Studies On The Absorption Mechanism Of PX And The Development Of PX Tablets

Paroxetine hydrochloride (PX) is a new type of SSRI depressant, which is more selective than traditional TCAs and MAOIs and has fewer side-effects. PX is safe and effective in treating various mental disorders, including depression, obsessivecompulsive disorder (OCD), generalized anxiety disorder (GAD), panic disorder (PD), social phobia, and posttraumatic stress disorder (PTSD). Compared to other SSIRs, PX is the only one permitted for GAD treatment by US.FDA. In the year 2003, a new PX-CR tablet was licenced by US.FDA for controlling women premenstrual dysphoric disorder (PMDD). Besides, PX is variously used for treatment of premature ejaculation, drug addiction and functional dyspepsia.In the pharmacokinetics process, PX is characterized by the first pass metabolism in the liver after oral administration in vivo. The metabolism process is nonlinear and variable among different people. It is validated that both average plasma concentration and the elimination half life at steady state after multi-doses administration varied greatly among different people, especially in elderly people. Therefore, dose adjustment is necessary.Considering PX pharmacokinetics, this research begins with the study of PX absorption mechanism, in which an in situ method is performed and evaluated. From the study we can come to the conclusion that PX is passively absorbed in rats and this absorption process complied with first-order regulation mechanism, under the dosage of 0.94,2.82,9.42 mg·kg^-1, PX is poorly absorbed in stomach with the average absorption rate are 3.20%,3.85% and 1.77% per hour, and well absorbed in all intestine segments with the average absorption rate constant K_a, of 0.599,0.608 and 0.601 h^-1 in duodenum, 0.605,0.632 and 0.579 h^-1 in jejunum, 0.616,0.590 and 0.632 h^-1 in ileum and 0.590, 0.607 and 0.625 h^-1 in colon respectively, and there is no evidence that showed the difference in absorption rate among different intestine segments under the dosage range of 10-100 mg·d^-1.According to this result we then developed one kind of fast-releasing tablet, and prepared three batches of PX tablets for further study. The development focused on the PX-excipient compatibility test and dissolution behavior. Finally it is decided that R21 is chosen as the formula to prepare PX tablet.In the following study, we developed a simple, precise and reliable HPLC method for content, impurity and dissolution determination of PX tablets. The relative factors influence tests indicated that light may have some influence on the stability of PX, so tablets need to be well sealed under opacity cover. The examination results of 3 batches of PX tablets showed that they were qualified and constant in 18 months.The further study of clinical evaluation will be performed after the permission of SFDA.