Controlled release of metformin hydrochloride and repaglinide from sandwiched osmotic pump tablet

The marketed compound tablet of metformin hydrochloride (MH) and repaglinide (RG) exhibits perfect multidrug therapeutic effect of type 2 diabetes. However, due to the short half life of the drugs, the tablet has to be administered 2 to 3 times a day, causing inconvenience to patient and fluctuations of plasma concentration. Here, a sandwiched osmotic pump tablet was developed to deliver the two drugs simultaneously at zero-order rate, in which MH and RG were loaded in different layers separated by a push layer. The osmotic pump tablet was prepared by a combination of three tableting procedure and film coating method. The factors including type and amount of propellant, osmotic active agents, amount of porogenic agent, coating weight, orifice diameter were optimized. The pharmacokinetic study was performed in beagle dogs, and the drug concentration in plasma samples was assayed by HPLC-MS/MS method. Simultaneous, controlled release of MH and RG in the first 12 and 8 h was achieved from the optimized formulation. A significantly decreased C_max, prolonged T_max and satisfactory bioavailability of the osmotic pump tablet were obtained, and a good in vivo-in vitro correlation of the two drugs was also established. In summary, the sandwiched osmotic pump tablet released the MH and RG simultaneously at zero-order rate, and exhibited significant sustained release effect in vivo and good in vivo-in vitro correlation. The designed controlled release system for MH and RG proposed a promising replacement for the marked compound product in the therapy of type 2 diabetes.