Comparative Pharmacokinetic Evaluation of Controlled Release Matrix Tablet of Milnacipran Hydrochloride in Rabbit

摘要

Milnacipran hydrochloride (MIL) is a selective serotonin and norepinephrine dual reuptake inhibitor used for the treatment of depression and fibromyalgia. The aim of present work was to carry out comparative pharmacokinetics evaluation of in-house developed oral controlled release (CR) and marketed immediate release (IR) tablet formulation of MIL. Three prototype CR formulations (i) MIL with HPMC 100K, single hydrophilic polymeric matrix tablet [MSH], (ii) MIL with HPMC 100K and sodium CMC, binary hydrophilic polymeric matrix tablet [MBH] and (iii) MIL with hydrophilic and hydrophobic wax polymeric matrix tablets using HPMC 100K and paraffin wax [MHW] were formulated. One optimized formulation from each prototype formulation was selected for in-vivo study in rabbits. In-vivo plasma concentration data were obtained from 6 healthy male New Zealand albino rabbits after administration of IR and CR tablets of MIL. Plasma samples were analyzed by in-house developed RP-HPLC method. Remarkable differences in plasma drug profile were observed between IR and CR formulations, expressed by lower C_(max), delayed T_(max) and extended MRT values for CR tablets. The mean C_(max) and T_(max) values from CR tablets were found to be 480.28 ± 31.27 to 586.53 ± 15.24 ng/mL and 8 to 10 h respectively whereas for IR formulation these were 1075.25± 50.38 ng/mL and 1 h respectively. The MRT was found twice in CR formulation than IR formulation. Level A in-vitro and in-vivo correlation was also established for developed CR formulations with correlation coefficient 0.896 to 0.930, which indicates a fair correlation between in-vitro release and in-vivo absorption of MIL from dosage form.