Preparation And In Vivo/in Vitro Evaluation Of Paroxetine Enteric-coated Sustained Release Suspension

Paroxetine Hydrochloride（PX）is a serotonin reuptake blockers（SSRIs）antidepressants,and can be used clinically for the treatment of various types of depression,especially for patients with major depression.At present,there were only ordinary tablets and enteric-coated sustained-release tablets of paroxetine hydrochloride on the market in China.For special patients,such as the elderly and patients with dysphagia,solid preparations have the disadvantage of being difficult to swallow.In addition,solid preparations also have disadvantages such as inconvenience in divided doses and poor taste,and conventional solid preparations need to be taken more times,blood drug concentration fluctuates greatly,and patient compliance is poor.The preparation of paroxetine hydrochloride liquid preparation with enteric-coated sustained-release effect can effectively solve the shortage of solid preparation and reduce the adverse reactions of PX itself to gastrointestinal tract.Therefore,in this project,PX was selected as the model drug,Amberlite^?IRP88 weak acid cation exchange resin（polacrilin potassium）was used as the drug carrier,paroxetine hydrochloride drug resin complex（PX-DRC）was prepared by ion exchange technology,and then paroxetine hydrochloride enteric-coated sustained-release suspension was prepared by fluidized bed coating process.1.Preparation of paroxetine hydrochloride resin complexThe preparation conditions of PX-DRC were investigated.Finally,PX-DRC was prepared by bath method.The best preparation conditions for the drug resin complex:500 mg Amberlite（?）IRP88 weak acid cation exchange resin was added to 100 m L of PX solution with a concentration of 5 mg·m L^-1,magnetically stirred for 2 hours,and the temperature was controlled at 25.0℃±0.5℃.The drug loading Q_∞of the final resin was 0.95 mg PX/1 mg Amberlite（?）IRP88 resin,and the drug utilization rate E was 95.71%.The results characteristics of thermodynamics and kinetics showed that the reaction was endothermic and could proceed spontaneously to the right.2.Characterization and in vitro release of PX-DRCThe prepared PX-DRC was characterized by SEM,XRD,DSC and FTIR.SEM was used to analyze the surface morphology,while XRD,DSC and FTIR were used to investigate the binding mechanism.The comparative analysis of each spectrum proved that PX-DRC is obtained by ion exchange between PX and resin,rather than ordinary physical adsorption.The release process of PX-DRC in vitro under different conditions（counter ion type,ionic strength,temperature,rotating speed,and medium volume）was investigated.The final release conditions were as follows:release medium was 900 m L 0.1 mol·L^-1HCl,rotational speed was 50 r·min^-1,and temperature was 37.0℃±0.5℃.3.Study on the coating process and prescription of PX-DRCFirstly,polyethylene glycol 4000 was used to impregnate the PX-DRC,and then the PX-DRC was coated by fluidized bed bottom spray coating technology.The PX-coated microcapsule（PX-CM）was prepared by using CAP compound as coating material,dichloromethane and ethanol as solvent,and diethyl phthalate as plasticizer.Taking the release of PX-CM in vitro as the index,the single factor method was used to investigate the process and prescription of fluidized bed coating.Finally,the optimal coating process for PX was determined as follows:the air inlet volume was 40 m³·h^-1,the air inlet temperature was 45℃,and the spray rate was 1m L·min^-1.The solid content of the coating solution was 6%,the weight gain of the coating was 30%,and the curing time of the heat treatment was 1.0 h.4.Preparation of PX enteric-coated sustained-release suspensionThe particle size and wettability of suspended particles（PX-CM）as well as the sedimentation volume ratio and redispersibility of suspension were investigated.The results showed that all indicators met the requirements.The stability related indicators of the suspension（content,drug leakage,sedimentation volume ratio,redispersibility,properties and in vitro release curve）were investigated.The results showed that the stability of self-made PX enteric-coated sustained-release suspension was good,and the inspection items could meet the quality requirements.5.In vivo pharmacokinetic study of PX enteric-coated sustained-release suspensionIn this chapter,SD rats were used as the animal model,and verapamil hydrochloride was used as the internal standard to establish the in vivo detection methodology of PX.The marketed paroxetine hydrochloride tablets and self-made PX enteric-coated sustained-release suspension were intragastrically administered to rats,and the drug concentration-time curve and pharmacokinetic parameters of the two preparations were studied.The results showed that the t_1/2of paroxetine hydrochloride tablets and PX enteric-coated sustained-release suspension were 2.362 h and 4.539 h,C_maxwere 0.443μg·m L^-1and 0.237μg·m L^-1,T_maxwere 4 h and 7 h,respectively.Compared with the marketed ordinary paroxetine hydrochloride tablets,the t_1/2of the self-made PX enteric-coated sustained-release suspension was prolonged by 2 hours,the C_maxwas reduced by 0.2μg·m L^-1,the T_maxwas delayed by 3 hours,and the drug concentration-time curve was gentler,indicating that the self-made suspension has obvious sustained-release effect.The AUC of the commercially available PX tablets was 2.852μg·h·m L^-1,and the AUC of the self-made PX enteric-coated sustained-release suspension was2.937μg·h·m L^-1.The relative bioavailability of the two preparations was 102.98%,which indicated that the two formulations were bioequivalent.