Development and optimization of sitagliptin and dapagliflozin loaded oral self-nanoemulsifying formulation against type 2 diabetes mellitus.

ABSTRACT

Control of hyperglycemia and prevention of glucose reabsorption (glucotoxicity) are important objectives in the management of type 2 diabetes. This study deals with an oral combined dosage form design for two anti-diabetic drugs, sitagliptin and dapagliflozin using self-nanoemulsifying drug delivery systems (SNEDDS). The SNEDDS were developed using naturally obtained bioactive medium-chain/long-chain triglycerides oil, mixed glycerides and nonionic surfactants, and droplet size was measured followed by the test for antioxidant activities. Equilibrium solubility and dynamic dispersion experiments were conducted to achieve the maximum drug loading. The in vitro digestion, in vivo bioavailability, and anti-diabetic effects were studied to compare the representative SNEDDS with marketed product Dapazin®. The representative SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. Characterization of the SNEDDS showed nanodroplets of around 50-66.57 nm in size (confirmed by TEM analysis), in addition to the high drug loading capacity without causing any precipitation in the gastro-intestinal tract. The SNEDDS provided higher antioxidant activity compared to the pure drugs. The in vivo pharmacokinetic parameters of SNEDDS showed significant increase in C max (1.99 ± 0.21 µg mL-1), AUC (17.94 ± 1.25 µg mL-1), and oral absorption (2-fold) of dapagliflozin compared to the commercial product in the rat model. The anti-diabetic studies showed the significant inhibition of glucose level in treated diabetic mice by SNEDDS combined dose compared to the single drug therapy. The combined dose of sitagliptin-dapagliflozin using SNEDDS could be a potential oral pharmaceutical product for the improved treatment of type 2 diabetes mellitus.