Study On Time-Controlled Release Pellets Of Nimesulide

With the development of chronobiology, it had been well realized that circadian rhythms existed in many physiological phenomena and some diseases these years. The conventional drug delivery system could not fit these diseases well. Time-controlled delivery system could release drug at the required time so that we can obtain the optimum therapy.In this study, nimesulide (NIM) was chosen as the model drug which had been designed for bedtime dosing and released drug in the early morning to cure rheumatoid arthritis.The precise and simple UV and HPLC method were choosen to assay NIM in vitro and in vivo, which provided a basis for the further studies of pharmaceutics and pharmacokinetics in dogs.In situ single-pass perfusion model was used to study the absorption kinetics of nimesulide in rats. Nimesulide could be absorbed in general intestinal segments. The constants of absorption rate were (0.077±0.008), (0.067±0.007), (0.074±0.011), (0.059±0.008)min-1 at duodenum, jejunum, ileum, and colon, respectively. The absorption of nimesulide in the intestine was a first-order process through passive diffusion mechanism.This preparation consisted of four layers from center to outside:the core, swelling agent, subcoat, insoluble polymer membrane in this order. The theory of this system consisted of the following processes. First, water come into the swelling layer through the contolled layer and subcoat which was hydrated to cause stress against the membrane. As soon as the swollen power exceeded the outer membrane strength, membrane destructed and drug released. The core pellets were prepared by extrusion-spheronization. CMS-Na was put into the cores in order to control the release of drug. The time-controlled release pellets were prepared by coating on a mini-fluidized bed spray coater. CC-Na was selected as the swelling agent, HPMC (E50) as the subcoat agent, EC as the controlled release layer.According to these factor researches, the central composite design was chosen to optimize the formulations and the optimum formulation was as follows:the amount of CC-Na (X1) was 33%, the amount of HPMC (X2) was 5%, the amount of EC (X3) was 8%. The lag time of the prepared pellets was 4h and the release time was 3.3 h. In addition, the results of stability experiments showed that the lag time of pellets reduced in high humidity but was stable on other conditions.The release behavior in vivo of the pellets was evaluated in dogs after a parallel oral administration of NIM time-controlled release pellets (test formulation) and core pellets (reference formulation). The result demonstrated that NIM time-controlled release pellets could release drug after 3.3 h lag time and that Tmax was 8.0 h. The in vitro-in vivo correlations was studied by using Wagner-Nelson equation, which indicated that test formulation had good vivo-vitro correlativity (r=0.9773).