Study On Nimesulide Oral Biphasic Drug Delivery System

Nimesulide is a new type of non-steroidal anti-inflammatory drug (NSAID), which is the first selective cycloxygenase-2 (COX-2) inhibitor, indicated for the management of a variety of painful and inflammatory conditions like post operative pain, primary dysmenorrheal and painful osteoarthritis. The results of pharmacokinetic study show its half life period is short, resulting to fluctuation of blood drug level after administrating conventional dosage form. In order to reduce the administration times and further decrease the gastrointestinal tract side effects, nimesulide sustained-release tablets and nimesulide sustained-release capsules are marketed in our country, which enhance the patient compliance. However, the onset of action is slow.Ideal oral sustained-release preparation should offer both immediate and sustained blood level, and oral biphasic drug delivery system is introduced with the advantage and character. According to the pharmacokinetic feature of the non-steroidal anti-inflammatory drug nimesulide, its oral biphasic drug delivery system is designed and prepared, for immediate relief from pain and effective management of morning stiffness and other symptoms.Firstly, the Ultraviolet spectrophotometry (UV) method was established for determining the content and accumulative release percentage of nimesulide. Physical and chemical properties of nimesulide such as equilibrium solubility and apparent oil-water partition coefficient were investigated for designing the oral biphasic delivery system. According to the pharmacokinetics principle, the dose ration of immediate-release layer and sustained-release layer and the total dose were designed for immediate-release and long-acting. The total dose of designed nimesulide oral biphasic drug delivery system was 200mg, and the dose of immediate-release layer and sustained-release layer were 50mg,150mg, respectively. Double-layer sustained-release tablet was selected as the dosage form.Based on the above dosage form design, the nimesulide oral biphasic drug delivery system was developed by using double-layer compression technique. The optimal formulation of immediate-release layer was determined in the indication of the dissolution rate of nimesulide, with starch and lactose as diluent agent, CCNa as disintegrant, and the optimal formulation of immediate-release layer was starch 12.5%, CCNa 7.5%. The optimal formulation of sustained-release layer was determined by using the central composite design in the indication of the accumulative release percentage of nimesulide, with HPMC as matrix material. And the optimal formulation of sustained-release layer was HPMC 32%, HPMC K100LV 38% of HPMC. The results of drug release pattern shows the drug in immediate-release layer released completely in 0.5h, the drug in sustained-release layer released in a predetermined fashion for 24h. The drug release pattern of sustained-release layer was fitted for the Ritger-Peppas model, and the drug release mechanism was drug diffusion and matrix erosion together, however the drug release mechanism was mainly matrix erosion.Finally, the pharmacokinetic study of beagle dogs was carried out for validating the designed nimesulide oral biphasic drug delivery system with the nimesulide dispersible tablet as the reference preparation. The pharmacokinetics parameters were AUC0-t 188717ng.h/mL and 180783ng.h/mL, Cmax 25200ng/mL and 34950ng/mL, Tmax 3.Oh and 4.0h, MRT 7.64h and 7.09h. The results indicated: the two dosage forms were bioequivalent and that Cmax of the test preparation was lower than that of the reference preparation, Tmax of the test preparation was shorter than that of the reference preparation, MRT of the test preparation was longer than that of the reference preparation. The results showed the nimesulide oral biphasic drug delivery system had immediate-release and long-acting, and reached the designed target.In terms of the dosage form and the dose design, formulation selection and preparation process study, and in vivo pharmacokinetic validation, the nimesulide oral biphasic drug delivery system was studied for clinical requirement and providing one effective chronic disease drug.