloride.The content of Pore formerⅡand coating level were selected as response variable,the accumulative drug release in each sampling time as casual factors,and zero order release for 12 hours as optimized object.The optimal formulation gave satisfactory release profile,since the observed result coincided well with the optimized object.This study filtrated Enteric polymerⅠandⅡfor enteric coating,and finally selected Enteric polymerⅡto be coated to the pellets optimized by ANN.The enteric controlled release pellets were filled in gelatin hard capsules to carry out in vitro release and quality standard study.Forced degradation studies were performed to provide an indication of the stability-indicating properties and specificity of the procedure.The observed degradations were resolved from the paroxetine peak.The result of stability study showed that the capsules were unstable to hot and moist,stable to light.Pellets should be kept in cool and dry condition.The content and physical character of capsules had no marked change,which placed under 40℃,75%±5%RH for two months.Since the former preparation method wascomplicated,a new kind of enteric controlled release pellets were developed,in which Enteric polymerⅡwere added to EC coating formulation as a pore former.To optimize the formulation of the EC/ Enteric polymerⅡpellets by a central composite design/response surface methodology. Independent variables were Enteric polymerⅡcontent,coating level and Cremophor EL content,release amount in acid dissolution media and sustained release grade were dependent variables.Response surfaces were delineated according to best-fit mathematic models,and optimum formulation was selected.Optimum formulation was proposed to contain Enteric polymerⅡ2.59g,Cremophor EL 0.18g and 6.40%coating level.The optimum formulation reached the optimized object,accomplished the purpose of simplifying the preparation technics.