| Objective:To screen the optimalizing prescription of sustained release tablet of atomoxetine hydrochloride, establish the assay method of the drug concentration in plasma and review the pharmacokinetic character.Methods:In this paper, the releasing degree in vitro was used as indicator to evaluate the effects of HPMC viscosity, moistening agent, adhesive and squash pressure on the sustained release tablet of atomoxetine hydrochloride. HPMC was selected as hydrophilic gel matrix, lactose and ethylcellulose (EC) as the diluents and the release regulator, and 70% alcohol as moistening agent. The prescription of sustained release tablet of atomoxetine hydrochloride was excellently screened with L9 (34) orthogonal design, and three influencing factors such as HPMC, EC and lactose were selected. The levels of HPMC were 80,100 and 120mg; the level of EC 10,20 and 30mg; the level of lactose 40,50 and 60mg, respectively. The releasing rate of each prescription in vitro was determined and analyzed so as to choose the best. By high performance liquid chromatography (HPLC) method, the atomoxetine hydrochloride plasma concentrations in rats were determined and the pharmacokinetic character was studied.Results:The releasing mechanism of sustained-release tablet was primarily studied. Several drug-releasing models were simulated and showed that the drug-releasing curve in vitro was consistent with Weibull equation Lnln(1/(1-F))=1.0221nt-1.9942, r=0.9989, The release parameter n obtained from Ritger-Peppas equation was 0.6563, between 0.45 and 0.89, indicating that the release mechanism was diffusion as well as matrix erosion, which accords with retard tablets.HPLC method was developed to determine the releasing degree in vitro. The concentration of atomoxetine hydrochloride and the peak areas were linear over the range of 1μg.ml-1～20μg.ml-1, A= 520744C+132594 (r=0.9999).The mean absolute recoveries of low, middle and high concentrations were 99.33%,99.37%,100.6%. The inter-day RSD were 1.3%,0.8%,and 0.7%; and the intra-day RSD were 1.4%, 1.1%, and 1.0%, The two kinds of RSD were both lower than 2% which showed this method was accurate, reliable and reproducible.HPLC method was established to determine the concentration of atomoxetine hydrochloride in plasma. The atomoxetine hydrochloride concentration had a good linear correlation in the range of 20-800ng-ml-1,Y=0.0044X+0.0071 (r=0.9993) The lowest detectable limit was 20ng·ml-1.The mean absolute recoveries of low, middle and high concentrations were 83.46%,80.55%,77.59%; The method recovery rates were 91.12%,96.1%,96.63%; The inter-day RSD were 3.1%,2.6%and 3.4%; and the intra-day RSD were 4.0%,3.0%and 2.9%, The two kinds of RSD were both lower than 5%.The pharmacokinetic parameters and character:one compartment model, Weight=1/C2, ke=0.0842h-1,ka=0.1529 h-1, t1/2a=4.54h, t1/2e=8.25h, Tmax=8.69h, Cmax=464.59ng/ml, AUC=11484(ng/ml).h.Conclusions:This preparation prescription is reasonable, and the preparation technology is feasible. This assay method is sensitive, accurate, simple and feasible. |
PDF Full Text Request