Studies On Glipizide Sustained-release Pellets

Glipizide is a second-generation oral hypoglycemic agent that belongs to the sulfmylurea class of compounds. Glipizide is widely used in the management of typeⅡ(non-insulin-dependent) diabetes mellitus. It has been shown to stimulate insulin action through extra pancreatic effects that affect insulin-receptor binding and enhance tissue responsiveness to insulin. Glipizide has demonstrated the capacity to lower the level of plasma glucose and to maintain this effect despite a short half-life(2-4h). So it’s necessary to develop a sustained-release glipizide formulation with good bioavailability and stability to reduce the frequency of administration and side effects, and thus improve patients’compliance. The products of glipizde sold in commercial are mainly two-layers osmotic pump tablet and matrix sustained-release pellets. Therefore, the glipizide film-controlled sustained-release pellets was systematic designed and prepared.In the preliminary study, UV spetrophotometry was developed for assaying the content in the preparation and drug release from GP sustained-release pellets. HPLC method was performed to detect the related substance of GP. A rapid and specific UPLC-MS/MS method has been developed for quantification of glipizide in plasma. The developed methods mentioned are liable, convenient and rapid, which all meet the requirements of analysis.Glipizide pellets were prepared by centrifugal granulation technology, using the powder layering theory. Through the formulation screening and procedure optimizing, it was discovered that the yield of the objective pellets (20-24 mesh cut) was above 85%. The results shown that the preparation process and formulation of glipizide pellets could reach the expected goals.A fluid-bed spray processor was adopted for the coating of the pellets. The influence of coating solution’s formulation and coating procedure on the release of sustained release pellets was observed. It was failed to prepare the pH-dependent sustained-release pellets coated with a combination of Eudragit NE30D and Eudragit L30D-55. The non-pH-dependent sustained-release pellets were coated with Eudragit RL30D. The technology and formulation was optimized, respectively. The drug release mechanism of film-controlled sustained-release pellets was studied, the results demonstrated that self-prepared glipizide sustained-release pellets showed obviously suatained-release effect, and the drug release profiles in-vitro followed first-order model.With the commercial glipizide controlled-release tablets and matrix suatained-release pellets as the references, the in vivo pharmacokinetics of self-prepared glipizide sustained-release pellets was studied with six beagles. Concentration of glipizide in plasma was determined by UPLC-MS/MS. The pharmacokinetic parameters of the test and references were as follows:Cmax were 187.59±120.57 ng·mL-1、1419.69±624.93 ng·mlL-1 and 915.38±431.48 ng·mL-1, Tmax were 7.83±2.99h、6.83±3.25 h and 10.67±2.94 h, t1/2 were 8.19±6.06 h、5.85±1.73 h and 5.86±3.96 h, AUC0-36 were 1765.08±1167.52 ng·h·mL-1、14589.50±8123.155 ng·h·mL-1 and 13704.02±7620.27 ng·h·mL-1, AUC0-∞were 1911.84±1155.64 ng·h·mL-1、17141.70±7211.66 ng·h·mL-1 and 14275.95±7589.25 ng·h·mL-1 respectively. The relative bioavailability of glipizide were 16.8% and 30.8%. It was demonstrated that self-prepared sustained-release pellets was not bioequivalent to references. The in-vitro release condition in pH7.4 PBS could not simulate the IVIVC of glipizide film-controlled sustained-release pellets.