Studies On Tow-Layer Osmotic Pump Tablets Of Glipizide

Glipizide is a second-generation oral hypoglycemic agent that belongs to the sulfmylurea class of compounds. Glipizide is widely used in the management of type II (non-insulin-dependent) diabetes mellitus. It has been shown to stimulate insulin action through extra pancreatic effects that affect insulin-receptor binding and enchance tissue responsiveness to insulin. Glipizide has demonstrated the capacity to lower the level of plasma glucose and to maintain this effect for a time. Glipizide delivered orally from 2.5 mg to 5 mg casual. Glipizide has a short half-life of 2 to 4 hours, so it is needed frequently administration when daily dose exceeds 15 mg. This will lead to the blood-drug concentration vary greatly, and induce toxicity and side-effect easily. So it’s necessary to develop a controlled-release glipizide formulation with good bioavailability and stability to reduce the frequency of administration and side-effect, and thus improve patients’ compliance.Insoluble glipizide was selected as the model drug to prepare two-layer osmotic pump tablets. In the preparation, Polyethylene oxide(PEO), sodium chloride(NaCl), carboxy methylcellulose sodium (CMC-Na) and hydroxypropyl methylcelluse (HPMC) were used to make the tablet core. Cellulose acetate (CA) and polyethylene glycol 4000 (PEG4000) were selected as the coating materials and acetone solvent was employed as the coating medium. The effects of many factors including formulation of drug layer、push layer、coating membrane and the conditions of drug release on the release behavior of the this controlled release tablets were investigated. The similarity factors(f2) between the in vitro accumulative drug release was used as evalution standard and obtained the optimal formulation. The optimal formulations had excellent zero-order release character from 2 to 16 hours (F1:r= 0.9946, F2:r=0.9919) and had good similarity to reference product(Glucotrol XL) (F1: f2=69.7, F2:f2=65.3). In addition, the results of stability experiments indicated that the products were sensitive to humidity and high temperature. Exposed on the conditions of RH 92.5% and 60℃after 10 days, something like grume effused from the orifice.With two-crossover design, the pharmacokinetics of glipizide of self-made tablets in 4 dogs was studied comparing with the reference tablets (Glucotrol XL). The pharmacokinetic parameters of the reference tablets were as follows:t1/2 was (12.06±8.48) h, Tmax was (8.25±1.71) h, Cmax was (158.14±143.39) ng·mL-1, AUC0-36 was (1407.56±807.40) ng·h·mL-1, AUC0-∞was (1654.24±858.07) ng·h·mL-1; The pharmacokinetic parameters of the test tablets were as follows:t1/2 was (6.98±8.63) h, Tmax was (8.50±1.73) h, Cmax was (161.40±36.15) ng·mL-1, AUC0-36 was (1384.24±391.42) ng·h·mL-1, AUC0-∞was (1499.46±331.97) ng·h·mL-1. The relative bioavailability of test formulation to reference formulation was (118.28±35.60)%. The results of two one-sided t-test and 90% confidence interval analysis demonstrated that the self-made tablets and reference tablets were not bioequivalent. The results indicated that the self-product have better in vitro-in vivo correlation which was studied by Wagner-Nelson.