Study On The Controlled Release Preparation Of Combined Hypoglycemic Drugs With Synergistic Effect

The combination of metformin hydrochloride and glipizide can improve the hypoglycemic efficacy by synergistic interaction.Controlled release formulation based on osmotic technology is superior to conventional formulation in less frequency of dosage and lower fluctuation of plasma drug concentration,thus can improve the compliance and safety of medication.In this study,the combination of metformin hydrochloride and glipizide,a freely water-soluble drug and a poorly water-soluble one,was used to prepared elementary osmotic pump tablet.Release of glipizide was driven by the continuous release of metformin hydrochloride,and a synchronized and controlled release of two drugs was then achieved.Cellulose acetate and pore-forming agent were used as the film material in this study.The elementary osmotic pump could release drugs at a certain rate by adjusting the composition of the core and the film.Results of the formulation study indicate that formulation of the semi-permeable film affect the dissolution release rate most,while instrument parameters of dissolution apparatus,such as dissolution medium and rotate rate of the paddle,have few impact in release rate.Face-centred central composite design and response surface method was adopted to optimize formula of the film.The ratio of cellulose acetate and pore-forming agent was 5.4:1 and the weight gain of the coating film was 2.9%.Release profiles of the optimum formula showed that drug release was followed by zero-order pattern in 2 h to 10 h,and the cumulative release was over 90%in 12 h.There was no significant difference between the release profiles of metformin hydrochloride and glipizide.The preparation could control the release of two drugs synchronized.Choosing marketed conventional tablet as reference,relative bioavailability and pharmacokinetic study of self-made preparation were performed in six beagle dogs by two-circle crossover design.Relative bioavailability of metformin hydrochloride and glipizide in self-made preparation was 99.1%and 96.9%,respectively.The two formulations were bioequivalence on AUC.But the Cmax of self-made preparation was lower and the Tmax was obviously longer than the reference,which proved that self-made preparation did have a synchronized and controlled release of both drugs.The in vitro-in vivo correlations of the self-made preparation were evaluated by using Wagner-Nelson method and indicated a good correlation.